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Core Submission Dossier PTJA11
Cefiderocol For the treatment of infections due to aerobic Gram-negative organisms in adults with limited
treatment options
Submitted by: Shionogi
Disclaimer: The sole responsibility for the content of this document lies with the submitting manufacturer and neither the European Commission nor EUnetHTA are responsible for any use that may be made of the information contained therein.
Contact details for administrative purposes Shionogi BV 33 Kingsway London WC2B 6UF Email address: admineurope@shionogi.eu
For agency completion Date of receipt: 14-04-2020 Version 3: Amended dossier reflecting additional PK/PD analysis. Identifier: PTJA11
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Abbreviations
A Aerobic
AAT Appropriate antibacterial therapy
ABC transporter ATP-binding cassette transporter
ABSSSI Acute bacterial skin and skin structure infection
Ac-BSI Acinetobacter spp. Bacteraemia
AE Adverse event
AET Appropriate empirical therapy
ALAT Asociación Latinoamericana del Tórax
AMK Amikacin
AMR Antimicrobial resistance
AN Anaerobic
AR Antimicrobial-resistance
AS Antimicrobial susceptibility
AST Antimicrobial susceptibility tests
AT Antibacterial therapy
ATS American Thoracic Society
AUC Area under the curve
BAT Best available therapy
BD Becton Dickinson
BIA Budget impact analysis
BIM Budget impact model
BAL Bacterial β-lactamase
BLI β-lactamase inhibitor
BSI Bloodstream infection
BSIMRS Bloodstream infection mortality risk score
CAI Community-acquired infection
CarbNS Carbapenem non-susceptible
CASR Carbapenem- and ampicillin-sulbactam-resistant
CAZ Ceftazidime/avibactam
CDC Centres for Disease Control and Prevention
CDI Clostridium difficile infection
CFU Colony forming unit
CHMP Committee for Medicinal Products for Human Use
CI Confidence interval
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cIAI Complicated intra-abdominal infection
CLSI US Clinical & Laboratory Standards Institute
CNSE Carbapenem-non-susceptible Enterobacteriaceae
CPE Carbapenemase Producing Enterobacteriaceae
CPFX Ciprofloxacin
CR Carbapenem-resistant
CRAB Carbapenem-resistant A. baumannii
CRAc Carbapenem-resistant Acinetobacter spp.
CRE Carbapenem-resistant Enterobacteriaceae
CRGNB Carbapenem-resistant Gram-negative
CRGNIs Carbapenem-resistant Gram-negative infections
CRPA Carbapenem-resistant P. aeruginosa
CSE Carbapenem-susceptible Enterobacteriaceae
CSPA Carbapenem-susceptible P. aeruginosa
CTX Cefotaxime
cUTI Complicated urinary tract infection
DALYs Disability-adjusted life-years
DBO Diazabicyclooctane
DGI German Society for Infectious Diseases Association
DRG Disease-related groups
EA Early assessment
EAU European Association of Urology
ECDC European Centre for Disease Prevention and Control
EEA European Economic Area
eHRB Emerging highly antibacterial resistant bacteria
EMA European Medicines Agency
EMEA Europe, Middle East, and Africa
EOT End of treatment
ERS European Respiratory Society
ESBLs Extended-spectrum β-lactamases
ESCMID European Society of Clinical Microbiology and Infectious
Diseases
ESICM European Society of Intensive Care Medicine
EU European Union
EUCAST European Committee on Antimicrobial Susceptibility Testing
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FA Facultative anaerobic
FDA U.S. Food and Drug Administration
FUP Follow-up
G3CREC Third-generation cephalosporin-resistant E. coli
G3CSEC third-generation cephalosporin-susceptible E. coli
GDP Gross domestic product
GEIH-SEIMC Spanish Society of Infectious Diseases and Clinical
Microbiology
GNO Gram-negative organisms
GVD Global Value Dossier
HAI Hospital-acquired infection
HAP Hospital acquired pneumonia
HAS Haute Authorite de la Sante
HCAI Healthcare-associated infection
HCAP Healthcare-associated pneumonia
Hr Hour
HTA Health Technology Assessment
HTAB Health Technology Assessment Body
(c)IAI (complicated) Intra-abdominal infection
IAT Inappropriate antibacterial therapy
ICD International Classification of Disease
ICU Intensive care unit
ID-CAMHB Iron-depleted cation-adjusted Mueller Hinton broth
IDSA Infectious Disease Society
IET Inappropriate empiric therapy
IMP IMP-type carbapenemases
IPM/CS Imipenem/Cilastatin
IQR Inter-quartile range
IRAB Imipenem-resistant Acinetobacter baumannii
ITT Intention-to-treat
IV Intravenous
KAPE Klebsiella pneumoniae, Acinetobacter baumannii,
Pseudomonas aeruginosa, and Enterobacter
KPC Klebsiella pneumoniae carbapenemase
LOS Length of stay
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MA Marketing Authorization
MAA Marketing Authorization Application
MBLs Metallo-β-lactamases
MCO Managed care organization
MCR-1 Plasmid-mediated colistin-resistance
MDR Multidrug resistant
MDRA Multidrug resistant Acinetobacter
MDRAB Multidrug resistant A. baumannii
MDRP Multidrug resistant P. aeruginosa
MDS Multidrug-sensitive
ME Microbiologically evaluable
(HD) MEPM (high dose) Meropenem
MIC Minimum inhibitory concentration
mITT Microbiological intention to treat
MoA Mode of action
NDA New drug application
NDM New Delhi metallo-β-lactamase
NHS National Health Service
NI Nosocomial infections
NICE National Institute of Health and Care Excellence
NR Non-resistant
NS Non- survivors
OM Osteomyelitis
OMT Outer membrane transporters
OR Odds ratio
OXA Oxacillinase
PBC Positive blood culture
PBPs Penicillin-binding proteins
PCR Polymerase Chain Reaction
PD Pharmacodynamic
PDCO Paediatric Committee
PDR Pan-drug-resistant
PEG Percutaneous endoscopic gastroscopy
PER Pseudomonas extended resistant β-lactamases
PK Pharmacokinetic
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PP Per Protocol
PTA Probability of target attainment
q8h Every 8 hours
R Resistant
RCT Randomized controlled trial
RESP Respiratory tract
RR Relative risk
r-GNR Resistant gram-negative rod
RTI Respiratory tract infection
S Survivors
SAE Serious adverse event
SC Subcutaneous
SCCM Society of Critical Care Medicine
SD Standard deviation
SEFH Spanish Society of Hospital Pharmacies
SEMPSPH Spanish Society of Preventive Medicine, Public Health and
Hygiene
SICU Surgical intensive care unit
SIS Surgical Infection Society
SMC Siderophore monobactam conjugate
sNDA Supplemental new drug application
SOC Standard of care
spp Species
SSI Surgical site infection
TOC Test of Cure
tRNA Transfer ribonucleic acid
UTI Urinary tract infection
VAP Ventilator-acquired pneumonia
VABP Ventilator-associated bacterial pneumonia
VIM Verona integrin-encoded metallo-β-lactamase
w/wo With or without
WHO World Health Organization
WSES World Society of Emergency Surgery
XDR Extensively drug-resistance
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Contents
EXECUTIVE SUMMARY .......................................................................................... 14 1 Description and technical characteristics of the technology .......................... 23 1.1 Characteristics of the technology ................................................................... 25
1.1.1 Cefiderocol Structure .......................................................................... 26 1.1.2 Mechanism of action and cell entry .................................................... 27
1.1.3 Stability against β-lactamases ............................................................ 28 1.2 Regulatory status of the technology .............................................................. 29 2 Health problem and current clinical practice .................................................. 31 2.1 Overview of the disease or health condition .................................................. 32
2.1.1 Overview of Gram-negative bacteria .................................................. 33 2.1.2 Antimicrobial resistance ...................................................................... 35 2.1.3 Overview of infection sites .................................................................. 39
2.1.4 Risk and prognostic factors for MDR and CR infections ..................... 41 2.1.5 Epidemiology ...................................................................................... 42 2.1.6 Mortality .............................................................................................. 47 2.1.7 Quality of Life ...................................................................................... 48
2.1.8 Disability Adjusted Life Years (DALYs) ............................................... 48 2.1.9 Delayed effective therapy ................................................................... 49
2.2 Target population ........................................................................................... 52
2.3 Clinical management of the disease or health condition ................................ 57 2.3.1 Key information on currently available treatments in Europe .............. 59
2.3.2 Site-specific vs. pathogen-specific guidelines..................................... 63 2.3.3 Specific recommendations.................................................................. 63
2.3.4 Specific considerations of CR infections ............................................. 63 2.4 Comparators in the assessment .................................................................... 87
2.4.1 General considerations ....................................................................... 87 2.4.2 Selection of relevant comparators for the assessment ....................... 89
3 Current use of the technology........................................................................ 94
3.1 Current use of the technology........................................................................ 95 3.2 Reimbursement and assessment status of the technology ........................... 96
4 Investments and tools required...................................................................... 97 4.1 Requirements to use the technology ............................................................. 98
4.1.1 Conditions for use ............................................................................... 99
4.1.2 Good stewardship and societal considerations................................... 99 5 Clinical effectiveness and safety .................................................................. 102 5.1 Identification and selection of relevant studies ............................................ 105
5.1.1 PRISMA Chart .................................................................................. 111
5.1.2 Study categorisation ......................................................................... 111 5.2 Relevant studies .......................................................................................... 112 5.3 Main characteristics of studies..................................................................... 134
5.3.1 APEKS-cUTI STUDY ........................................................................ 144 5.3.2 APEKS-NP STUDY .......................................................................... 151
5.3.3 CREDIBLE-CR STUDY .................................................................... 155 5.3.4 Summary of compassionate use cases and published evidence ...... 160
5.4 Individual study results (clinical outcomes) .................................................. 164 5.4.1 Individual study results (in vitro surveillance outcomes) ................... 164
5.4.2 Individual study results (PK/PD data, study report S-649266-CPK-004-B) ...................................................................................................... 189
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5.4.3 Retrospective analysis of cefiderocol and comparators by population PK/PD simulation .............................................................................. 192
5.4.4 Clinical study results (clinical outcomes) .......................................... 194 5.4.5 Resistance against Cefiderocol ........................................................ 233
5.5 Individual study results (safety outcomes) ................................................... 259 5.5.1 Overall safety results: pooled analysis and individual studies: APEKS-
cUTI, APEKS-NP, and CREDIBLE CR ............................................. 259 5.5.2 Safety analyses by clinical trial ......................................................... 265
5.6 Conclusions ................................................................................................. 287 5.6.1 Evidence to support use of cefiderocol in patients with infections by
suspected MDR/CR pathogens: ....................................................... 289 5.6.2 Evidence to support use of cefiderocol in patients with infections by
confirmed CR pathogens: ................................................................. 291 5.6.3 Quality of Life .................................................................................... 293 5.6.4 Comparators ..................................................................................... 293
5.7 Strengths and limitations ............................................................................. 297 5.7.1 Risk of bias assessment ................................................................... 297
5.7.2 Discussion ........................................................................................ 301
REFERENCES ....................................................................................................... 306
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List of Figures Figure 1: Cefiderocol structure ............................................................................................ 27 Figure 2: Cefiderocol mechanism of cell entry ..................................................................... 28 Figure 3: Antibacterial activity against β-lactamase-producing pathogens ........................... 28 Figure 4: Classification of Gram-negative bacteria .............................................................. 34 Figure 5: Global burden of AMR .......................................................................................... 35 Figure 6: Mechanisms of beta lactam bacterial resistance .................................................. 37 Figure 7: Hospital-acquired infections in acute care hospitals (EU/EEA 2011-2012) ........... 40 Figure 8: Worldwide carbapenem resistance ...................................................................... 42 Figure 9: Prevalence of CR Gram-negative infections in the EU-5 ...................................... 43 Figure 10: Epidemiology of carbapenemases in EU 5 ......................................................... 44 Figure 11: Confirmed carbapenemase-producing Enterobacteriaceae isolates (Public Health England: 2008–17) .............................................................................................................. 45 Figure 12: Distribution of carbapenem resistance mechanisms in Enterobacteriaceae species in the Europe.......................................................................................................... 45 Figure 13: Summary of effect of appropriate versus inappropriate initial antibacterial therapy on mortality ......................................................................................................................... 51 Figure 14: Summary of effect of delay versus no delay in receiving initially appropriate antibacterials on mortality ................................................................................................... 51 Figure 15: Summary of effect of appropriate versus inappropriate therapy on treatment failure .................................................................................................................................. 52 Figure 16 - Treatment of patients with highly suspected infection by CR or other MDR GN pathogens ........................................................................................................................... 55 Figure 17: Treatment of patients with confirmed infection by carbapenem-resistant or other MDR Gram-negative pathogen ........................................................................................... 55 Figure 18: Current treatment approach for bacterial infections ............................................ 57 Figure 19: Current clinical reasoning for the treatment of serious MDR Gram-negative infections ............................................................................................................................. 59 Figure 20 - Search strategy for OVD MEDLINE ALL ......................................................... 106 Figure 21 - PRISMA flow diagram of record selection process .......................................... 111 Figure 22: APEKS-cUTI study design ............................................................................... 144 Figure 23: Subject disposition (all randomized subjects) ................................................... 145 Figure 24: Distribution of uropathogens (mITT population) ................................................ 150 Figure 25: APEKS-NP study design and patient flow ........................................................ 152 Figure 26: Patient demographics and baseline characteristics .......................................... 153 Figure 27: CREDIBLE-CR study design and patient flow .................................................. 156 Figure 28: Subjects disposition (all randomized subjects) ................................................. 157 Figure 29: APEKS-cUTI study design and endpoints ........................................................ 196 Figure 30: Primary efficacy results: Composite outcome at TOC in the MITT population .. 197 Figure 31: Primary efficacy results: Composite outcome at TOC by predefined subgroups198 Figure 32: Maximum Network Chart for Network Meta-analysis ........................................ 209 Figure 33: Network Diagram for Microbiological Eradication Secondary Outcome ............ 209 Figure 34: Microbiological Eradication Rates at TOC - Frequentist Analysis ..................... 210 Figure 35: Microbiological Eradication Rates at TOC - Bayesian Analysis ........................ 210 Figure 36: Network Diagram for Clinical Cure Outcome .................................................... 210 Figure 37: Clinical cure rates at TOC - Frequentist Analysis ............................................. 211 Figure 38: Clinical Cure rate at TOC - Bayesian Analysis ................................................. 211 Figure 39: Clinical cure rates at FU - Frequentist Analysis ................................................ 211 Figure 40: APEKS-NP study design .................................................................................. 213 Figure 41: All-cause Mortality (mITT) ................................................................................ 214 Figure 42: Primary efficacy results: Day 14 All-cause Mortality by Subgroups .................. 215 Figure 43: Day 14 and Day 28 all-cause mortality according to MIC for meropenem ........ 218 Figure 44: Microbiological eradication by MIC at EOT ....................................................... 219 Figure 45: CREDIBLE CR study design ............................................................................ 223
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Figure 46: Clinical cure by Clinical Diagnosis and time point ............................................. 224 Figure 47: Microbiological eradication by Clinical Diagnosis and time point ...................... 224 Figure 48: Clinical and Microbiological Outcomes at TOC in Enterobacteriaceae by Carbapenemase or Porin Channel Mutation (CR Micro-ITT Population) ........................... 226 Figure 49: Clinical and Microbiological Outcomes in Metallo Β-lactamase Producing Gram-negative Pathogens (CR Micro-ITT Population) ................................................................ 226 Figure 50: All-cause Mortality Rates by Type of Infection .................................................. 227 Figure 51: Mortality rates comparison across studies ........................................................ 230 Figure 52: Network Diagram for Safety Analysis ............................................................... 271 Figure 53: Safety Analysis for All Adverse Events - Frequentist Analysis .......................... 271 Figure 54: Network for safety analysis for Treatment related AEs ..................................... 271 Figure 55: safety analysis for Treatment related AEs – Frequentist analysis ..................... 271
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List of Tables Table 1: Features of the technology .................................................................................... 25
Table 2: Administration and dosing of the technology ......................................................... 25
Table 3: Regulatory status of the technology ...................................................................... 29
Table 4: List of the highest priority bacteria (WHO) ............................................................. 35
Table 5: In vitro activity profile of antibacterials for GN Infections with limited treatment options ................................................................................................................................ 39
Table 6: Most common CR causal pathogens across available EU-5 data sources ............ 43
Table 7: Proportion of CR infection sites in the EU-5........................................................... 44
Table 8: Overview of disease burden according to the infection site ................................... 46
Table 9: In Vitro Gram-negative activity profiles .................................................................. 54
Table 10a: Relevant guidelines for diagnosis and management – MDR/GN Bacteria ......... 65
Table 11b: Relevant guidelines for diagnosis and management – HAP/VAP(HCAP) .......... 70
Table 11c: Relevant guidelines for diagnosis and management – cUTI .............................. 75
Table 11d: Relevant guidelines for diagnosis and management – BSI/Sepsis .................... 78
Table 11e: Relevant guidelines for diagnosis and management- cIAI ................................. 83
Table 12: Cefiderocol assessment ...................................................................................... 90
Table 13: Overview of the reimbursement status of the technology in European countries . 96
Table 14: Databases and information sources searched ................................................... 107
Table 15: Inclusion and exclusion criteria .......................................................................... 109
Table 16: List of all relevant studies .................................................................................. 113
Table 17: Study characteristics ......................................................................................... 135
Table 18: Patient demographics and baseline characteristics (mITT population) .............. 147
Table 19: Patient demographics and baseline characteristics (mITT population) .............. 154
Table 20: Top 5 baseline Gram-negative pathogens, n (%) .............................................. 154
Table 21: Patient demographics and baseline characteristics (ITT population) ................. 158
Table 22: Summary of study regimen for Gram-negative pathogen at day 1 and day 2 (CR-mITT population) ............................................................................................................... 159
Table 23: Baseline Gram-negative pathogens, n (%) ........................................................ 160
Table 24: Patient demographics and baseline characteristics ........................................... 162
Table 25: SIDERO Surveillance studies ............................................................................ 165
Table 26: In vitro activity data for all tested clinical strains (SIDERO-WT-2014/2015/2016 and Proteeae) of cefiderocol (at MIC of 4mg/L) versus ceftazidime-avibactam, ceftolozane-tazobactam, and colistin .................................................................................................... 167
Table 27: In vitro activity of cefiderocol and comparators against Gram-negative bacilli isolated by 55 clinical laboratories in Europe in 2015 (n=5352) ......................................... 170
Table 28: In vitro activity of cefiderocol and comparators against non-fermenters ............. 172
Table 29: Breakpoints for non-susceptibility used in definition of DTR (μg/mL) ................. 173
Table 30: Susceptibility of cefiderocol and comparators to pathogens .............................. 173
Table 31: In vitro activity data for CR Gram-negative pathogens (SIDERO-WT-2016-2017) of cefiderocol versus ceftazidime-avibactam, ceftolozane-tazobactam and colistin ............... 174
Table 32: Number of MEM-NS isolates by year and species ............................................. 175
Table 33: Number of MEM-NS isolates by country and species ........................................ 175
Table 34: Susceptibility breakpoints according to the CLSI (cefiderocol) and/or EUCAST (all comparators) ..................................................................................................................... 176
Table 35: Percentage of susceptibility of MEM-NS A. baumannii complex by country ....... 177
Table 36: Percentage of susceptibility of MEM-NS P. aeruginosa complex by country ...... 177
Table 37: Percentage of susceptibility of MEM-NS K. pneumoniae by country .................. 177
Table 38: Percentage of susceptibility of other MEM-NS Enterobacteriaceae by country .. 177
Table 39: In vitro activity data for all tested clinical strains (SIDERO-CR 2014-2016) of cefiderocol versus ceftazidime-avibactam, ceftolozane-tazobactam, and colistin .............. 178
Table 40: MIC of cefiderocol and comparators in Germany ............................................... 179
Table 41: MIC of cefiderocol and comparators in Greece .................................................. 180
Table 42: MIC of cefiderocol and comparators in Spain .................................................... 181
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Table 43: MIC of cefiderocol and comparators against in United Kingdom and Ireland ..... 182
Table 44: Activity of antimicrobial agents tested against carbapenem-resistant P. aeruginosa and S. maltophilia ............................................................................................................. 183
Table 45: MIC of cefiderocol and comparators for MDR-GN isolated ................................ 184
Table 46: Number of cefiderocol non-susceptible isolated in global surveillance studies (MIC ≥8 μg/mL).......................................................................................................................... 185
Table 47: EUCAST breakpoints for cefiderocol ................................................................. 186
Table 48: Susceptibility to Cefiderocol and comparators in all sites of infections for MDR3 pathogens ......................................................................................................................... 187
Table 49- Theoretical success of antibacterial therapy in Gram‐negative 3MDR pathogens in gastrointestinal site of infections (A) Pneumonia; (B) cUTI; (C) BSI; (D) Gastrointestinal .. 187
Table 50: Summary table Theoretical percentage of success for Gram‐negative antibacterial
therapy on aerobic Gram‐negative pathogens in different infection type ........................... 188
Table 51: PTA per infectious disease renal function, and dose ......................................... 190
Table 52. Estimated CFR for MIC distributions corresponding to Enterobacterales and Pseudomonas spp. More simulation results for corresponding PTA, MIC and T>MIC target values are shown in Appendix C. The applied MIC distributions can be seen in Appendix D of the study report. ............................................................................................................ 193
Table 53: Endpoint Analysis as per EUnetHTA Request ................................................... 194
Table 54: Summary for Composite of Clinical and Microbiological Outcome by Time Point (Microbiological Intent-to-Treat Population) ....................................................................... 197
Table 55: Composite of Clinical Response and Microbiological Outcome per Pathogen at TOC (microbiological ITT population) ................................................................................ 199
Table 56: Summary of Clinical Outcomes per Subject by Time Point (Microbiological Intent-to-Treat Population) .......................................................................................................... 200
Table 57: Summary of Clinical Outcome per Uropathogen (E. coli, K. pneumoniae, P. aeruginosa, and P. mirabilis) by Time Point (Microbiological ITT Population) .................... 201
Table 58: Summary of Microbiological Outcome per Subject by Time Point (Microbiological ITT Population) ................................................................................................................. 203
Table 59: Summary of Microbiological Outcome per Uropathogen (E. coli, K. pneumoniae, P. aeruginosa, P. mirabilis) by Time Point (Microbiological ITT Population)........................... 205
Table 60: Day 14 All-cause Mortality (mITT and ME-PP Populations) ............................... 214
Table 61: Secondary Endpoints (mITT Population) ........................................................... 216
Table 62: Secondary Endpoints (mITT Population) ........................................................... 216
Table 63: Clinical and microbiological outcome per baseline pathogen ............................. 217
Table 64: Microbiological and Clinical Outcome for the Meropenem-non-susceptible Subgroup (mITT Population) ............................................................................................. 219
Table 65: Susceptibility and effectiveness model predicting outcomes for Cefiderocol versus comparators in UTI ........................................................................................................... 221
Table 66: Susceptibility and effectiveness model predicting outcomes for Cefiderocol versus comparators in Pneumonia ............................................................................................... 221
Table 67: Clinical cure and microbiological eradication by baseline CR-pathogen ............ 225
Table 68: Summary for All-cause Mortality in the Study (Intent to treat Population) .......... 227
Table 69: Summary for all-cause mortality overall by pathogens subgroup (Enterobactereacea and non-fermenters) .......................................................................... 229
Table 70: CREDIBLE-CR study: Mortality subgroup Analysis for Subjects with A. baumannii (safety population) ............................................................................................................ 229
Table 71: Mortality and serious adverse events ................................................................ 231
Table 72: Summary of MIC shift ........................................................................................ 234
Table 73a: Methods of data collection and analysis of Mortality ........................................ 235
Table 80b: Methods of data collection and analysis of Clinical outcomes .......................... 237
Table 80c: Methods of data collection and analysis of Composite microbiological eradication and cure ............................................................................................................................ 245
Table 80d: Methods of data collection and analysis of Microbiological outcomes .............. 249
Table 80e: Methods of data collection and analysis of Susceptibility rates ........................ 258
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Table 81: Dose and Duration of Exposure to cefiderocol* (Number of Patients by Indication) ......................................................................................................................................... 259
Table 82: Subjects with Treatment Related Adverse Events by System Organ Class and Preferred Term (All Phase II/III Studies) Safety Population ............................................... 261
Table 83: Summary of duration of exposure (safety population) ........................................ 266
Table 84: Summary of treatment-emergent adverse events (safety population) ................ 266
Table 85: Number (%) of subjects with adverse events by maximum severity (safety population) ........................................................................................................................ 268
Table 86: Number (percent) of subjects with serious adverse events (SAEs) by organ class and preferred term (safety population) .............................................................................. 269
Table 87: Number (%) of subjects with treatment-related serious adverse events (SAEs) 270
Table 88: Overview of Treatment-emergent Adverse Events (Safety Population) ............. 272
Table 89 – Number (percent) of subjects with serious adverse events (SAEs) by organ class and preferred term (safety population) .............................................................................. 275
Table 90: Overview of Treatment-emergent Adverse Events (Safety Population) ............. 279
Table 91: Subjects with Treatment-related Adverse Events by Preferred Term (Safety Population) ........................................................................................................................ 280
Table 92: Subjects with Serious Adverse Events by System Organ Class and Preferred Term (Safety Population) .................................................................................................. 281
Table 93: Limitations to detect adverse events in clinical trial programmes ....................... 283
Table 94: Methods of data collection and analysis of AE, TEAE and SAE ......................... 284
Table 95 - Comparator overview ....................................................................................... 294
Table 96: Risk of bias on study level – Randomized trials with cefiderocol ........................ 300
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EXECUTIVE SUMMARY
AMR is a major, growing threat to public health
Anti-microbial resistance (AMR) is a major and growing threat to global public health [1].
Infection by multi-drug-resistant (MDR) and particularly carbapenem-resistant (CR) pathogens
is associated with a high mortality rate and increased morbidity and economic burden [2, 3].
In 2015 in the EU, 33,110 deaths were attributable to infections due to antibacterial-resistant
bacteria [4] and it has been estimated that, if significant action is not taken by the year 2050,
10 million lives will be lost each year due to AMR [1].
Nosocomial MDR infections (including CR), caused by Gram-negative (GN), aerobic bacteria
including CR Escherichia coli, CR Klebsiella pneumoniae, CR Pseudomonas aeruginosa, CR
Acinetobacter baumannii (WHO priority pathogens; [5-7]) and intrinsically CR
Stenotrophomonas maltophilia [8, 9] are particularly relevant, as there are limited treatment
options for these and particularly for carbapenem resistant pathogens [5, 6]. They primarily
occur in vulnerable hospitalised patients resulting in hospital acquired pneumonia and
ventilator acquired pneumonia (HAP/VAP), bloodstream infections (BSI), complicated urinary
tract infection (cUTI) and complicated intra-abdominal infections (cIAI), amongst other
infections [10-12].
Currently, an antibacterial susceptibility test (AST) is needed for a definitive prescription, which
can take more than 3 days [13, 14], so patients with infections involving resistant pathogens
are more difficult to treat and therefore, patients are more likely to receive multiple courses of
inappropriate therapies before an effective treatment is initiated. This delay can lead to
increased mortality and clinical burden, poorer outcomes, increasing the likelihood of
developing new resistances [15-21]. Furthermore, where CR infection is suspected in critically
ill patients, an antibacterial regimen is started immediately, despite incomplete information on
pathogen susceptibility, with the antibacterial (or combination of antibacterials) that has the
highest likelihood of success. The selection of antibacterial(s) should be guided by knowledge
of local epidemiology (local resistance profile and local pathogen distribution), as well as by
site of infection and patient specific factors, such as severity of illness and previous
antibacterial exposure or comorbidities. Treatment may be de-escalated to a more targeted
treatment once the AST results have been obtained [13]. This further emphasizes the critical
importance of susceptibility testing and the need for antibacterials with a wider spectrum of
activity targeting MDR/PDR strains, especially because studies found that inappropriate initial
treatment and the subsequent delay in effective treatment results in worse outcomes including
increased mortality, length of stay and treatment costs [15-21].
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Given the lack of treatment options, there are few defined standard of care (SoC) or guidelines
defining the most appropriate treatment strategy for MDR and CR Gram-negative bacteria
(GNB) [22]. Specific treatments for MDR-GNB infections are predominantly multiple drug
combinations that include one or more of the following: aminoglycosides (amikacin,
gentamicin); tetracyclines (tigecycline; eravacycline; minocycline) carbapenems (e.g.
ertapenem; imipenem-cilastatin, meropenem; meropenem/vaborbactam;
imipenem/relebactam/cilastatin); β-lactamase inhibitor combinations (ceftazidime/avibactam;
ceftolozane/tazobactam); fosfomycin; or polymyxins (colistin and polymyxin B) [23-27].
Carbapenems, due to their potency, broad-spectrum activity, and less frequent resistance,
have until recently for reasons of antimicrobial stewardship, been reserved for use in treatment
of patients with resistant bacterial infections that could not be treated with other beta-lactams.
Current treatment options, for treatment of CR pathogens [28], have either suboptimal efficacy
(e.g. carbapenems), limited pathogen and/or mechanism of resistance coverage (e.g.
ceftolozane/tazobactam; ceftazidime/avibactam; meropenem/vaborbactam) [29, 30] and/or
significant safety and tolerability concerns [e.g. colistin, tigecycline]) [31-34].
Even recently approved combinations of cephalosporins with established β-lactam/β-
lactamase inhibitors have activity against MDR Gram-negative infections, including P.
aeruginosa, but their limitations include a lack of activity against metallo-β-lactamase-
producing organisms and these new antibacterials remain vulnerable to resistance
mechanisms due to porin channel mutations or overexpression of efflux pumps [28, 35-43].
Despite having high rates of renal toxicity, the broad Gram-negative spectrum of colistin and
polymyxin B mean that they are still used in the absence of alternative effective treatment
options for increasingly emerging CR in Gram-negative bacteria [31].
New treatments that can overcome the known resistance mechanisms, are therefore needed,
contributing to more effective eradication of MDR pathogens and increase antibacterial
diversity, thus, supporting good stewardship and the overall effectiveness of the existing
arsenal of antibacterials.
CEFIDEROCOL overcomes the 3 main mechanisms of antibacterial resistance present
in Gram-negative pathogens and is active on WHO critical priority pathogens
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Cefiderocol is the first siderophore cephalosporin [44] to be approved. The cephalosporin core
of cefiderocol exerts it’s activity through inhibition of Gram-negative bacterial cell wall
biosynthesis leading to cell lysis. Its unique molecular structure catecholate siderophore
moiety, exploits the bacteria’s own active iron uptake mechanism via siderophores to enter
the periplasmic space of GNB where it exerts its bactericidal activity. This is a novel
mechanism of bacterial cell entry which means that cefiderocol, unlike other antibacterials,
bypasses pathways traditionally used by other antibacterials such as efflux pumps or porin
channels, which bacteria can regulate to reduce their exposure to antibacterials. Cefiderocol
also has a higher stability to both serine- and metallo-type β -lactamases, key enzymes
rendering resistance to β–lactam antibacterials, including carbapenems. All these factors
contribute to cefiderocol’s unique breadth of activity and efficacy, covering a wide range of
aerobic, GN bacteria, demonstrated by its potent activity (both in vitro and in-vivo) against all
three WHO priority CR pathogens (Enterobacteriaceae, A. baumannii and P. aeruginosa) [29,
30, 45-49]. In addition, cefiderocol has in vitro activity against intrinsically CR Stenotrophomas
maltophilia and Burkholderia cepacia [30].
The dosing regimen of cefiderocol is 2g administered every 8 hours by IV infusion over 3 hour
period, with treatment duration dependent on the site of infection, e.g. 5-10 days for cUTI and
cIAI and 7-14 days for hospital-acquired pneumonia, but treatment up to 21 days may be
required [50].
The indication for cefiderocol is expected to be:
Fetcroja is indicated for the treatment of infections due to aerobic Gram-negative
organisms in adults with limited treatment options.
This indication will therefore be pathogen focused, not restricted to any specific site of infection and supports the use of cefiderocol in two types of patients:
Hospitalised patients with suspected (but prior laboratory confirmation) MDR/CR
infection who are critically ill and require immediate antibacterial treatment that
provides full cover against CR pathogens and potential resistant mechanisms, to
avoid the risk of rapid clinical deterioration (with the option to de-escalate to a more
targeted treatment when the pathogen and susceptibility profile is subsequently
confirmed)
Hospitalised patients where CR infection has been confirmed and cefiderocol is
best option based on pathogen susceptibility information and/or where other
treatment choices are inappropriate (efficacy, contra-indication or tolerability).
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OVERVIEW OF PRE-CLINICAL AND CLINICAL EVIDENCE
Unlike other therapeutic areas, the evaluation of the effectiveness of an antibacterial relies on
the combined consideration of in vitro, Pharmacokinetic (PK)/Pharmacodynamic (PD) and
clinical data. Cefiderocol’s favourable in vitro minimum inhibitory concentrations (MICs)
correlate well with in vivo efficacy in PK/PD in vivo efficacy in validated animal models of
infection, including MDR pathogens. Randomized clinical trials in patients with complicated
urinary tract infections (cUTI) [51], nosocomial pneumonia (HAP/VAP/HCAP), and BSI have
provided confirmation of the good efficacy and safety of cefiderocol in key target patient
populations.
In vitro evidence shows cefiderocol has activity in >95% of CR Gram-negative isolates
In vitro activity of cefiderocol has been studied in two large surveillance studies (SIDERO-
WT/Proteeae and SIDERO-CR 2014/2016) [29, 30, 45, 46] and many country specific smaller
similar studies. The SIDERO-WT study tested the in vitro antibacterial activity of cefiderocol
against Gram-negative bacteria [29]. A total of 30,459 clinical isolates of Gram-negative bacilli
were systematically collected from USA, Canada, and 11 European countries between 2014
and 2017. Cefiderocol demonstrated activity against 99.5% of Gram-negative isolates at a
MIC of 4 mg/L. Isolates were less susceptible to the comparators including colistin (95.5%),
ceftazidime-avibacatam (90.2%) and ceftolozane-tazobactam (84.3%).
In the SIDERO-CR-2014-2016 study [30], which was a global study of 52 countries, focusing
only on CR isolates, cefiderocol demonstrated potent in vitro activity at a MIC of 4 mg/L against
96.4% of isolates of carbapenem-nonsusceptible pathogens including all of the WHO priority
pathogens and Stenotrophomas maltophilia. Cefiderocol was found to provide a wider Gram-
negative coverage, and more potent in vitro antimicrobial activity than comparators including
ceftazidime/avibactam (39.8%), ceftolozane/tazobactam (37%), and colistin (91.5%).
PK/PD studies predict (probability >90%) that the dosing regimen achieves a
concentration of free drug in plasma > MIC for 75% dosing period
As for other cephalosporins, %fT>MIC is the best predictor of efficacy for cefiderocol. A dosing
regimen delivering 75% T>MIC succeeded achieving at least 1 log10 kill reducing the number
of viable bacterial cells in both murine thigh infection and murine lung infection by at least 90%
regardless of the isolate used to induce the infection (E. coli, K. pneumoniae, P. aeruginosa,
A. baumannii or S. maltophilia).
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A 3-compartment model was used to describe the plasma concentrations of cefiderocol. A 3-
compartment pharmacokinetic population model was developed based on pharmacokinetic
data from healthy volunteers, patients with renal impairment and patients from the clinical
trials. Probability of Target Attainment (PTA) for 75% fT>MIC was above 97% for a MIC of 4
mg/L regardless of the site of infection or the renal function. In the epithelial lining fluid (ELF),
PTA for 75% fT>MIC was above 88% for a MIC of 4 mg/L confirming the adequacy of the
dosing regimen in the different patient populations. The dosing regimen therefore ensures
sufficient drug exposure to maximise the efficacy of cefiderocol.
Evidence from a streamlined clinical trial programme supports the in vitro data
An improved in vitro potency in addition to a well-characterized favorable PK/PD profile are
crucial to achieve both adequate exposure to the antibacterial over the MIC for the pathogen,
and clinical cure in patients infected with drug-resistant pathogens [52]. Therefore, clinical
studies in antimicrobials, provide only supportive safety and efficacy evidence to the pivotal in
vitro and PK/PD data. Furthermore, in the context of antibacterial resistance, the standard
clinical trial approach aiming at demonstrating superiority over existing treatments is not
feasible. Treatment options for MDR infections do not allow a superiority trial and it would be
unethical to wihthold effective treatment to pateints in such trials [52]. Hence, clinical trials
have an important role to confirm clinical efficacy, but a limited role in providing comparative
evidence outside the trial, as only pathogens that fall within the in vitro spectrum of the tested
treatments and comparators are included in the study. This is particularly relevant for
antimicrobial treatment selection in the absence of antibiogram.
The clinical efficacy and safety of cefiderocol was demonstrated in 2 randomised double-
blinded clinical trials and 1 open label, descriptive study.
The APEKS-NP study compared treatment with cefiderocol against the combination of high-
dose (HD), prolonged infusion meropenem in patients with nosocomial pneumonia caused by
MDR Gram-negative pathogens. Three hundred (300) patients were randomized 1:1 to
cefiderocol or HD meropenem, a regimen only used in more difficult-to-treat pathogens which
optimizes exposure and efficacy for meropenem. Cefiderocol met the primary endpoint of non-
inferiority in all-cause mortality (ACM) at day 14 versus HD meropenem (12.4% for cefiderocol
and 11.6% for HD meropenem; [95 % CI: -6.6, 8.2]) and similar results maintained for ACM at
Day 28 and end of study (EOS). Rates of clinical cure and microbiological eradication at TOC
were also similar between the treatment groups. Although patients with CR-pathogens known
prior to randomization were excluded from the study, in a meropenem-nonsusceptible
subgroup (MIC>8mg/L) later identified, the rates of ACM at Day 14 were 17.1% in the
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cefiderocol group and 20.0% in the HD meropenem group. Adverse events were similar
between cefiderocol and HD meropenem and cefiderocol safety profile was consistent with
other cephalosporins.
APEKS-cUTI was an international, multicenter, randomised, double-blind, active-controlled,
parallel-group, non-inferiority study to investigate the efficacy and safety of cefiderocol vs
imipenem/cilastatin (IPM/CS) in cUTI caused by Gram-negative MDR pathogens in hospitalisd
adults [51, 53]. 448 patients were randomized, of whom 300 received cefiderocol and 148
received IPM/CS. The primary efficacy endpoint was the composite of clinical response and
microbiological response rate at TOC assessment, in the MITT (microbiological Intent-to-treat)
population. The results demonstrated that 73% of patients in the cefiderocol group achieved
the primary endpoint, vs only 55 % of patients in the IPM/CS group, with an adjusted treatment
difference of 18.6% (95 % CI: 8.2, 28.9). This difference showed superiority in favour of
cefiderocol in a post-hoc analysis. Adverse events were similar in type and rate between
treatment groups and cefiderocol safety profile was consistent with other cephalosporins.
A Network Meta-Analysis (NMA) was feasible for cUTI, given the similarity of patients and
pathogens included across trials. All results were consistent with APEKS-cUTI trial and
showed no statistically significant differences compared to ceftazidime/avibactam and
ceftolozane/tazobactam in a similar patient population with similar pathogen distribution.
The CREDIBLE CR study was a small, exploratory, open label, randomised, descriptive study
to evaluate efficacy of cefiderocol and best available therapy (BAT) in critically ill patients with
confirmed CR infections, but was not designed or powered for statistical comparison between
arms. The study included 150 severely ill patients, (48 allocated to BAT) consistent with
compassionate use cases, with a range of infection sites including nosocomial pneumonia,
cUTI, BSI/sepsis. Many patients had end stage comorbidities and had failed multiple lines of
therapy. Clinical and microbiological outcomes were similar between the 2 arms, but there
were marked imbalances in some baseline clinical relevant characteristics and pathogen
distribution of the cefiderocol and BAT arms.
Cefiderocol has proven efficacy in complex compassionate use cases to date
More than 200 patients to date have been treated with cefiderocol within the compassionate
use programme around the world, highlighting the unmet medical need for alternative
antibacterials active against CR Gram-negative pathogens. Confirmed information on 74
patients who have completed treatment in this program showed that over 60% of the severely
ill patients infected with CR Gram-negative pathogens survived when no other treatment
option was available to them.
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In the absence of AST results, cefiderocol is estimated to provide better predicted
susceptibility rates and projected clinical success rates considering the European
Gram-negative pathogen epidemiology
When critically ill patients require immediate treatment in the absence of AST results, the
likelihood of treatment success with cefiderocol and comparators can be predicted through an
effectiveness model based on estimates of pathogen prevalence for the specific site of
infection, combined with pathogen susceptibility results for each infection site (taken from the
SIDERO surveillance studies); relying on the drug’s ability to achieve effective concentrations
at the site of infection. Such methodologies are used when ethical considerations limit the
prospective clinical evaluation of treatments by randomized control trials, i.e. where the risk of
exposing patients to potentially ineffective drugs in a clinical trial setting is too great.
Results from this effectiveness model showed that cefiderocol is expected to have higher
predicted susceptibility rates than comparators across different infection sites in the European
prevalent Gram-negative bacteria, and higher projected treatment success rates in cUTI and
pneumonia. These were consistent with trials results from APEKS cUTI and APEKS NP for
cefiderocol, but not for comparators as it includes pathogens for which they are not
susceptible. This modelling approach highlights the limitations of the existing clinical trials, and
the potential difference for the effectiveness rates, when antimicrobials are used in the
absence of AST.
Cefiderocol presents a safety profile consistent with other cephalosporins
The clinical safety for cefiderocol was established in the three randomised clinical trials,
including 549 treated patients, and showed a similar profile compared to other cephalosporins.
Pooled adverse event analyses showed that there were overall less treatment emergent
adverse events with cefiderocol (344/549 [67.1%]) vs comparators (252/347 [72.6%]), as well
as less treatment related AEs, (56/549 [10.2%]) with cefiderocol vs compartors (45/347
[13.0%]).
In the nosociomial pneumonia study treatment-emergent adverse events (TEAEs) and
treatment-related TAEs were balanced between arms. SAEs occurred in 36% of patients
treated with cefiderocol and 30% of patients treated with meropenem. The most frequently
observed AE was urinary tract infection (15.5% in cefiderocol and 10.7% in meropenem
group), hypokalemia (10.8% vs 15.3%) and anemia (8.1% vs 8%).
In the cUTI study the proportion of patients who experienced at least one adverse event (AE)
was lower in the cefiderocol group than in the IPM/CS group (41 % vs 51%). The most
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frequently observed AEs were gastrointestinal, such as diarrhoea [experienced by 4.3% and
6.1% of cefiderocol- and IPM/CS-treated subjects, respectively], and there was an numerical
increased incidence of C. difficile colitis in the IPM/CS arm compared with cefiderocol. Serious
adverse events (SAE) occurred less in cefiderocol-treated patients than in IPM/CS-treated
patients (5% vs 8%).
CR study (CREDIBLE-CR): The cefiderocol group had a lower incidence of AEs and
treatment-related AEs, but a higher incidence of death, SAEs and discontinuation due to AEs,
than was observed for patients receiving BAT. The incidence of treatment-related AEs leading
to discontinuation was similar between treatment groups. A blinded adjudication committee
concluded that none of the deaths in the cefiderocol arm was due to a drug-related AE,
although one death due to acute kidney injury in the BAT arm was attributed to colistin-based
therapy. Furthermore, whereas the mortality rate in the cefiderocol group was consistent with
previous studies in similar populations the evidence suggests that the mortality rate in the BAT
group was unexpectedly low for the population randomised.
CONCLUSION
Cefiderocol is an innovative, effective and well tolerated treatment for aerobic GN infections
in patients with limited treatment options. Cefiderocol overcomes the common resistance
mechanisms of GN pathogens and covers a broad range of aerobic, GN bacteria including all
three WHO priority CR pathogens (Enterobacteriaceae, A. baumannii and P. aeruginosa) and
the CR Stenotrophomas maltophilia and Burkholderia cepacia. It provides an important
alternative for physician managing patients with MDR/CR infections.
Cefiderocol’s favourable in vitro MICs across all relevant pathogens correlates well with in vivo
efficacy in PK/PD analyses. Randomized clinical trials in patients with cUTI, nosocomial
pneumonia (HAP/VAP/ HCAP), and BSI and sepsis have provided confirmation of the good
efficacy and safety of cefiderocol in key target patient populations, alongside compassionate
use case reports.
The combination of in vitro, PK/PD, and clinical data predicts that cefiderocol has a greater
likelihood of obtaining clinical success rates, in patients with suspected MDR/CR infections
than relevant comparators across different infection sites.
Cefiderocol provides an important new option for treating critically ill, hospitalised patients
where MDR/CR infection is suspected and time to effective treatment must be minimised, and
for patients where an MDR/CR infection has been confirmed and it is the most appropriate
option, due to pathogen susceptibility or where other treatment choices are inappropriate.
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1 Description and technical characteristics of the technology
Summary of the characteristics of the technology
Cefiderocol is the first siderophore cephalosporin [44] to be approved. It’s unique
molecular structure and novel mechanism of cell entry allow it to overcome the three
major resistance mechanisms found in Gram-negative pathogens (i.e., degradation by
β-lactamase enzymes, porin channel mutations and overexpression of efflux pumps):
o Cefiderocol has improved stability to hydrolysis by β-lactamases, including all
4 types of carbapenemases, key enzymes rendering resistance to β–lactam
antibacterials, including carbapenems.
o Cefiderocol exploits the bacteria’s need for iron and mimics the action of
bacterial own siderophores. A chelate complex with free iron is formed, which
is then actively transported into the bacterial cell via iron transporters,
circumventing pathways traditionally used by other antibacterials such as efflux
pumps or porin channels, which bacteria can regulate to reduce their exposure
to antibacterials.
Cefiderocol is active against a wider range of aerobic, GN bacteria than its
comparators (including all WHO priority pathogens: CR Enterobacteriaceae, CR P.
aeruginosa and CR A. baumannii). In addition, cefiderocol is also active against
intrinsically CR Stenotrophomas maltophilia and Burkholderia cepacia.
In Europe, Shionogi seeks a pathogen-focused indication for cefiderocol, and it is
expected to be approved for the treatment of infections due to aerobic GN organisms
in adults with limited treatment options. Within this indication, it is proposed that
cefiderocol offers most value in two clinical scenarios, and evidence for cefiderocol
and its relevant comparators is provided for each:
o Hospitalised patients with suspected (but prior laboratory confirmation)
MDR/CR infection who are critically ill and require immediate antibacterial
treatment that provides full cover against CR pathogens and potential resistant
mechanisms, to avoid the risk of rapid clinical deterioration (with the option to
de-escalate to a more targeted treatment when the pathogen and susceptibility
profile is subsequently confirmed).
o Hospitalised patients where CR infection has been confirmed and cefiderocol
is best option based on pathogen susceptibility information and/or where other
treatment choices are inappropriate (efficacy, contra-indication or tolerability).
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Cefiderocol was approved by the U.S. Food and Drug Administration (FDA) on
November 14, 2019, for treatment of cUTI in adult patients with limited or no alternative
treatment options. Based on the results of the recently presented APEKS NP study
Shionogi is preparing a sNDA submission to FDA for approval of cefiderocol for
pneumonia in 2020.
Evaluation of the effectiveness of an antibacterial requires the integrated analysis of in
vitro, PKPD and clinical data.
o Two large susceptibility studies, SIDERO-WT/Protea and SIDERO-CR
2014/2016), showed cefiderocol to have activity against 99.5% of GN isolates
and 96.2% of CR GN isolates respectively. This was higher than other tested
antibacterials, according to CLSI breakpoints. This was replicated in several
small country specific studies, with consistency results.
o Cefiderocol’s favourable in vitro MICs correlate well with in vivo efficacy in
PK/PD analyses conducted.
o Three clinical trials (APEK cUTI, APEKS NP and CREDIBLE CR) have
provided confirmation of the efficacy and safety of cefiderocol in key infection
types: cUTI, nosocomial pneumonia (HAP/VAP/HCAP), and BSI.
o In the absence of AST results, and in an integrated effectiveness model
analysis of European pathogen epidemiology, in vitro/in vivo data, and clinical
data, cefiderocol provides the best predicted susceptibility rates and projected
clinical success rates considering for the EU setting.
Cefiderocol provides an important new option for treating critically ill, hospitalised
patients where MDR/CR infection is suspected and time to effective treatment must
be minimised, and also for patients where an MDR/CR infection has been confirmed
and it is the most appropriate option, due to pathogen susceptibility or where other
treatment choices are inappropriate
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1.1 Characteristics of the technology
1. In Table 1 provide an overview of the technology.
Table 1: Features of the technology
Non-proprietary name Cefiderocol
Proprietary name FETCROJA
Marketing
authorisation holder
Shionogi B.V., Amsterdam, Netherlands
Class Antibacterials for systemic use
Active substance(s) Siderophore cephalosporin
Pharmaceutical
formulation(s)
Powder for concentrate for solution for infusion (powder for concentrate).
White to off-white powder.
ATC code J01DI04 cefiderocol
Mechanism of action Cefiderocol is a siderophore cephalosporin. In addition to passive
diffusion through outer membrane porin channels, cefiderocol can bind to
extracellular free iron via its siderophore side chain, allowing active
transport into the periplasmic space of Gram-negative bacteria through
siderophore uptake systems. Cefiderocol subsequently binds to penicillin
binding proteins (PBPs), inhibiting bacterial peptidoglycan cell wall
synthesis which leads to cell lysis and death.
2. In Table 2, summarise the information about administration and dosing of the
technology.
Table 2: Administration and dosing of the technology
Method of administration Intravenous use; administered by intravenous infusion over 3
hours.
Doses 1 g/vial; the recommended dose for individuals with normal
renal function is 2g over 3h infusion
Dosing frequency Every 8 hours (three times daily)
Average length of a course of
treatment
3-hour infusion of 2g; Overall duration of treatment is in
accordance with the site of infection.
Anticipated average interval
between courses of treatments
Each treatment cycle lasts 8 hours; 3h of infusion and then 5h
until the next cycle begins.
Anticipated number of repeat
courses of treatments
For complicated urinary tract infections including
pyelonephritis and complicated intra-abdominal infections the
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recommended treatment duration is 5 to 10 days. For hospital-
acquired pneumonia including ventilator-associated
pneumonia the recommended treatment duration is 7 to 14
days. Treatment up to 21 days may be required.
Dose adjustments Dose adjustments are necessary for patients with renal
impairment (reduced dose) or augmented renal function
(increased dose)
3. State the context and level of care for the technology (for example, primary healthcare,
secondary healthcare, tertiary healthcare, outside health institutions or as part of public
health or other).
Cefiderocol is administered by intravenous infusion over 3h every 8h. It is intended for
hospitalised, critically ill patients and therefore, is intended for hospital-use only.
4. State the claimed benefits of the technology, including whether the technology should
be considered innovative.
Cefiderocol is the first siderophore cephalosporin [44] to be approved. Its unique molecular
structure catecholate siderophore moeity, exploits the bacteria’s own active iron uptake
mechanism via siderophores to enter the periplasmic space of GNB where it exerts its
bactericidal activity by inhibiting bacteria cell wall synthesis. This is a novel mechanism of
bacterial cell entry which means that, unlike other antibacterials, cefiderocol bypasses
pathways traditionally used by other antibacterials such as efflux pumps or porin channels,
which bacteria can regulate to reduce their exposure to antibacterials. Cefiderocol also has a
higher stability to both serine- and metallo-type β -lactamases, key enzymes rendering
resistance to β–lactam antibacterials, including carbapenems. All these factors contribute to
cefiderocol’s unique breadth of activity and efficacy, covering a wide range of aerobic, GN
bacteria, demonstrated by its potent activity (both in vitro and in vivo) against all three WHO
priority CR pathogens (Enterobacteriaceae, A. baumannii and P. aeruginosa) [29, 30, 45-49].
In addition, cefiderocol has in vitro activity against intrinsically CR Stenotrophomas maltophilia
and Burkholderia cepacia [30].
1.1.1 Cefiderocol Structure
Cefiderocol has a pyrrolidinium group on the C-3 side chain, which improves antibacterial
activity and stability against β-lactamases (Figure 1) [48]. The major difference in the chemical
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structure of cefiderocol and other cephalosporins is the addition of a chlorocatechol group on
the end of the C-3 side chain, which confers the siderophore activity (Figure 1) [48].
Figure 1: Cefiderocol structure
Source: Sato, 2019 [54]
Cefiderocol has been granted with an ATC code J01DI04: cefiderocol.1 The J01D group (other
β-lactam antibacterials) comprises beta-lactam antibacterial, other than penicillins.
1.1.2 Mechanism of action and cell entry
The low levels of free iron in the human body during an infection induce pathogens to
upregulate iron acquisition factors, such as secretion of iron-binding small molecules called
siderophores into their environment and production of membrane-bound active iron
transporters [44, 55-58]. Bacterial siderophores tightly bind to host iron, forming a chelated
iron complex, which then penetrates through the outer membrane via active iron transporters
located in the GN outer membrane [44, 54].
Cefiderocol exploits the bacteria’s need for iron for cell growth and uses the bacteria’s own
active iron uptake mechanism to enter the periplasmic space of GN bacteria where it binds to
penicillin binding proteins (PBPs), inhibiting the bacterial cell wall synthesis causing killing the
bacteria [44, 48, 59].
1 https://www.whocc.no/ddd/lists_of_new_atc_ddds_and_altera/new_atc/?order_by=1
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Cefiderocol has been designed to chelate iron to form an iron complex similar to a bacterial
catecholate siderophore (Figure 1) [44, 54]. When bound to iron, the cefiderocol iron complex
mimics a bacterial siderophore-iron complex and therefore is actively transported through the
outer membrane using the bacteria’s active iron transporters, bypassing pathways traditionally
used by other antibacterials such as efflux pumps or porin channels, which bacteria can
regulate to reduce their exposure to antibacterials [44, 54, 60]. Even in the absence of forming
a complex with iron, cefiderocol can still function as other antibacterials, entering the bacterial
periplasm via passive diffusion through porin channels (Figure 2) [59].
Cefiderocol activity against bacterial strains with porin channel mutations and overexpression
of efflux pumps has been demonstrated in two in vitro studies [61, 62].
Figure 2: Cefiderocol mechanism of cell entry
Source: Image adapted from Zhanel 2019 [44]
1.1.3 Stability against β-lactamases
Figure 3: Antibacterial activity against β-lactamase-producing pathogens
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*Color-coding based on the pathogen susceptibility: Green – Activity reported, yellow – undetermined
activity reported, and red – no clinically relevant activity reported. Source: Thalhammer F, 2018 [63],
Theuretzbacher, 2019 [64]
The structure of cefiderocol also presents higher stability to hydrolysis across a wide range of
bacterially produced β-lactamase enzymes (including carbapenemases of the serine and
metallo-β-lactamase classes) and thus overcomes the primary mechanism of bacterial
resistance to beta–lactam antibacterials, without adding a β-lactamase inhibitor.
The image above (Figure 3) shows that whilst there are effective alternatives for Extended
Spectrum Β-lactamase (ESBL), there are limited treatment options for serine cabapenemases,
and metallo-bectalactamases, as well as other mechanisms of resistance. This is particulary
relevant for non-fermenters Pseudomonas aeruginosa, Acinetobacter baumanii, and
Stenotrophomonas maltophilia.
All these factors contribute to cefiderocol’s unique breadth of activity and demonstrated
efficacy, covering a wide range of aerobic, GN bacteria and cefiderocol’s demonstrated potent
activity (both in vitro and in vivo) against all three WHO priority carbapenem resistant
pathogens (Enterobacterales, A. baumannii and P. aeruginosa). In addition, cefiderocol has
in vitro activity against carbapenem resistant Stenotrophomas maltophilia and Burkholderia
cepacia.
1.2 Regulatory status of the technology
1. Complete Table 3 with the marketing authorisation status of the technology.
Table 3: Regulatory status of the technology
Organisation
issuing
approval
Verbatim wording of the (expected)
indication(s)
(Expected)
Date of
approval
Launched
(yes/no).
If no include
proposed date of
launch
FDA
FETROJA is a cephalosporin
antibacterial indicated in patients 18
years of age or older who have limited
November 14,
2019
Not launched.
Expected to be
launch in Q1 2020
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or no alternative treatment options, for
the treatment of complicated urinary
tract infections (cUTI), including
pyelonephritis caused by susceptible
Gram-negative microorganisms
EMA
Fetcroja is indicated for the treatment of
infections due to aerobic Gram-negative
organisms in adults with limited
treatment options
May, 2020
Not launched
Expected to launch
in 2H, 2020
EMA: European Medicines Agency, FDA: U.S. Food and Drug Administration
2. State any other indications not included in the assessment for which the technology
has marketing authorisation.
Not applicable. This corresponds to a new marketing authorization for a new chemical entity.
3. State any contraindications or groups for whom the technology is not recommended.
It is recommended that Fetcroja should be used to treat patients that have limited treatment
options only after consultation with a physician with appropriate experience in the
management of infectious diseases.
Cefiderocol should not be given to the following patients:
Patients with hypersensitivity to the active substance or to any of the excipients
listed
Patients with hypersensitivity to any cephalosporin antibacterial medicinal product.
Patients with severe hypersensitivity (e.g. anaphylactic reaction, severe skin
reaction) to any other type of beta-lactam antibacterial agent (e.g. penicillins,
monobactams or carbapenems).
The safety and efficacy of cefiderocol in children below 18 years of age has not yet been
established. No data are available. Patients with Central Nervous System infections were also
not included in the cefiderocol clinical trials.
4. List the other countries in which the technology has marketing authorisation.
Currently cefiderocol only has marketing authorization in the United States of America, under
the brand name of Fetroja, with the indication mentioned in Table 3.
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2 Health problem and current clinical practice
Summary of issues relating to the health problem and current clinical practice
AMR is a major and growing, threat to global public health. Infections by MDR (and
particularly CR) pathogens are associated with a high mortality rate and increased
morbidity and economic burden. In 2015 in the EU, 33,110 deaths were attributable to
infections due to antibacterial-resistant bacteria and it has been estimated that, if
significant action is not taken by the year 2050, 10 million lives will be lost each year
due to AMR. [4]
MDR and particularly CR infections are predominantly caused by Gram-negative,
aerobic bacteria. Given the increasing prevalence of resistant pathogens, WHO has
declared that the availability of new treatments for CR Gram-negative pathogens to be
a critical priority for CR strains of Enterobacteriaceae, Pseudomonas aeruginosa and
Acinetobacter baumannii including them on the WHO “Priority One CRITICAL List”
[65].
Current treatment options, including antibacterial combinations, have either suboptimal
efficacy (carbapenems), limited pathogen and mechanism of resistance coverage
(ceftolozane/tazobactam; ceftazidime/avibactam; meropenem-vaborbactam), and/or
significant safety and tolerability concerns (e.g. colistin, tigecycline).
o Treatment of confirmed CR infections must be tailored to each patient based
on results of AST results, knowledge of hospital and regional pathogen
epidemiology and patient specific factors, such as severity of concomitant
illness and infection. Therefore, few guidelines exist in Europe identifying a
specific treatment approach in CR infection.
o resistance to many antimicrobial classes almost invariably reduces the
probability of adequate empirical coverage, with possible unfavourable
consequences
o In the absence of an AST results (which commonly takes 3 days) and
suspected MDR/CR infection, treatment should start immediately in critically ill
patients to avoid risk of rapid deterioration. However, resistance to many
antimicrobial classes almost invariably reduces the probability of adequate
initial treatment, with possible unfavourable consequences vs those where the
pathogen is susceptible, and therefore easier to treat with available treatments
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(46.5% vs. 11.8%, p < 0.001). These patients experience delays in receiving
effective treatment which may lead to worse outcomes, increased mortality,
and increased length of hospital stay and treatment costs.
The integrated cefiderocol data-set (susceptibility, PK/PD and clinical trials) shows it
has a greater likelihood of treatment success in patients with MDR/CR infections than
relevant comparators. Cefiderocol therefore provides an important new option for
treating critically ill, hospitalised patients where MDR/CR infection is suspected and
time to effective treatment must be minimised, and also for patients where an MDR/CR
infection has been confirmed and it is the most appropriate option, due to pathogen
susceptibility or where other treatment choices are inappropriate.
The availability of cefiderocol as an additional effective agent against Gram-negative
bacteria can contribute to good antibacterial stewardship by allowing physicians to
increase the diversity of prescribing, reducing selective pressure on any one agent and
minimize development of resistance.
2.1 Overview of the disease or health condition
1. Define the disease or health condition in the scope of this assessment.
The human body harbours over 1000 types of bacteria constituting the normal microbial flora.
In healthy individuals, these bacteria do not usually cause infection and exist on the host for
long periods without causing harm [66]. However, invasion of the host by pathogenic
microorganisms that proliferate results in tissue injury [67]. Pathogenic bacteria can infect any
part of the human body. Infections can be acquired in the community setting (community-
acquired infection [CAI]), acquired in hospital setting (Hospital-acquired infection – [HAI] or
nosocomial infection) or acquired in long-term care facilities (Healthcare-associated infection
[HCAI]) such as intensive care wards, ambulatory settings, nursing homes or rehabilitation
facilities. Infections caused by multidrug-resistant bacteria (MDR) are more likely to be a HAI.
Nosocomial infections primarily occur in vulnerable hospitalised patients. These patients are
often ≥ 50 years of age, likely to be severely ill, e.g. transplanted patients, possibly in intensive
care units (ICU), or undergoing chemotherapy, or patients who have compromised
immunogenicity, and generally wuth multiple comorbidities (e.g. heart disease, diabetes or
kidney disease) [68, 69]. Infections caused by MDR pathogens can occur at many sites
including the urinary tract (complicated urinary tract infections [cUTI]), lungs (Hospital-
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acquired and ventilator-associated pneumonia [HAP/ VAP]), blood (bloodstream infections
[BSI]), and intra-abdominal sites (complicated intra-abdominal infections [cIAI]).
The International Classification of Disease (ICD, version 10) contains separate codes for
pathogens as well as for infections sites. ICD-codes for nosocomial Gram-negative infections
are included as an appendix [70].
2.1.1 Overview of Gram-negative bacteria
Gram-negative bacteria can be classified into fermenters and non-fermenters based on their
ability to ferment glucose [71]. While non-fermenting Gram-negative bacteria (non-fermenters)
are usually found in nature, they are harmful when colonizing and infecting
immunocompromised people or when the infections are a consequence of trauma or invasive
procedures (e.g. surgery, intravenous catheters, respiratory care equipment or endotracheal
tubes) [71]. Bacteria are also differentiated based on cellular morphology (most commonly
bacilli and cocci) and oxygen requirements (aerobes and anaerobes) (Figure 4) [72].
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Figure 4: Classification of Gram-negative bacteria
Pathogens highlighted in blue are of interest when exploring the topic of carbapenem resistance
Source: The Ohio State University, 2017 [73]; Adeolu, 2016 [74]
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2.1.2 Antimicrobial resistance
Anti-microbial resistance (AMR) is a major, and growing, threat to global public health.
Treatment of pathogens has become more and more challenging due to the emergence of
resistance, especially to carbapenems which are usually reserved for use where other
alternative options have failed [5, 6, 75-79]. AMR is estimated to contribute to 700,000 deaths
every year globally, with 33,110 lives lost per year in Europe [1, 4, 80]. The burden of infections
with bacteria resistant to antibacterials in the European population is comparable to that of
influenza, tuberculosis and HIV/AIDS combined [81]. It has been estimated that, if significant
action is not taken, by the year 2050 10 million lives will be lost each year due to AMR (Figure
5) [1]. While the global consumption in antibacterials is predicted to rise three-fold by 2030,
the current treatment options may address only a subset of resistance mechanisms [1].
Figure 5: Global burden of AMR
Source: O’Neill [1]
An overview of medically important GN bacteria classified based on WHO’s priority criteria
for Drug development is provided in Table 4 [1].
Table 4: List of the highest priority bacteria (WHO)
Priority Pathogen
Critical Carbapenem-resistant Acinetobacter baumannii,
Carbapenem-resistant Pseudomonas aeruginosa,
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Carbapenem-resistant/3rd generation cephalosporin-resistant Enterobacterales,
(including Klebsiella pneumonia, Escherichia coli, Enterobacter spp., Serratia spp.,
Proteus spp., and Providencia spp, Morganella spp.)
High Clarithromycin-resistant Helicobacter pylori,
Fluoroquinolone-resistant Campylobacter
Fluoroquinolone-resistant Salmonella spp
3rd generation cephalosporin-resistant/fluoroquinolone-resistant Neisseria gonorrhoeae,
Medium Ampicillin-resistant Haemophilus influenzae
Fluoroquinolone-resistant Shigella spp
Source: WHO 2017 [5, 6]
GN pathogens are challenging to treat due to their potential intrinsic resistance to
antibacterials and the emergence of acquired resistance [75]. This development has been
recognized to be a major public health threat. Outbreaks of infections with resistant strains
have been reported in several European countries [82, 83]).
Facultative anaerobes E. coli, A. baumannii, K. pneumoniae and P. aeruginosa, are a
cause of great concern with regard to antimicrobial resistance (AMR) [8, 79]. Non-
fermenters such as P. aeruginosa, A. baumannii, and S. maltophilia, are often resistant to
a large number of antibacterial treatments and also differ in their pathogenic potential and
transmissibility [84].
The widespread use of antibacterials has led to new mechanisms of resistance to develop
[85]. Bacteria have adjusted by producing new types of β-lactamases, which can cleave
the otherwise resistant carbapenems [86]. Additional resistance-causing mutations can
modify and/or downregulate the cell wall proteins, porin channels and other molecules that
the antibacterials use to enter and kill the bacteria. Some bacteria have acquired the ability
to up-regulate efflux pumps to eliminate the antibacterial faster. Figure 6 illustrates the
main mechanisms of beta lactam bacterial resistance.
Additionally, bacteria have developed the ability to transfer resistant genes not only
vertically, but also horizontally to other members of their own or even different species [87]
[88, 89] [90], thus became a global problem of interspecies transmission.
Carbapenems, due to their potent efficacy, broad-spectrum activity, and relative resistance to
hydrolysis by the majority of β-lactamases, are usually reserved for use when other options
have failed [28].
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Figure 6: Mechanisms of beta lactam bacterial resistance
Β-lactamases and carbapenemases are the most common cause of resistance to beta-
lactam antibacterials (e.g. penicillin) in GN bacteria [75, 91]. Β-lactamases hydrolyse the
beta-lactam ring of beta-lactam antibacterials and render them inactive [92, 93]. They can
be classified into four molecular classes (A-D). Carbapenemases, a subset of β-
lactamases that hydrolyse carbapenems as well as almost all beta-lactam antibacterials,
include enzymes from classes A, B and D [86, 94]. Class A carbapenemases, the most
common carbapenemases primarily identified in Enterobacterales can hydrolyse
carbapenems as well as cephalosporins, penicillins, and aztreonam [86, 91, 95]. Class B
carbapenemases, found in K. pneumoniae and A. baumannii, usually exhibit resistance to
penicillins, cephalosporins, carbapenems, and the available β-lactamase inhibitors [91,
96]. Β-lactamases from class D, also known as OXA β-lactamases, can confer resistance
to penicillins, cephalosporins, extended-spectrum cephalosporins, and carbapenems
(OXA-type carbapenemases) and are poorly inhibited by currently available β-lactamase
inhibitors. These enzymes are expressed in A. baumannii and P. aeruginosa [91, 95, 97].
While resistance based on carbapenemases is mostly acquired, it can be intrinsic in some
species, such as S. maltophilia [98].
Changes to porin channels, reducing the permeability of the outer membrane, is a common
mechanism of intrinsic antibacterial resistance in GN bacteria [99]. These changes include
both reducing the number of porin channels and altering their conformation resulting in a
reduced ability of antimicrobial agents to cross the outer membrane and reach the
intracellular antibacterial target [75]. In Enterobacterales, P. aeruginosa, and A.
baumannii, reductions in porin expression significantly contribute to resistance to
carbapenems and cephalosporins [99].
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Another common mechanism of resistance is overexpression of efflux pumps. Efflux
pumps actively pump antibacterials from the bacterial cytoplasm, inhibiting their function
within the cell [99]. When overexpressed, efflux pumps can confer high levels of resistance
to previously clinically useful antibacterials such as carbapenems [100]. Efflux pumps are
a common mechanism of resistance in non-fermenting bacteria such as P. aeruginosa,
and A. baumannii [101].
All these mechanisms can co-exist in the same organism.
Furthermore, while use of colistin was largely abandoned due to the high rates of renal
toxicity, in recent years, the increasing emergence of CR GN bacteria has led to its clinical
renaissance [102], given its wider spectrum of activity and lack of effective alternatives.
However, resistance to colistin is rapidly increasing. In Europe for instance, 28% of CR K.
pneumoniae have been identified as resistant to colistin [103]. Also, reports of resistance
to the recently approved treatments such as ceftolozane/tazobactam and
ceftazidime/avibactam have raised concerns [42, 43].
Table 5 shows the limited in vitro efficacy of several antibacterials against different GN
bacteria (Enterobactereacea, Pseudomonas aeruginosa, Acinetobacter baumannii,
Stenotrophomonas maltophilia), particularly for CR non-fermenters and pathogens,
including serine carbapenemases. ([104]). Stenotrophomonas maltophilia is intrinsically
resistant against carbapenems [98, 105].
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Table 5: In vitro activity profile of antibacterials for GN Infections with limited treatment options
CP: carbapenemase; CR: carbapenem resistant. OXA-48, KPC, MBL, AmpC: types of carbapenemases.
Green – Activity reported, yellow – undetermined activity reported, and red – no clinically relevant activity
reported. Source: Adapted from Thalhammer F. (2018). [63]
2.1.3 Overview of infection sites
Aerobic GN pathogens are the most common causes of nosocomial infections and are most
commonly seen pneumonia, BSI and UTI, which together represent over 50% of the HAI in
Europe.
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Figure 7: Hospital-acquired infections in acute care hospitals (EU/EEA 2011-2012)
HAI, hospital-acquired infection
Source: ECDC, 2012 [10]
2.1.3.1 Nosocomial Pneumonia
According to the European Centre for Disease Prevention and Control (ECDC) prevalence
survey database, pneumonia is the most common infection site accounting for 23% of HAIs
[10], of which 67.6% are caused by GN pathogens, and can be defined as HAP, VAP or
healthcare-associated pneumonia (HCAP) (Figure 7) [106]. The main causal pathogens of
HAP/VAP include Pseudomonas aeruginosa, Acinetobacter spp. and Enterobacterales [11].
Patients with HAP/VAP are at risk of experiencing acute respiratory failure and may require
mechanical ventilation [107]. In the 2012 ECDC report, intensive care unit (ICU)-acquired
pneumonia was reported to be associated with 5,495 deaths annually resulting in an
attributable mortality rate of approximately 3.5% [108].
2.1.3.2 Complicated urinary tract infection (cUTI)
According to the ECDC prevalence survey database, UTI accounts for 19% of HAIs, of which
76.7% are caused by GN pathogens [10, 106]. The main causal pathogens of cUTI include
Escherichia coli, Enterococcus spp., Klebsiella spp., Pseudomonas aeruginosa and Proteus
spp. [11]. Patients with cUTI can develop bacteraemia and sepsis in 10% to 30% of cases,
with risk of death reaching up to 40% [109, 110].
2.1.3.3 Bloodstream infection and sepsis
Bloodstream infections account for 11% of HAIs, of which 43.8% are caused by Gram-
negative pathogens [10, 106]. It is defined as the presence of bacteria in the blood and can
be also referred to as bacteraemia. In some cases, it can result in sepsis developing, which is
a life-threatening condition mediated by the inflammatory response to infection [27]. The main
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causal pathogens of BSI include Staphylococcus spp., Streptococcus pneumonia,
Enterobacterales and Enterococcus spp. [11]. In the 2012 ECDC report, ICU-acquired BSI
was reported to be associated with 4,505 deaths annually resulting in an attributable mortality
rate of approximately 5% ([108].
2.1.3.4 Complicated intra-abdominal infection
Complicated intra-abdominal infections account for 1 to2.8% of CR infections [111] [4, 112].
The percentage of IAI caused by Gram-negative pathogen is 15.9% [106]. It is associated with
either abscess formation or peritonitis [113]. cIAI generally extends beyond local viscera into
peritoneal or retroperitoneal spaces and are associated with systemic signs and symptoms of
illness [114]. The main causal pathogens of cIAI are Enterobacterales, Streptococci and
Anaerobes (particularly Bacteroides fragilis) [23].
2.1.4 Risk and prognostic factors for MDR and CR infections
2.1.4.1 Risk factors
Risk factors for CR Gram-negative infections consist of a combination of patient clinical
setting/healthcare exposure and patient-level characteristics [115-117] and include risk factors
that are common to all nosocomial infections (e.g. long term hospitalisation, invasive
procedures, long-term ventilation, or depressed host immune system), and some are more
specific to CR infections (e.g. previous colonization or infection with CR pathogen, prior
exposure to carbapenems, and recent hospitalisation in a endemic CR infections country, or
where there was a recent outbreak). Risk factors can vary by infection site (e.g. ventilation is
more frequently reported in pneumonia). [85, 118-122].
A summary of the most commonly reported risk factors according to different pathogens is
included as an appendix [123] (see Table 6.1:Most commonly reported risk factors per
pathogen).
2.1.4.2 Prognostic factors
Time to effective therapy impacts patient’s overall outcomes. Delays in the determination of
the pathogen identity and AST results frequently lead to inadequate initial treatment, which
causes increased morbidity and mortality. The impact of treatment delay of appropriate
treatment was analysed in an SLR [124, 125] reviewing 145 studies and considering three
types of outcome comparisons: delay vs. no delay in receiving appropriate therapy, duration
of delay of appropriate therapy, and appropriate vs. inappropriate initial therapy. A delay in
patients receiving appropriate effective treatment was shown to lead to worse patient
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outcomes, including higher mortality rates. Early treatment with appropriate initial therapy
represents an important prognostic factor in the treatment of patients with GN infections with
limited treatment options. This is further detailed in this section
2. Present an estimate of prevalence and/or incidence for the disease or health condition
including recent trends.
2.1.5 Epidemiology
The rate of infections caused by multidrug-resistant (MDR) bacteria continues to increase and
limit the utility of existing antibacterial agents. In its surveillance report (2018), European
Centre for Disease Prevention and Control (ECDC) reported an increase in resistance to
currently available treatments across some Gram-negative pathogens between 2015 and
2018 [126]. ECDC estimate that nearly 700,000 infections and 33,000 deaths in the EU and
European Economic Area (EEA) in 2015 are a consequence of MDR bacterial infection [4].
Carbapenem-resistance (CR) in Pseudomonas aeruginosa, Klebsiella pneumoniae and
Acinetobacter spp. contributed significantly to the number of estimated deaths (in total
approximately 9,000 deaths).
Reports on CR isolates are highly heterogeneous across the globe (Figure 8), but the
prevalence of carbapenem resistance has been found to be particularly high in Mediterranean
countries, South America and Asia-Pacific countries, with the exception of Japan [127, 128].
Figure 8: Worldwide carbapenem resistance
Source: CDC 2013[80]; ECDC 2017[79]; Mendes et al.[129]; Kiratisin et al.[130]
In the EU-5, the number of CR Gram-negative infections has been reported to be 65,592 in
2015, 123,069 in 2018 and 124,630 in 2019 with P. aeruginosa and A. baumannii as the most
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frequently diagnosed CR pathogens [4, 79, 111]. Across EU-5 countries, prevalence of CR
Gram-negative infections is reported to range between 0.14 per 100,000 in the UK to 3.05 per
100,000 in Italy (Figure 9) [4].
Figure 9: Prevalence of CR Gram-negative infections in the EU-5
Source: Cassini, 2018[4]
Prevalence estimates are available from multiple sources, generated thorugh different
methodologies. Furthermore, pathogen resistance is a constantly evolving, and therefore,
results may vary significantly with time, and region/country. Also relevant to account is the fact
that the epidemiology varies across the different pathogens, and infections sites:
Non-fermenters P. aeruginosa and Acinetobacter spp. are the most common
pathogens. P. aeruginosa was found in 17% to 61% of CR infections and
Acinetobacter spp. in 19% to 50%. The second most common CR pathogen is K.
pneumoniae (6% to 20% of infections) followed by E.coli (0.1% to 2.8%) [4, 79, 111].
The most prevalent CR Gram-negative infection site is the respiratory tract with
reported ranges from approximately 41% [4] to 57%[111], followed by UTI and
BSI/Sepsis (Table 7).
Table 6: Most common CR causal pathogens across available EU-5 data sources
Pathogen % of causal pathogen for CR Gram-negative infections
P. aeruginosa 17%-60.7%
A. baumannii 19%-50%
K. pneumoniae 6%-20.0%
S. maltophilia 1%a
E. coli 0.1%-2.8%
1,20
0,31
3,05
0,64
0,14
1,07
France Germany Italy Spain UK EU-5 average
Cases/100,000
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A proportion of S. maltophilia that caused HAIs Suetens 2018[106]
Sources: ECDC 2018[79]; Cassini et al, 2018[4] and DRG 2017[111]
Table 7: Proportion of CR infection sites in the EU-5
Infection site % of infection sites for CR Gram-negative infection
Respiratory tract 41.3%-57%
Urinary tract 17.0%-19.1%
Bloodstream 11.2%-21%
Abdomen 2.0%
Skin/wound 10.7%-12.8%
Other 7.8%
Sources: Cassini et al, 2018[4] ; DRG 2017[111]
While there appears to be geographical variation in different types of carbapenemases, recent
surveillance study reports an overall increase in these enzymes.
While carbapenem resistance affects both non-fermenters and fermenters in all regions,
mechanisms of resistance appear to vary geographically [48, 128].
Analyses from SIDERO-CR surveillance studies [131] confirmed the diversity in
carbapenemases across Europe, reporting prevalences of carbapenemas producing
Enterobacteriaceae (CRE), P. aeruginosa (CRP), and A. baumannii (CRA) (Figure 10).
Overall there is an increase in the prevalence of isolates with carbapenemases with significant
divrsity (Figure 11) [103] and non-carbapenemase mechanisms of resistance are present in a
significant proportion of isolates, particularly in E. coli. (Figure 12) [103, 132]
Figure 10: Epidemiology of carbapenemases in EU 5
Source: Shionogi data on file (Data adapted from SIDERO-CR study)[131]
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Figure 11: Confirmed carbapenemase-producing Enterobacteriaceae isolates (Public Health
England: 2008–17)
Source: ESPAUR, 2019[132]
Figure 12: Distribution of carbapenem resistance mechanisms in Enterobacteriaceae species in
the Europe
Source: Nordmann, 2019 [128]
3. Describe the symptoms and burden of the disease or health condition for
patients.
Multi Drug Resistant Gram-negative infections primarily occur in vulnerable hospitalized
patients. These pateints are often ≥ 50 years of age, severely transplanted patients, possibly
in intensive care units (ICU), or undergoing chemotherapy, or patients who have compromised
immunogenicity, and generally wuth multiple comorbidities (e.g. heart disease, diabetes or
kidney disease) [68, 69].
The clinical burden of bacterial infection has an impact on key outcomes such as longer
treatment, extended hospital admission, additional healthcare professional time, healthcare
resource use, adverse events, greater disability (morbidity) and increased risk of death
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(mortality) [76]. The need to treat patients empirically before pathogen susceptibility has been
confirmed means that this initial treatment choice in MDR is often inappropriate and this can
have a significant impact on the individual patient due to the negative clinical consequences
of a delay on effective treatment [133, 134].
An overview of signs and symptoms of common CR infections by infection site is provided in
Table 8.
Table 8: Overview of disease burden according to the infection site
Site of infection Signs and Symptoms2 Mortality
pneumonia Dyspnoea a Productive cough a Fever a Chest pain a Loss of appetite a
5,495 annual number of deaths in Europe due to ICU-acquired
pneumonia (2008–12)[108]
Attributable mortality rate: ~3.5%
cUTI Fever b Increased urinary frequency b and urgency b Haematuria b Dysuria b Suprapubic/flank pain b
Can develop bacteraemia and sepsis in 10% to 30% of cases,
with risk of death reaching up to 40%[109, 110]
BSI Fever c Chills c Tachycardia c Tachypnoea c Potential complications: Infective endocarditis d Osteomyelitis d Infectious arthritis d Septic shock/sepsis d
4,505 Annual number of deaths in Europe due to ICU-acquired
bloodstream infections (2008–12) [108]
Attributable mortality rate: ~5%
sepsis Dyspnoea e Confusion e Tachycardia e Fever/shivering/feeling very cold e Extreme pain e Clammy/sweaty skin e
A rate of hospital mortality for sepsis: 17%-26% in severe cases
[135]
Extrapolation to global estimates: ~ 5.3 million deaths annually
from sepsis
cIAI Fever f Tachycardia f Tachypnoea f
Hypotension f Abdominal pain f Nausea and vomiting f Diarrhea f Abdominal fullness e Obstipation e
Severe infections: mortality rate of 30-50%
In case of sepsis: mortality rate > 70%g
Sources: a. https://www.blf.org.uk/support-for-you/pneumonia/symptoms ; b. Sabih et al, 2019[136]; c. MedlinePlus -
Medical Dictionary[137] d. Hassoun et al, 2017 [138];
Symptoms of MDR (including CR) Gram-negative infections vary according to the infection
site, but for the same infection site, are no different than that caused by other serious
infections.
2 Symptoms of MDR (including CR) Gram-negative infections do not differ from those of other serious
infections.
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2.1.6 Mortality
Multidrug resistant infections, including CR, are associated with 1.6 to 5.0 times higher
mortality risk compared non-MDR/CR infections [21, 139, 140]. Mortality rates can reach up
to 70% in the most severe cases such as bacteraemia [141]. In Europe, the mortality
associated with MDR and CR Gram-negative infections is estimated to be 35% [142-148] .
The extent of the clinical burden of infections with Gram-negative pathogen depends on the
severity of infection but generally the burden increases when coinciding with resistant
pathogens. The risk of mortality is more than doubled when the cause of an infection is MDR
Gram-negative bacilli, in comparison to susceptible organisms [134] For carbapenem-
resistant Gram-negative infections, mortality has been estimated to range between 26-44% in
one meta-analysis [149], and between 30-75% in another review of studies [150].
Clinical outcomes and burden from Gram-negative bacterial infection can vary depending on
the site of infection:
HAP/VAP: Mortality rate estimates in patients with pneumonia ranged from 48.6% to 64.7%
[115]. The crude mortality rate associated with VAP has been observed to range from 25% to
76% [151] but mortality directly attributed to VAP could be less than 10% because patients
with VAP are already being treated for life-threatening illnesses and may die from the comorbid
disease [152-154].
BSI: Hospital-acquired BSI has been associated with substantial morbidity and mortality [155,
156]. According to ECDC, patients with BSIs due to carbapenem-resistant Enterobacteriaceae
have mortality rates reaching 50% [157].
In Europe, sepsis caused by the most frequent resistant bacteria is responsible for
approximately 25,000 deaths per year, and that two-thirds of these are due to Gram-negative
pathogens [158].
UTI: Patients with cUTI can develop, in 10% to 30% of the cases, bacteraemia being
associated with a mortality rate ranging between 30% and 40% [110].
The clinical burden of Gram-negative bacilli infections varies depending on the causal
pathogen. Infection by Gram-negative pathogens, and specifically MDR Gram-negative
pathogens such as E. coli, K. pneumoniae, P. aeruginosa, and Acinetobacter spp. can result
in significant clinical burden due to the increase in the length of hospital stay, lack of clinical
efficacy, treatment-related adverse events, morbidity and mortality. The reported hospital
mortality rates were highest for A. baumannii (23.4 to 50%) and P. aeruginosa (50 to 59.5%),
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followed by K. pneumonia (14.4 to 24%) and E. coli (2.5%) [115] [159] [160] [142, 161].
However, quantifiable research at the pathogen level is limited and influenced by global
variation in epidemiology, small study sizes and varying definitions of resistance to
antimicrobials, leading to difficulties with cross-pathogen comparisons of the pathogen-
specific impact of an AMR Gram-negative infection.
Patient factors such as health status and functional status can further contribute to the clinical
burden of Gram-negative infection. Mortality associated with CR infections can reach up to
100% in severe cases such as mechanically ventilated patients with bacteraemia [115]. In
addition, admission to a hospital with a high prevalence of MDR Gram-negative pathogens
and inpatient stay due to invasive procedures (e.g. surgery, ventilators, catheters) increases
the risk of infection and thus the risk of poor clinical outcome if the procedure [134].
2.1.7 Quality of Life
There is limited and confounded information available on the impact of infections over the
quality of life of these patients, as these are severely ill patients who are frequently treated in
ICU units and may be intubated and unconscious, and unable to complete these
questionnaires. The quality of life of these patients is also impacted by their underlying
disease, and most importantly by the severity of the infection and the infection site (i.e. patients
with BSI and sepsis are expected to have lower quality of life compared to a patient with cUTI).
The fact that these patients are hospitalised already has detrimental impact on their quality of
life. The ward in the hospital also impacts the patient’s quality of life (i.e. patients on ICU or
isolation, are expected to have lower quality of life compared to general ward), although this
may be correlated with the severity of the infection and underlying condition. All these factors
make investigating quality of life in antimicrobial clinical trials difficult and infrequent. However,
any therapy that resolves the infection and/or reduces length of hospitalization is expected to
improve patient’s quality of life.
2.1.8 Disability Adjusted Life Years (DALYs)
The estimated burden of infections with antibacterial-resistant bacteria in Europe is substantial
compared with that of other infectious diseases [4]. A study based on EARS-Net data from
2015 estimated that infections due to antibacterial-resistant bacteria3 accounted for 33,110
attributable deaths and 874,541 DALYs [4]. Infections with colistin-resistant or CR pathogens
The included antibacterial resistance-bacterium combinations were colistin-resistant, carbapenem-resistant, or multidrug-resistant Acinetobacter spp; vancomycin-resistant Enterococcus faecalis and Enterococcus faecium; colistin-resistant, carbapenem-resistant, or third-
generation cephalosporin-resistant
Escherichia coli; colistin-resistant, carbapenem-resistant, or third-generation cephalosporin-resistant Klebsiella pneumoniae; colistin-resistant, carbapenem-resistant, or multidrug-resistant Pseudomonas aeruginosa; meticillin-resistant
Staphylococcus aureus (MRSA); and penicillin-resistant and macrolide-resistant Streptococcus pneumoniae
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accounted for 38.7% of the total DALYs. The highest burden in terms of lost DALYs and deaths
was noted in Italy and Greece.
The burden due to DALYs associated with antibacterial-resistant bacteria including CR and
colistin-resistant infections is reported to have increased between 2007 and 2015. The
proportion of the DALYs due to all CR infections increased from 18% in 2007 to 28% in 2015.
With regards to specific pathogens, the proportion of the DALYs due to CR K. pneumoniae
and CR E. coli doubled from 4.3% in 2007 to 8.79% in 2015.
In terms of infection sites, the highest DALYs burden was associated with BSI reaching up to
71,201 DALYs, and with respiratory infections, reaching up to 19,132 DALYs. The main CR
pathogen contributing to DALY was P. aeruginosa except in Italy, where the most burdensome
pathogen was K. pneumoniae. The annual number of DALYs attributable to P. aeruginosa
ranged from 1,576 to 34,717. In Italy, CR K. pneumoniae was associated with 37,394 DALYs.
2.1.9 Delayed effective therapy
Given that conventional pathogen identification and AST results can take up to 3 days to
provide a diagnostic result, the current treatment approach for patients with bacterial infections
suspected to be caused by an MDR pathogen, involves initial administration of empiric therapy
with wider-spectrum of activity antimicrobial followed by de-escalation to targeted therapy
when AST results are available [13, 14]. However, in many instances, the antibiogram is not
retrieved. The Point prevalence survey of healthcare-associated infections and antimicrobial
use in European acute care hospitals 2011–2012 indicated that between 40.2% and 80.5% of
HAIs are documented with microbiological results [11]. The percentage of pathogens with
known AST results is reported to vary between 47.4% and 100% [11].
Increasing antibacterial resistance has made the empiric antibacterial selection more difficult
particularly as fewer appropriate treatments for resistant pathogens are available [162]. As a
result, many patients with severe bacterial infections receive inappropriate therapy and
consequently experience delays in receiving appropriate effective therapy. As the severity of
infection increases, patients are more likely to be cycled through a number of inappropriate
therapies in the attempt to successfully treat the infection. According to two recent systematic
literature reviews ((1) 2015, n=27 and (2) 2019, n=122), patients receiving inappropriate
empiric treatment were reported to have a higher mortality risk [163, 164].
A systematic literature review including studies on the incidence and outcome of
inappropriate in-hospital empiric antibacterials for severe infections published
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between 2004 and 2014 reported that the percentage of inappropriate empiric
antibacterial treatment ranges between 14.1% and 78.9% [163].
A retrospective cohort study including 40,137 patients with Enterobactereacea in
UTI, pneumonia or sepsis reported that patients with CR Enterobactereacea
(CRE) were three times more likely to receive inappropriate empiric treatment
(IET) than non-CRE (46.5% vs. 11.8%, p < 0.001) [165].
A systematic literature review (2007-2018, n=37) assessing the impact of delay in
appropriate antibacterial therapy for patients with severe bacterial infections
treated in hospital settings concluded that approximately 27% of patients
experience delays [166].
A delay in effective treatment of an infection may lead to sepsis, a life-threatening condition,
irrespective of the initial infection site. A range of studies have confirmed that inappropriately
treated patients had 5-times higher mortality risk, twice longer hospital stays and increased
risk of readmission, compared to patients receiving appropriate initial therapy. Moreover,
patients who fail initial therapies and reach last resort antibacterials are exposed to additional
burden associated with severe adverse events and toxicity [167].
In a more recent (2019) systematic literature review, Bassetti et al reported significantly lower
mortality rates in patients with appropriate therapy compared to those with inappropriate
therapy (OR 0.44 [95% CI, 0.39–0.50]) and these findings were consistent across all time
points (Figure 13) [164]. In a pooled subgroup analysis, mortality rates were significantly lower
in patients with bacteraemia, sepsis and septic shock in patients with pneumonia who had
received appropriate therapy compared to those having inappropriate treatment [164]. This
burden increases with resistant pathogens, whereby patients with CR P. aeruginosa infections
who receive initial inappropriate treatment have mortality risk that is twice as high as that seen
in susceptible patients (27.3% vs 13.8% respectively) [15].
In another recent systematic literature review of 37 studies by Zasowki et al. (2019), patients
receiving initial appropriate therapy had significantly lower mortality rates (OR 0.57, 95% CI:
0.45–0.72]) in comparison to those receiving initial inappropriate treatment and a consequent
delay in effective treatment (Figure 14) [166]. These findings were consistent across all time
points. Published literature reports that patient prognosis worsens with each day and hour of
delay in appropriate treatment. A retrospective cohort study including 480 patients with BSIs
due to carbapenemase-producing Enterobacteriaceae (CPE) reported an increase in mortality
risk with each day of delay (HR=1.02; (95% CI: 1.01, 1.04; p < .0001) [168].
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Figure 13: Summary of effect of appropriate versus inappropriate initial antibacterial therapy on
mortality
Source: Bassetti, 2019[164]
Figure 14: Summary of effect of delay versus no delay in receiving initially appropriate
antibacterials on mortality
Source: Zasowski, 2019[166]
Inappropriate antibacterial therapy is associated with higher rates of treatment failure. Bassetti
et al assessed the impact of appropriate versus inappropriate initial antibacterial therapy on
the treatment failure. The findings suggest that patients receiving appropriate had a
significantly lower incidence of treatment failure compared to patients with inappropriate
therapy (OR 0.33; 95% CI: 0.16, 0.66) (Figure 15) [164]. These findings were consistent
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across all time points and subgroup of patients with UTIs or acute pyelonephritis and with
bacteremia or sepsis (Figure 15) [164].
Figure 15: Summary of effect of appropriate versus inappropriate therapy on treatment failure
Source: Bassetti, 2019[164]
2.2 Target population
1. Describe the target population and the proposed position of the target population in
the patient pathway of care.
The indication for cefiderocol is expected to be:
Fetcroja is indicated for the treatment of infections due to aerobic Gram-negative
organisms in adults with limited treatment options. Limited treatment options can be
pragmatically translated into infections by MDR (including CR) pathogens.
This indication will therefore be pathogen focused, not restricted to any specific site of infection
and predicts 2 different populations:
Hospitalised critically ill patients with suspected (but prior AST results availability)
MDR/CR infection where effective treatment should be administered as soon as
possible (followed by de-escalation to a more targeted treatment when the
pathogen and susceptibility profile is subsequently confirmed), resistance to many
antimicrobial classes almost invariably reduces the probability of adequate
empirical coverage, with possible unfavourable consequences. In this light, readily
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available patient’s medical history and updated information about the local
microbiological epidemiology remain critical for defining the baseline risk of MDR-
GNB infections and firmly guiding empirical treatment choices, with the aim of
avoiding both undertreatment and overtreatment ([13, 14] and Clinical guidelines
overview). Given its wide Gram-negative spectrum of activity, and safety profile,
cefiderocol would be an appropriate treatment choice for these patients.
Hospitalised patients where CR infection has been confirmed the selection of
treatment is predominantly based on AST results regarding pathogen, its
mechanism of resistance, and susceptibility results for the different antibacterials
tested. Based on its in vitro data, cefiderocol would be an appropriate option, in
aerobic Gram-negative pathogens, particularly non-fermenters such as P.
aeruginosa, A. baumannii and S. maltophilia, and presence of metallo-β-
lactamases, where there is limited in vitro activity from newer regimens, and other
treatment choices may be inappropriate due to safety and tolerability concerns.
The treatment of these patients will require an expert and complex clinical reasoning, taking
into account the peculiar characteristics of the target population, but also the need for
adequate empirical coverage and the more and more specific enzyme-level activity of novel
antimicrobials with respect to the different resistance mechanisms of MDR-GNB, resulting to
variations in the use of specific treatments even within regions of countries [169]. Thus,
treatment decisions differ for patients with suspected or confirmed infection by MDR/CR
pathogens.
2. Provide a justification for the proposed positioning of the technology and the definition of
the target population.
The intended indication for cefiderocol is for the treatment of aerobic, Gram-negative infections
in adults with limited treatment options (i.e. confirmed or suspected MDR infections, including
CR infections).
Cefiderocol can be used when the antibacterial susceptibility results have been obtained and
show that no other treatment is likely to have an effect against the disease pathogen,
particularly in non-fermenters and Acinetobacter baumanii, Stenotrophomonas maltophilia
and Pseudomonas aeruginosa, as well as in the metallo-carbapenemases in
Enterobacteriaceae, as per Table 9 below. It can also be used earlier, as a pre-emptive
treatment to ensure appropriate antibacterial coverage as early as possible given its wider
spectrum of activity as per image below in Gram-negative pathogens.
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Table 9: In Vitro Gram-negative activity profiles
Predicted clinical activity based on CSLI breakpoints; *Color-coding based on the pathogen susceptibility
Source: Thalhammer F, 2018 [63], Theuretzbacher, 2019 [64]
The target population thus comprises two groups:
Critically ill, adult patients with highly suspected infection by a carbapenem-resistant or other
MDR Gram-negative pathogen.
These patients often require immediate treatment. Initiation of treatment for these
patients cannot be deferred until antibiogram is available.
Knowledge of local pathogen epidemiology and patient-specific factors can
support initial antibacterial treatment decisions.
Aligned with stewardship recommendations, when results from susceptibility tests
are available, de-escalation to other treatments should occur whenever possible
to avoid undertreatment and overtreatment.
For these patients, cefiderocol has demonstrated broad efficacy according to
current evidentiary standards for antimicrobials (in vitro, PK/PD and clinical data,
see sections 5.3-5.5.). They include patients with common infections such as cUTI,
pneumonia, blood infection/sepsis, and IAI.
In line with good antimicrobial stewardship, cefiderocol should be regarded as a
first treatment choice in this context, replacing current treatment attempts with
carbapenems in high dose and/or in combinations and where there is high
suspicion of susceptibility to cefiderocol.
Placing cefiderocol in the management of hospitalised patients with suspected
difficult to treat GNI as first treatment choice, replacing current treatment attempts
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with carbapenems in high dose and/or in combinations, or recently approved
medicines, followed by de-escalation to reduce the risk of development of
resistance [170]. This strategy reduces time to effective treatment and is
associated with lower mortality as well as LOS in patients with severe sepsis and
septic shock Fout! Verwijzingsbron niet gevonden.[171, 172]. In line with good
antimicrobial stewardship, cefiderocol should be regarded as an early, targeted
treatment based on advanced risk determination methods (Figure 16) [124].
Figure 16 - Treatment of patients with highly suspected infection by CR or other MDR GN pathogens
Adult patients with confirmed infection by a carbapenem-resistant Gram-negative pathogen
or multidrug resistant Gram-negative pathogen including carbapenem-resistant
Enterobacteriaceae (CRE) such as K. pneumoniae and E. coli, and non-fermenters such as
A. baumannii, P. aeruginosa, and S. maltophilia.
For these patients, cefiderocol has demonstrated broad efficacy according to
current evidentiary standards for antimicrobials (in vitro, PK/PD and clinical data,
see section 5.4). They include patients with common infections such as cUTI,
pneumonia, blood infection/sepsis, and IAI. (Figure 17)
In line with good antimicrobial stewardship, cefiderocol should be regarded as a
first treatment choice in this context, replacing current treatment attempts with
colistin in combination with several other antimicrobials from different classes,
which carry a very substantial side effect burden (see chapter 2.1).
Figure 17: Treatment of patients with confirmed infection by carbapenem-resistant or other MDR
Gram-negative pathogen
3. Estimate the size of the target population. Include a description of how the size of the
target population was obtained and whether it is likely to increase or reduce over time.
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As outlined in section 2.1 MDR/CR, resistances are increasing with estimates of deaths related
to serious infections being updated frequently. The European Centre for Disease Prevention
and Control (ECDC) estimate that nearly 700,000 infections and 33,000 deaths in the EU and
European Economic Area (EEA) in 2015 are a consequence of MDR bacterial infection [4]
WHO the predicted annual deaths by AMR is expected to rise from 700,000 cases in 2014 to
10,000,000 in 2050 (WHO, 2014, Review on AMR [78]. The prevalence of resistance to last-
resort antibacterials, particularly with regards to carbapenems and colistin, has been
increasing globally. An alarming spread of CR Gram-negative infections through healthcare
facilities has been reported and is expected to transfer to the community [8, 76]. Even for the
more recently approved antibacterials such as ceftolozane/tazobactam and
ceftazidime/avibactam, there have been reported cases of resistance [40-43]. This is also
expected to expand to the community, similarly to what has been previously observed with
ESBL-producing pathogens, via environment and traveling [76, 173]. For example, in 2018,
Sweden and Norway reported a cluster of returning travellers who carried or were infected
with carbapenemase (OXA-48)-producing K. pneumoniae that were associated with hospital
admissions in Gran Canaria [173].
The size target population for cefiderocol in Europe is difficult to estimate, as incidence
strongly depends on:
epidemiology data (local resistance profile and local pathogen distribution, which
is constantly evolving),
potentially regional outbreaks may occur changing substantially the patient
numbers,
patient population characteristics and risk factors (e.g. travels to CR endemic
countries),
introduction of new medicines with overlapping activity profile that will change the
unmet need,
how data is reported: there is a wealth of epidemiology information available, but
using different methodologies, increasing the uncertainty of the actual numbers of
MDR or CR infections,
also, the 2 different target populations are interlinked and self-exclusive.
Cassini, et al, [4] estimates that there are 107,801 Carbapenem resistant infections in Europe,
not account for those caused by Stenotrophomonas maltophilia, and as mentioned in the
previous section, this is likely to increase in the future [4]. Only a Dynamic infection disease
modeling considering the mentioned factors, upcoming treatments and future trends could
provide plausible predictions [123], but still with significant degree of uncertainty.
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2.3 Clinical management of the disease or health condition
1. Describe the clinical pathway of care for different stages and /or subtypes of the
disease being considered in the assessment.
With the emergence of antibacterial resistance, antimicrobial stewardship programs have
been put in place in various healthcare settings to attempt achieve as rapid as possible,
identification of pathogens causing bacterial infections and the most appropriate treatment.
Treatment is determined by clinical state and local epidemiology to minimise the chance of
ineffective therapy. The current treatment approach for patients with bacterial infections when
there is suspicion of MDR pathogen, involves initial administration of empiric therapy with
wide-spectrum antimicrobial (or combination of antibcterials) followed by de-escalation to
targeted antimicrobials antibacterials when the antibiogram is available (i.e., identification of
the underlying pathogen and susceptibility testing (Figure 18)) [13].
Figure 18: Current treatment approach for bacterial infections
Treatment selection is based on information on pathogen identification as well as susceptibility
and mechanism of resistance. According to proportions of main pathogens in the infection and
in vitro susceptibility of potential treatments the treatment with the highest predicted treatment
success is being selected [13].
Resistance to many antimicrobial classes in MDR pathogens almost invariably reduces the
probability of adequate empirical coverage, with possible unfavorable consequences. Timely
administration of antibacterials is vital to improve patient’s outcomes [14] and in line with
antimicrobial stewardship, includes treatment with the most appropriate drug regimen [174,
175]. While microbiological testing is carried out (this can take up to 3 days), early clinical
decisions are based on environmental and patient factors including clinical state and local
epidemiology to minimize the chance of ineffective therapy. Empirical treatment with wide-
spectrum antibacterials is usually administered to severely ill patients when a quick treatment
decision is required [13]. However, this creates pressure for the selection or development of
resistant organisms over time [13, 176].
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If the patient is confirmed to have multidrug resistant (MDR) including carbapenem resistant
(CR) infection, treatment is selected based on the susceptibility results. [170]. Good
antibacterial stewardship mandates more restrictive use of antibacterials and regardless which
treatment is being used, guidelines always urge to de-escalate the treatment whenever
possible [170] (see below).
Clinical reasoning for the treatment of suspected MDR-GNB infections in critically ill patients
aims to reduce time to effective therapy [124]. Current standard practice for this population is
not well defined, and highly variable across different geographies and infection sites.
Traditionally however, carbapenems in higher dose regimens tha toptimizes exposure, and/or
combination with other antibacterials, have been used but with limited success in resistant
pathogens [177]. Recently approved antibacterials such as ceftazidime/avibactam and
ceftolozane/tazobactam, have also been used in this setting, as already proposed by Bassetti
et al. [177]
However, there is still no defined standard of care for the treatment of severe MDR (including
CR) Gram-negative infections. A recent literature review of current and upcoming therapeutic
approaches for severe MDR Gram-negative infections in critically-ill patients reported that the
availability of newly approved antibacterials such as ceftolozane/tazobactam,
ceftazidime/avibactam, meropenem/vaborbactam, plazomicin and eravacycline, have
addressed some challenges due to antimicrobial resistance [177]. However, these treatment
options are reported to have suboptimal activity against some pathogens especially against
CR A. baumannii and against carbapenem-resistant Enterobacteriaceae (CRE) of novel beta-
lactam/β-lactamase inhibitors is dependent of the type of carbapenemase conferring
resistance to carbapenems [177]. The existing therapies for MDR including CR infections
include newly approved beta-lactam/β-lactamase inhibitor combinations such as
ceftolozane/tazobactam, ceftazidime/avibactam and meropenem/vaborbactam, novel
aminoglycoside plazomicin and a novel fluorocycline eravacycline. Other treatments include
polymyxins (polymyxin E [colistin] and polymyxin B), glycylcyclines (e.g., tigecycline), and
aminoglycosides [177]. Figure 19 gives an overview of current clinical reasoning for the
treatment of serious MDR-GNB infections in critically-ill patients.
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Figure 19: Current clinical reasoning for the treatment of serious MDR Gram-negative infections
DR-GNB, Multi-drug resistant Gram-negative bacteria; CRE, carbapenem-resistant Enterobacterales; CRPA, carbapenem-
resistant Pseudomonas aeruginosa; CRAB, carbapenem-resistant Acinetobacter baumannii; BL-BLI, b-lactam/b-lactamase
inhibitors; VAP, ventilator-associated pneumonia. Source: Bassetti, 2019[177]
2.3.1 Key information on currently available treatments in Europe
As outlined before, treatment options for infections with MDR/CR aerobic Gram-negative
pathogens are very limited. Susceptibility tests have shown that to date broad coverage,
including pathogens affecting patients with limited treatment options (such as CR A.
baumannii, CR P. aeruginosa, S. maltophilia, and CR Enterobacteriaceae) is only achieved
by cefiderocol [29, 30]. In a recent analysis of the global clinical antibacterial pipeline by WHO,
cefiderocol was reported to be the only antibacterial providing coverage against all three
critical priority pathogens: CR A baumannii, CR P aeruginosa, and CR Enterobacteriaceae
(Figure 7) [64].
Ceftazidime/avibactam is a recently approved combination of a well-known beta-lactam with
a novel β-lactamase inhibitor for cIAI, cUTI, HAP/VAP and aerobic Gram-negative infections
in adults with limited treatment options (EU)[178]. It is active against class A (e.g., KPC) and
class D (e.g., OXA) carbapenemase-producing CRE and has demonstrated activity against
some CR P. aeruginosa isolates [177]. Recent results of in vitro study, SIDERO-WT, reported
CRE
• Ceftazidime/avibactam (as preferred empiricalchoice when both KPC and OXA carbapenemases are reported locally) or meropenem/vaborbactam
• Although in the lack of high-level evidence, for both empirical and targetedtreatment a combination with old (collistin, polymyxin B, tigecycline, oldaminoglycosides, fosformycin) or novel agents (plazomicin, eravacycline, double BL-BLI combinations) could be considered in the attempt of delayig emergence ofrestistance, after having carefully balanced potentional additional toxicity on a case-by-case basis (expert opinion)
• In case of resistance to novel BL-BLI, consider polymyxins-based or aminoglycosides-based combination with carbepenems and/or (tigecyclineor eravacycline) and/orfosformycin
• Consider concomitant adminitration of inhaled polymyxins/aminoglycosides whenthey are used intravenously for VAP
• Ceftolozane/tazobactam (as preferred empirical choice in absence of concomitantrisk of CRE) or ceftazidime/avibactam
• For empirical therapy, administer a second anti-pseudomonal agent (an aminoglycosideor a polymyxin or fosformycin)
• Although in the lack of high-level evidence, for targeted therapy combination withold (collistin, polymyxin B, old aminoglycosides, fosformycin) or novel agents(plazomicin, double BL-BLI combinations) could be considered in the attempt ofdelaying emergence of restistance, after having carefully balanced potential additional toxicity on a case-by-case basis (expert opinion)
• In case of restistance to novel BL-BLI, consider polymyxins-based or aminoglycosides-based combinations with carbapernems and/or fosformycin and/or rifampin
• Consider concomitant administration of inhaled polymyxins/aminoglycosides whenthey are used intravenously for VAP
CRPA
CRAB
• Administer a polymyxin as the backbone agent• Consider combination with old (carbapenems, old aminoglycosides, tigecycline,
fosformycin, rifampin) or novel agents (plazomicin, eravacyclin)• Consider concomitant administration of inhaled polymyxins/aminoglycosides when
they are used intravenously for VAP
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a poor activity of ceftazidime/avibactam against CR A. baumannii with minimum inhibitory
concentration (MIC50) for meropenem-non-susceptible A. baumannii of 32 mg/L3 [46] and
stenotrophomonas maltophilia. Currently widely available on the EU countries, with
reimbursement.
Ceftolozane/tazobactam is a novel combination of a beta-lactam antimicrobial with a well
known β-lactamase inhibitor, with EMA approval for cIAI and cUTI [179]. It has demonstrated
a potent in vitro activity against CR P. aeruginosa isolates; however, without activity against
CRE [177]. Tazobactam (β-lactamase inhibitor) protects ceftolozane from degradation by
Class A β-lactamase enzymes [179], but has not demonstrated activity against KPC Class A
carbapenemases, and Class B (metallo-), or Class D β-lactamases [179]. Currently widely
available on the EU countries, with reimbursement.
Meropenem/vaborbactam is a novel combination of a well know carbapenem in a higher
dose, and a novel β-lactamase inhibitor approved for cIAI, cUTI, HAP/VAP, and infections due
to aerobic Gram-negative organisms in adults with limited treatment options [180]. It has
activity against class A (e.g., KPC) carbapenemase-producing CRE. Vaborbactam has limited
activity against Class D β-lactamases and no activity against Class B (metallo-) β-lactamases
and does not improve the activity of meropenem against CR A. baumannii, P. aeruginosa or
S. maltophilia [181]. However, is it not yet reimbursed in most of the European markets.
Currently approved by EMA, but not yet reimbursed in many countries and therefore, not
widely available on the European countries.
Eravacycline is a novel synthetic fluorocycline that was approved by EMA for the treatment
of cIAI [182]. It has demonstrated activity against Gram-negative pathogens including CRE
and CR A. baumannii with exception of P. aeruginosa and Burkholderia cepacia [177, 183,
184]. Currently approved by EMA, but not yet reimbursed in many countries and therefore, not
widely available on the European countries.
While colistin once was abandoned due to the high rates of renal toxicity in recent years, the
increasing emergence of MDR Gram-negative bacteria appears to have led to its
reintroduction in clinical practice [102]. Colistin has antibacterial activity against a wide variety
of Gram-negative pathogens including E. coli, Klebsiella spp., Enterobacter spp., P.
aeruginosa, and Acinetobacter spp. [185]. Some Gram-negative pathogens such as Proteus
spp., Providencia spp. and most isolates of Serratia spp. are intrinsically resistant to colistin
[185]. While it covers a broad spectrum of Gram-negative pathogens, colistin is associated
with severe adverse events [102, 134]. Among the more severe adverse events are
neurotoxicity, nephrotoxicity, and ototoxicity [102, 134]. Renal failure is reported to reach up
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to 60% in patients treated with colistin[186]. A recent systematic literature review (n=224)
including data on 33,573 patients reported that the overall rate of nephrotoxicity in patients
treated with polymyxins was 0.277 (95% CI: 0.252, 0.303). Nephrotoxicity rates were found to
differ between patients treated with CMS, colistin and PMB (0.260 [95% CI: 0.216, 0.30]),
0.274 [95% CI: 0.239, 0.312] and 0.348 [95% CI: 0.301, 0.397], respectively; p=0.016) [187].
Aminoglycosides have been frequently used for the treatment of CR infections, particularly
in case of polymyxin resistance [177]. However, their efficacy is hindered by their impaired
safety profile (i.e., nephrotoxicity and ototoxicity) and increasing rates of resistance [177] [188].
While nephrotoxicity often can be reversed, the hearing loss is irreversible [188].
Aminoglycosides have been also associated with neuromuscular blockade [189].
Tigecycline, a glycylcycline antibacterial, is active against CRE and CR A. baumannii [177].
P. aeruginosa is inherently resistant to tigecycline with > 90% of pathogens reported to be
resistant to it [177, 190]. Of note, tigecycline is reported to have been associated with
increased mortality in comparison with other regimens in patients with VAP [177]. Currently
approved by EMA for cIAI and cABSSI.
Relebactam/imipenem/cilastatin has recently been granted positive CHMP opinion for
approval in Europe for Gram-negative infections in patients with limited treatment options. It
shows activity against resistant strains of P. aeruginosa and K. pneumoniae carbapenemase
in CR bacterial infections, but not those of A. baumannii or S. maltophilia (Merck and CID) or
metallo-betalactamases. Currently with positive CHMP opinion and not yet widely available on
the European countries.
While clinical guidelines on the management of multidrug resistant (MDR) including
carbapenem resistant (CR) Gram-negative infections are usually included in infection-site
specific treatment guidelines, they have not yet caught up to date with the new EMA regulatory
guidance that is focused on pathogens. Therefore, there is a lack of integrated
recommendations for the management of these resistant infections looking at pathogens,
regardless of infection site, and therefore a lack of well-defined standard of care. A survey
from 2017 including >100 hospitals in the US and Europe, reported that almost half of the
respondents (54/111, 48.6%) had no guidelines for the treatment of infections caused by CR
Gram-negative pathogens [22]. As outlined before the treatment of Gram-negative infections
is based on multiple factors, including the underlying condition, infection sites, and local
epidemiology, but most importantly taking into account local resistance. This leads to
variations in the use of specific treatments even within regions of countries.
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The management of carbapenem-resistant Gram-negative infections is particularly
challenging due to the paucity of antimicrobials active against these bacteria; various
treatment options are used, very often in double or triple combinations with no consensus on
the most appropriate treatment strategy [22]. Current treatment options have limited activity
and/or have safety concerns. Recently marketed treatment options only partially cover
carbapenem resistance, and for example, none can address all 3 critical pathogens identified
by the WHO [38, 191]; ceftazidime/avibactam covers K. pneumoniae carbapenemase (KPC)-
producing carbapenem-resistant Enterobacteriaceae (CRE), ceftolozane/tazobactam covers
P. aeruginosa carbapenem-resistant strains and tigecycline, rather used as combination
therapy, covers carbapenem-resistant Enterobacteriaceae and A. baumannii [192, 193].
Polymyxins provide additional treatment options; recently re-introduced as a last alternative
due to the increasing CR resistance, they provide broader coverage for carbapenem-resistant
Gram-negative infections [33], but polymyxin resistance is already prevalent both in North
America and Europe [102] and these agents have serious side effects, such as nephrotoxicity
and neurotoxicity [194, 195]. Trimethoprim/sulfamethoxazole is considered as the treatment
of choice for S. maltophilia infections, though limited by toxicities [196].
In summary, available treatments consist of last resource drugs and multiple antibacterial
combinations, often with limited pathogen and/or mechanism of resistance coverage, and/or
with significant safety/tolerability concerns (e.g. colistin, tigecycline) [23-27].
2. Clinical guidelines overview
Search approach
A targeted search for relevant guidelines and review articles on the treatment of Gram-
negative bacteria was conducted in December 2019 and complemented by Internet searches
for national guidelines from Denmark, England (UK), France, Germany, Italy, Norway, Spain
and Sweden. Focus of selection and analysis were recommendations for treatment of
infections with MDR Gram-negative bacteria as well as for CR infections in hospital settings
[197]. Key results are provided in the tables below.
Summary of findings
Recommendations refer either to most common infection sites (e.g. pneumonia, sepsis, IAI,
cUTI) or, more recently, to pathogen types, e.g., infections with MDR/CR Gram-negative
bacteria (UK: [122] Spain: [198, 199] Italy Klebs:[200]) or more specific, ESBL-producing
bacteria or CR bacteria [201].
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Fewer guidelines refer to specific treatments [202, 203]. As clinical data are rare,
recommendations are often based on evidence derived from in vitro susceptibility testing
results, case studies, observational studies, and expert opinion, which is standard and the
most appropriate approach in antimicrobial treatment decisions. In general, all guidelines
recommend that treatment should be started early for suspected infections (within hours),
support the antibacterial de-escalation strategy and recommend that empirical antibacterial
therapy should be implemented in accordance with local microbiological data and previous
treatment.
2.3.2 Site-specific vs. pathogen-specific guidelines
While infection-site-specific guidelines have been issued regularly for many years,
recommendations for treatment of MDR/CR Gram-negative infections dependent on the type
of resistance and pathogen with reference to the infections site have been developed at an
increasing rate in recent years by International/European/National Societies [23-25, 122, 201,
204].
2.3.3 Specific recommendations
Mono- and combination therapies of carbapenems (e.g. meropenem, imipenem, ertapenem),
or in combination with polymixins (colistin), colistin in combination with tigecycline, or newer
treatments such as ceftolozane/tazobactam prevail. Accordingly for CR Gram-negative
infections, guideline recommendations include combination treatment of colistin with
meropenem or with tigecycline, ceftazidime/avibactam, high dose tigecycline, fosfomycin and
colistin [23-25, 27, 122, 201].
An overview of recent guideline recommendations for MDR/CR Gram-negative infections as
well as for respective infection sites is provided in Table 10a-Table 11e.
The guidelines identified for MDR/CR Gram-negative infections are aligned in terms of
recommendations on the first line empiric therapies, use of mono- or combination therapies
and recommended antibacterial class(es) across indications, but may differ in use of specific
antibacterials within the same class. There was no evidence of incompatible recommendation
(e.g., one country recommending a treatment that another country specifically excludes).
2.3.4 Specific considerations of CR infections
International consensus guidelines recommend that patients with CR Gram-negative
infections including Enterobacteriaceae (CRE), A. baumannii (CRAB) and P. aeruginosa
(CRPA) are managed with polymyxin B or colistin in combination with one or more additional
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agents to which the pathogen is susceptible. If additional susceptible agents are unavailable,
polymyxin B or colistin should be used in combination with a non-susceptible agent (e.g., a
carbapenem) in patients with CRE and CRPA, and in monotherapy in patients with CRAB [24].
Recent national guideline recommend targeted combination therapies according to type of
carbapenemases [122, 200, 205] and include newer agents ceftazidime/avibactamand
ceftolozane-tazobactam. Therapeutic approaches with infusion of high-dose antimicrobials is
considered for meropenem [201, 205] and ceftolozane/tazobactam [204] in high risk patients.
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Table 10a: Relevant guidelines for diagnosis and management – MDR/GN Bacteria
Name of society/organisation issuing guidelines Date of
issue or
last update
Country (s)
to which
guideline
applies
Summary of
recommendations
-MDR infections-
Summary of
recommendations
-CR infections-
AWMF (Registry Nr. 092/001 (S3 guideline:
Strategies to ensure rational use of antibacterials in
hospitals)
[206] 1
2018 Germany Reports on measures to
prevent or reduce resistant
germs in hospitals.
NR
Paul-Ehrlich-Gesellschaft für Chemotherapie e.V.
(PEG)
AWMF 082-006
Chapter 16. Infections with MDR gram neg sticks
(Stäbchen) – ESBL-producing bacteria,
Carbapenemase-producing Enterobact083eriaceae,
Carbapenem-resistant Acinetobacter baumannii
[201]2
2019 Germany Pneumonia/Sepsis:
• meropenem plus colistin
• colistin plus tigecycline
(potentially plus fosfomycin)
CR Enterobacteriaceae
Pneumonia/sepsis:
• meropenem plus colistin
• colistin plus tigecycline
(potentially plus fosfomycin);
CR Acinetobacter-baumannii
Pneumonia/sepsis/wound/cUTI:
colistin, sulbactam, high dose
tigecycline; (cotrimoxazole
only for cUTI)
Infectious Diseases Working
Party (AGIHO) of the German Society of
Haematology and
Medical Oncology (DGHO)
(2015)
(Publication
year)
(Europe)
Stenotrophomonas maltophilia
pneumonia:
• High dose trimethoprim–
sulfamethoxazole;
Pseudomonas aeruginosa
pneumonia:
• Combination therapy
Piperacillin (±tazobactam),
All rights reserved 66
[207] • tigecycline-based therapy ceftazidime, imipenem/
cilastatin, meropenem and
cefepime
Gruppo Italiano Trapianto Midollo Osseo (GITMO),
Associazione Microbiologi Clinici Italiani (AMCLI),
Società Italiana Malattie Infettive e Tropicali (SIMIT),
and the Centro Nazionale Trapiantt (CNT)
[200]
2015 Italy NR CRKp-targeted antibacterial
therapy: combination therapy
including at least two among
colistin/polymyxin B,
tigecycline and gentamicin;
addition of meropenem, and
eventually fosfomycin preferred
Helsedirektoratet. Antibiotikabruk i sykehus,
Nasjonal faglige retningslinje.
[208] 3
2018 Norway Resistant to 3rd generation
cephalosporins:
• Meropenem
• Imipenem / cilastatin
• Doripenem or Ertapenem
[Not for Pseudomonas or
Acinetobacter]
Resistant to 3rd generation
cephalosporins
• Colistin
• Tigecycline
Infectious Diseases and Clinical Microbiology
(SEIMC) 2015
[199]
2015 Spain Fosfomycin (as part of a
combination regimen including
at least one more active agent)
NR
Spanish Society of Chemotherapy
[198]
(2018) Spain • Colistin,
• Amikacin
NR
All rights reserved 67
“Antibacterial selection in the treatment of acute
invasive infections by Pseudomonas aeruginosa:
Guidelines by the Spanish Society of Chemotherapy”
(Review article)
(Publication
year)
• Ceftolozane/ tazobactam
• High doses of β-lactam
antibacterials
Spanish Society of Transplantation (SET)/ Group for
Study of Infection in Transplantation of the Spanish
Society of Infectious Diseases and Clinical
Microbiology (GESITRA-EIMC)/ Spanish Network for
Research in Infectious Diseases (REIPI)
[204]
2018 Spain • Amoxicillin-clavulanic acid
• Piperacillin-tazobactam
• Meropenem
• Aztreonam
• Tigecycline
• Fosfomycin
• Ceftazidime-avibactam
• Ceftolozane-tazobactam
• Colistin
NR
Spanish Society of Infectious Diseases and Clinical
Microbiology (SEIMC) and the Spanish Association
of Haematology and Hemotherapy (SEHH)
[205] 4
2019 Spain (ESBL)-producing
Enterobacteriaceae:
• beta-lactam/β-lactamase
inhibitor (BLBLI)
• Piperacillin-tazobactam
and meropenem (extended
infusion)
AmpC-producing
Enterobacteriaceae
• Cefepime and
fluoroquinolones
KPC-producing
Enterobacteriaceae:
• at least two active drugs from
the options included in the
antibiogram (meropenem,
colistin, tigecycline,
fosfomycin and
aminoglycosides)
strains with meropenem MICs <
16 mg/L:
All rights reserved 68
• Piperacillin-tazobactam
• combination regimen should
include high-dose meropenem
(extended infusion)
KPC-producing or OXA-48-
producing Enterobacteriaceae:
• Ceftazidime-avibactam
Extensively drug-resistant
(XDR) and pandrug-resistant
(PDR):
• single-agent treatment,
prioritizing the use of (in
following order) beta-lactams,
sulbactam (in infections due to
A. baumannii) and colistin.
XDR or PDR P. Aeruginosa
infections:
• Ceftolozane-tazobactam or
ceftazidime-avibactam
ESBL-producing intestinal bacteria Knowledge base
with proposals for management to limit the spread of
Enterobacteriaceae with ESBL
2014 Sweden • Cephalosporins and
quinolones
Cephalosporins should not be
reduced by increasing the
consumption of carbapenems,
All rights reserved 69
[209] 5 • Alternative: Piperacillin-
tazobactam for sepsis,
pneumonia, abdominal
infections; also, to reduce
cephalosporins consumption
as this increases the risk of
selection of carbapenem-
resistant strains.
British Society for Antimicrobial
Chemotherapy/Healthcare Infection Society/British
Infection Association. Joint Working Party
[122]
2018 UK ESBL and AmpC-producing
Enterobacteria
• Meropenem, imipenem or
ertapenem
Susceptibility of past/current
infection not known (inpatient
setting):
• Meropenem and imipenem
or Meropenem-sparing:
temocillin (if urinary),
ceftolozane/ tazobactam
Susceptibility of past/current
infection known, along with
urinary infection:
• Co-amoxiclav or
piperacillin/tazobactam or
gentamicin or amikacin
IKPC-carbapenemase: Colistin
& meropenem (if unknown/S in
past)
(Consider tigecycline to colistin
or ceftazidime/avibactam to
meropenem)
OXA-48: Aztreonam or
ceftazidime Ceftazidime/
avibactam if R or unknown.
Metallo-carbapenemase:
Fosfomycin and colistin,
consider tigecycline, Use co-
trimoxazole if
Stenotrophomonas
1https://www.awmf.org/uploads/tx_szleitlinien/092-001l_S3_Strategien-zur-Sicherung-rationaler-Antibiotika-Anwendung-im-Krankenhaus_2019-04.pdf
2https://www.awmf.org/uploads/tx_szleitlinien/082-006l_S2k_Parenterale_Antibiotika_2019-08.pdf
3https://www.helsedirektoratet.no/Retningslinjer/Antibiotika-i-sykehus
All rights reserved 70
4https://seimc.org/contenidos/documentoscientificos/seimc-dc-2019-Febrile_Neutropenia.pdf
5https://www.folkhalsomyndigheten.se/contentassets/f4df42e7e643414ba3499a9ee1801915/esbl-producerande-tarmbakterier.pdf
Table 11b: Relevant guidelines for diagnosis and management – HAP/VAP(HCAP)
Name of society/organisation
issuing guidelines
Date of
issue or
last
update
Country (s)
to which
guideline
applies
Summary of recommendations
-MDR infections-
Summary of
recommendations
-CR infections-
ERS/ESICM/ESCMID/ALAT
guidelines EU
[210]
2017 Europe • No septic shock: single agent (carbapenem,
cephalosporin, piperacillin/ tazobactam or
fluoroquinolone)
• Severely ill or in septic shock: combination therapy
(antipseudomonal β-lactam plus a second agent
such as an aminoglycoside or an antipseudomonal
fluoroquinolone or, in some cases polymyxins)
Combination therapy; similar
approach as in MDR patients
(carbapenem-resistant
Enterobacteriaceae)
pro. medicin Information til
sundhedsfaglige -
Antibiotikavejledning
[211] 1
2020 Denmark
No specific recommendation for MDR infections
Pneumonia: Phenoxymethylpenicillin or
Clarithromycin
HAP: Piperacillin/Tazobactam or Cefuroxime
Mycoplasma and Chlamydophila pneumonia:
Clarithromycin or Roxithromycin
Legionella pneumonia: Clarithromycin or
Roxithromycin or Ciprofloxacin
Chlamydophila psittaci: Doxycycline
NR
All rights reserved 71
The French Society of
Anaesthesia and Intensive Care
Medicine and the French
Society of Intensive
Care
[212]
Leone et al: Summary of French
guidelines for the prevention,
diagnosis and treatment of
hospital‐acquired pneumonia in
ICU (Review article)
2017
(2018
publication
year)
France Late pneumonia ≥5 days or nonfermenting GNB: in
case of ESBL: Imipenem-cilastatin or meropenem +
amikacin or ciprofloxacin
HAP (when no other antibacterials can be used):
nebulised colimycine (sodium colistiméthate) and/or
aminoglycosides
NR
AWMF (Registry Nr: 020-013)
(S3 guideline Epidemiology,
diagnosis and therapy of adult
patients with nosocomial
pneumonia)
[213] 2
Update
2017
Germany At risk of MDR:
• Piperacillin/Tazobactam
or
• Cefepime
• Ceftazidime
or
• Imipenem/Cilastatin
• Meropenem
Plus/minus
• Fluorchinolon (Ciprofloxacin, Levofloxacin)
or
• Aminoglycosides (Gentamicin, Tobramycin,
Amikacin)
Colistin in combination with
Aminoglycosides
or
Fosfomycin,
or
Carbapenem
or
Ceftazidime/Avibactam
(depending on in vitro-Tests and
adverse reactions)
All rights reserved 72
In suspected MRSA: combination with Glycopeptid or
Oxazolidinone, Vancomycin or Linezolid
AWMF (Registry Nr: 082-006)
(Calculated initial parenteral
therapy for bacterial diseases in
adults - update 2018)
[201] 3
2019 Germany • Nosocomial pneumonia:
Group 3a cephalosporins, aminopenicillin / β-
lactamase inhibitor combinations,
• or pneumococcal fluoroquinolones
However, it should be noted that the use of group 3
cephalosporins increases the selection of vancomycin-
resistant enterococci (VRE), ESBL-producing
Enterobacteriaceae and beta-lactam antibacterial-
resistant Acinetobacter spp. Fluoro-quinolones should
also be used with caution due to the frequent
resistance selection.
ESBL strains with additional
resistance to carbapenems,
• Colistin in combination
therapy
• Ceftazidime / Avibactam.
“Guidelines for the management
of community-acquired
pneumonia in the elderly
patient”
[214]
2014 Spain • Patients without frailty:
Outpatient setting - Amoxicillin/clavulanate or
cefditoren + clarithromycin or moxifloxacin or
levofloxacin
•Treatment at admission - Amoxicillin/ clavulanate or
ceftriaxone + azithromycin or moxifloxacin or
levofloxacin
• Patients with frailty:
Mild cases - Amoxicillin/clavulanate or ceftriaxone
+ azithromycin or moxifloxacin or levofloxacin
Moderate-severe cases – Ertapenem or
amoxicillin/clavulanate
Pseudomonas aeruginosa:
Piperacillin/tazobactam or
imipenem or meropenem or
cefepime + levofloxacin or
ciprofloxacin or amikacin or
tobramycin
All rights reserved 73
• Enterobacteriaceae/anaerobes: Ertapenem or
amoxicillin/clavulanate
Infectious Diseases and Clinical
Microbiology (SEIMC) 2015
[199]
2015 Spain KPC-producing Klebsiella pneumonia:
• Combination therapy: carbapenem (see preferred
drug and recommended dose below) plus one or two
fully active drugs (including colistin, tigecycline, and
aminoglycoside or fosfomycin, the latter preferably
as a third drug) is recommended if the carbapenem
MIC is ≤8 mg/L; this applies mainly to patients with
severe infections caused by
NR
Spanish Society of
Transplantation (SET)/ Group
for Study of Infection in
Transplantation of the Spanish
Society of Infectious Diseases
and Clinical Microbiology
(GESITRA-EIMC)/ Spanish
Network for Research in
Infectious Diseases (REIPI)
[204]
2018 Spain VAP or Enterobacteriaceae with MIC ≥1 mg/L:
• Tigecycline
P. aeruginosa: High-dose
ceftolozane-tazobactam could
be prescribed to solid organ
transplantation (SOT) recipients
Spanish Society of Infectious
Diseases and Clinical
Microbiology (SEIMC) and the
Spanish Association of
Haematology and Hemotherapy
(SEHH)
2019 Spain • Cefepime
• Piperacillin-tazobactam
• Imipenem or meropenem
+/-
• Fluoroquinolones, aminoglycosides, colistin
NR
All rights reserved 74
[205] 4 In critically ill patients, or patients previously
colonized/infected with multidrug-resistant gram-
negative bacilli, it is advisable to use a dual therapy
strategy, according to local epidemiology.
NICE guideline [NG139]:
Pneumonia (hospital-acquired):
antimicrobial prescribing”
[215] 5
2019 UK • Piperacillin with tazobactam
• Ceftazidime
• Ceftriaxone
• Cefuroxime
• Meropenem
• Ceftazidime/ avibactam
Antibacterials to be added if suspected or confirmed
MRSA infection (dual therapy with an IV antibacterial
for empirical therapy)
• Vancomycin, Teicoplanin, Linezolid
NR
1https://pro.medicin.dk/Specielleemner/Emner/318019
2https://www.awmf.org/uploads/tx_szleitlinien/020-013l_S3_Nosokomiale_Pneumonie_Erwachsener_2017-11.pdf
3https://www.awmf.org/uploads/tx_szleitlinien/082-006l_S2k_Parenterale_Antibiotika_2019-08.pdf
4https://seimc.org/contenidos/documentoscientificos/seimc-dc-2019-Febrile_Neutropenia.pdf
5https://www.nice.org.uk/guidance/ng139/resources/pneumonia-hospitalacquired-antimicrobial-prescribing-pdf-66141727749061
All rights reserved 75
Table 11c: Relevant guidelines for diagnosis and management – cUTI
Name of
society/organisation
issuing guidelines
Date of
issue or
last update
Country (s) to
which
guideline
applies
Summary of recommendations
-MDR infections-
Summary of recommendations
-CR infections-
European Association of
Urology EAU [25]
2018 Europe No specific recommendation for MDR
infections.
Recommendations:
• 3rd generation cephalosporin as empirical
treatment of cUTI with systemic symptoms
No specific recommendation for CR
infections.
Comparison of
antibacterial treatment
guidelines for urinary tract
infections in 15 European
countries: Results of an
online survey ([216]
Guidelines
from 2012-
2017
(one from
2004,
Serbia)
Europe (15
countries)
Dosage according to resistance pattern
• Ampicillin iv
• Gentamicin
• Amoxicillin / clavulanic acid
• Trimethoprim / sulfamethoxazole
• Cefuroxime iv
• Ciprofloxacin
NR
pro. medicin Information til
sundhedsfaglige -
Antibiotikavejledning
[211] 1
2019 Denmark
No specific recommendation for MDR
infections
NR
All rights reserved 76
Complicated cystitis/ Acute pyelonephritis:
Pivmecillinam or Ciprofloxacin in penicillin
allergy
With urosepsis: Mecillinam +/- Gentamicin or
Ampicillin +/- Gentamicin or
Piperacillin/Tazobactam
UTI in catheter carriers: Pivmecillinam or
Ciprofloxacin
Update on a proper use of
systemic fluoroquinolones
in adult patients –
Recommendations
[202]
2015 France Severe pyelonephritis: ESBL-producing
Enterobacteriaceae 1st-line treatment,
systematically with an aminoglycoside
NR
French Infectious Diseases
Society (SPILF)
[217]
Updated
2015,
changes
decided in
2017
included
France Combination treatment: β-lactam,
aminoglycoside
ESBL-E: Amikacin (risk of cross-resistance is
substantially lower with amikacin than with
gentamicin or tobramycin).
NR
AWMF (Registry Nr: 082-
006) (Calculated initial
parenteral therapy for
bacterial diseases in adults
- update 2018)
[201]2
2018
(2019
publication
year)
Germany nosocomial acquired or catheter-associated
UTIs •Group 3b cephalosporins, including
the cephalosporin / BLI combinations
ceftolozane / tazobactam and ceftazidime /
avibactam, or 4 (cefepime),
• Group 2 or group 3 fluoroquinolones
• Group 1 carbapenems
• Ceftolozane / tazobactam
• Ceftazidime / avibactam
All rights reserved 77
Spanish Society of Clinical
Microbiology and Infectious
Diseases (SEIMC)
[218]3
2016 Spain • Patients with healthcare acquired acute
polynephritis (non-severe and severe):
Antipseudomonal carbapenem plus
ceftolozane-tazobactam or piperacillin-
tazobactam
• Severe sepsis: Amikacin
• CA APN (complicated and uncomplicated):
APN with specific risk factors for ESBL
producing Enterobacteriaceae: First choice:
ertapenem is an acceptable option, Second
choice: other carbapenems or piperacillin-
tazobactam
• CA-APN with penicillin allergy: Amikacin or
sodium fosfomycin
NR
Spanish Society of
Infectious Diseases and
Clinical Microbiology
(SEIMC) and the Spanish
Association of
Haematology and
Hemotherapy (SEHH)
[205]4
2019 Spain • Cefepime
• Piperacillin-tazobactam
• Imipenem or carbapenem
• Consider the addition of an aminoglycoside
or glycopeptide in critically ill patients, those
with indwelling urinary catheters, and/or a
history of colonization/infection with multidrug-
resistant microorganisms
NR
All rights reserved 78
British Society for
Antimicrobial
Chemotherapy/
Healthcare Infection
Society/British Infection
Association
Joint Working Party
[122]
2018
UK Pyelonephritis and cUTI caused by MDR
GNB:
• Meropenem or, ceftolozane/tazobactam or
temocillin
• Piperacillin/tazobactam
• Amikacin
• Ceftazidime/avibactam or non-b-lactam
agents in combination with meropenem
1https://pro.medicin.dk/Specielleemner/Emner/318019
2https://www.awmf.org/uploads/tx_szleitlinien/082-006l_S2k_Parenterale_Antibiotika_2019-08.pdf
3https://pdfs.semanticscholar.org/95c8/f85c6122ced97ad0d4076427b4fcba7e0214.pdf
4https://seimc.org/contenidos/documentoscientificos/seimc-dc-2019-Febrile_Neutropenia.pdf
Table 11d: Relevant guidelines for diagnosis and management – BSI/Sepsis
Name of society/organisation issuing guidelines Date of
issue or
last update
Country (s)
to which
guideline
applies
Summary of
recommendations
-MDR infections-
Summary of
recommendations
-CR infections-
Surviving Sepsis Campaign
[27]
Update
2018
International
(Europe and
North
America)
Combination therapy: two drugs
from different classes of
antibacterials- usually a β-
lactam with a
Combination therapy:
broad coverage
antibacterial + pathogen-
specific agent:
All rights reserved 79
fluoroquinolone,
aminoglycoside or macrolide
Broad-spectrum
carbapenem (e.g.,
meropenem,
imipenem/cilastatin or
doripenem) or extended-
range penicillin/β-
lactamase inhibitor
combination (e.g.,
piperacillin/tazobactam or
ticarcillin/clavulanate.
third- or higher generation
cephalosporins can also
be used, especially as part
of a multidrug regimen.
pro. medicin Information til sundhedsfaglige -
Antibiotikavejledning
https://www.pro.medicin.dk.
[211]1
2019
(bacterial
section
Revised
13.01.2020)
Denmark
No specific recommendation for
MDR infections
Septic shock: Ampicillin +
Gentamicin or Piperacillin /
Tazobactam + Gentamicin
Suspected/detected
Enterococci: add Vancomycin
NR
All rights reserved 80
Suspected/detected
Pseudomonas aeruginosa:
Ceftazidime + Gentamicin
AWMF (Registry Nr: 079/001) (Prevention, diagnosis,
therapy and aftercare of sepsis)
[219] 2
2010
(currently
under
revision)
Germany Treatment of Sepsis:
It is recommended to use a
Pseudomonas-effective
antibacterial ureidopenicillins
(piperacillin) or third-party or
fourth generation
cephalosporins (ceftazidime
or cefepime) or carbapenems
(imipenem or meropenem)
under consideration use local
resistance patterns
NR
Infectious Diseases Working Party of the German
Society of Haematology and Medical Oncology
[220]
2012 Germany CVC-related bloodstream
infections (CRBSI) caused by
Stenotrophomonas maltophilia:
• Co-trimoxazole
NR
Infectious Diseases Working Party of the German Society
of Haematology and Medical
Oncology
[221]
2014 Germany Neutropenic patients with
sepsis:
• Imipenem/cilastatin or
piperacillin/ tazobactam
• Combination treatment with
aminoglycoside in case of
severe sepsis
NR
All rights reserved 81
Helsedirektoratet, Antibiotikabruk i sykehus, Nasjonal
faglig retningslinje
https://www.helsedirektoratet.no/Retningslinjer/Antibiotika-
i-sykehus
[208]3
Update
2018
Norway • Broad-spectrum beta-lactam
antibacterial if suspected
resistant microorganisms
• Aminoglycosides
(gentamicin or tobramycin)
for severe sepsis and septic
shock
• Septic shock and suspected
gram-negative aetiology:
gentamicin or ciprofloxacin
No specific
recommendation for CR
infections
Infectious Diseases and Clinical Microbiology (SEIMC)
2015
[199]
2015 Spain • Enterobacteriaceae:
carbapenem
• Nosocomial sepsis and
previous receipt of
cephalosporins:
fluoroquinolones or
carbapenems
NR
Spanish Society of Transplantation (SET)/ Group for Study
of Infection in Transplantation of the Spanish Society of
Infectious Diseases and Clinical Microbiology (GESITRA-
EIMC)/ Spanish Network for Research in Infectious
Diseases (REIPI)
[204]
2018 Spain • Enterobacteriaceae:
Tigecycline
• mild infections: Carbapenem
monotherapy (extended-
infusion)
• SOT recipients
diagnosed with BSI and/or
pneumonia caused by P.
aeruginosa resistant to
carbapenems and other β-
lactams, if the strain shows
in vitro susceptibility:
All rights reserved 82
High-dose ceftolozane-
tazobactam
Spanish Society of Clinical Microbiology and Infectious
Diseases (SEIMC), Spanish Society of Intensive Care
Medicine and Coronary Units (SEMICYUC)
[222]
2018 Spain Based on local epidemiology:
piperacillin-tazobactam,
carbapenems, a fourth-
generation cephalosporin,
aztreonam, quinolones or
aminoglycosides
NR
Spanish Society of Infectious Diseases and Clinical
Microbiology (SEIMC) and the Spanish Association of
Haematology and Hemotherapy (SEHH)
[205]4
2019 Spain Use of carbapenems is
recommended for patients with
sepsis or septic shock criteria
The UK joint specialist societies guideline on the diagnosis
and management of acute
meningitis and meningococcal sepsis in immunocompetent
adults”
[223]
2016 UK Suspected cases:
Ceftriaxone/cefotaxime
>60 years old &
immunocompromised patients:
Ampicillin/amoxicillin +
cephalosporin
GN diplococci: continued
Ceftriaxone/cefotaxime
Suspected ESBL infection:
Meropenem
Confirmed Neisseria
meningitidis:
Ceftriaxone/cefotaxime,
NR
All rights reserved 83
benzylpenicillin,
ciprofloxacin (if not given
ceftriaxone)
1https://pro.medicin.dk/Specielleemner/Emner/318019
2https://www.awmf.org/uploads/tx_szleitlinien/079-001l_S2k_Sepsis_2010-abgelaufen.pdf
3https://www.helsedirektoratet.no/Retningslinjer/Antibiotika-i-sykehus
4https://seimc.org/contenidos/documentoscientificos/seimc-dc-2019-Febrile_Neutropenia.pdf
Table 11e: Relevant guidelines for diagnosis and management- cIAI
Name of
society/organisation
issuing guidelines
Date of
issue or
last
update
Country (s) to
which
guideline
applies
Summary of recommendations
-MDR infections-
Summary of recommendations
-CR infections-
World Society of
Emergency Surgery
(WSES) and World Society
of Abdominal Compartment
Syndrome (WSACS)
[224]
Check update?
2017 Global Ceftolozone/tazobactam and
ceftazidime/avibactam (both in combination
with metronidazole)
-Aminoglycosides with β-lactams
-Polymyxins and fosfomycin (in critically ill
patients)
Tigecycline (against carbapenemase-
producing Enterobacteriaceae and
Stenotrophomonas maltophilia)
-Ceftazidime/avibactam (against
carbapenemase producing K.
pneumoniae)
All rights reserved 84
The Surgical Infection
Society ([24]
2017 USA • High risk patients with Pseudomonas
aeruginosa: ceftolozane-tazobactam +
metronidazole
• High-risk patients with Klebsiella pneumoniae
carbapenemase (KPC)-producing
Enterobacteriaceae: ceftolozane-avibactam
+ metronidazole
NR
pro. medicin Information til
sundhedsfaglige -
Antibiotikavejledning
https://www.pro.medicin.dk.
[211]1
2019 Denmark No specific recommendation for MDR
infections
Piperacillin / tazobactam + metronidazole +
fluconazole
or
Cefuroxime + metronidazole + fluconazole
in penicillin allergy
NR
Update on a proper use of
systemic fluoroquinolones
in adult patients –
Recommendations
[202]
2015 France Shigella sonnei diarrhea: ciprofloxacin or
ofloxacin
First-line use of fluoroquinolones not
recommended in IAI; instead ciprofloxacin or
ofloxacin
NR
Société française
d'anesthésie et de
réanimation (Sfar)
[225]2
2015 France • Amoxicillin / clavulanic acid + gentamicin
• Cefotaxime or ceftriaxone + imidazoles.
NR
All rights reserved 85
Severe IAI: piperacillin / tazobactam
gentamicin.
Haute Autorité de Santé
(HAS), la Société de
pathologie infectieuse de
langue française (SPILF) et
la Société de réanimation
de langue française (SRLF)
[226]3
2019 France In IA EBLSE infections: piperacillin-
tazobactam
• With septic shock: carbapenem (imipenem
or meropenem).
IA Enterobacteriaceae resistant to C3G by
hyperproduction of cephalosporinase and
without production of ESBL: cefepime
combined with metronidazole or ornidazole
Serious IAI: piperacillin-tazobactam
combined with amikacin
NR
AWMF (Registry Nr: 082-
006) (Calculated initial
parenteral therapy for
bacterial diseases in adults
- update 2018)
[201]4
2018 Germany The following antibacterials are recommended
if suspected pathogens are suspected:
MRSA Tigecycline
Linezolid+
Vancomycin+
VRE Tigecycline
Linezolid+
ESBL
(E. coli,
Klebsiella
spp.)
Tigecycline
Ceftolozane/Tazobactam
Ceftazidim/Avibactam
Imipenem
Meropenem
Ertapenem
The following antibacterials are
recommended if suspected pathogens
are suspected to be CR
Tigecycline
Colistin
Ceftazidim/Avibactam
Meropenem (High doses)
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Fosfomycin
(no Monotherapy)
Acinetobacter
spp.
Colistin
Tigecycline
Sulbactam
Pseudomonas
spp.
Imipenem, Meropenem
Piperacillin/Tazobactam
Cefepime
Gentamicin, Amikacin
Ciprofloxacin2,
Levofloxacin2
Ceftolozane/Tazobactam
Ceftazidim/Avibactam
1https://pro.medicin.dk/Specielleemner/Emner/318019
2https://www.infectiologie.com/UserFiles/File/medias/Recos/2014-inf-intra-abdo-SFAR.pdf
3https://www.infectiologie.com/UserFiles/File/spilf/recos/2019-synthese-infections-enterobacteries.pdf
4https://www.awmf.org/uploads/tx_szleitlinien/082-006l_S2k_Parenterale_Antibiotika_2019-08.pdf
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2.4 Comparators in the assessment
1. Based on the alternatives presented, identify the technologies to be used as
comparator(s) for the assessment.
2.4.1 General considerations
In general, in antibacterial research and development, in vitro, PK/PD models and clinical trials
provide integrated sources of information for comparative analysis of effectiveness.
Clinical trials can provide reliable information regarding comparative efficacy when the
pathogens have confirmed or expected susceptibility to both drugs. This is consistent with
prescription based on AST results, which occurs in patients with confirmed CR infections.
In this setting, Network meta-analysis (NMA) if feasible provide additional reliable information
of comparative effectiveness, in the absence of direct comparative data, but rendered to show
no significant differences between treatments included in the NMA, as all clinical trials are
designed as non-inferiority and conducted in a population where all pathogens are expected
to be susceptible to both treatments.
However, in patients with infections suspected to be caused by MDR/CR pathogens,
clinical trials only provide limited comparative evidence regarding the efficacy of new
antibacterials. This is because trials must include only pathogens for which the tested agents
and comparators are effective, as it would be unethical to knowingly allow patients to have
ineffective treatment. In this setting, standard NMAs also provide little information, as they
never account for pathogens not susceptible to the treatment regimens included in the
network. A comparison of efficacy against all relevant comparators can only be obtained from
in vitro surveillance studies. Hence approaches integrating all available evidence from in vitro,
PK/PD and clinical data (such as effectiveness models), are the necessary to predict
susceptibility rates and clinical effectiveness rates.
Specific findings supporting the chosen comparators
The guideline review revealed that the comparators used in the clinical trials of cefiderocol
were commonly used across different countries. For suspected MDR infections, carbapenems
are (alone or in combination) recommended throughout, while for confirmed MDR/CR
resistance, colistin-based regimens are considered (A. Baumannii, S. maltophilia, metalloβ-
lactamases). Newer treatments are recommended in case of P. Aeruginosa
(ceftolozane/tazobactam) and Enterobactereacea (ceftazidime/avibactam) for suspected and
confirmed MDR pathogens.
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This review results confirm that the comparators in clinical trials APEKS-NP, APEKS-cUTI and
CREDIBLE-CR reflect the guideline recommendations for the different target populations. The
trials have been designed in line with recommendations from regulatory authorities and
allowed clinicians to select specific treatments (“best available care”) in the CR population
(CREDIBLE-CR trial), for which different treatment options may be combined to combat very
difficult-to-treat infections.
Comparator in APEKS-NP (Meropenem - high-dose and prolonged infusion)
For APEKS-NP high-dose and prolonged infusion (HD) of meropenem was the selected
comparator, as per FDA recommendations, given the severity of the population expected in
the trial and likelihood of including patients with infections resistant to carbapenems (confirmed
after trials inclusion). This regimen optimises exposure and time over MIC for Carbapenems,
can be active in pathogens with MIC up to 16mg/L and has shown to improve prognosis in
severe infections compared with short-term infusions (Microbiology (SEIMC) and the Spanish
Association of Haematology and Hemotherapy (SEHH), Gudiol 2019)). In alignment with this
strategy, some guidelines recommend high doses of β-lactam antibacterials for treatment of
acute invasive infections by Pseudomonas aeruginosa (Mensa, Antibacterial selection in the
treatment of acute invasive infections by Pseudomonas aeruginosa: Guidelines by the
Spanish Society of Chemotherapy” (2018).
The fact that this HD meropenem was a regimen not used in other clinical trials as comparator,
as well as including pathogens which other antibacterials were not active against (e.g. A.
baumannii) did not allow a network to be built and therefore, an NMA could not be performed
in patients with nosocomial infections. For more information on this topic please refer to the
systematic literature review and feasibility assessment for a network meta-analysis of
treatments of Gram-negative bacterial infections [227].
Comparator in APEKS-cUTI (imipenem/cilastatin)
Given the probability of resistance to 3rd-class cephalosporins, imipenem / cilastatin was
among the recommended treatments (e.g. Helsedirektoratet. Antibiotikabruk i sykehus,
Kortversjon av Nasjonal faglige retningslinje for antibiotikabruk i sykehus 2014 [208]) and
chosen as the comparator alongside imipenem, a recommended and commonly used
carbapenem for the treatment of cUTI.
In addition to the trial-based comparison, an NMA was possible in cUTI, given the overlapping
pathogen profile and similar patient baseline characteristics, across all relevant published
studies. Treatments for suspected MDR Gram-negative infection were identified through a
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systematic review of the literature. Trials focusing on efficacy and safety of current treatments
for Gram-negative urinary tract infections were identified (see APEKS-cUTI section of chapter
5.4.3), including all trials that compared any parenteral antibacterials for the treatment of
Gram-negative infection to placebo or another parenteral antibacterial. Based on selection
according to bacteria, the potential network was designed in line with the intended label for
cefiderocol. The NMA results were consistent with APEKS-cUTI trial results and expectedly
found no statistically significant difference between cefiderocol and other comparators, given
the considerations in section 2.4.1. For more information on this topic please refer to the
relevant appendix [227].
This NMA provides supportive comparative information for patients with infections caused by
confirmed CR resistant pathogens.
Comparator in CREDIBLE-CR (BAT based on combinations with colistin)
As requested by regulatory authorities, the comparator in CREDIBLE-CR was BAT in order to
enable the variable treatment approaches required where there are very limited options and
given variable local epidemiology and resistance patterns. The heterogeneity of BAT drug
combinations reflects the current treatment reality and selection of treatment choice according
to most likely effective treatment in a given place and setting, consisting predominantly of
colistin based regimens.
2.4.2 Selection of relevant comparators for the assessment
Following the EMA’s guidance and expected label approval, the comparators are defined
predominantly based on pathogens (as opposed to infection sites). To address the high priority
pathogens and based on recommendations and susceptibility tests, the following comparators
are most relevant for each target treatment population
- Suspected MDR infection - carbapenems (including meropenem and imipenem, in
monotherapy with high dose & prolonged infusion or combinations),
ceftolozane/tazobactam, and ceftazidime/avibactam.
- Confirmed MDR infection- colistin-based (combination) regimens for (A. Baumannii, S.
maltophilia, and other Gram-negative pathogens containing metalloβ-lactamases);
ceftolozane/tazobactam (P. Aeruginosa), ceftazidime/avibactam (Enterobactereacea)
Given the important role of in vitro surveillance studies for antibacterials, an assessment of
cefiderocol needs to be based on a combination of comparisons of surveillance data and
clinical evidence, as outlined below (Table 12).
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Table 12: Cefiderocol assessment
Population Comparator Data source Result (cefiderocol vs. comparator)
Suspected MDR/CR
High dose Meropenem SIDERO WT surveillance
Broader coverage of Gram-negative, aerobic pathogens. Lower MIC value and preserved efficacy in the presence of carbapenemases.
APEKS-NP RCT
Non-inferior with regard to mortality (primary outcome) and all clinical and microbiological secondary outcomes.
High dose Meropenem Ceftalozane-tazobactam, Ceftazidime-avibactam
Integrated epidemiology and in vitro data analysis
Cefiderocol presents higher weighed susceptibility rates in cUTI, pneumonia, BSI, and gastrointestinal samples vs comparators
High dose Meropenem Ceftalozane-tazobactam, Ceftazidime-avibactam
Effectiveness model integrating epidemiology, in vitro data and clinical data
Cefiderocol presents higher likelihood of clinical and microbiological effectiveness in pneumonia and cUTI vs comparators.
Imipenem/Cilastatin APEKS-cUTI RCT
Non-inferior to comparator, but proven superiority in a post-hoc analysis, on the primary endpoint of combined microbiological eradication / clinical cure at TOC, and secondary endpoint microbiological eradication at TOC.
Ceftalozane-tazobactam, ceftazidime-avibactam, doripenem, imipenem/cilastatin
network meta-analysis for cUTI
In similar patient populations with similar pathogen distribution across different trials, and consistent with APEKS-cUTI there was statistical significant difference in microbiological eradication at TOC vs Imipenem/cilastatin, but in all other endpoints there was no statistically significant difference, including clinical cure rates and adverse events
Ceftolozane/tazobactam SIDERO WT surveillance
Lower MIC90 (0.25 vs. 8 for Pseudomonas, 0.25 vs. 32 for Acinetobacter, 1 vs. 64 for Enterobacteriaceae)4 Higher % isolates susceptible to cefiderocol
Ceftazidime/avibactam SIDERO WT surveillance
Same MIC90 for Enterobacteriaceae (1 vs. 1), otherwise superiority of cefiderocol Higher % isolates susceptible to cefiderocol
Confirmed CR
Colistin-based (combination) regimens (most relevant for for A. Baumanii, S. maltophilia,
SIDERO CR surveillance
Higher % isolates susceptible to cefiderocol; Similar in vitro efficacy. Colistin is known to have severe side effects, especially kidney toxicity. Resistances against colistin have
4 Longshaw et al., 2019 ID Week
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pathogens with metalloβ-lactamases)
been reported to increase in epidemiological studies.
Ceftolozane/tazobactam (most relevant for P. aeruginosa, except pathogens with metalloβ-lactamases)
SIDERO CR surveillance
Higher percent susceptibility for cefiderocol against Acinetobacter and Pseudomonas across all included countries (MEM-NS pathogens)5
Ceftazidime/avibactam (most relevant for Enterobacterales, except pathogens with metalloβ-lactamases)
SIDERO CR surveillance
Higher percent susceptibility for cefiderocol against Acinetobacter and Pseudomonas across all included countries (MEM-NS pathogens)
Best available therapy (BAT), predominantly (combination) regimens (most relevant for A. Baumanii, S. maltophilia, pathogens with metalloβ-lactamases)
CREDIBLE-CR Descriptive results only. Evidence of eradication of resistant pathogens. Numerical, non-significant disadvantage with regard to mortality for cefiderocol compared to BAT.
The important question, raised during the scoping process, was: Given the large amount of
heterogeneity in the treatment recommendation and the limited number of comparators in the
surveillance data and the clinical studies, how can clinicians determine when to use
cefiderocol over another potential candidate?
The answer combines the intended label with the target populations, as follows:
The indication for cefiderocol is expected to be:
Fetcroja is indicated for the treatment of infections due to aerobic Gram-negative
organisms in adults with limited treatment options.
This indication will therefore be pathogen focused, not restricted to any specific site of infection
and supports the use of cefiderocol in two types of patients:
Hospitalised patients with suspected (but prior laboratory confirmation) MDR/CR
infection who are critically ill and require immediate antibacterial treatment that
provides full cover against CR pathogens and potential resistant mechanisms, to avoid
the risk of rapid clinical deterioration (with the option to de-escalate to a more targeted
treatment when the pathogen and susceptibility profile is subsequently confirmed).
Hospitalised patients where CR infection has been confirmed and cefiderocol is best
option based on pathogen susceptibility information and/or where other treatment
choices are inappropriate (efficacy, contra-indication or tolerability).
5 Sato et al. 2019 ID Week
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Thus, clinicians will encounter three types of patients in their clinical practice that would be
treated according to the identified guidelines:
1) Patients with infections for which there are sufficient treatment options
listed in the guidelines. These fall out of the scope of the cefiderocol
label and are thus not relevant for the current assessment.
2) At the other end of the spectrum, patients with confirmed MDR/CR
infections, for which the antibacterial susceptibility test shows that
there are no other options but cefiderocol. These patients would gain
an important new, last-resort option with cefiderocol.
3) Patients with suspected MDR/CR options, for which local surveillance
data indicate that many of the currently available comparators will not
provide cover against certain possible carbapenem-resistant
pathogens, and who are critically ill and at risk of clinical deterioration.
These patients would gain a new treatment option to reduce the risk
of insufficient pathogen coverage leading to a delay in appropriate
treatment and consequent clinical deterioration
The clinician could optimize the chances of success by considering different treatment options
based on their indications, the MICs and breakpoints published by EUCAST, and the
outcomes in trials of susceptible patient populations. Based on the local epidemiology, the
clinician would then select an agent (or combination of agents) that would maximize the
likelihood to cover the suspected pathogen.
All this data was integrated into an effectiveness model, where European epidemiological data
for MDR pathogen prevalence rates for specific infection sites was used alongside with results
from the SIDERO surveillance studies, and clinical cure rates from clinical trials, to estimate
the likelihood of success of cefiderocol compared with the most relevant comparators.
The results indicate that cefiderocol would have the highest likelihood of success of clinical
cure and microbiological eradication at these infection sites. For more information please see
section 5.4.1 and 5.4.3
These calculations would have to be adjusted for individual cases by taking into account local
variability of pathogen frequencies, but the approach illustrates a practical solution for the
complex challenge of optimizing treatments in patients with suspected MDR/CR infections.
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Once the antibacterial susceptibility test becomes available, doctors should again follow the
guideline recommendations and de-escalate the treatment to the choice with the narrowest
and specific spectrum for the identified pathogen.
In summary, the combined consideration of international guidelines, the growing unmet need
of antimicrobial resistance, the fact that delays in appropriate treatment cause worse
outcomes, indicate that cefiderocol constitutes a valuable addition to the current treatment
landscape of Gram-negative pathogens for patients with limited treatment options.
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3 Current use of the technology
Summary of issues relating to current use of the technology
Cefiderocol is not yet approved in Europe with the only current use being in
compassionate use programmes. Over 200 patients globally were treated to date under
the compassionate use programme of cefiderocol, underlining the clear unmet need in
patients with highly resistant infections with no treatment options.
o The criteria for fulfilling these requests are highly restrictive. All other available
treatments must be ruled out through susceptibility testing and/or where there is
evidence of treatment failure (efficacy or safety).
o In addition, patients must be unable to enrol in clinical studies of cefiderocol.
Case reports for three patients in the compassionate use programme have been
published.
o A patient was treated successfully for endocarditis due to extensively drug resistant
(XDR) Pseudomonas aeruginosa.
o A patient with multiple comorbidities and a complicated intra-abdominal infection
(IAI) due to MDR Pseudomonas aeruginosa was released from hospital care within
six weeks of completion of cefiderocol treatment.
o A patient with VAP and BSI caused by XDR Acinetobacter baumannii and
carbapenemase-producing Klebsiella pneumoniae had potentially serious organ
failure from older anti-infectives. Six weeks after cefiderocol administration, chest
X-rays showed complete resolution of infection.
An abstract submitted (not accepted) for ECCMID 2020 summarizes results from a case
series of seven severely ill patients with CR Acinetobacter infections treated with
cefiderocol. The two patients who died had received cefiderocol for only two days prior to
death.
While the compassionate use program is restricted to the use of cefiderocol for the
treatment of XDR infections with no other options, the EMA-approved indication will be
broader and encompass early targeted treatment of suspected MDR/CR/difficult-to-treat
infections in addition to treatment of confirmed resistant pathogens.
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3.1 Current use of the technology
1. Describe the experience of using the technology, for example the health conditions
and populations, and the purposes for which the technology is currently used. Include
whether the current use of the technology differs from that described in the (expected)
authorisation.
Since cefiderocol is currently not approved in Europe, the only use has been within the
compassionate use program. This program is registered in https://www.clinicaltrials.gov/
registry under NCT03780140: Expanded Access to Cefiderocol for the Intravenous Treatment
of Severe Gram-Negative Bacterial Infections. Expanded access may be provided for
cefiderocol for qualified patients who have limited treatment options and are not eligible for a
clinical trial.
Case reports for three patients in the compassionate use programme have been published.
o A patient was treated successfully for endocarditis due to extensively drug resistant (XDR)
Pseudomonas aeruginosa.
o A patient with multiple comorbidities and a complicated intra-abdominal infection (IAI) due
to MDR Pseudomonas aeruginosa was released from hospital care within six weeks of
completion of cefiderocol treatment.
o A patient with VAP and BSI caused by XDR Acinetobacter baumannii and
carbapenemase-producing Klebsiella pneumoniae had potentially serious organ failure
from older anti-infectives. Six weeks after cefiderocol administration, chest X-rays showed
complete resolution of infection.
To date over 200 patients have been treated with cefiderocol through this programme.
Detailed information on 74 patients which have completed treatment with cafiderocol are
presented in section 5.4 and are part of the data pacage that substantiates the efficacy of
cefiderocol in patients with confirmed CR infections alongside CREDIBLE CR.
The criteria for compassionate use of cefiderocol are highly restrictive. All other available
treatments must be ruled out through susceptibility testing, and/or there must be evidence of
treatment failure (efficacy or safety). Enrolled patients will have confirmed CR infection and
are likely to be consistent with the target population where patients have confirmed CR
infections. However, EMA-approved indication will be broader and encompass both the
treatment of confirmed resistant infection and patients with infections by suspected MDR
pathogens.
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2. Indicate the scale of current use of the technology, for example the number of people
currently being treated with the technology, or the number of settings in which the
technology is used.
200 patients have been treated to date with cefiderocol in this programme. Results from 74
patients are available (see section 5.4).
Compassionate use of cefiderocol is restricted to seriously ill, hospitalised patients.
Cefiderocol is and will be used in critically ill hospitalised patients, many of whom will be
treated in ICU units. These patients will often be unconscious, and on many occasions require
ventilation (intubation). This is consistent with existing intravenous use of antibacterials in
critically ill hospitalised patients.
3.2 Reimbursement and assessment status of the technology
1. Complete Table 13 with the reimbursement status of the technology in Europe.
Table 13: Overview of the reimbursement status of the technology in European countries
Country and
issuing
organisation
Status of recommendation
(positive/negative/ongoing/not
assessed)
If positive, level of reimbursement*
NA NA NA
Include a reference to any publicly available guidance documents
*For example, full reimbursement or only partial reimbursement. If partial reimbursement gives a
percentage of reimbursement.
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4 Investments and tools required
Summary of issues relating to the investments and tools required to introduce
the technology
The use of cefiderocol is for hospital use only, and is not expected to require any
specialized equipment, or to demand additional resources beyond the standard ability to
store, prepare and administer intravenous infusion treatments, alongside susceptibility
testing to cefiderocol and standard monitoring microbiological evaluation tests, as it is
current practice with all hospital use antibacterials in nosocomial infections.
Cefiderocol is formulated as a freeze-dried (lyophilized) powder (1g/vial) for powder for
concentrate for solution for infusion. Following reconstitution, it is administered as a 3-
hour infusion of 2g every eight hours.
o Consideration should be given to official guidance on the appropriate use of
antibacterial agents. Treatment should commence for pathogens highly suspected
to be susceptible to cefiderocol, and susceptibility should be confirmed through
appropriate diagnostic testing as soon as possible.
o It is recommended that cefiderocol should be used to treat patients that have limited
treatment options only after consultation with a physician with appropriate
experience in the management of infectious diseases.
o Cefiderocol may be used in combination with other antibacterial agents active
against anaerobic pathogens and/or Gram-positive pathogens when these are
known or suspected to be contributing to the infectious process.
o Dose adjustments are necessary for patients with renal impairment, but not for
hepatic impairment. No adjustment is required in elderly populations. The safety
and efficacy of cefiderocol in children below 18 years of age has not yet been
established.
Treatment of severe MDR-GNB infections in critically ill patients will require an expert and
complex clinical reasoning, taking into account the peculiar characteristics of the target
population, but also the need for adequate empirical coverage and the more and more
specific enzyme-level activity of novel antimicrobials with respect to the different
resistance mechanisms of MDR-GNB.
The unmet need of developing additional effective antibacterials is accompanied by needs
to further establish improved antimicrobial stewardship programs, to provide an
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alternative treatment option when there are limited effective alternatives, and reducing the
likelihood of initial inappropriate pre-emptive therapy, while the identification of pathogens
and their susceptibility patterns is not available.
o For hospitalised patients with infection by suspected (but unconfirmed by an
antibiogram) GN MDR/CR pathogens who are critically ill and cannot wait for
results of an AST, cefiderocol will fill an important unmet need providing a more
likely initial appropriate treatment. With these factors, therefore it is likely that
patient outcomes improve, and length of stay associated with reduced time to
effective therapy are minimised. Early appropriate treatment with cefiderocol is
more likely to avoid delays in effective treatment. This may reduce healthcare
resource utilization and costs associated with prolonged stay in, or admission to,
intensive care units and/or delays in hospital discharge.
o Cefiderocol can be added to a combination regimen in case of multiple pathogens
with diverse Gram status or administered alone for the treatment of Gram-negative
MDR bacteria.
Additional reductions in healthcare resource utilization are possible, when considering the
broad context of AMR and how cefiderocol as a new treatment option contributes to it;
i.e., possible fewer hospital quarantine due to spread of CR bacteria (within hospitals and
across countries), potential reduction of complications when treating immunosuppressed
patients (e.g., cancer patients with febrile neutropenia, who require effective antimicrobial
treatment options). These additional values of new antibacterials have recently been
highlighted by several European initiatives (see EEPRU report in the UK) focusing on
innovative reimbursement models that aim to capture the full value that new antibacterials
convey.
4.1 Requirements to use the technology
1. If any special conditions are attached to the regulatory authorisation more information
should be provided, including reference to the appropriate sections of associated
documents (for example, the EPAR and SPC). Include:
conditions relating to settings for use, for example inpatient or outpatient,
presence of resuscitation facilities
restrictions on professionals who can use or may prescribe the technology
conditions relating to clinical management, for example patient monitoring,
diagnosis, management and concomitant treatments.
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4.1.1 Conditions for use
Cefiderocol is used as IV infusion and intended for hospital use only in patients that are
hospitalised. It is recommended that cefiderocol should be used to treat patients that have
limited treatment options only after consultation with a physician with appropriate experience
in the management of infectious diseases.
Consideration should be given to official guidance on the appropriate use of antibacterial
agents. Treatment should commence for pathogens highly suspected to be susceptible to
cefiderocol, and susceptibility should be confirmed through appropriate diagnostic testing as
soon as possible
4.1.2 Good stewardship and societal considerations
As applicable to all antibacterials, cefiderocol should be used according to good stewardship
practices. Such use holds the promise to decrease the total use of resources in the hospital
and area, due to the ability of new, infective antimicrobials to decrease resistances to existing
last-resort agents and to avoid hospital shutdowns.
Antimicrobials thus provide additional value to society that is not measured in clinical trials.
These elements of value have been summarized in a recent report based on a multi-
stakeholder conference in 2017 [228-231]. They include transmission, insurance, diversity,
novel action, enablement, and spectrum value. “Transmission value” refers to the fact that
novel antibacterials contribute to slowing the spread of resistant genes. Insights from the
evaluations of vaccines can be useful to support a quantitative assessment of this value.
“Insurance value” means that the general population is protected from catastrophic
outbreaks by having a last-resort antibacterial available. This value is independent of the
actual quantities used in the clinics and applies even if a new, last-resort treatment is being
kept for emergency use only. “Diversity value” means that additional treatments increase
the value of older treatments over time, because those become effective. Few other
therapeutic areas deal with medicines that provide such value, and standard HTA procedures
are optimized to compare alternative options in head-to-head comparisons but do not yet
account for such additional, synergistic value. “Novel-action value” refers to the fact that
antibacterials with new mechanisms of action are especially valuable due to the lower risk of
cross-resistance. “Enablement value” arises when the availability of antibacterials ensures
safe surgeries and chemotherapies. Due to the availability of effective treatments, this can
easily be taken for granted and may be challenged by resistant bacteria in the foreseeable
future. “Spectrum value” means that antibacterials with a narrower (i.e.,“more specific”)
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spectrum are more valuable for the treatment of susceptible pathogens than those with a
broader spectrum due to the lower risk of inducing additional resistances.
These additional elements of value due to improved resource utilization are important
considerations for the evaluation of novel antibacterials, which have the potential to lead to
substantial savings of resources if used in accordance with good stewardship practices.
Finally, antimicrobial stewardship includes the rapid identification of bacterial infections and
treatment with the most appropriate drug regimen [174, 175]. Improved early-detection and
characterization methods for bacterial infections used in hospital environments in which
cefiderocol and/or other modern antibacterials are available can thus lead to further resource
optimization, by allowing antibacterials use to be optimized for patients with infections
susceptible to certain treatments. While these resources are not a requirement for the use of
cefiderocol, they may help to optimize its use and effectiveness.
No special conditions are attached to the regulatory authorisation for cefiderocol with respect
to settings for use of cefiderocol. It will be used in critically ill hospitalised patients, many of
whom will be treated in ICU units. This is consistent with normal intravenous use of
antibacterials in these patients.
Clinical Particulars of the SmPC [232] highlight the following information:
Consideration should be given to official guidance on the appropriate use of
antibacterial agents. Treatment should commence for pathogens highly suspected
to be susceptible to cefiderocol, and susceptibility should be confirmed through
appropriate diagnostic testing as soon as possible.
It is recommended that Fetcroja should be used to treat patients that have limited
treatment options only after consultation with a physician with appropriate
experience in the management of infectious diseases
Cefiderocol may be used in combination with antibacterial agents active against
anaerobic pathogens and/or Gram-positive pathogens when these are known or
suspected to be contributing to the infectious process.
Dose adjustments are necessary for patients with renal impairment, but not for
hepatic impairment. No adjustment is required in elderly populations. The safety
and efficacy of cefiderocol in children below 18 years of age has not yet been
established.
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Pathogen susceptibility should be determined as quickly as possible to identify the most
appropriate antibacterial to achieve microbiological eradication. AST is an integral part of
antibacterial treatment in the hospital. Use of cefiderocol will not require any capital investment
for AST beyond standard diagnostic microbiology lab equipment and consumables.
Shionogi is working with several diagnostics manufacturers and the EUCAST Development
Laboratory (EDL) to ensure a standard Kirby–Bauer test assay (disc-diffusion sensitivity
assay) is available for cefiderocol. This widely used assay will be accredited and cross-
referenced to both microdilution (BMD) Minimum Inhibitory Concentration (MIC) results, with
corresponding EDL breakpoints and inhibition zone diameter correlates. If microbiology
laboratories have the appropriate KB discs, AST determination for cefiderocol can be
conducted alongside other drugs with no need for specialised equipment or growth media.
There will also be a available methodology for BMD MIC determination which in the manual
read version requires no specialist devices other than standard incubation and plate reading
equipment.
Shionogi also has collaborations with several diagnostics manufacturers to develop other AST
technologies, including epsilometer strips (eTest), inclusion in various automated AST panels
and ready-made BMD strips for MIC determination. These should be commercially available
shortly after launch.
2. Describe the equipment required to use the technology.
Cefiderocol is provided as a 1g powder for concentrate for solution for infusion. For each
complete infusion, 2 vials are needed. It needs to be stored in a refrigerator (2 to 8°C) and
should be stored in the original carton in order to protect it from light (see SmPC). Each vial is
for single use only.
The use of cefiderocol is not expected to require any other specialized equipment, or to
demand additional resources beyond those already required to administer an intra-venous
antibacterial to hospitalised patients and to determine pathogen susceptibility.
3. Describe the supplies required to use the technology.
The powder should be reconstituted with 10 mL of either sodium chloride 9 mg/ml (0.9%)
solution for injection or 5% dextrose injection taken from the 100 mL bags that will be used to
prepare the final infusion solution. Standard infusion equipment and training is required.
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5 Clinical effectiveness and safety
Summary of the effectiveness (combined evaluation of in vitro, PK/PD, and clinical
data)
The anti-microbial efficacy of cefiderocol has been investigated in several major in vitro
susceptibility studies (SIDERO-WT/Proteeae 2014/2015/2016 surveillance studies),
including both European and US clinical isolates. In addition multiple smaller, country
specific replicate studies were also conducted with similar results. These studies support
the use of cefiderocol in both target populations: suspected and confirmed infections in
several infection sites with MDR/CR/difficult-to-treat pathogens.
o Patients with infection caused by suspected MDR pathogen: The SIDERO-
WT-2014-2016 study (which tested the in vitro antibacterial activity of
cefiderocol against Gram-negative bacteria in 30,459 isolates across the world
that included MDR and difficult-to-treat strains), cefiderocol demonstrated
potent inhibition activity against 99.5% of Gram-negative isolates at a MIC of 4
mg/L (as defined by CLSI) including European clinical isolates, of K.
pneumoniae, P. aeruginosa, A. baumannii, S. maltophilia and B. cepacia
complex. Isolates were less susceptible to the comparators including
ceftazidime-avibactam (90.2%) and ceftolozane-tazobactam (84.28%).
o Patients with infection caused by a confirmed CR pathogen: The SIDERO-
CR-2014-2016 study (which tested the in vitro antibacterial activity of
cefiderocol against CRE and MDR non-fermenters), cefiderocol demonstrated
potent in vitro activity at a MIC of 4 mg/L (as defined by CSLI) against 96.2%
of isolates of carbapenem non-susceptible pathogens including all of the WHO
priority pathogens and Stenotrophomonas maltophilia. Cefiderocol was found
to have a wider Gram-negative coverage, and more potent in vitro activity than
comparators (cefepime, ceftazidime/avibactam, ceftolozane/tazobactam,
ciprofloxacin, colistin, and meropenem) against a range of CR-GN isolates,
including those non-susceptible to colistin.
The antimicrobial efficacy results from the in vitro studies are further supported by
in-vivo studies in animal models showing that cefiderocol penetrates into the target
tissues at therapeutic doses.
The clinical efficacy and safety of cefiderocol was demonstrated in two randomised
double-blinded clinical trials and one open label, randomised descriptive study.
The two randomised double-blinded clinical trials (APEKS NP and APEKS cUTI)
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provide confirmatory clinical evidence of cefiderocol’s efficacy and safety in
patients with suspected MDR/difficult-to-treat infections at risk of carbapenem
resistance. Reports of compassionate use cases also contribute to the overall
efficacy characterization of cefiderocol.
o APEKS-NP trial, compared treatment with cefiderocol against the high-dose,
prolonged infusion (HD) meropenem in patients with nosocomial pneumonia
caused by MDR Gram-negative pathogens. Cefiderocol met the primary
endpoint of non-inferiority in ACM at day 14 versus HD meropenem (12.4% for
cefiderocol and 11.6% for meropenem; (95 % CI: -6.6, 8.2)) and similar results
were obtained between arms for ACM at Day 28 and EOS. Rates of clinical
cure and microbiological eradication at TOC and other time points were also
similar between the treatment groups.
o APEKS-cUTI, cefiderocol demonstrated an adjusted treatment difference vs
imipenem/cilastatin of 18.6% (95 % CI: 8.2, 28.9), which proven superiority in
a post-hoc analysis, in cUTI caused by Gram-negative MDR pathogens in
hospitalized adults, in the primary composite endpoint (microbiological
eradication and clinical cure).
A Network Meta-Analysis (NMA) was feasible for cUTI, given the similarity of
patients and pathogens included across trials. All results showed no statistically
significant difference compared with ceftazidime/avibactam and
ceftolozane/tazobactam in a similar patient population with similar pathogen
distribution.
Furthermore, in an effectiveness model that incorporated European pathogen
epidemiology and susceptibility rates (based on EUCAST breakpoints), and
clinical trials data, cefiderocol provides the best predicted susceptibility rates and
estimated clinical and microbiological success rates, in the absence of an
antibiogram for the critically ill patients with infections caused by suspected MDR
pathogen infection requiring immediate treatment.
The third, small, descriptive, exploratory, open-label study in patients with
confirmed carbapenem-resistant pathogen infections, supports cefiderocol’s use
in the confirmed-resistant population alongside with the compassionate use cases:
o CREDIBLE CR study was a small, exploratory, randomised, open label,
descriptive study, conducted to evaluate efficacy in patients with confirmed CR
infections for cefiderocol and BAT, but not designed or powered for statistical
comparison between arms. The study included 150 severely ill patients,
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consistent with compassionate use cases (many patients had end stage
comorbidities and had failed multiple lines of therapy), with a range of infection
sites including nosocomial pneumonia, cUTI, BSI/sepsis. Clinical and
microbiological outcomes were similar between the 2 arms, but there were
marked clinical differences in some baseline characteristics and pathogen
distribution of the cefiderocol and BAT arms.
Summary of safety
Overall, cefiderocol was generally well tolerated, and the safety profile of
cefiderocol was found to be consistent with that of other cephalosporin
antibacterials. The clinical safety for cefiderocol as observed in the three
randomised clinical trials, including 549 treated patients.
o Pooled adverse event analyses there overall less treatment emergent
adverse events with cefiderocol (344/549 [67.1%]) vs comparators
(252/347 [72.6%]). The most common adverse reactions for cefiderocol
were diarrhoea (8.2%), constipation (4.6%), pyrexia (4.0%) and UTI
(4.7%).
o In the total sample, 56/549 (10.2%) patients treated with cefiderocol
experienced treatment related AEs and 45/347 (13.0%) patients treated
with comparators.
The clinical safety for cefiderocol has been investigated in three randomised
clinical trials, two specific to different infection sites and one specific to
carbapenem-resistant pathogens.
o HAP/VAP/ HCAP study (APEKS-NP): Overall, TEAEs and treatment-
related TEAEs were balanced between treatment arms. Serious adverse
events occurred in 36% of patients treated with cefiderocol and 30% of
patients treated with meropenem. The most frequently observed AE was
urinary tract infection (15.5% in cefiderocol group and 10.7% in
meropenem group), hypokalaemia (10.8% in cefiderocol group and 15.3%
in meropenem group) and anaemia (8.1% in cefiderocol group and 8% in
meropenem group).
o cUTI study (APEKS-cUTI): The proportion of patients who experienced at
least one adverse event (AE) was lower in the cefiderocol group than in
the IPM/CS group (41 % vs 51%). Gastrointestinal disorders, such as
diarrhoea and constipation, were the most common adverse events and
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there was an increased incidence of C. difficile colitis in the
imipenem/cilastatin arm compared with cefiderocol. Serious adverse
events (SAE) occurred in a numerically lower proportion of cefiderocol-
treated patients than of IPM/CS-treated patients (5% vs 8%). The most
frequently observed AEs were gastrointestinal, such as diarrhoea
[experienced by 4.3% (13/300) and 6.1% (9/148) of cefiderocol- and
IPM/CS-treated subjects, respectively.
o CR study (CREDIBLE-CR): The cefiderocol group had lower incidence of
AEs and treatment-related AEs, but higher incidence of death, SAEs and
discontinuation due to AEs, compared with BAT. The incidence of
treatment-related AEs leading to discontinuation was similar between
treatment groups. An imbalance in mortality was observed in the
cefiderocol arm compared to BAT (18/49 vs 5/25). No deaths were found
to be causally associated with cefiderocol through assessment by the
investigator and two independent committees. Furthermore, whereas the
mortality rate in the cefiderocol group was consistent with previous studies
in similar populations the evidence suggests that the mortality rate in the
BAT group was unexpectedly low for the population randomised. No single
factor that would explain the imbalance was identified. Small patient
numbers and multiple confounders preclude definitive conclusions.
Like in any other beta-lactam antibacterial, patients who have a history of
hypersensitivity to carbapenems, penicillins or other beta-lactam antibacterial
medicinal products may also be hypersensitive to cefiderocol. Before initiating
therapy with cefiderocol, careful inquiry should be made concerning previous
hypersensitivity reactions to beta-lactam antibacterials.
5.1 Identification and selection of relevant studies
The research question for this assessment is: “Do patients with aerobic Gram-negative
infections and limited treatment option benefit from cefiderocol as an additional treatment
option?”
Cefiderocol is expected to be approved for adult patients with aerobic, Gram-negative
infections with limited treatment options. This indication comprises:
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critically ill patients with suspected infection by a carbapenem-resistant Gram-
negative pathogen or other Gram-negative pathogen difficult to treat with limited
treatment options
and
patients with confirmed infection by a carbapenem-resistant Gram-negative
pathogen or other Gram-negative pathogen difficult to treat with limited treatment
options.
As outlined in chapter 2.4, clinical trials can only provide limited evidence regarding the
efficacy of new antibacterials because trials must focus on pathogens for which the tested
agents and comparators are effective. Comparison of efficacy against all relevant comparators
in the antibacterial setting can only be obtained from in vitro surveillance studies. Unlike in
other therapeutic areas, the evaluation of the effectiveness of an antibacterial relies on the
combined consideration of in vitro, PK/PD and clinical data.
To identify all relevant studies for cefiderocol and comparators for the two patient populations
a comprehensive systematic literature review was conducted comprising in vitro and in-vivo
studies, as well as any comparative or non-comparative studies and RCTs (including cross-
over RCTs).
The search strategy was broad to ensure that all relevant studies were captured. The only
restriction was that cefiderocol or any of its synonyms had to be an intervention in the study.
The search strategy is shown below in Figure 20.
Figure 20 - Search strategy for OVD MEDLINE ALL
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Through this methodology, all studies of cefiderocol in various populations were captured and
a complete study pool defined as the primary evidence base:
Surveillance studies provide evidence for the expected efficacy of cefiderocol
compared to other treatment options for patients with suspected MDR/CR
infection.
o Site-specific clinical studies in patients with suspected MDR/CR infections
amend the evidence pool.
o In addition, to amend the evidence for cefiderocol versus comparators for the
population with suspected infection, a systematic literature review was
conducted, to retrieve data for a potential network meta-analyses of cefiderocol
versus approved comparators in the indication cUTI and nosocomial
pneumonia. Details and results are described in chapter 5.4.3.
Surveillance studies from confirmed infections provide evidence for expected
efficacy of cefiderocol versus comparators in patients with suspected MDR/CR
infection.
o The evidence is amended by subpopulations from RCTs, descriptive clinical
study and by compassionate use cases.
The combined evidence is appropriate for the assessment of cefiderocol considering the
scope outlined in EUnetHTA project plan.
In addition, a systematic literature was conducted to evaluate the feasibility of conducting 2
NMAs: 1 in cUTI and another in nosocomial pneumonia, identifying all relevant comparators
and their clinical data for each NMA. All information on this SLR is available in the appendix
[227].
1. State the databases and trial registries searched and, when relevant, the platforms
used to do this.
A literature search in the following databases and information resources (Table 14) identified
a total of 428 records.
Table 14: Databases and information sources searched
Database / information source Interface / URL Coverage
MEDLINE ALL Ovid SP Biomedical journal literature
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Database / information source Interface / URL Coverage
PubMed https://www.ncbi.nlm.nih.gov/p
ubmed/ Biomedical journal literature
Embase OvidSP Biomedical journal literature
Cochrane Central Register of
Controlled Trials (CENTRAL) Wiley Cochrane Library
Randomized and quasi-
randomized controlled trials
Cochrane Database of
Systematic Reviews Wiley Cochrane Library Systematic reviews
Database of Abstracts of Reviews
of Effects (DARE) CRD website Systematic reviews
Health Technology Assessment
(HTA) CRD website Health technology assessment
Web of Science http://apps.webofknowledge.co
m/
Science, social science, arts,
humanities
BIOSIS Citation Index http://apps.webofknowledge.co
m/
Life sciences and biomedical
research
ClinicalTrials.gov https://www.clinicaltrials.gov/ct Records for registered clinical
studies
WHO International Clinical Trials
Registry Platform (WHO ICTRP) http://www.who.int/ictrp/en/ Trial registration data sets
The PubMed search was restricted to records not yet fully indexed for MEDLINE. The trials
register sources listed above (ClinicalTrials.gov and ICTRP) were searched to identify
information on studies in progress.
Recent research published as conference abstracts were identified by searching Embase
(which indexes a significant number of conference publications). In addition, where the
following conferences (identified as highly relevant by the research team) were not indexed in
Embase from 2016 to 2019, we conducted hand-searches for abstracts via conference
webpages:
European Congress of Clinical Microbiology & Infectious Diseases (ECCMID)
IDWeek
European Respiratory Society (ERS) International Congress.
Reference lists of any relevant reviews or systematic reviews for eligible records were also
checked.
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2. State the date the searches were done and any limits (for example date, language)
placed on the searches.
The searches were conducted between 7th October 2019 and 11th October 2019. A
supplementary set of abstracts relevant to cefiderocol from the IDWeek 2019
conference (October 2-9, Washington DC, USA) was obtained in a grey literature
search on December 19, 2019.
3. Include as an appendix the search terms and strategies used to interrogate each
database or registry.
The report “Systematic Searches and Study Selection to Identify Clinical and Non-
Clinical Evidence Available for Cefiderocol” contains the full strategies (including
search dates) for all sources searched [233].
4. In Table 15, state the inclusion and exclusion criteria used to select studies and justify
these.
Table 15: Inclusion and exclusion criteria
Criterion Inclusion criteria Exclusion criteria
Population
Cell based (bacteria, human or animal)
Animal (healthy and infected)
Human (healthy and infected)
NA
Intervention Cefiderocol Any other
intervention
Comparators Any intervention, placebo or best standard of care
Studies with no comparator NA
Outcomes
Clinical cure
Microbiological eradication
All-cause mortality
Adverse events
Microbiology
Pharmacodynamic
Pharmacokinetic
Toxicology
NA
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Criterion Inclusion criteria Exclusion criteria
Study designs
RCTs of any duration
Cross-over RCTs if data are presented at time of
cross-over
Any comparative or non-comparative studies both
prospective and retrospective
In vitro studies
In vivo studies
Systematic
reviews, reviews,
opinion pieces (for
listing in the final
report only)
Limits No date or language limits
Note that the search strategy shown above included all cefiderocol references,
regardless of the measured outcomes. A second screening step then assigned the
identified publications to different topics of interest (see below).
5. Provide a flow chart showing the number of studies identified and excluded. The
PRISMA statement can be used; the PRISMA flow chart is included below, as an
example.
Figure 21 shows the PRISMA flow diagram of the numbers of records included and excluded
at each stage of the selection process.
Following deduplication, 254 records remained for assessment. Twelve records were
excluded after an assessment of the information in the title and abstract. 242 full text
documents were assessed and 129 records were included.
Additional eligible records identified through reference checking of reviews or systematic
reviews which had not been identified through the database searches or hand searched
conferences, have been included in the PRISMA flow diagram as identified from other
sources.
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5.1.1 PRISMA Chart
Figure 21 - PRISMA flow diagram of record selection process
5.1.2 Study categorisation
Studies were first categorised into the following five primary categories:
In vitro
In vivo
Clinical
Multiple categories
Modelling simulation
Systematic review protocol
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Then, for each study, the type of outcome data was reported:
Efficacy
Frequency of spontaneous resistance
Method reproducibility
Mode of action
Pharmacokinetic/pharmacodynamic
Pharmacokinetic
Pharmacodynamic
Safety
Additionally, based on the identified scope, we screened the identified publications for possible
results regarding hospital utilization and quality of life. No such studies were identified, as
expected in the context of antibiotic treatment trials.
Of the 129 identified records:
39 were conducted in vitro, two of which were letters reporting data on cefiderocol
37 records reported in vitro investigations of specifically identified clinical isolates
16 records reported in vivo investigations
25 records reported details of clinical studies, eight of these records reported
protocol information only
Five records reported details of mixed study investigations e.g. both in vitro and in
vivo
Six records reported details of modelling simulations
One record reported details of a Cochrane systematic review protocol which
cefiderocol is an eligible intervention
The supplementary search of the IDWeek 2019 conference (October 2-6, 2019), the
presentations of which became available after the cut-off date for the SLR (October 7-
11, 2019), yielded 12 additional relevant presentations involving company staff from the
manufacturer of cefiderocol. These presentations were added to the table of identified
studies and screened for relevant content. References were added to Table 16 – List
of all relevant studies - below.
5.2 Relevant studies
1. In Table 16 provide a list of the relevant studies identified.
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Table 16: List of all relevant studies
Study reference/ID Available documentation* Status
(ongoing**/
complete)
In vitro
Surveillance
SIDERO WT Tsuji M, Hackel M, Yamano Y, Echols R, Longshaw C, Manissero D, et al. Cefiderocol in vitro activity against
gram-negative clinical isolates collected in Europe: result from three SIDERO-WT surveillance studies between
2014-2017. In: ECCMID, 2019.
Hackel MA, Tsuji M, Yamano Y, Echols R, Karlowsky JA, Sahm DF. In vitro activity of the siderophore
cephalosporin, cefiderocol, against a recent collection of clinically relevant gram-negative bacilli from North
America and Europe, including carbapenem-nonsusceptible isolates (sidero-wt-2014 study). Antimicrob Agents
Chemother. 2017;61(9):1-9.
Ito A, Kuroiwa M, Rokushima M, Hackel M, Sahm D, Tsuji M, et al. Characterization of isolates showing high
MICs to cefiderocol from global surveillance study SIDERO-WT-2014. In: ASM Microbe 2019, San Francisco;
2019.
Kazmierczak KM, Tsuji M, Wise MG, Hackel M, Yamano Y, Echols R, et al. In vitro activity of cefiderocol, a
siderophore cephalosporin, against a recent collection of clinically relevant carbapenem-non-susceptible Gram-
negative bacilli, including serine carbapenemase- and metallo-β-lactamase-producing isolates (SIDERO-WT-
2014 Study). Int J Antimicrob Agents. 2019;53(2):177-84.
Tsuji M, Hackel M, Yamano Y, Echols R, D S. Surveillance of cefiderocol in vitro activity against gram-negative
clinical isolates collected in Europe: SIDERO-WT-2014. In: ECCMID, 2017.
Continuous
collection of world-
wide isolates
(currently ca. 38k
isolates)
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Tsuji M, Hackel M, Echols R, Yamano Y, D S. Global surveillance of cefiderocol (S-649266) against Gram-
negative clinical strains collected in North America: SIDERO-WT-2014. In: ASM Microbe 2017, New Orleans;
2017.
Tsuji M, Kazmierczak K, Hackel M, Echols R, Yamano Y, D S. Cefiderocol susceptibility against globally isolated
meropenem-non-susceptible gram-negative bacteria containing serine-and metallo-carbapenemase genes:
SIDERO-WT-2014 and -2015. In: ASM Microbe, San Francisco; 2019.
Yamano Y, Tsuji M, Echols R, Hackel M, Sahm D. In vitro activity of cefiderocol against gram-negative clinical
isolates from respiratory specimens: Sidero-WT-2014. Am J Respir Crit Care Med. 2018;197
Tsuji M, Hackel M, Echols R, Yamano Y, D S. In vitro activity of cefiderocol against gram-negative clinical
isolates collected from urinary track source: SIDERO-WT-2014/SIDERO-WT-2015 In: IDWeek, 2017.
Nguyen S, Hackel M, Hayes J, Sahm D, Echols R, Tsuji M, et al. In vitro antibacterial activity of cefiderocol
against an international collection of carbapenem-non-susceptible gram-negative bacteria isolated from
respiratory, blood, skin/soft tissue and urinary sources of infection: SIDERO-WT2014-2016. In: ECCMID, 2019.
Mackenzie T, Nguyen S, Haynes J, Hackel M, Echols R, Sahm D, et al. Cefiderocol activity against North
American clinical isolates SIDERO-WT-2014–2017. In: ASM Microbe 2019, San Francisco; 2019.
Nguyen S, Hackel M, Hayes J, Sahm D, Echols R, Tillotson G, et al. In vitro antibacterial activity of cefiderocol
against carbapenem-non-susceptible gram-negative bacteria from hospitalized patients in the United States:
SIDERO-WT-2014–2017. In: ASM Microbe 2019, San Francisco; 2019.
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Karlowsky JA, Hackel MA, Tsuji M, Yamano Y, Echols R, Sahm DF. In vitro activity of cefiderocol, a siderophore
cephalosporin, against gram-negative bacilli isolated by clinical laboratories in north america and europe in
2015-2016: SIDERO-WT-2015. Int J Antimicrob Agents. 2019;53(4):456-66.
Tsuji M, Hackel M, Echols R, Yamano Y, D S. In vitro antibacterial activity of cefiderocol (S-649266) against
gram-negative clinical strains collected in North America and Europe: SIDERO-WT-2015. In: ASM Microbe
2017, New Orleans; 2017.
Tsuji M, Hackel M, Echols R, Yamano Y, D S. Global surveillance of cefiderocol against gram-negative clinical
strains collected in North America: SIDERO-WT-2015. In: IDWeek, 2018.
Tsuji M, Hackel M, Echols R, Yamano Y, D S. In vitro antibacterial activity of cefiderocol against gram-negative
clinical strains collected in North America and Europe: SIDERO-WT-2016. In: ASM Microbe 2019, San
Francisco; 2019.
SIDERO CR Hackel MA, Tsuji M, Yamano Y, Echols R, Karlowsky JA, Sahm DF. In vitro activity of the siderophore
cephalosporin, cefiderocol, against carbapenem-nonsusceptible and multidrug-resistant isolates of gram-
negative bacilli collected worldwide in 2014 to 2016. Antimicrob Agents Chemother. 2018;62(2):1-13.
Tsuji M, Kazmierczak K, Hackel M, Wise M, Echols R, Sahm D, et al. Cefiderocol susceptibility and geographical
analysis against globally isolated meropenem non-susceptible gram-negative bacteria containing serineand
metallo-carbapenemase gene In: ECCMID, 2019.
Ito A, Hackel M, Sahm D, Tsuji M, Y Y. Characterization of isolates showing high MICs to cefiderocol from global
surveillance study SIDERO-CR-2014/2016. In: ECCMID, 2019.
Completed
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Tsuji M, Hackel M, Echols R, Yamano Y, D S. In vitro activity of cefiderocol against globally collected
carbapenem-resistant gramnegative bacteria isolated from urinary track source: SIDERO-CR-2014/2016. In:
IDWeek, San Diego; 2017. 1199
Tsuji M, Hackel M, Yamano Y, Echols R, Longshaw C, Manissero D, et al. Cefiderocol in vitro activity against
Gram-negative clinical isolates collected in Europe: result from SIDERO-CR-2014/2016. In: ECCMID, 2019.
Yamano Y, Tsuji M, Hackel M, Echols R, Sahm D. In vitro activity of cefiderocol against gram-negative clinical
isolates collected from Asia and South Pacific in 2014-2016 (SIDERO-CR Study). Int J Antimicrob Agents.
2017;50(Supplement 2):S48.
Yamano Y, Tsuji M, Hackel M, Echols R, D S. In vitro activity of cefiderocole against globally collected
carbapenem-resistant Gramnegative bacteria including isolates resistant to ceftazidime/avibactam,
ceftolozane/tazobactam and colistin: SIDERO-CR-2014/2016 study. In: ECCMID, 2017.
Independent
Studies
Kresken M, Berwian E, Wernicke S, Frank A, G A. In vitro activity of cefiderocol against gram-negative
pathogens circulating in Germany. In: ECCMID, 2019.
Falagas ME, Skalidis T, Vardakas KZ, Legakis NJ, Hellenic Cefiderocol Study G. Activity of cefiderocol (S-
649266) against carbapenem-resistant gram-negative bacteria collected from inpatients in Greek hospitals. J
Antimicrob Chemother. 2017;72(6):1704-08.
Falagas ME, Skalidis T, Vardakas K, N L. Activity of cefiderocol (S-649266) against carbapenem-resistant gram-
negative bacteria collected from inpatients in Greek hospitals. In: ECCMID, 2017.
Completed
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Tsuji M, Yamaguchi T, Nakamura R, Kanazawa S, Ito-Horiyama T, Sato T, et al. S-649266, a novel siderophore
cephalosporin: in vitro activity against gram-negative bacteria isolated in Japan including carbapenem resistant
strains. In: IDWeek, San Diego; 2015.
Hackel M, Tsuji M, Echols R, D S. In vitro antibacterial activity of s-649266 against gram-negative clinical strains
collected in North America and Europe. In: IDWeek, 2016.
Hsueh SC, Huang YT, Liao CH, Lee YJ, Hsueh PR. In vitro activities of cefiderocol (S-649266),
ceftazidimeavibactam, ceftolozane-tazobactam, and other comparative drugs against pseudomonas
aeruginosa, acinetobacter baumannii and stenotrophomonas maltophilia associated with bloodstream
infections. Int J Antimicrob Agents. 2017;50(Supplement 2):S48-S49.
Hsueh S-C, Lee Y-J, Huang Y-T, Liao C-H, Tsuji M, Hsueh P-R. In vitro activities of cefiderocol,
ceftolozane/tazobactam, ceftazidime/avibactam and other comparative drugs against imipenem-resistant
pseudomonas aeruginosa and acinetobacter baumannii, and stenotrophomonas maltophilia, all associated with
bloodstream infections in Taiwan. J Antimicrob Chemother. 2019;74(2):380-86.
Mushtaq S, Sadouki Z, Vickers A, Livermore D, N W. In vitro activity of cefiderocol against extensively drug-
resistant pseudomonas aeruginosa and acinetobacter baumannii from the UK. In: ECCMID, 2019.
Mushtaq S, Vickers A, Hussain A, Livermore D, N W. In vitro activity of cefiderocol (S-649266) against multidrug-
resistant enterobacteriaceae from the UK. In: ECCMID, 2017.
Other
Mode of Action Coppi M, Antonelli A, Baglio G, Giani T, GM R. Activity of cefiderocol on a reference collection of
carbapenemase-,ESBL-, and acquired class C β-lactamases-producing gram-negative pathogens. In: ECCMID,
2019.
Completed
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Dobias J, Denervaud V, Poirel L, P N. Activity of the novel siderophore cephalosporin cefiderocol (S-649266)
against Gramnegative pathogens. In: ECCMID, 2017.
Hackel MA, Tsuji M, Yamano Y, Echols R, Karlowsky JA, Sahm DF. Reproducibility of broth microdilution MICs
for the novel siderophore cephalosporin, cefiderocol, determined using iron-depleted cation-adjusted Mueller-
Hinton broth. Diagn Microbiol Infect Dis. 2019;94(4):321-25.
Huband MD, Ito A, Tsuji M, Sader HS, Fedler KA, Flamm RK. Cefiderocol mic quality control ranges in iron-
depleted cation-adjusted mueller-hinton broth using a clsi m23-a4 multi-laboratory study design. Diagn Microbiol
Infect Dis. 2017;88(2):198-200.
Ito A, Kohira N, Bouchillon SK, West J, Rittenhouse S, Sader HS, et al. In vitro antimicrobial activity of S-649266,
a catechol-substituted siderophore cephalosporin, when tested against non-fermenting gram-negative bacteria.
J Antimicrob Chemother. 2016;71(3):670-7.
Ito A, Nishikawa T, Matsumoto S, Fukuhara N, Nakamura R, Tsuji M, et al. S-649266, a novel siderophore
cephalosporin: II. Impact of active transport via iron regulated outer membrane proteins on resistance selection.
Abstract F-1563. In: ICAAC, 2014.
Ito A, Nishikawa T, Matsumoto S, Yoshizawa H, Sato T, Nakamura R, et al. Siderophore cephalosporin
cefiderocol utilizes ferric iron transporter systems for antibacterial activity against pseudomonas aeruginosa.
Antimicrob Agents Chemother. 2016;60(12):7396-401.
Ito A, Sato T, Ota M, Takemura M, Nishikawa T, Toba S, et al. In vitro antibacterial properties of cefiderocol, a
novel siderophore cephalosporin, against gram-negative bacteria. Antimicrob Agents Chemother. 2018;62(1):1-
11.
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Ito A, Ishibashi N, Ishii R, Tsuji M, Maki H, Sato T, et al. Changes of responsible iron-transporters for the activity
of cefiderocol against pseudomonas aeruginosa depending on the culture conditions. In: ASM Microbe 2019,
San Francisco; 2019.
Ito A, Nishikawa T, Ishii R, Kuroiwa M, Ishioka Y, Kurihara N, et al. Mechanism of Cefiderocol high MIC mutants
obtained in non-clinical FoR studies In: IDWeek, 2018.
Luscher A, Moynie L, Auguste PS, Bumann D, Mazza L, Pletzer D, et al. TonB-dependent receptor repertoire
of pseudomonas aeruginosa for uptake of siderophore-drug conjugates. Antimicrob Agents Chemother.
2018;62(6):1-11.
Nordmann P, Vazquez-Rojo L, L P. Stability of cefiderocol against clinically-significant broad-spectrum
oxacillinases. In: ECCMID, 2018.
Poirel L, Kieffer N, Nordmann P. Stability of cefiderocol against clinically significant broad-spectrum
oxacillinases. Int J Antimicrob Agents. 2018;52(6):866-67.
Robertson G, Henderson A, Paterson DL, P H. In vitro activity of cefiderocol (S-649266) against clinical isolates
of burkholderia pseudomallei. In: ECCMID, 2019.
Takemura M, Ito A, Nishikawa T, Oota M, Horiyama T, Satou T, et al. Stability and low induction potential of
cefiderocol against chromosomal AmpC β-lactamases of pseudomonas aeruginosa and enterobacter cloacae.
In: ECCMID, 2018.
Tsuji M, Hackel M, Yamano Y, Echols R, D S. Correlations between cefidercol broth microdilution MICs and
disk diffusion inhibitory zone diameters among target gram-negative organisms. In: ECCMID, 2018.
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Tsuji M, Ito A, Toba S, Nishikawa T, Oota M, Kanazawa S, et al. S-649266, a novel siderophore cephalosporin:
binding affinity to PBP and in vitro bactericidal activity. In: ECCMID, Copenhagen; 2015.
Tsuji M, Jakielaszek C, LCL M. S-649266, a novel siderophore cephalosporin: in vitro activity against biothreat
pathogen. In: IDWeek, 2016.
Tsuji M, Nakamura R, Kohira N, Ito A, Sato T, Y Y. S-649266, a novel siderophore cephalosporin: in vitro
combination effect of S-649266 and other antibacterials against gram-negative bacteria. In: ECCMID, 2016.
Rolston KVI, Gerges B, Raad I, Aitken SL, Reitzel R, R P. In vitro activity of cefiderocol and comparator agents
against gramnegative isolates from cancer patients. In: IDWeek, 2018.
Ito A, Ota M, Nakamura R, Tsuji M, Sato T, Y Y. In vitro and in vivo activity of cefiderocol against
stenotrophomonas maltophilia clinical isolates. In: IDWeek, 2018.
Tsuji M, Ito-Horiyama T, Nakamura R, Sato T, Y Y. S-649266, a Novel Siderophore Cephalosporin:
Pharmacodynamic assessment by using MIC in Iron-depleted Cation-adjusted Mueller Hinton Broth (ID-
CAMHB) In: IDWeek, 2016.
Tsuji M, Nakamura R, Sato T, Hackel M, Sahm D, Echols R, et al. Use of iron depleted mueller hinton broth
(IDMHB) for microdilution testing of S649266, a novel siderophore cephalosporin. In: ECCMID, 2016.
Ito A, Miyagawa S, Ishibashi N, Nishikawa T, Kohira N, Sato T, et al. Anti-Acinetobacter activity of cefiderocol
(S-649266), a novel siderophore cephalosporin: bactericidal activity due to penicillin-binding proteins inhibition
and antibacterial activity against globally collected clinical isolates, abstr SATURDAY-115. In: ASM Microbe
2017, New Orleans; 2017.
Resistance Aoki T, Yoshizawa H, Yamawaki K, Yokoo K, Sato J, Hisakawa S, et al. Cefiderocol (S-649266), A new
siderophore cephalosporin exhibiting potent activities against pseudomonas aeruginosa and other gram-
Completed
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negative pathogens including multi-drug resistant bacteria: structure activity relationship. Eur J Med Chem.
2018;155:847-68.
Aoki T, Yoshizawa H, Yamawaki K, Yokoo K, Sato J, Hisakawa S, et al. Cefiderocol (S-649266): A new
siderophore cephalosporin exhibiting potent activities against pseudomonas aeruginosa and other gram
negative-pathogens including multi-drug resistant bacteria: structure activity relationship. Abstr. Pap. Am. Chem.
Soc. 2017;254
Boyd S, Anderson K, Albrecth V, Campbell D, Karlsson MS, JK R. In vitro activity of cefiderocol against multi-
drug resistant carbapenemase-producing gramnegative pathogens. In: IDWeek, 2017.
Delgado-Valverde M, Conejo MC, Serrano-Rocha L, Fernandez-Cuenca F, AP H. Activity of cefiderocol (S-
649266), a new siderophore cephalosporin, against multidrug-resistant Enterobacteriaceae, Acinetobacter
baumannii, Pseudomonas aeruginosa and Stenotrophomonas maltophilia. In: ECCMID, 2019.
Dobias J, Denervaud-Tendon V, Poirel L, Nordmann P. Activity of the novel siderophore cephalosporin
cefiderocol against multidrug-resistant Gram-negative pathogens. Eur J Clin Microbiol Infect Dis.
2017;36(12):2319-27.
Ishii Y, Horiyama T, Nakamura R, Fukuhara N, Tsuji M, Yamano Y, et al. S-649266, a novel siderophore
cephalosporin: III. Stability against clinically relevant β-lactamases. In: ICAAC, 2014. 1557
Ito A, Nishikawa T, Ota M, Ito-Horiyama T, Ishibashi N, Sato T, et al. Stability and low induction propensity of
cefiderocol against chromosomal AmpC β-lactamases of pseudomonas aeruginosa and enterobacter cloacae.
J Antimicrob Chemother. 2018;73(11):3049-52.
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Ito A, Nishikawa T, Ota M, Ito-Horiyama T, Ishibashi N, Sato T, et al. Stability and low induction propensity of
cefiderocol against chromosomal AmpC β-lactamases of pseudomonas aeruginosa and enterobacter cloacae.
J Antimicrob Chemother. 2019;74(2):539.
Ito-Horiyama T, Ishii Y, Ito A, Sato T, Nakamura R, Fukuhara N, et al. Stability of novel siderophore
cephalosporin S-649266 against clinically relevant carbapenemases. Antimicrob Agents Chemother.
2016;60(7):4384-6.
Jacobs M, Bbajaksouzian S, Good C, Hujer K, Hujer A, R B. In vitro activity of cefiderocol (S-649266), a
siderophore cephalosporin, against carbapenem-susceptible and resistant non-fermenting gram-negative
bacteria. In: ECCMID, 2018.
Jacobs MR, Abdelhamed AM, Good CE, Rhoads DD, Hujer KM, Hujer AM, et al. ARGONAUT-I: activity of
cefiderocol (S-649266), a siderophore cephalosporin, against gram-negative bacteria, including carbapenem-
resistant nonfermenters and enterobacteriaceae with defined extended-spectrum β-lactamases and
carbapenemases. Antimicrob Agents Chemother. 2019;63(1):1-9.
Jacobs MR, Abdelhamed AM, Good CE, Rhoads DD, Hujer KM, Hujer AM, et al. In vitro activity of cefiderocol
(S-649266), a siderophore cephalosporin, against enterobacteriaceae with defined extended-spectrum β-
lactamases and carbapenemases. In: IDWeek, 2018.
Kanazawa S, Sato T, Kohira N, Ito-Horiyama T, Tsuji M, Yamano Y. Susceptibility of imipenem-susceptible but
meropenem-resistant blaIMP-6-carrying enterobacteriaceae to various antibacterials, including the siderophore
cephalosporin cefiderocol. Antimicrob Agents Chemother. 2017;61(7):1-3.
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Kohira N, West J, Ito A, Ito-Horiyama T, Nakamura R, Sato T, et al. In vitro antimicrobial activity of a siderophore
cephalosporin, S-649266, against enterobacteriaceae clinical isolates, including carbapenem-resistant strains.
Antimicrob Agents Chemother. 2016 ;60(2) :729-34.
Kohira N, Nakamura R, Ito A, Nishikawa T, Ota M, Sato T, et al. Resistance acquisition studies of cefderocol by
serial passage and in vitro pharmacodynamic model under human simulated exposure. In: ASM Microbe,
Atlanta; 2018.
Kohira N, Oota M, Nishikawa T, Kuroiwa M, Ishioka Y, Naoko K, et al. Frequency of resistance acquisition and
resistance mechanisms to cefiderocol. In: ASM Microbe, Atlanta; 2018.
Tsuji M, Ito A, Nakamura R, Yamano Y, J S. S-649266, a novel siderophore cephalosporin: in vitro activity
against gram-negative bacteria including multidrug-resistant strains. In: IDWeek, 2014. 252
Tsuji M, Kazmierczak K, Hackel M, Echols R, Yamano Y, D S. Cefiderocol (S-649266) susceptibility against
globally isolated meropenem non-susceptible gram-negative bacteria containing serine- and metallo-
carbapenemase genes. In: ASM Microbe, New Orleans; 2017.
Tsuji M, Matsumoto S, Kanazawa S, Nakamura R, Sato T, Y Y. S-649266, a novel siderophore cephalosporin:
in vitro activities against multidrug-resistant and carbapenem resistant gram-negative pathogens in an in vitro
pharmacodynamic model. In: IDWeek, San Diego; 2015. 767
Yamano Y, Tsuji M, Hackel M, Sahm D, R E. Mode of action of cefiderocol, a novel siderophore cephalosporin,
active against highly resistant gram-negative bacteria including carbapenem-resistant strains of
Enterobacteriaceae and non-fermenting bacteria. In: ECCMID, 2017.
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Tsuji M, Hackel M, Echols R, Tillotson G, Fam D, Yamano Y, et al. In vitro and in vivo activity of cefiderocol
against burkholderia cepacia complex clinical isolates. In: ECCMID, 2019.
Tsuji M, Hackel M, Echols R, Yamano Y, D S. The in vitro activity of cefiderocol, a novel siderophore
cephalosporin, against a global collection of stenotrophomonas maltophilia. In: ECCMID, 2017.
Tsuji M, Hackel M, Yamano Y, Echols R, D S. Cefiderocol, a novel siderophore cephalosporin: in vitro activity
against Stenotrophomonos maltophillia isolated globally. In: ECCMID, 2018.
A. Ito, H. Yoshizawa, R. Nakamura, M. Tsuji, Y. Yamano, Shimada J. S-649266, a novel siderophore
cephalosporin: I. In vitro activity against gram-negative bacteria including multidrug-resistant strains. ICAAC
Abstracts. 2014
PK/PD data
Animal models
Thigh Monogue ML, Tsuji M, Yamano Y, Echols R, Nicolau DP. Efficacy of humanized exposures of cefiderocol (S-
649266) against a diverse population of gram-negative bacteria in a murine thigh infection model. Antimicrob
Agents Chemother. 2017;61(11):1-10.
Nakamura R, Toba S, Ito A, Tsuji M, Yamano Y, Shimada J. S-649266, a novel siderophore cephalosporin. V.
Pharmacodynamic assessment in murine thigh infection models, abstr F1-1559. In: ICAAC, 2014.
Ghazi IM, Monogue ML, Tsuji M, Nicolau DP. Pharmacodynamics of cefiderocol, a novel siderophore
cephalosporin, in a pseudomonas aeruginosa neutropenic murine thigh model. Int J Antimicrob Agents.
2018;51(2):206-12.
Completed
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Horiyama T, Toba S, Nakamura R, Tsuji M, Yamano Y, Shimada J. S-649266, a novel siderophore
cephalosporin: vii. Magnitude of pk/pd parameter required for efficacy in murine thigh infection model. In: ICAAC,
2014. 1561
Monogue M, Tsuji M, Yamano Y, Echols R, DP N. In vivo efficacy of humanized exposures of cefiderocol
compared with cefepime (FEP) and meropenem (MEM) against Gram-negative bacteria in a murine thigh model.
In: IDWeek, 2017.
Stainton S, Monogue M, Tsuji M, Yamano Y, Echols R, DP N. Efficacy of humanized cefiderocol exposures over
72 hours against a diverse group of gram-negative isolates in the neutropenic murine thigh infection model. In:
IDWeek, 2018.
Stainton SM, Monogue ML, Tsuji M, Yamano Y, Echols R, Nicolau DP. Efficacy of humanized cefiderocol
exposures over 72 hours against a diverse group of gram-negative isolates in the neutropenic murine thigh
infection model. Antimicrob Agents Chemother. 2019;63(2):1-7.
Lung Horiyama T, Singley CM, Nakamura R, Tsuji M, Roger E, Rittenhouse S, et al. S-649266, a novel siderophore
cephalosporin: viii. Efficacy against pseudomonas aeruginosa and acinetobacter baumannii in rat lung infection
model with humanized exposure profile of 2 gram dose with 1 hour and 3 hours infusion. In: ICAAC, 2014. 1556
Matsumoto S, Singley CM, Hoover J, Nakamura R, Echols R, Rittenhouse S, et al. Efficacy of cefiderocol against
carbapenem-resistant gram-negative bacilli in immunocompetent-rat respiratory tract infection models
recreating human plasma pharmacokinetics. Antimicrob Agents Chemother. 2017;61(9):1-8.
Takemura M, Matsumoto S, Miyagawa S, Satou T, Tsuji M, Y Y. Efficacy of humanized cefiderocol exposure
against Stenotrophomonas maltophilia in a rat respiratory tract infection mode. In: ECCMID, 2018.
Completed
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Takemura M, Nakamura R, Satou T, Tsuji M, Y Y. In vivo pharmacokinetic/pharmacodynamic (PK/PD)
assessment of cefiderocol against Stenotrophomonas maltophilia in a neutropenic murine lung infection model.
In: ECCMID, 2018.
Lung & Thigh Horiyama T, Toba S, Nakamura R, Tsuji M, Yamano Y, Shimada J. S-649266, a novel siderophore
cephalosporin: vi. Magnitude of pk/pd parameter required for efficacy in murine lung infection model. In: ICAAC,
2014. 1560
Nakamura R, Ito-Horiyama T, Takemura M, Toba S, Matsumoto S, Ikehara T, et al. In vivo pharmacodynamic
study of cefiderocol, a novel parenteral siderophore cephalosporin, in murine thigh and lung infection models.
Antimicrob Agents Chemother. 2019;63(9)
Tsuji M, Ito-Horiyama T, Nakamura R, Sato T, Y Y. S-649266, a Novel Siderophore Cephalosporin:
Pharmacodynamic assessment by using MIC in Iron-depleted Cation-adjusted Mueller Hinton Broth (ID-
CAMHB) In: IDWeek, 2016.
Tsuji M, Ito-Horiyama T, Nakamura R, Sato T, Y Y. S-649266, a Novel Siderophore Cephalosporin:
Pharmacodynamic assessment by using MIC in Iron-depleted Cation-adjusted Mueller Hinton Broth (ID-
CAMHB) In: IDWeek, 2016.
Yamano Y, Nakamura R, Sato T, Tsuji M, R E. Good correlation of cefiderocol between in vivo efficacy murine
thigh/lung infection models and mic determined in iron-depleted conditions. In: IDWeek, 2017.
Completed
Kidney Matsumoto S, Kanazawa S, Nakamura R, Tsuji M, Sato T, Y Y. In vivo efficacy of cefiderocol against
carbapenem-resistant gram-negative bacilli in murine urinary tract infection models. In: IDWeek, 2017.
Completed
Multiple Nakamura R, Toba S, Tsuji M, Yamano Y, Shimada J. S-649266, a novel siderophore cephalosporin: IV. In vivo
efficacy in various murine infection models. In: ICAAC, 2014. 1558
Completed
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Ito A, Ota M, Nakamura R, Tsuji M, Sato T, Y Y. In vitro and in vivo activity of cefiderocol against
stenotrophomonas maltophilia clinical isolates. In: IDWeek, 2018.
Tsuji M, Hackel M, Echols R, Tillotson G, Fam D, Yamano Y, et al. In vitro and in vivo activity of cefiderocol
against burkholderia cepacia complex clinical isolates. In: ECCMID, 2019.
Human
Thigh Ghazi IM, Monogue ML, Tsuji M, Nicolau DP. Humanized exposures of cefiderocol, a siderophore
cephalosporin, display sustained in vivo activity against siderophore-resistant pseudomonas aeruginosa.
Pharmacology. 2018;101(5-6):278-84.
Completed
Lung Shionogi. Cefiderocol Concentrations in the Lungs of Hospitalized Patients With Bacterial Pneumonia. Identifier:
NCT03862040. In: ClinicalTrials.gov [internet]. Bethesda: US National Library of Medicine: 2019. Available from
https://ClinicalTrials.gov/show/NCT03862040.
Terminated due to
slow enrolment on
November 26,
2019
Kidney Contreras DA, Fitzwater SP, Nanayakkara DD, Schaenman J, Aldrovandi GM, Garner OB, et al. Co-infections
of two strains of NDM-1 and OXA-232 co-producing klebsiella pneumoniae in a kidney transplant patient.
Antimicrob Agents Chemother. 2019;16:1-12.
Echols R, Katsube T, F A, C J, Krenz H. S-649266, a siderophore cephalosporin for Gram-negative bacterial
infection: pharmacokinetics and safety in subjects with renal impairment. In: ESCMID, Denmark; 2015.
Katsube T, Echols R, Arjona Ferreira JC, Krenz HK, Berg JK, Galloway C. Cefiderocol, a siderophore
cephalosporin for gram-negative bacterial infections: pharmacokinetics and safety in subjects with renal
impairment. J Clin Pharmacol. 2017;57(5):584-91.
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Katsube T, Kawaguchi N, Echols R, Wajima T. Population pharmacokinetic and
pharmacokinetic/pharmacodynamic analyses of cefiderocol in subjects without infection and patients with
complicated urinary tract infection and acute uncomplicated pyelonephritis. In: IDWeek, 2017.
Katsube T, Miyazaki S, Narukawa Y, Hernandez-Illas M, Wajima T. Drug-drug interaction of cefiderocol, a
siderophore cephalosporin, via human drug transporters. Eur J Clin Pharmacol. 2018;74(7):931-38.
Clinical Studies
Early Katsube T, Saisho Y, Shimada J, Furuie H. Intrapulmonary pharmacokinetics of cefiderocol, a novel siderophore
cephalosporin, in healthy adult subjects. J Antimicrob Chemother. 2019;74(7):1971-74.
Miyazaki S, Katsube T, Shen H, Tomek C, Narukawa Y. Metabolism, excretion, and pharmacokinetics of [14 C]-
cefiderocol (S-649266), a siderophore cephalosporin, in healthy subjects following intravenous administration.
J Clin Pharmacol. 2019;59(7):958-67.
Saisho Y, Katsube T, White S, Fukase H, Shimada J. Pharmacokinetics, safety, and tolerability of cefiderocol,
a novel siderophore cephalosporin for gram-negative bacteria, in healthy subjects. Antimicrob Agents
Chemother. 2018;62(3):1-12.
Sanabria C, Migoya E, Mason JW, Stanworth SH, Katsube T, Machida M, et al. Effect of cefiderocol, a
siderophore cephalosporin, on QT/QTc interval in healthy adult subjects. Clin Ther. 2019;41(9):1724-36.e4.
Shimada J, Saisho Y, Katsube T, White S, Fukase H. S-649266, a novel cephalosporin for gram negative
bacterial infection: pharmacokinetics (PK), safety and tolerability in healthy subjects. In: ICAAC, 2014 2014. F-
1564
Completed
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Shiro M, Katsube T, Narukawa Y, E M. Metabolism and excretion of [14C]-cefiderocol, a siderophore
cephalosporin, and drug-drug interaction potential via transporters of cefiderocol in healthy subjects. In:
ECCMID, 2018.
Kawaguchi N, Katsube T, Echols R, Wajima T. Population pharmacokinetic analysis of cefiderocol, a parenteral
siderophore cephalosporin, in healthy subjects, subjects with various degrees of renal function, and patients
with complicated urinary tract infection or acute uncomplicated pyelonephritis. Antimicrob Agents Chemother.
2018;62(2):1-11.
RCT
Results
Blind Bass A, Echols R, Portsmouth S, A H. Heterogeneity of recent phase 3 cUTI clinical trials with new antibacterials.
In: IDWeek 2018.
Portsmouth S, van Veenhuyzen D, Echols R, Machida M, Ferreira JCA, Ariyasu M, et al. Cefiderocol versus
imipenem-cilastatin for the treatment of complicated urinary tract infections caused by gram-negative
uropathogens: a phase 2, randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2018;18(12):1319-
28.
Portsmouth S, van Veenhuyzen D, Echols R, Mitsuaki M, Camilo Arjona Ferreira J, Ariyasu M, et al. Cefiderocol
compared with imipenem/cirastatin in the treatment of adults with complicated urinary tract infections with or
without pyelonephritis or acute uncomplicated pyelonephritis: results from a multicenter, double-blind,
randomized study. In: ECCMID, 2017.
Portsmouth S, Van Veenhuyzen V, Echols R, Machida M, Arjona Ferreira JC, Ariyasu M, et al. Clinical response
of cefiderocol compared with imipenem/cilastatin in the treatment of adults with complicated urinary tract
Completed
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infections with or without pyelonephritis or acute uncomplicated pyelonephritis: results from a multicenter, double
blind, randomized study (APEKS-cUTI). In: IDWeek, 2017.
Shionogi. A randomized study in hospitalised patients with complicated urinary tract infections caused by gram-
negative bacteria to compare the efficacy and safety of S-649266 to imipenem/cilastin, both administered by
intravenous infusion. Identifier: EUCTR2014-000914-76-HU. In: London [internet]. European Medicines
Agency: 2014. Available from http://www.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2014-000914-76-HU.
Shionogi. A Study of Efficacy/Safety of Intravenous S-649266 Versus Imipenem/Cilastatin in Complicated
Urinary Tract Infections. Identifier: NCT02321800. In: ClinicalTrials.gov [internet]. Bethesda: US National
Library of Medicine: 2014. Available from https://ClinicalTrials.gov/show/NCT02321800.
Matsunaga Y, Echols R, Katsube T, Yamano Y, Ariyasu M, Nagata T. Cefiderocol (S-649266) for nosocomial
pneumonia caused by gram-negative pathogens: study design of apeks-NP, a phase 3 double-blind parallel-
group randomized clinical trial. Am J Respir Crit Care Med. 2018;197
Shionogi. Clinical Study of S-649266 for the Treatment of Nosocomial Pneumonia Caused by Gram-negative
Pathogens. Identifier: NCT03032380. In: ClinicalTrials.gov [internet]. Bethesda: US National Library of
Medicine: 2017. Available from https://ClinicalTrials.gov/show/NCT03032380.
Open-label Shionogi. Study of S-649266 or Best Available Therapy for the Treatment of Severe Infections Caused by
Carbapenem-resistant Gram-negative Pathogens. Identifier: NCT02714595. In: ClinicalTrials.gov [internet].
Bethesda: US National Library of Medicine: 2016. Available from https://ClinicalTrials.gov/show/NCT02714595.
Shionogi. RCT Cefiderocol vs BAT for Treatment of Gram Negative BSI. Identifier: NCT03869437. In:
ClinicalTrials.gov [internet]. Bethesda: US National Library of Medicine: 2019. Available from
https://ClinicalTrials.gov/show/NCT03869437.
Completed
Recruiting
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Compassionate
Use
Edgeworth JD, Merante D, Patel S, Young C, Jones P, Vithlani S, et al. Compassionate use of cefiderocol as
adjunctive treatment of native aortic valve endocarditis due to extremely drug-resistant pseudomonas
aeruginosa. Clin Infect Dis. 2019;68(11):1932-34.
Stevens RW, Clancy M. Compassionate use of cefiderocol in the treatment of an intraabdominal infection due
to multidrug resistant pseudomonas aeruginosa: a case report. Pharmacotherapy. 2019;24:1-14.
Trecarichi EM, Quirino A, Scaglione V, Longhini F, Garofalo E, Bruni A, et al. Successful treatment with
cefiderocol for compassionate use in a critically ill patient with XDR acinetobacter baumannii and KPC-producing
klebsiella pneumoniae: a case report. J Antimicrob Chemother. 2019;01:3399–401.
Ongoing program.
200 patients
treated to date.
Three case reports
published.
Expanded Access Shionogi. Expanded Access to Cefiderocol for the Intravenous Treatment of Severe Gram Negative Bacterial
Infections. Identifier: NCT03780140. In: ClinicalTrials.gov [internet]. Bethesda: US National Library of Medicine:
2018. Available from https://ClinicalTrials.gov/show/NCT03780140.
Ongoing
Modelling/SLR protocol
Katsube T, Tenero D, Wajima T, T I. S-649266 modeling and simulation for prediction of efficacy and dose
optimization. In: IDWeek, Philadelphia; 2014.
Katsube T, Wajima T, Ishibashi T, Arjona Ferreira JC, Echols R. Pharmacokinetic/pharmacodynamic modeling
and simulation of cefiderocol, a parenteral siderophore cephalosporin, for dose adjustment based on renal
function. Antimicrob Agents Chemother. 2017;61(1):1-12.
Katsube T, Wajima T, Ishibashi T, Arjona Ferreira JC, R E. S-649266 dose adjustment for patients with impaired
renal function. In: ECCMID, 2015.
Completed
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Katsube T, Wajima T, Ishibashi T, Arjona Ferreira JC, R. E. Dose adjustment of S-649266, a siderophore
cephalosporin, for patients requiring haemodialysis. . In: ECCMID, 2016.
McCullough A, Scott AM, Macindoe C, Clark J, Hansen MP, Beller EM, et al. Adverse events in patients taking
cephalosporins versus placebo for any indication. Cochrane Database Syst Rev. 2016(11)
IDweek 2019 Jason M. Pogue, Hemanth Kanakamedala, Yun Zhou, Bin Cai. Burden of Illness in Carbapenem-resistant
Acinetobacter baumannii Infections in US Hospitals (2014 to 2018)
Ryan K. Shields, Hemanth Kanakamedala, Yun Zhou, Bin Cai. Burden of Illness in Patients with Urinary Tract
Infections with or without Bacteremia Caused by Carbapenem-resistant Gram-negative Pathogens in US
Hospitals (2014 to 2018)
Thomas Lodise, Hemanth Kanakamedala, Wen-Chun Hsu, Bin Cai. Association between Days to Initiate
Appropriate Therapy and Hospital Length of Stay among Adult Hospitalized Patients with Gram-negative
Bloodstream Infections (GN-BSI)
Thomas Lodise, Hemanth Kanakamedala, Wei-Chun Hsu, Bin Cai. Analysis of Adult, Hospitalized Patients with
Carbapenem-resistant (CR) Gram-negative Bloodstream Infections (GN-BSIs) due to Lactose Fermenters (LFs)
and Non-Lactose Fermenters (NLFs): Is there a Difference in Outcomes?
Simon Portsmouth, Roger Echols, Mitsuaki Machida, Juan Camilo Arjona Ferreira, Mari Ariyasu, Tsutae Den
Nagata. Efficacy and Safety of Cefiderocol According to Renal Impairment in Patients with Complicated Urinary
Tract Infection (cUTI) in a Phase 2 Study
Simon Portsmouth, Kiichiro Toyoizumi, Tsutae Den Nagata, Glenn S. Tillotson, Roger Echols. Structured Patient
Interview in Complicated Urinary Tract Infections to Assess Clinical Outcomes versus Investigator’s Evaluation
in the APEKS-cUTI Study.
All rights reserved 133
Takafumi Sato, Masakatsu Tsuji, Krystyna M. Kazmierczak, Meredith Hackel, Roger Echols, Yoshinori Yamano,
Daniel F Sahm. Cefiderocol Susceptibility Against Molecularly Characterized Carbapenemase-Producing Gram-
negative Bacteria in North America and Europe between 2014 and 2017: SIDERO-WT-2014 to -2016 Studies.
Sonia Rao, Sean Nguyen, Melinda Soriano, Jennifer Hayes, Meredith Hackel, Daniel Sahm, Glenn Tillotson,
Roger Echols, Masakatsu Tsuji, Yoshinori Yamano. In Vitro Antibacterial Activity of Cefiderocol against a Multi-
national Collection of Carbapenem-non-susceptible Gram-negative Bacteria from Respiratory Infections:
SIDERO-WT-2014–2017.
Chris Longshaw, Masakatsu Tsuji, Meredith Hackel, Daniel F. Sahm, Yoshinori Yamano. In Vitro Activity of
Cefiderocol (CFDC), a Novel Siderophore Cephalosporin, Against Difficult-to-Treat Resistant (DTR) Gram-
negative Bacterial Pathogens from the Multi-national Sentinel Surveillance Study, SIDERO-WT (2014–2017).
Yoshinori Yamano, Masakatsu Tsuji, Roger Echols. Synergistic Effect of Cefiderocol Combined with Other
Antibiotics Against Cefiderocol High MIC Isolates from the Multi-national SIDERO-WT Studies.
Takayuki Katsube, Roger Echols, Toshihiro Wajima. Prediction of Cefiderocol Pharmacokinetics and Probability
of Target Attainment in Pediatric Subjects for Proposing Dose Regimens.
Richard G. Wunderink (Presenting Author), Yuko Matsunaga, Mari Ariyasu, Roger Echols, Anju Menon, Tsutae
Den Nagata. Efficacy and Safety of Cefiderocol versus High-Dose Meropenem in Patients with Nosocomial
Pneumonia – Results of a Phase 3 Randomized, Multicenter, Double-Blind, Non-Inferiority Study. (Late-
breaking abstract).
*Include references to all linked documents and indicate the expected date of publication for any unpublished clinical studies
**Include expected date of completion
All rights reserved 134
5.3 Main characteristics of studies
For a rigorous comprehension of the evidence package, it is fundamental to understand the
challenges associated to the design of clinical trials to assess the efficacy of antibacterials.
The development of clinical trials can be challenging for a number of reasons [234, 235]:
Clinical trials for antimicrobials must be designed as non-inferior studies. The clinical
studies must focus on specific pathogens for which the tested agents and comparators are
effective; otherwise, they would be un-ethical.
For serious bacterial diseases, there is a need to urgently initiate early targeted antibacterial
drug therapy, which may obscure the effect of the antibacterial drug under study because
patients receive effective antibacterial therapy before enrolling in the trial.
Patients with serious acute bacterial diseases can be acutely ill (e.g., delirium in the setting
of acute infection) and obtaining informed consent and performing other trial enrolment
procedures in a timely fashion may be difficult.
There may be diagnostic uncertainty with respect to the aetiology of the patients’ underlying
disease, including identifying a bacterial aetiology.
There may be a need for concomitant antibacterial drug therapy with a spectrum of activity
that may overlap with the antibacterial drug being studied.
The recruitment of patients with infections due to specific pathogens and with limited
treatment options that would be required for inferential testing is challenging. MDR/CR
pathogens are still rare, and this rigorous selection strategy must be applied to include
patients with resistant pathogens. Otherwise large patient numbers and subgroup analyses
are required.
A comparison of efficacy against all relevant comparators can only be obtained from in vitro
surveillance studies. The evaluation of the effectiveness of an antibacterial is derived from
the combined consideration of in vitro, PK/PD and clinical data.
1. In Table 17, describe the main characteristics of the studies.
2. For each study provide a flow diagram of the numbers of patients moving through the
trial.
3. For each study provide a comparison of patients (including demographic, clinical and
social information [if applicable]) in treatment arms at baseline.
Cefiderocol studies are summarized with patient flow diagram and comparison of patients
after Table 17.
All rights reserved 135
Table 17: Study characteristics
Study
reference/ID
Objective Study design Eligibility criteria Intervention and
Comparator
(N enrolled)
Primary outcome
measure and
follow-up time
point
Secondary
outcome
measures and
follow-up time
points
SIDERO-WT
analysis*
To calculate the
indices related to
the antibacterial
activity of
cefiderocol and the
ratio of susceptible
strains of
cefiderocol and
other reference
compounds based
on the breakpoint
criteria of Clinical
and Laboratory
Standards Institute
(CLSI) standards.
In vitro surveillance Study tested the in
vitro antibacterial
activity of cefiderocol
against Gram-negative
bacteria clinically
isolated from medical
institutions in the EU
and USA
Cefiderocol,
ceftazidime-
avibactam (CZA),
ceftolozane-
tazobactam (C/T),
colistin (CST),
cefepime (FEP),
meropenem
(MEM), and
ciprofloxacin (CIP)
(30,459 Gram-
negative isolates) +
To determine the
minimum inhibitory
concentration
(MIC) of
cefiderocol against
Gram-negative
bacteria clinically
isolated from
medical institutions
in the EU and USA
Annual analysis;
Cumulative
recurrent annual
analysis
Analysis in the
difficult to treat
pathogens
Analysis of MDR
3 and MDR 4
pathogens
SIDERO-CR-2014-
2016 study*
To test the in vitro
activity of
cefiderocol and
comparators
In vitro surveillance Study tested the in
vitro antibacterial
activity of cefiderocol
against CRE and MDR
Cefiderocol,
ceftazidime-
avibactam (CZA),
ceftolozane-
To determine the
minimum inhibitory
concentration
(MIC) of
Annual analysis;
Cumulative
recurrent annual
analysis
All rights reserved 136
against a collection
of 1,873 clinical
isolates of Gram-
negative bacilli
provided by a
worldwide network
of laboratories (52
countries) in 2014-
2016, using current
CLSI broth
microdilution
methodology
non-fermenters
(defined as resistant to
carbapenems,
fluoroquinolones, and
aminoglycosides)
collected globally
tazobactam (C/T),
colistin (CST),
cefepime (FEP),
meropenem
(MEM), and
ciprofloxacin (CIP)
(1,873 MDR and
CarbNS isolates
Gram-negative
Bacilli) +
cefiderocol against
CRE and MDR
non-fermenters
(defined as
resistant to
carbapenems,
fluoroquinolones,
and
aminoglycosides)
collected globally
Analysis in the
difficult to treat
pathogens
Several
independent
national validations
studies*
To determine
cefiderocol activity
against difficult-to-
treat CR pathogens
gathered from
various countries
including Germany,
Greece, Italy,
Spain, UK/Ireland,
and the US
In vitro surveillance to investigate the in
vitro antimicrobial
activity of cefiderocol
and that of
commercially available
comparator
antibacterials against
a collection of
contemporary, clinical,
carbapenem-resistant
Gram-negative
bacteria from
Cefiderocol,
ceftazidime-
avibactam (CZA),
ceftolozane-
tazobactam (C/T),
colistin (CST),
cefepime (FEP),
meropenem
(MEM), and
ciprofloxacin (CIP),
tigecycline
To determine
MIC50 and MIC90
of the
antibacterials for
the tested bacterial
isolates and their
respective
resistance
percentages
All rights reserved 137
inpatients from various
hospitals
Independent world-
wide collection*
To determine
cefiderocol activity
against difficult-to-
treat CR pathogens
gathered from a
worldwide
collection
In vitro To evaluate
antimicrobial activity of
cefiderocol and other
Gram-negative
antibiotics (aztreonam,
amikacin, cefepime,
ceftazidime,
ceftazidime–
avibactam,
ceftolozane–
tazobactam,
ciprofloxacin,
meropenem, colistin,
and tigecycline)
against a panel of
multidrug-resistant
bacterial isolates from
human clinical sources
with characterized
antibacterial
resistance
mechanisms.
Cefiderocol,
aztreonam,
amikacin,
cefepime,
ceftazidime,
ceftazidime–
avibactam,
ceftolozane–
tazobactam,
ciprofloxacin,
meropenem,
colistin, and
tigecycline
To determine
MIC50 and MIC90
of the
antibacterials for
the tested bacterial
isolates and their
respective
resistance
percentages
All rights reserved 138
Identify
mechanisms of
resistance studies*
To investigate
features of
cefiderocol, namely
antibacterial
activity against
AmpC
overproducers,
stability against
AmpC b-
lactamases and
propensity for
AmpC induction
using
Pseudomonas
aeruginosa and
Enterobacter
cloacae.
In vitro resistance
and mechanism of
action studies
To reveal cefiderocol
features relating to
antibacterial activity
against AmpC
overproducers,
stability against AmpC
b-lactamases, and
propensity for AmpC
induction for E.
cloacae and P.
aeruginosa.
Cefiderocol,
ceftazidime-
avibactam (CZA),
ceftolozane-
tazobactam (C/T),
colistin (CST),
cefepime (FEP),
meropenem
(MEM), and
ciprofloxacin (CIP),
tigecycline
To determine
MIC50 and MIC90
of the
antibacterials for
the tested bacterial
isolates and their
respective
resistance
percentages
Single ascending
dose
(SAD)/multiple
dose (MAD) study
(1203R2111)
To evaluate the
safety, tolerability
and PK of
cefiderocol in 70
healthy Japanese
and Caucasian
adult subjects
Randomized,
double-blind,
placebo controlled,
ascending single
and multiple dose
study
Healthy adult subjects 70 subjects split
into two study
parts
Evaluate the
safety, tolerability,
and PK
All rights reserved 139
The renal
impairment study
(1222R2113)
Evaluate the
influence of renal
impairment and
hemo-dialysis on
PK
A multi-centre,
open-label, non-
randomized study
Healthy adult
subjects and
subjects with various
degrees of renal
impairment
38 subjects
enrolled in 5
cohorts
Evaluate the
influence of renal
impairment and
hemo-dialysis
onPK
APEKS-cUTI To compare the
composite outcome
efficacy and safety
of cefiderocol with
IPM/CS in a subject
population cUTI by
MDR Gram-
negative
pathogens, with or
without
pyelonephritis or
acute
uncomplicated
pyelonephritis at
the Test of Cure
(TOC, defined as 7
days following the
End of Treatment
(EOT).
International, multi
centre,
randomised,
double-blind,
Phase II, active-
controlled, parallel-
group, non-
inferiority
Adults (≥18 years) who
had a symptomatic
cUTI, defined as a
clinical syndrome
characterized by
pyuria and a
documented or
suspected microbial
pathogen on culture of
urine or blood,
accompanied by local
and systemic signs
and symptoms,
including fever (i.e.,
temperature ≥ 38ºC),
chills, malaise, flank
pain, back pain, and /
or costovertebral angle
pain or tenderness that
(in the case of cUTI
Cefiderocol
compared to
imipenem/cilastatin
(N=452
randomised 2:1 for
cefiderocol)
The primary
efficacy endpoint
was the composite
of clinical response
and
microbiological
response at the
test of cure (TOC)
assessment in
MITT population,
defined as 7 days
(±2 days) after the
end of antibacterial
treatment.
Secondary
endpoints were
safety, clinical and
microbiological
response at early
assessment, end of
treatment, and
follow-up,
microbiological and
clinical response
per-pathogen and
per-patient at early
assessment, end of
treatment, test of
cure, and follow-up.
All rights reserved 140
with or without
pyelonephritis)
occurred in the
presence of a
functional or
anatomical
abnormality of the
urinary tract or in the
presence of
catheterization and
who required
hospitalization for the
IV treatment of cUTIs
were enrolled in the
study.
Number of patients
with acute
uncomplicated
pyelonephritis was
restricted
APEKS-NP To compare all-
cause mortality at
Day 14 of
cefiderocol with
high-dose,
prolonged infusion
Phase 3,
multicentre
(multinational),
double-blind,
parallel-group,
randomized,
Adults (≥18 years) who
have a documented
nosocomial
pneumonia
(HABP/VABP/HCABP)
caused by an aerobic
Cefiderocol plus
linezolid,
compared to high
dose, prolonged
infusion
meropenem (plus
The primary
endpoint was all-
cause mortality at
Day 14
Secondary
endpoints included
safety, clinical and
microbiological
outcomes at the
test of cure (TOC),
All rights reserved 141
meropenem, in
adults with
hospital-acquired
bacterial
pneumonia (HAP),
ventilator-
associated
bacterial
pneumonia (VAP),
or healthcare-
associated
bacterial
pneumonia (HCAP)
caused by Gram-
negative
pathogens
active-controlled
study
Gram-negative
pathogen only, or in
combination with an
aerobic Gram-positive
or anaerobic
pathogen, and who
require hospitalization
for the parenteral
(intravenous)
treatment of the
infection may be
enrolled in the study
linezolid for at least
5 days, and up to
21 days)
(N=300,
randomised 1:1)
clinical and
microbiological
outcomes at early
assessment, end of
treatment, and
follow-up, all-cause
mortality at day 28,
during treatment,
and at follow-up,
and resource
utilization.
CREDIBLE-CR The primary
objective of
CREDIBLE CR
study was to
assess at TOC, the
clinical outcome of
treatment with
cefiderocol and
BAT in adult
Phase 3,
descriptive, multi
centre, open label,
parallel group,
randomized study
Adult patients (≥18
years) with gram-
negative pathogen
infection, with
evidence of
carbapenem
resistance prior to
randomisation
Cefiderocol
compared with
best available
therapy (BAT)
(N=152,
randomised 2:1 to
cefiderocol); BAT
was chosen by the
investigator before
The primary
endpoints were:
Clinical cure per
patient at TOC in
patients with
HAP/VAP/HCAP
or BSI/sepsis
Microbiologic
Secondary
endpoints included:
Clinical outcome
per
patient/pathogen at
EOT, and TOC
(cUTI)Microbiologic
outcome (for Gram-
negative pathogen)
All rights reserved 142
patient’s hospital
acquired
pneumonia
(HAP)/ventilator
associated
pneumonia
(VAP)/healthcare-
associated
pneumonia (HCAP)
or bloodstream
infections/sepsis
(BSI/sepsis)
caused by
carbapenem-
resistant Gram-
negative
pathogens. Only
descriptive
statistics were
performed.
randomization and
could include up to
3 different
medicines;
cefiderocol could
be added 1 other
molecule
eradication per
patient at TOC in
patients with cUTI
per
patient/pathogen at
EOT, TOC, and
FUP (HAP / VAP /
HCAP or
BSI/sepsis)
Safety
Compassionate
use studies
Expanded Access
to Cefiderocol for
the Intravenous
Treatment of
Severe Gram-
Cefiderocol has
been provided
upon request from
attending
physicians to
patients with
The criteria for fulfilling
these requests are
highly restrictive
including that all other
available treatments
must be ruled out
Over 200 patients
have been treated
with cefiderocol
through this
programme
Clinical cure per
patient
All rights reserved 143
negative Bacterial
Infections
serious CR Gram-
negative infections
who have no other
treatment options
through susceptibility
testing and/or
evidence of treatment
failure in efficacy or
safety, and patients
must be unable to
enrol in clinical studies
of cefiderocol
*Detailed comparisons of patients and patient flow diagrams are not available for in vitro studies
+Ongoing studies, to date (January 2020), 38288 samples have been tested in SIDERO-WT program.
All rights reserved 144
5.3.1 APEKS-cUTI STUDY
A Multicenter, Double-blind, Randomized, Clinical Study to Assess the Efficacy and Safety of
Intravenous S-649266 (Cefiderocol) in Complicated Urinary Tract Infections With or Without
Pyelonephritis or Acute Uncomplicated Pyelonephritis Caused by Gram-Negative Pathogens
in Hospitalized Adults in Comparison With Intravenous Imipenem/Cilastatin.
APEKS-cUTI was an international, multicenter, randomised, double-blind, Phase II, active-
controlled, parallel-group, non-inferiority study to investigate the efficacy and safety of
intravenous cefiderocol vs imipenem/cilastatin (IPM/CS) in cUTI with or without pyelonephritis
or acute uncomplicated pyelonephritis (restricted to ≤ 30%) caused by Gram-negative
pathogens in hospitalized adults with MDR infections (Figure 22). 448 patients were
randomized, of whom 300 received cefiderocol and 148 received IPM/CS (Figure 23). The
primary efficacy endpoint was the composite of clinical response and microbiological response
at TOC assessment in MITT population according to FDA guidance document. Secondary
endpoints were safety, clinical and microbiological response at EA, EOT and FU,
microbiological and clinical response per-pathogen and per-patient at EA, EOT, TOC and FU.
Safety was assessed daily while the subject was hospitalized and specifically at EOT, TOC,
and FU.
Figure 22: APEKS-cUTI study design
All rights reserved 145
Figure 23: Subject disposition (all randomized subjects)
Overall, 495 patients were screened for inclusion. One subject withdrew during screening and
8.5% (42/495) of subjects were screen failures (mostly for lack of symptoms and signs
confirming eligibility). The flow diagram of the numbers of patients moving through the trial is
provided in Figure 23.
Of the 452 subjects randomized, 448 subjects were treated and 421 subjects completed the
study: 93.4% (283/303) of subjects in the cefiderocol group and 92.6% (138/149) of subjects
in the IPM/CS group. The most frequent reasons in the total population for discontinuing from
the study were “lost to follow up” (3.1% [14/452]) and “withdrawal by subject” (1.3% [6/452]).
By treatment group, 3.3% (10/303) of subjects in the cefiderocol group and 2.7% (4/149) of
subjects in the IPM/CS group were “lost to follow up,” and 1.0% (3/303) of subjects in the
All rights reserved 146
cefiderocol group and 2.0% (3/149) of subjects in the IPM/CS group did not complete the study
due to “withdrawal by subject.”
Completion of treatment was defined as achieving 5 or more days of study treatment. The
most frequent reasons for subjects not completing treatment (2.4% [11/452] in the total
population) were withdrawal by subject (0.7% [2/303] of subjects in the cefiderocol group and
1.3% [2/149] of subjects in the IPM/CS group) and “other” (1.0% [3/303] of subjects in the
cefiderocol group and 0.7% [1/149] of subjects in the IPM/CS group).
5.3.1.1 Demographics and baseline characteristics
The demographics and baseline characteristics are provided in the overview Table 18 below.
The mean age of the Micro-ITT Population was 62.0 years (range 18 to 93 years), and 55.0%
(204/371) of subjects were ≥ 65 years. For clinical diagnosis at baseline, 25.3% (94/371) of
subjects had cUTI with pyelonephritis, 47.7% (177/371) of subjects had cUTI without
pyelonephritis, and 27.0% (100/371) of subjects had acute uncomplicated pyelonephritis.
Complicated urinary tract infection was complicated most commonly by obstructive uropathy
(33.2% [123/371] of subjects). For the severity of disease, 18.9% (70/371) of subjects had
severe disease as judged by the investigator, and 71.2% (264/371) of subjects had moderate
disease. The remaining subjects had mild disease. A greater proportion of subjects in the
cefiderocol group (19.8% [50/252]) had severe disease compared with subjects in the IPM/CS
group (16.8% [20/119]). This may be due to a greater proportion of subjects in the cefiderocol
group with a diagnosis of cUTI compared with the IPM/CS group that had more acute
uncomplicated pyelonephritis.
Prior infection history was reported for 40.4% (150/371) of subjects, and the most frequently
reported prior infection was cUTI (29.9% [111/371] of subjects). Prior antimicrobial medication
treatments were reported for 9.4% (35/371) of subjects, and most received treatment for UTI
(7.5% [28/371] of subjects).
Baseline subject characteristics for the Micro-ITT Population were broadly similar to the ME
Population, ITT Population, and Safety Population.
All rights reserved 147
Table 18: Patient demographics and baseline characteristics (mITT population)
All rights reserved 148
All rights reserved 149
Patient baseline characteristics were generally well balanced between the 2 treatment arms
(Table 18) and were consistent with more complicated infections whereby 7% of patients had
BSI [51, 236]. The main pathogen reported at the baseline in the microbiologically evaluable
population was E. coli (Figure 24) [51, 236]. The cefiderocol-treated group had 53% cefepime-
and levofloxacin-resistant K. pneumoniae strains and 17% cefepime-resistant and 38%
levofloxacin-resistant E. coli strains; which were similar in the IPM/CS group [51, 236].
All rights reserved 150
Figure 24: Distribution of uropathogens (mITT population)
MITT, modified intent-to-treat. Source: Portsmouth, 2018 [51]; Data on file [236]
The most frequently reported Gram-negative uropathogens isolated at baseline for both cUTI
with or without pyelonephritis or acute uncomplicated pyelonephritis in the Micro-ITT
Population were E. coli (60.3% [152/252] of subjects in the cefiderocol group and 66.4%
[79/119] of subjects in the IPM/CS group) and K. pneumoniae (19.0% [48/252] of subjects in
the cefiderocol group and 21.0% [25/119] of subjects in the IPM/CS group) (Figure 24). In
subjects diagnosed with cUTI with or without pyelonephritis, E. coli was isolated in 51.3%
(96/187) of subjects in the cefiderocol group and 60.7% (51/84) of subjects in the IPM/CS
group, and K. pneumoniae was isolated in 22.5% (42/187) of subjects in the cefiderocol group
and 23.8% (20/84) of subjects in the IPM/CS group. In subjects diagnosed with acute
uncomplicated pyelonephritis, E. coli was isolated in 86.2% (56/65) of subjects in the
cefiderocol group and 80.0% (28/35) of subjects in the IPM/CS group, and K. pneumoniae
was isolated in 9.2% (6/65) of subjects in the cefiderocol group and 14.3% (5/35) of subjects
in the IPM/CS group.
Gram-negative uropathogens isolated at baseline for the ME Population were similar to the
Micro-ITT Population in subjects diagnosed with cUTI with or without pyelonephritis or acute
uncomplicated pyelonephritis for both E. coli and K. pneumoniae and in both treatment groups.
A similar distribution was noted in the ME Population. E. coli was the most frequently identified
Gram-negative pathogen isolated from the blood culture for the Micro-ITT Population: 14/252
(5.6%) subjects in the cefiderocol group and 7/119 subjects (5.9%) in the IPM/CS group.
For E. coli, the most frequent uropathogen, MIC distribution for cefiderocol in both treatment
groups was similar and all strains were susceptible to IPM. For K. pneumoniae at baseline, a
lower percentage (86.7% [39/45]) of isolates were susceptible to IPM in the cefiderocol group
All rights reserved 151
compared with the IPM/CS group (95.7% [22/23] of isolates). A greater percentage of K.
pneumoniae isolates were susceptible to cefepime (44.4% [20/45] in the cefiderocol group
compared with 34.8% [8/23] in the IPM/CS group). E. coli and K. pneumoniae rates of
resistance to levofloxacin were similar between treatment groups. For the MIC of other Gram-
negative baseline uropathogens, the numbers of subjects with isolates were too small to make
a meaningful comparison between treatment groups.
The summary of MIC of baseline Gram-negative pathogens isolated from the blood culture
that were the same as the uropathogen at baseline in ME Population is consistent with the
findings in the Micro-ITT Population [237].
5.3.2 APEKS-NP STUDY
A Multicenter, Randomized, Double-blind, Parallel-group, Clinical Study of S-649266
(Cefiderocol) Compared With Meropenem for the Treatment of Hospital-acquired Bacterial
Pneumonia, Ventilator-associated Bacterial Pneumonia, or Healthcare-associated Bacterial
Pneumonia Caused by Gram-negative Pathogens.
The APEKS-NP study was a Phase 3, multicenter, randomized, double-blind, parallel-group,
active-controlled study to assess the efficacy and safety of cefiderocol vs high dose prolonged
infusion (HD) meropenem in subjects with nosocomial pneumonia caused by Gram-negative
bacteria. Subjects meeting eligibility criteria and assessed by the investigator as requiring 7 to
14 days of intravenous (IV) treatment in the hospital were randomized (1:1) to either
cefiderocol, 2 g, administered IV over 3 hours every 8 hours (q8h) or meropenem, 2 g,
administered IV over 3 hours, q8h. The dose of meropenem was increased from the labelled
dose of 1 g to 2 g and extended to a 3-hour infusion to optimize the exposure to meropenem
thereby the antibacterial activity of meropenem in this MDR pathogens, at risk of carbapenem
resistance. Dose adjustment based on renal function was required for cefiderocol and
comparator. Linezolid was administered for at least 5 days to subjects in both arms to provide
coverage for methicillin-resistant Staphylococcus aureus (MRSA), maintain the study blind
and, in the cefiderocol arm, provide coverage for Gram-positive bacteria. The recommended
duration of treatment with IV study drugs was 7 to 14 days in the hospital, but treatment could
have been extended up to 21 days based on the investigator’s clinical assessment of the
subject.
All rights reserved 152
Figure 25: APEKS-NP study design and patient flow
EA, early assessment; EOS, end of study; EOT, end of treatment; PE, Primary Endpoint; FUP, follow up; HD, high dose; Q8h,
every 8 hours; TOC, test of cure
A total of 300 subjects (150 in the cefiderocol group and 150 in the HD meropenem group)
were randomized 1 to 1 to cefiderocol or HD meropenem. All randomized subjects who
received at least 1 dose of study treatment were included in the Intent-to-treat (ITT)/Safety
population (298 subjects: 148 in the cefiderocol group and 150 in the HD meropenem group).
The primary efficacy population was the mITT population (145 in the cefiderocol group and
147 in the HD meropenem group), which included all ITT subjects with evidence of a Gram-
negative infection of the lower respiratory tract and those who had evidence of a lower
respiratory tract infection but whose culture or other diagnostic tests did provide a
microbiological diagnosis; subjects with Gram-positive only infections were excluded. Figure
26 below provides an overview of the patient flow.
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Figure 26: Patient demographics and baseline characteristics
5.3.2.1 DEMOGRAPHICS AND BASELINE CHARACTERISTICS
Demographic characteristics of gender, age, race, and region in the ITT population were
generally similar between the treatment groups (Table 19).[238] Most subjects were male
(68.2% in the cefiderocol group and 69.3% in the HD meropenem group) and white (68.9% in
the cefiderocol group and 66.7% in the HD meropenem group). The mean age was 64.7 years
in the cefiderocol group and 65.6 years in the HD meropenem group; 27.0% of subjects in the
cefiderocol group and 31.3% in the HD meropenem group were ≥ 75 years of age. Most
subjects were enrolled from Europe (66.9% in the cefiderocol group and 66.7% in the HD
meropenem group); 29.1% of subjects in the cefiderocol group and 29.3% in the HD
meropenem group were enrolled from the Asia-Pacific region.
Baseline characteristics of clinical diagnosis, ventilation status, baseline pathogens, and blood
culture status in the ITT population were also similar between the treatment groups. The
percentage of subjects with VABP was 40.5% in the cefiderocol group and 43.3% in the HD
meropenem group; the percentage with HABP was 40.5% in the cefiderocol group and 40.7%
in the HD meropenem group, and the percentage with HCABP was 18.9% in the cefiderocol
group and 16.0% in the HD meropenem group. Subjects on ventilation at baseline represented
61.5% of the cefiderocol group and 58.0% of the HD meropenem group.
All rights reserved 154
Table 19: Patient demographics and baseline characteristics (mITT population)
ITT Population Cefiderocol (N=148)
HD meropenem (N=150)
Gender (Male), n (%) 101 (68.2) 104 (69.3)
Age, mean 64.7 65.6
Race (White), n (%) 102 (68.9) 100 (66.7)
Clinical diagnosis at baseline, n (%)
VABP 60 (40.5) 65 (43.3)
HABP 60 (40.5) 61 (40.7)
HCABP 28 (18.9) 24 (16)
Ventilation status at randomisation, n (%)
Ventilated 91 (61.5) 87 (58)
Non-ventilated 57 (38.5) 63 (42)
APACHE II, n (%)
≤ 15 75 (50.7) 78 (52)
16-19 32 (21.6) 26 (17.3)
≥ 20 41 (27.7) 46 (30.7)
Renal function, n (%)
Mild renal impairment (50-80 ml/min)
44 (29.7) 37 (24.7)
Moderate renal impairment (30-50 ml/min)
29 (19.6) 32 (21.3)
Severe renal impairment (<30 ml/min)
20 (13.5) 20 (13.3)
APACHE, Acute Physiology, Age, Chronic Health Evaluation; HD, high dose; Source: Data on file [239]
Most subjects in both treatment groups had only Gram-negative pathogens at baseline (76.4%
in the cefiderocol group and 70.0% in the HD meropenem group). The most frequently
occurring Gram-negative pathogen in both treatment groups at baseline was Klebsiella
pneumoniae (32.4% in the cefiderocol group and 29.3% in the HD meropenem group),
followed by Pseudomonas aeruginosa (16.2% and 16.0% in the cefiderocol and HD
meropenem groups, respectively) and Acinetobacter baumannii (15.5% and 16.0% in the
cefiderocol and HD meropenem group, respectively), as shown in Table 20. Blood cultures
positive for Gram-negative pathogens were observed in 5.4% of subjects in the cefiderocol
group and 6.7% of the HD meropenem group. The mean APACHE II score was 16.1 in the
cefiderocol group and 16.3 in the HD meropenem group.
Table 20: Top 5 baseline Gram-negative pathogens, n (%)
ITT Population Cefiderocol (N=148)
HD meropenem (N=150)
Klebsiella pneumoniae 48 (32.4) 44 (29.3)
Pseudomonas aeruginosa 24 (16.2) 24 (16)
Acinetobacter baumannii 23 (15.5) 24 (16)
Escherichia coli 19 (12.8) 22 (14.7)
Enterobacter cloacae 7 (4.7) 8 (5.3)
Source: Data on file [239]
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5.3.3 CREDIBLE-CR STUDY
A Descriptive, Open-label, Multicenter, Randomized, Clinical Study of cefiderocol or Best
Available Therapy for the Treatment of Severe Infections Caused by Carbapenem-resistant
Gram-negative Pathogens
The small, descriptive CREDIBLE-CR study is a pathogen-focused randomised clinical trial
that investigated the efficacy and safety of cefiderocol versus an individualized best available
therapy (BAT) in 150 seriously ill patients with confirmed carbapenem-resistant (CR) Gram-
negative infections, independent of the host’s infection site (HCAP/HAP/VAP, cUTI,
BSI/sepsis are included). The objective of the study was to provide descriptive evidence of the
efficacy and safety of cefiderocol for the target population of patients with CR infections,
including the non-fermenters. The study was conducted in patients with evidence of CR Gram-
negative infections at 100 sites in 17 countries covering 4 regions: Asia-Pacific, Europe, North
America, and South America.
This study was not designed or powered to conduct hypothesis but to start gaining experience
in patients with CR infections, with life-threatening, or end-of-life conditions with a high risk of
mortality, often failing multiple lines of therapy (i.e. salvage therapy). No stratification for
pathogen or terminal disease was done and differences in baseline characteristics between
the two arms were observed. Study design and patient flow are presented in Figure 27:
CREDIBLE-CR study design and patient flow
The study key inclusion criteria were [240, 241]:
Patients who were diagnosed with HAP/VAP/HCAP, BSI or sepsis, or cUTI and
Documented or suspected CR Gram-negative infections [240, 241].
Key exclusion criteria were [240, 241]:
Effective antibacterial regimen for the current CR infection within 72 hrs prior to
randomization for a continuous duration of ≥24 hrs in cUTI, or ≥36 hrs in
HAP/VAP/HCAP or BSI/sepsis,
Moderate or severe hypersensitivity or allergic reaction to any beta-lactam antibacterial
Requirement of >3 systemic antibacterials for the treatment of the current infection if
randomised to the BAT arm
Infections: endocarditis, osteomyelitis, meningitis and co-infections with invasive mold
Conditions: cystic fibrosis/bronchiectasis, refractory septic shock or severe
neutropenia (<100 cells/μL blood)
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Patients with Acute Physiology and Chronic Health Evaluation II (APACHE II) score >
30Patients (n = 152) were randomised 2:1 to either cefiderocol, 2 g, administered IV over 3
hours every 8 hours (q8h) or BAT (
Figure 28) [240, 241]. Patients with cUTI received cefiderocol as monotherapy, whereas for
patients with HAP/VAP/HCAP or BSI/sepsis, physicians could choose to add one additional
antibacterial [240, 241]. Patients were stratified by primary clinical diagnosis
(HAP/VAP/HCAP, BSI/sepsis, cUTI), APACHE II score (≤15 or ≥16–≤30 at screening), and
region (North America, South America, Europe, Asia-Pacific) [240]. Of note, the stratification
did not account for pathogens at baseline or other severity indicators such as mechanical
ventilation status, shock, and location in the intensive care unit (ICU).
Best Available Therapy was chosen by the investigator before randomization, and could
include up to three antibacterials with Gram-negative coverage used in combination [240,
241]. Best Available Therapy was chosen by the investigator before randomization, and could
include up to three antibacterials with Gram-negative coverage used in combination [240,
241]. Due to the enrolment of patients with a broad range of CR Gram-negative bacteria and
infection types, BAT was considered to be the appropriate comparator reflecting the variation
in the combination of treatments within the clinical practice [240, 241]. This was also in
accordance with the regulatory guidance by EMA [240].
Figure 27: CREDIBLE-CR study design and patient flow
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Figure 28: Subjects disposition (all randomized subjects)
5.3.3.1 BASELINE CHARACTERISTICS
The population in the CREDIBLE-CR study was expected to be very heterogeneous as it was
a pathogen-focussed study which included subjects with many underlying conditions, different
infection sites and infections due to a variety of Gram-negative CR pathogens also including
non-fermenters (Acinetobacter spp. and Stenotrophomonas spp) [240, 242]. The study
included a substantial number of patients with life-threatening, or end-of-life conditions with a
high risk of mortality reflecting a compassionate use scenario. Baseline demographics were
generally balanced between the 2 treatment arms (Table 21) with some clinical exceptions
that can influence the results [242]. There was a higher proportion of patients of ≥ 65 years
old (63.4% vs 44.9%) and patients with moderate (22.8% vs 16.3%) and severe renal
impairment (19.8% vs 14.3%) in cefiderocol group than in BAT arm (Table 21) [242]. Due to
the heterogeneity of the population the treatment groups do not appear to be balanced for
baseline characteristics such as shock (which has a major impact on mortality) in the subgroup
of subjects with A. baumannii infections. Twenty-six out of 150 (17%) patients in CREDIBLE-
CR trial had polymicrobial infections at baseline, and all patients with 3-4 co-pathogens were
randomised to the cefiderocol arm (Table 21).
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Table 21: Patient demographics and baseline characteristics (ITT population)
Parameter Cefiderocol n=101
BAT n=49
Sex, (%) Men (%) 65.3 71.4
Age, y Median 69.0 (19, 92) 62.0 (19, 92)
≥65 (%) 63.4 44.9
CrCl, mL/min Median (min, max) 59.2 (9.4, 539.6) 69.4 (4.6, 270.8)
CrCl renal grading group in mL/min, n (%)
<50 (Moderate and Severe) (%) 42.6 30.6
Clinical diagnosis at baseline, n (%)
HAP/VAP/HCAP (%) 44.6 44.9
BSI/sepsis (%) 29.7 34.7
cUTI (%) 25.7 20.4
APACHE II score Median (min, max) 15 (2, 29) 14 (2, 28)
SOFA Score Median (min, max) 4.0 (0, 17) 4.0 (0, 16)
Clinical Pulmonary Infection Score
Median (min, max) 5.0 (2, 9) 5.0 (0, 7)
BAT, best available therapy; BSI, bloodstream infection; cIAI, complicated intra-abdominal infection; cUTI, complicated urinary
tract infection; HAP, hospital-acquired pneumonia; HCAP, healthcare-associated pneumonia; ITT, intent-to-treat;
VAP, ventilator-associated pneumonia. Source: Data on file [242]
5.3.3.2 Baseline Study Drug Regimen
In the cefiderocol group, 82.5% (66/80) of the subjects received monotherapy, while 28.9%
(11/38) of the subjects in the BAT group received monotherapy (Table 22). A colistin-based
regimen was given to 65.8% (25/38) of the subjects in the BAT group. Other than colistin
monotherapy (received by 6 subjects in the BAT group), 5 subjects in the BAT group received
other monotherapy (amikacin, ceftazidime/avibactam, doripenem, fosfomycin, and
gentamicin).
Colistin was a prohibited medication in the cefiderocol group; however, one patient received
cefiderocol and colistin. In the cefiderocol group only 1 additional drug for Gram-negative
pathogens could be added; however, one patient received cefiderocol, gentamicin, and
tigecycline. Overall there was a significant diversity of regimens in combination with colistin.
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Table 22: Summary of study regimen for Gram-negative pathogen at day 1 and day 2 (CR-
mITT population)
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5.3.3.3 Baseline Pathogens
The study was not considering pathogens as a stratification factor, therefore, there was an
imbalance on the baseline pathogens, where cefiderocol arm contained more patients with
multiple pathogens and more non-fermenters, particularly Stenotrophomonas spp. All
infections caused by S. maltophilia were randomised to the cefiderocol arm (Table 23) [242].
Table 23: Baseline Gram-negative pathogens, n (%)
Diagnosis Pathogen [a]
Cefiderocol (N = 86)
n (%)
BAT (N = 44)
n (%)
All Infection Sites Combined N' = 86 N' = 44
Acinetobacter baumannii 39 (45.3) 17 (38.6)
Klebsiella pneumoniae 34 (39.5) 16 (36.4)
Pseudomonas aeruginosa 17 (19.8) 12 (27.3)
Escherichia coli 6 (7.0) 3 (6.8)
Stenotrophomonas maltophilia 5 (5.8) 0
Acinetobacter nosocomialis 2 (2.3) 0
Enterobacter cloacae 2 (2.3) 0
Acinetobacter radioresistens 1 (1.2) 0
Chryseobacterium indologenes 1 (1.2) 0
Klebsiella oxytoca 1 (1.2) 0
Klebsiella variicola 1 (1.2) 1 (2.3)
Serratia marcescens 1 (1.2) 0
Enterobacter asburiae 0 1 (2.3)
Morganella morganii 0 1 (2.3) BAT, best available therapy; Micro-ITT, microbiological intent-to-treat
Source: Data on file
Of note, of the subjects with HAP/VAP/HCAP, 64.3% in the cefiderocol group and 47.6% in
the BAT group had A. baumannii at baseline (Attachment: R2131_CREDIBLE-CR Final Study
Summary) [243].
A comparison of the characteristics of APEKS-NP and CREDIBLE-CR and CREDIBLE-CR
with HAP/VAP/HCAP (ITT population) is on file [243]. An analysis of APEKS NP subgroup
with CR infection is presented in chapter 5.4.3.
5.3.4 Summary of compassionate use cases and published evidence
Cefiderocol has been provided upon request from attending physicians to patients with serious
CR Gram-negative infections who have no other treatment options [244]. The criteria for
fulfilling these requests are highly restrictive including that all other available treatments must
be ruled out through susceptibility testing and/or evidence of treatment failure in efficacy or
safety, and patients must be unable to enroll in clinical studies of cefiderocol [244]. Data for
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74 patients completed cefiderocol therapy in compassionate use [244], and are presented
here.
5.3.4.1 Patient characteristics in the compassionate use program
The mean age of patients in the compassionate use program was 46.8 years which is lower
compared to other studies of cefiderocol, mainly due to the inclusion of children and infants in
the compassionate use program [245]. There were 9/74 patients who were < 18 years with
the youngest patients of 5 months old [245]. In addition to the infection sites included in the
clinical trials of cefiderocol, compassionate use program also included patients with bone
infections (18.9%) (Table 24) [245]. With regards to causal pathogens, non-fermenter species
accounted for almost all isolates, with the most common being P. aeruginosa (n = 30); A.
baumannii (n = 24), Achromobacter xylosoxidans (n = 10), Burkholderia cepacia complex (n
= 9), Enterobacterales (n = 9), and S. maltophilia (n = 3) (Table 24) [244]. Eight patients had
mixed infections with various MDR organisms [244]. All isolates were MDR with some being
pan-resistant to currently available classes of antimicrobial agents [244]. The median duration
of cefiderocol treatment was 21 days (range: 1-94 days) and patients received up to seven
concomitant therapies alongside cefiderocol including polymixins (43.2%), cephalosporins
(33.8%), carbapenems (23%), β-lactams (21.6%), sulphonamides (18.9%) and
aminoglycosides (14.9%) [245]. (details of compassionate use program are provided in
chapter 3.).
Patients in compassionate us program are only eligible if all other available treatments have
been ruled out through susceptibility testing and/or evidence of treatment failure in efficacy or
safety. TheTheThe severity of infections included in compassionate and based on the
pathogen distribution reminds of the infections from the patient populationThe severity of
infection included in CREDIBLE CR and is more severe than observed in APEKS trials.
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Table 24: Patient demographics and baseline characteristics
Parameter Cefiderocol N=74
Gender (Male), n (%) 44 (59.5)
Age, mean 46.8
≥65 years, n (%) 19 (25.7)
Infection type at baseline, n (%)
BSI 21 (28.4)
Pneumonia and respiratory infection 25 (33.8)
Bone infection 14 (18.9)
Bacteraemia 4 (5.4)
Sepsis 3 (4.1)
cUTI 1 (1.4)
Other 6 (8.1)
Most common pathogen at diagnosis, n (%)
Pseudomonas aeruginosa 31 (41.9)
Acinetobacter baumannii 22 (29.7)
Burkholderia cenocepacia 10 (13.5)
Klebsiella pneumoniae 6 (8.1)
Escherichia coli 1 (1.4) BSI, bloodstream infection; cUTI, complicated urinary tract infection
Source: NDA briefing document[244]; Data on file [245]
5.3.4.2 Published case reports
Case reports for three patients from the expanded access program have been published so
far.
A patient was treated successfully for endocarditis due to extensively drug resistant (XDR)
Pseudomonas aeruginosa.(Edgeworth et al., 2019)[246]
A patient with multiple comorbidities and a complicated intra-abdominal infection (IAI) due to
MDR Pseudomonas aeruginosa was released from hospital care within six weeks of
completion of cefiderocol treatment. (Stevens et al., 2019)[247]
A patient with VAP and BSI caused by XDR Acinetobacter baumannii and carbapenemase-
producing Klebsiella pneumoniae had potentially serious organ failure from older anti-
infectives. Six weeks after cefiderocol administration, chest X-rays showed complete
resolution of infection (Trecarichi et al., 2019)[248]
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Single and Multiple Dose Study
A single-center, randomised, double-blind, placebo-controlled, ascending single and multiple
dose study to evaluate the safety, tolerability and PK of cefiderocol in 70 healthy Japanese
and Caucasian adult subjects. In the single-dose cohort, single doses of 100 mg, 250 mg, 500
mg, 1 g, and 2 g over a 1-hour infusion were tested. A single dose of 4 g was planned but was
not initiated according to the study protocol dose escalation guidelines; a cohort would not
proceed if the predicted maximum plasma concentration (Cmax) exceeds a 10-fold lower
exposure than the rat no-observed-adverse-effect-level (C0 = 1660 μg/mL). In the multiple-
dose cohort, once daily doses of 1 and 2 g over a 1-hour infusion on Day 1 followed by q8h
doses of 1 and 2 g over a 1-hour infusion for 8 days on Days 2 to 9 and a once daily dose of
1 and 2 g over a 1-hour infusion on Day 10 were tested. The active drug and the placebo were
administered to 6 subjects and 2 subjects, respectively, in each single-dose group and 8
subjects and 2 subjects, respectively, in each multiple-dose group [249].
Renal Impairment Study
A multicenter, open-label, nonrandomised study to evaluate the PK, safety and tolerability of
cefiderocol in subjects with varying degrees of renal impairment and in subjects with normal
renal function. The PK of a single-dose 1 g of cefiderocol in subjects with mild, moderate, or
severe renal impairment, or end-stage renal disease (ESRD) requiring haemodialysis (HD)
was compared with that of healthy subjects with normal renal function who were
demographically matched with moderate renal impairment. A total of 38 subjects were enrolled
in 5 cohorts.
The clearance of cefiderocol with HD was determined based on plasma concentration data
both before and after HD. Renal function was classified at screening visit based on creatinine
clearance estimated by Cockcroft-Gault equation (CrCl) for subjects with normal renal function
(≥ 90 mL/min) and estimated glomerular filtration rate (eGFR) using the modification of diet in
renal disease (MDRD) equation for subjects with renal impairment (mild, 60 to < 90; moderate,
30 to < 60; severe, 15 to < 30 mL/min/1.73 m2). A single-dose of 1 g cefiderocol over a 1-hour
infusion was administered to subjects with normal renal function or mild, moderate or severe
renal impairment. Subjects with ESRD requiring HD were dosed approximately 1 to 2 hours
after completion of a HD session on Day 1, and 2 hours prior to start of HD following at least
a 72-hour washout period [249].
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5.4 Individual study results (clinical outcomes)
1. Describe the relevant endpoints, including the definition of the endpoint, and method
of analysis (Table 73a - Table 80e).
2. Provide a summary of the study results for each relevant comparison and outcome.
Due to the need to consider in-vitro data in combination with PK/PD and supportive trial data
for an assessment of a novel antibacterial, such as cefiderocol, the data of the individual
studies cannot be summarized across trials. Each clinical study used its own comparator and
was conducted in different patient populations. For this reason, no overall results summary
table is shown here, and section 5.4 has been modified to account for the specific
circumstances.
The individual study results, including all requested stratifications by pathogen and time-point
during the scoping process, are discussed in sections 5.4.1 through 5.4.3 below; the standard
dossier section 5.4 has thus been split to accommodate all relevant results (in-vitro, PK/PD,
and clinical).
In addition, for the APEKs trials, a feasibility analysis for an NMA was conducted. This
feasibility analysis [227], showed that an NMA was feasible for APEKS-cUTI. Appendix F of
that document contains the summary tables of all relevant outcomes across the trials included
in the NMA.
5.4.1 Individual study results (in vitro surveillance outcomes)
In vitro activity of cefiderocol has been studied in large-scale multinational surveillance and
small independent national studies [250]. Large multinational surveillance studies include
SIDERO-WT studies initiated in North America and Europe and SIDERO-CR program
collecting CR isolates from Europe, North America, South America, and the Asia-Pacific region
(Table 25) [250]. In the section below, the results are reported for all global Gram-negative
isolates. Of note, the susceptibility to cefiderocol was assessed based on the CLSI
breakpoints. The EUCAST breakpoints are expected to be determined in February after the
Committee for Medicinal Products for Human Use (CHMP) opinion. Data for the US clinical
strains is reported in the appendix and data for European strains will be included after the
availability of EUCAST breakpoints [251].
In addition, several independent validation studies carried out to determine cefiderocol activity
have included collections of difficult-to-treat CR pathogens gathered from various countries
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including Italy, Germany, Greece, Spain, UK/Ireland, Switzerland, and the US [250]. The list
of these studies is reported in section “Study categorisation.”
Table 25: SIDERO Surveillance studies
SIDERO-WT in vitro studies
Scope Systematic surveillance studies of cefiderocol in vitro activity compared to key
antibacterials against a total of 30,459 Gram-negative isolates collecting
isolates from three consecutive 12-month periods from 2014 to 2015
(SIDERO-WT-2014), from 2015 to 2016 (SIDERO-WT-2015), and from 2016
to 2017 (SIDERO-WT-2016) as well as cumulative.
Geographic
location
North America and Europe
Comparator
treatments
Ceftolozane/tazobactam, ceftazidime/avibactam, cefepime, ciprofloxacin,
polymyxin E (colistin), and meropenem
Included
pathogens
Carbapenem susceptible and carbapenem non-susceptible pathogens
(CarbNS): Enterobacteriaceae (including but not limited to Escherichia coli,
K. pneumoniae, Enterobacter spp., Citrobacter spp., Serratia spp.), non-
fermenters (including but not limited P. aeruginosa, A. baumannii, S.
maltophilia, B. cepacia), and Proteeae (M. morgannii, P. vulgaris, P.
mirabilis).
SIDERO-CR
Scope In vitro study from 2014 – 2016 evaluating the activity of cefiderocol against
a total of 1,873 MDR and CarbNS isolates Gram-negative Bacilli.
Geographic
location
World-wide (Europe, North America, Latin America, Asia, South Pacific,
Africa, and the Middle East)
Comparator
treatments
Ceftolozane/tazobactam, ceftazidime/avibactam, cefepime, ciprofloxacin,
polymyxin E (colistin), and meropenem
Included
pathogens
CarbNS Enterobacteriaceae, MDR A. baumannii, MDR P. aeruginosa, S.
maltophilia and B. cepacia. The test isolates of MDR non-fermenters were
defined to be resistant to meropenem, amikacin and ciprofloxacin.
Source: Longshaw 2019 [47]; Hackel 2017 [29]; Hackel 2018 [30]
In vitro efficacy has been demonstrated in several independent world-wide pathogen
collections:
1. A total of 30,459 clinical isolates of Gram-negative bacilli were systematically collected
from USA, Canada, and 11 European countries between 2014 and 2017. All isolates were
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sent to a central laboratory, IHMA (Schaumburg, Illinois), where the isolates were further
evaluated and stored.
a. The SIDERO-WT analysis (study report S-649266-EB-344-N) was an extensive effort
to determine susceptibility of cefiderocol and relevant comparators against
cabapenem-susceptible and carbapenem-resistant pathogens. The purpose of this
study was to calculate the indices related to the antibacterial activity of cefiderocol and
the ratio of susceptible strains of cefiderocol and other reference compounds based
on the breakpoint criteria of Clinical and Laboratory Standards Institute (CLSI)
standards. MICs were determined by broth microdilution for a panel of 7 antibacterials,
including cefiderocol, ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C/T),
colistin (CST), cefepime (FEP), meropenem (MEM), and ciprofloxacin (CIP) according
to the Clinical & Laboratory Standards Institute (CLSI). Included herein are results from
the total sample and from the European subsample (overall and non-fermenters) [29,
45, 46, 49, 250].
b. A subsequent analysis focused on a Difficult-to-treat resistant (DTR) subset of
pathogens, which were non-susceptible to fluoroquinolones (CIP), extended-spectrum
cephalosporins (FEP), and carbapenems (MEM) according to CLSI M100-E28:2018
breakpoints. (Longshaw et al., Poster presentation, IDWeek 2019 [47]).
c. A molecular analysis based on the same collection investigated acquired
carbapenem-hydrolyzing enzymes (carbapenemases) identified in meropenem-
non-susceptible (MEM-NS) strains and antibacterial susceptibility by year and country
for the included strains. (Sato et al, Poster presentation, IDWeek 2019).
2. The SIDERO-CR-2014-2016 study (protocol S-649266-EF-115-N) included CR
Enterobacteriaceae and MDR non-fermenters (defined as resistant to carbapenems,
fluoroquinolones, and aminoglycosides) and demonstrated the potent in vitro activity of
cefiderocol against these pathogens [30].
3. Several independent national validation studies were carried out to determine
cefiderocol activity against difficult-to-treat CR pathogens gathered from various countries
including Germany, Greece, Italy, Spain, UK/Ireland, and the US [252-257]. In these
studies, cefiderocol demonstrated consistent activity against Gram-negative pathogens
regardless of the geographic origin.
4. A validation study by a Swiss team of scientists confirmed cefiderocol activity in an
independent world-wide collection of Gram-negative pathogens [258].
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5. Several studies followed up on the surveillance results and aimed to characterize rare
resistant pathogens and identify their mechanisms of resistance. [61, 62] (Ito et al.,
Poster presentation, ASM Microbe 2019).
Results from these studies and relevant published sub-analyses involving European samples
are summarized in the following sections, followed by a summary analysis of the expected
efficacy of cefiderocol based on in vitro susceptibility results, compared to other treatment
options.
It is important to highlight that there these studies are continuously being updated and new
isolates analysed and incorporated, with correspondent publications following, showing the
results by year, cumulative, or for specific groups of pathogens of interest.
5.4.1.1 1a) SIDERO-WT results for all Gram-negative isolates[45, 49, 250]
In the SIDERO-WT in vitro studies, cefiderocol demonstrated activity against the majority of
Gram-negative isolates at MIC of <4 µg/mL (only MIC90 for B. multivorans was 32 µg/mL) with
higher coverage rates than other comparators included in these studies [250]. The SIDERO-
WT program included 4 multinational surveillance analyses testing a total of 9205 Gram-
negative bacterial clinical isolates in 2014–2015, 8954 in 2015–2016, and 10 470 in 2016–
2017 [250] and continues to include more isolates every year. To date (January, 2020), 30,459
459samples have been tested. Of note, >99% of isolates had low cefiderocol MIC values in
each testing period [250]. The latest surveillance SIDERO-WT study (2016-2017) showed that
cefiderocol demonstrated activity against 99.45% of GN pathogens at MIC of 4 mg/L
compared to 90.2% for ceftazidime-avibactam, 84.28% for ceftolozane-tazobactam, and
95.49% for colistin (Table 26) [49].
With regards to in vitro activity across different pathogens, cefiderocol demonstrated potent in
vitro activity against Enterobacteriaceae (99.9%) and non-fermenters including A. baumannii,
P. aeruginosa, S. maltophilia, and B. cepacia (98.53%) which was higher than for other
available treatments (Table 26) [49].
Table 26: In vitro activity data for all tested clinical strains (SIDERO-WT-2014/2015/2016 and Proteeae) of
cefiderocol (at MIC of 4mg/L) versus ceftazidime-avibactam, ceftolozane-tazobactam, and colistin
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Organism Cefiderocol %
Polymyxin E (colistin) % S MIC ≤2 µg/mL
Ceftolozane / tazobactam %S MIC ≤2 µg/mL for Enterobacteriaceae, ≤4 µg/mL for non-fermenters
Ceftazidime / avibactam % S MIC ≤8 µg/mL
All Gram-negative (N=30,459) 99.45
95.49b (n=25372)
84.28 90.20
Enterobacteriaceae (N=20,949)
99.86 96.54c (n=16026)
91.43 99.23
Non-fermentersa (N=9,510)
98.53 93.67d (n=9346)
68.52 70.33
CR
Enterobacteriaceae (N=654)
(MEPM MIC ≥ 2 µg/mL)
98.16 75.55c (n=581)
8.40 77.67
CR (N=4,331)
(MEPM MIC ≥ 4 µg/mL) 97.57
86.85d (n=4208)
34.61 40.96
CR P. aeruginosa (N=1,154)
(MEPM MIC ≥ 4 µg/mL) 99.91 98.35 76.08 75.38
CR A. baumannii (N=1,891)
(MEPM MIC ≥ 4 µg/mL) 94.87 85.14 7.77 16.23
S. maltophilia (N=1,173)
99.82 78.17 34.27 42.88
Source: [49]. CarbNS - carbapenem non-susceptible; MEPM - meropenem; MIC - minimum inhibitory concentration. Green: More
than 80% susceptible; yellow: between 60-80% susceptible, red: less than 60% susceptible.
a Non-fermenters include P. aeruginosa, S. maltophilia, Burkholderia spp, and Acinetobacter spp.
b Burkholderia spp, Proteeae and Serratia spp. were excluded because they are intrinsically resistant to Polymyxin E
(Colistin)
c Serratia spp. and Proteeae was excluded.
d Burkholderia spp was excluded.
5.4.1.1.1 European sub-sample
The in vitro activities of cefiderocol and six comparators are summarized in Table 27 for the
5352 isolates from European clinical laboratories from the 2015 collection. (Karlowsky et al.,
2018). The concentration of antimicrobial agent inhibiting 50% (MIC50) and 90% (MIC90) of
Enterobacteriaceae isolates tested against cefiderocol were 0.25 and 1 mg/L for European
isolates (MIC range ≤0.002-8 mg/L). Cefiderocol inhibited 99.9% (6005/6013) of all isolates of
Enterobacteriaceae tested, from European clinical laboratories, at a concentration (MIC) of ≤4
mg/L. Of the eight isolates of Enterobacteriaceae with cefiderocol MICs of ≥8 mg/L, three were
European isolates (two isolates of E. coli and one isolate of Citrobacter freundii), all with
cefiderocol MICs of 8 mg/L. Each isolate of Enterobacteriaceae with a cefiderocol MIC ≥8
mg/L was from a unique clinical laboratory location. Seven of the eight isolates with cefiderocol
MICs of 8 mg/L were susceptible to both meropenem and ceftazidime-avibactam compared
with six isolates susceptible to colistin, four isolates susceptible to ciprofloxacin, and only one
isolate susceptible to cefepime and ceftolozane-tazobactam. Against meropenem-non-
susceptible (MIC ≥2 mg/L) isolates of Enterobacteriaceae from Europe (n = 196), cefiderocol
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MIC50 and MIC90 values were 2 and 4 mg/L, respectively; 99.6% (245/246) of all meropenem-
non-susceptible Enterobacteriaceae had MICs to cefiderocol of ≤4 mg/L.
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Table 27: In vitro activity of cefiderocol and comparators against Gram-negative bacilli isolated
by 55 clinical laboratories in Europe in 2015 (n=5352)
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An updated analysis of the European sample (Shionogi, data on file) investigated the in vitro
activity of cefiderocol and comparators specifically against non-fermenters (SIDERO-WT-
2014-2016; European isolates).
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Table 28: In vitro activity of cefiderocol and comparators against non-fermenters
Source: Shionogi, data on file.
Cefiderocol demonstrated greater potency than all comparators against the pathogens P.
aeruginosa and A. baumannii, based on MIC50 and MIC90 values:
o Against P. aeruginosa, and based on MIC90 values, cefiderocol (MIC90 0.5
mg/L) was 4 times more potent than colistin and ≥8 times more potent than all
other comparators.
o The activity of cefiderocol against A. baumannii (MIC90 2 mg/L) was ≥32 times
greater than cefepime, ceftazidime/avibactam, ceftolozane/tazobactam, and
meropenem, and was 4 times greater than colistin.
o Cefiderocol (MIC90 0.25 mg/L) also demonstrated activity against S. maltophilia
that was ≥256 times more potent than cefepime, ceftazidime/avibactam,
ceftolozane/tazobactam, and meropenem, and 32 times more potent than
ciprofloxacin and colistin.
o All comparators showed lower activity than cefiderocol (MIC90 0.5 mg/L) against
B. cepacia complex, with cefiderocol being ≥16 times more potent.
The cefiderocol MIC90 against CarbNS-P. aeruginosa was 1 mg/L and, with the exception of
colistin (MIC90 2 mg/L) and ciprofloxacin (MIC90 >8 mg/L), comparator MIC90s were ≥64 mg/L.
Cefiderocol maintained activity against CarbNS-A. baumannii (MIC90 2 mg/L), and
demonstrated >4 times greater potency than all comparators.
5.4.1.2 1b) SIDERO-WT-based analysis of difficult-to-treat resistant (DTR)
pathogens [47]
All antibacterials were tested in cation-adjusted Mueller-Hinton Broth (CAMHB) except
cefiderocol, for which iron-depleted CAMHB was used. Susceptibility was determined
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according to CLSI interpretive breakpoints (CLSI M100-E28: 2018) except CST, where
EUCAST breakpoints were used (Table 29).
Pathogens were defined as ‘Difficult-to-Treat Resistant’ (DTR) if they were non-susceptible to
fluoroquinolones (CIP), extended-spectrum cephalosporins (FEP), and carbapenems (MEM)
according to CLSI M100-E28:2018 breakpoints (Table 29). Pathogens were defined as
carbapenem non-susceptible if they had MICs to meropenem of >1 μg/mL (Enterobacterales);
>2 μg/mL (Pseudomonas spp./ Acinetobacter sppspp.); >4 μg/mL (Burkholderia cepacia
complex). Stenotrophomonas maltophilia was considered inherently non-susceptible to
carbapenems, however, an arbitrary breakpoint of >4 μg/mL was used. Among 30,459 Gram-
negative isolates collected between 2014 and 2017, 9.3% were non-susceptible to FEP, MEM,
and CIP and could be defined as DTR.
Table 29: Breakpoints for non-susceptibility used in definition of DTR (μg/mL)
Cefiderocol demonstrated activity in 94.5% of DTR A. baumannii, 99.8% of P. aeruginosa and
98.3% of Enterobacterales [47]. Susceptibility of these pathogens were lower for other
available treatments (Table 30) [47].
Table 30: Susceptibility of cefiderocol and comparators to pathogens
Pathogen Cefiderocola % Ceftazidime / avibactama %
Ceftolozane / tazobactama
Colistina %
DTR Enterobacterales (n=573)
98.3 78.2 2.05 68.2
DTR P. aeruginosa (n=470)
99.8 49.5 48.8 98.3
DTR A. baumannii
(N=3,451) 94.5 14.2 5.8 85
Table 31 below shows that 98.7% of CarbNS Enterobacteriaceae, and 96.4% of CarbNS non-
fermenters were calculated to be sensitive to cefiderocol at a MIC of ≤4 μg/mL.
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Table 31: In vitro activity data for CR Gram-negative pathogens (SIDERO-WT-2016-2017) of cefiderocol
versus ceftazidime-avibactam, ceftolozane-tazobactam and colistin
Pathogen Cefiderocola % Ceftazidime / avibactama %
Ceftolozane / tazobactama
Colistina %
CarbNSb Enterobacteriaceae (225)
98.7 81.3 11.1 71d
CarbNSb non-fermentersc (1427)
96.4 39.8 37.0 91.5e
CarbNSb P. aeruginosa
(406) 100 75.6 77.3 97.3
CarbNSb A. baumannii (565)
91 11.0 9.0 90.8
S. maltophilia (405)
100 38.8 31.4 86
CarbNS, carbapenem-non-susceptible
a Ratios (%) susceptible strains were calculated by using the following MIC criteria: Cefiderocol MIC ≤4 μg/mL,
ceftazidime/avibactam MIC ≤8 μg/mL, ceftolozane/tazobactam MIC ≤2 μg/mL for Enterobacteriaceae, ≤4 μg/mL for non-
fermenters, colistin MIC ≤2 μg/mL.
b CR strain was defined as meropenem MIC ≥2 μg/mL for Enterobacteriaceae, ≥4 μg/mL for non-fermenters
c Non-fermenters include P. aeruginosa, S. maltophilia, Burkholderia spp, and Acinetobacter spp.
d Serratia spp. and Proteeae were excluded.
e Burkholderia spp. was excluded.
Source: Tsuji 2019[49]
The DTR phenotype was most frequently observed in Acinetobacter spp. (55.5%), followed
by Burkholderia spp. (19%), Pseudomonas aeruginosa (9.5%) and Enterobacterales (2.7%).
From 1173 S. maltophilia isolates tested, 60.7% were non-susceptible to meropenem,
cefepime and ciprofloxacin, however, trimethoprim-sulfamethoxazole was not tested and
could be considered a treatment option for these infections, thus we were not able to state
how many isolates might be considered DTR.
In summary, the results from this analysis showed that cefiderocol demonstrated potent
activity against ‘Difficult-to-Treat Resistant’ Gram-negative pathogens which leave physicians
with limited options for high efficacy, low toxicity first-line treatment.
5.4.1.3 1c) Study of acquired carbapenem-hydrolyzing enzymes (carbapenemases) identified in meropenem-non-susceptible (MEM-NS) strains [48]
In a subgroup analysis of SIDERO-WT-2014-2016 studies including meropenem-non-
susceptible strains, cefiderocol demonstrated potent in vitro activity irrespective of the
presence of specific carbapenemases [48].The isolates were stratified per resistance
determinants detected through the conventional polymerase chain reaction (PCR) method and
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included VIM-, NDM-1-, KPC-, and OXA-producing Enterobacteriaceae, VIM-, IMP-, and GES-
producing P. aeruginosa, and OXA-, GES- and NDM-producing A. baumannii [48].
In all, 3691 Gram-negative isolates of MEM-NS A. baumannii complex, P. aeruginosa, K.
pneumoniae, other Klebsiella spp., Serratia marcescens, Enterobacter spp., Citrobacter spp.,
and Escherichia coli, from SIDERO-WT-2014 (Year 1: 2014–2015), SIDERO-WT-2015 (Year
2: 2015–2016), and SIDERO-WT-2016 (Year 3: 2016–2017) were molecularly characterized.
Information on the number of isolates by year and by country of collection is shown in Table
32 and Table 33, respectively.
Table 32: Number of MEM-NS isolates by year and species
Table 33: Number of MEM-NS isolates by country and species
5.4.1.3.1.1 Detection of β-lactamase genes
Screening for the carriage of genes encoding carbapenemases and sequencing are described
by Kazmierczak et al. Briefly, multiplex polymerase chain reaction assays were used to screen
oxacillin carbapenemase (OXA)-23-like, OXA-24/40-like, OXA-48-like, OXA-58-like, K.
pneumoniae carbapenemase (KPC), imipenemase metallo-β-lactamase (IMP), Verona
integron-encoded metallo-β-lactamase (VIM), New Delhi metallo-β-lactamase (NDM), Sao
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Paulo metallo-β-lactamase (SPM), Guiana-extended-spectrum β-lactamase (GES) and
German imipenemase (GIM) in Acinetobacter spp.; KPC, GES, OXA-24/40-like, IMP, VIM,
NDM, SPM, and GIM in P. aeruginosa; and KPC, GES, OXA-48-like, IMP, VIM, and NDM in
Enterobacteriaceae.
Genes encoding KPC, GES, IMP, VIM, and NDM carbapenemases were sequenced. Among
GES subtypes, GES-2, -4, -5, -6, -11, -12, -14, -15, -16, -18, 20, and -24 were considered
carbapenemases. All experiments were conducted at a central laboratory (International Health
Management Associates, Inc. in Schaumburg, IL, USA), where the isolates were stored.
5.4.1.3.1.2 Minimum inhibitory concentration (MIC) data
Antimicrobial susceptibility data reported in the SIDERO studies were used. MICs were
determined by the broth microdilution method according to the CLSI guidelines. For MIC
determination, iron-depleted cation-adjusted Mueller–Hinton broth (ID-CAMHB) medium was
used for testing of cefiderocol and CAMHB was used for testing of ceftazidime-avibactam,
ceftolozane-tazobactam, meropenem, cefepime, and colistin.
5.4.1.3.1.3 Susceptibility criteria
Susceptibility to each antibacterial agent was determined according to the CLSI M100-S29.
For the purpose of comparison, breakpoint values of ceftazidime-avibactam and ceftolozane-
tazobactam for P. aeruginosa were also applied to isolates of A. baumannii complex for which
breakpoint values have not been defined by the CLSI (Table 34).
Table 34: Susceptibility breakpoints according to the CLSI (cefiderocol) and/or EUCAST (all
comparators)
The following tables (Table 35 - Table 38) summarize the county-by country variability in the
frequency of resistant strains of A. baumannii, P. aeruginosa, K. pneumoniae, and
Enterobacteriaceae.
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Table 35: Percentage of susceptibility of MEM-NS A. baumannii complex by country
Table 36: Percentage of susceptibility of MEM-NS P. aeruginosa complex by country
Table 37: Percentage of susceptibility of MEM-NS K. pneumoniae by country
Table 38: Percentage of susceptibility of other MEM-NS Enterobacteriaceae by country
This analysis found the molecular diversity to be high in carbapenemases. Carbapenemase
detection rates, especially in P. aeruginosa and K. pneumoniae, greatly varied across
countries. The presence of metallo-carbapenemases, both NDM and VIM, is noteworthy in
some countries.
The results show that cefiderocol demonstrated potent in vitro activity against MEM-NS
strains, including isolates with reduced susceptibility to colistin, irrespective of the presence of
either serine-type or metallo-type carbapenemases. Of the antibacterials tested, only
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cefiderocol was broadly active against all species of MEN-NS clinical isolates regardless of
the geographic origin.
5.4.1.4 2) SIDERO-CR-2014-2016 study (protocol S-649266-EF-115-N)
The SIDERO-CR-2014-2016 study including CR Enterobacteriaceae and MDR non-
fermenters (defined as resistant to carbapenems, fluoroquinolones, and aminoglycosides)
demonstrated the potent in vitro activity of cefiderocol with a MIC90 ranging between 0.25 and
8 µg/mL [30, 250]. For MIC of ≤ 4 µg/mL, cefiderocol showed activity against 96.2% of these
pathogens and demonstrated higher in vitro activity than other available treatments (Table 39)
[30, 250]. Cefiderocol inhibited the growth of 97.0% of CR Enterobacteriaceae, 99.2% MDR
P. aeruginosa, 90.9% MDR A. baumanii and 100% S. maltophila at a concentration of 4 mg/L
(Table 39) [30, 250].
Table 39: In vitro activity data for all tested clinical strains (SIDERO-CR 2014-2016) of cefiderocol
versus ceftazidime-avibactam, ceftolozane-tazobactam, and colistin
Pathogen Cefiderocola % Ceftazidime / avibactama %
Ceftolozane / tazobactama
Colistina %
CarbNSb Enterobacteriaceae (1022)
97.0 77.0 1.7 77.8c
MDR P. aeruginosa (262)
99.2 36.3 24.1 99.6
MDR A. baumannii (368)
90.9 NA NA 94.6
S. maltophilia (217)
100 NA NA NA
CarbNS, carbapenem-non-susceptible; MDR, multi drug resistant; NA, susceptibility breakpoints not available
a Ratios (%) susceptible strains were calculated by using the following MIC criteria: Cefiderocol MIC ≤4 μg/mL,
ceftazidime/avibactam MIC ≤8 μg/mL, ceftolozane/tazobactam MIC ≤2 μg/mL for Enterobacteriaceae, ≤4 μg/mL for non-
fermenters, colistin MIC ≤2 μg/mL.
b CR strain was defined as meropenem MIC ≥2 μg/mL for Enterobacteriaceae, ≥4 μg/mL for non-fermenters
c Includes 39 Serratia species that are intrinsically resistant to colistin
Source: Hackel, 2018 [30]; Yamano [250]
In addition to demonstrating high activity of cefiderocol against different drug-resistant
species, the SIDERO-CR study showed antibacterial activity against isolates stratified per
resistance determinants detected through the PCR method [250]. This includes VIM-, NDM-,
KPC-, and OXA-producing Enterobacteriaceae, VIM-producing P. aeruginosa, MEPM-non-
susceptible but acquired β-lactamase negative P. aeruginosa, OXA-23 and OXA-24/40
carbapenemase-producing A. baumannii.
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5.4.1.5 3) Independent international validation studies
5.4.1.5.1 Germany [259]
Collection I comprised 213 first isolates from patients collected during a multicenter
surveillance study conducted by the Paul-Ehrlich-Society in 2013, namely 146
Enterobacterales (including 17 ESBL-producing strains), 13 Acinetobacter baumannii group
isolates, and 54 Pseudomonas aeruginosa. Collection II included 59 carbapenemase
producing Enterobacterales from our stock collection. Minimum inhibitory concentrations
(MICs) of cefiderocol and comparative antibacterial agents were determined using the
microdilution method according to the standard ISO 20776-1. The provisional CLSI breakpoint
of cefiderocol for susceptibility is ≤4 mg/L.
Cefiderocol inhibited 99% of the collection I at ≤4 mg/L (Table 40). MIC50/90 values of
cefiderocol for Enterobacterales isolates were 0.12/1 mg/L. However, cefiderocol was more
active against ESBL-negative isolates than against ESBL-producing Enterobacterales
(isolates with MIC >1 mg/L: 4/129 [3.1%] ESBL-negative isolates vs 7/17 [41%] ESBL-
producing isolates). In contrast, cefiderocol inhibited all Acinetobacter isolates at 0.12 mg/L
and all P. aeruginosa isolates at 1 mg/L (Table 40). The highest cefiderocol MICs observed
for collection II strains were 16 mg/L. Cefiderocol inhibited all seven carbapenemase-
producing A. baumannii at 0.25 mg/L. MIC50/90 values for Enterobacterales (n=30) and P.
aeruginosa (n=22) were 1/4 mg/L and 0.5/2mg/L, respectively.
Table 40: MIC of cefiderocol and comparators in Germany
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5.4.1.5.2 Greece [252]
A total of 471 (445 meropenem resistant and 26 meropenem intermediate) isolates, collected
from ICUs and wards of 18 Greek hospitals, were included [282 Enterobacteriaceae (244 K.
pneumoniae, 1 Klebsiella oxytoca, 14 Enterobacter cloacae, 11 Providencia stuartii, 7 E. coli,
4 Proteus mirabilis and 1 Serratia marcescens) and 189 non-fermentative Gram-negative
bacteria (107 A. baumannii and 82 P. aeruginosa). Table 41 shows the summary data of the
MIC range, MIC50 and MIC90 of the antibacterials for the tested bacterial isolates and their
respective resistance percentages.
Resistance to colistin was observed in 154 isolates [including: 91 K. pneumoniae isolates
(37.2% of all K. pneumoniae); 45 A. baumannii isolates (42.1% of all A. baumannii); 1 P.
aeruginosa isolate and 2 E. coli isolates]. The MIC range, MIC50 and MIC90 of cefiderocol did
not differ between colistin-resistant and colistin-susceptible A. baumannii isolates.
Table 41: MIC of cefiderocol and comparators in Greece
5.4.1.5.3 Italy [260]
42 MDR strains, previously characterized for their β-lactamases content, including 13
Klebsiella pneumoniae, 9 Escherichia coli, 5 Proteus mirabilis, 6 Pseudomonas aeruginosa, 6
Acinetobacter baumannii, 2 Enterobacter cloacae complex and 1 Aeromonas spp., were
tested for susceptibility to cefiderocol and comparators.
The cefiderocol MIC50 and MIC90 values (0.5 mg/L and 4 mg/L, respectively) were significantly
lower than comparators. In particular, cefiderocol showed a good in vitro activity (MIC≤4 mg/L)
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against: i) 20 carbapenemase-producing Enterobacterales (8 KPC, 3 VIM, 1 NDM, 4 OXA-48,
2 OXA-232, 2 NMC-A/IMI); ii) 6 ESBL-producing Enterobacterales (TEM-52,TEM-92,
PER1,VEB-6 + TEM-52, CTX-M-15, CTX-M-65); iii) one CMY-producing P. mirabilis; iv) 6
carbapenemase-producing P. aeruginosa (3 VIM, 1 FIM, 1 GES, 1 IMP);v) 5 A. baumannii (2
OXA-58, 1 OXA-23, 1 OXA-24, 1 ISAba1-OXA-51).
Cefiderocol was less active against a FOX-7-producing K. pneumoniae (MIC, 8 mg/L), an
NDM5-producing E. coli (MIC, >64 mg/L), an OXA-23-producing A. baumannii (MIC, >64
mg/L) and a PER-producing Aeromonas spp. (MIC, >64 mg/L).
High cefiderocol MIC values were not associated with any specific β-lactamase class.
5.4.1.5.4 Spain [257]
231 clinical isolates of Enterobacteriaceae (121 ESBL-and/or carbapenemase-producing K.
pneumoniae, and 4 carbapenemase-producing E. cloacae), 80 A. baumannii, six P.
aeruginosa, and 20 S. maltophilia were tested. Cefiderocol showed a potent in vitro activity
against the isolates analyzed, with MIC50 and MIC90 values between 0.125-8 mg/L and 0.5-8
mg/L, respectively, and 98% of isolates were inhibited at ≤4 mg/L. Only five isolates showed
a MIC of cefiderocol >4 mg/L, three ST2/OXA-24/40-producing A. baumannii, oneST114/ VIM-
1-producing E. cloacae, and one ST114 E. cloacae producing VIM-1 plus OXA-48. All KPC-
3-producing K. pneumoniae were susceptible to cefiderocol, even those resistant to
ceftazidime/avibactam (Table 42).
Table 42: MIC of cefiderocol and comparators in Spain
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5.4.1.5.5 United Kingdom and Ireland [253]
The test panel were 305 clinical Enterobacteriaceae submitted between 2008 -2016 and all
but 2 were from UK hospitals. The 2 non-UK isolates were from Ireland. The panel was
selected to represent diverse carbapenemase producers and those with carbapenem
resistance via combinations of porin loss with AmpC or ESBL activity. Carbapenemase genes
were identified by PCR or by whole genome sequencing.
Carbapenem resistance due to porin loss combined with ESBL or AmpC activity was inferred
from their previous susceptibility results and the absence of carbapenemases.
Comparator antibacterials comprised meropenem, ceftazidime, ceftazidime-avibactam,
cefepime, ceftolozane-tazobactam, aztreonam, colistin, amikacin, ciprofloxacin and
tigecycline. MICs were interpreted using CLSI guidelines where available, or EUCAST
breakpoints for ceftazidime-avibactam, tigecycline, and colistin.
Table 43: MIC of cefiderocol and comparators against in United Kingdom and Ireland
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Table 44: Activity of antimicrobial agents tested against carbapenem-resistant P. aeruginosa
and S. maltophilia
5.4.1.6 4) Independent validation study by Swiss scientists based on world-wide
pathogens [258]
A total of 753 clinical multidrug-resistant isolates were evaluated in this study. They were
representative of the most widespread and broad-spectrum mechanisms of resistance
currently observed worldwide in Gram-negative bacteria. The strains were collected from
hospitals worldwide (42 countries) from 2000 to 2016, with a majority dating from the 2012–
2016 period. They were of various origins (not always recorded) but mostly from urines,
broncho-alveolar specimens, blood, pus, and stools (Table 45).
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Table 45: MIC of cefiderocol and comparators for MDR-GN isolated
5.4.1.7 5) In vitro studies investigating resistance of pathogens against
cefiderocol [61, 62] [261]
Cefiderocol activity against strains with porin channel mutations and overexpression of efflux
pumps has been demonstrated in two in vitro studies [61, 62].
A study assessing contribution of active iron transporters and binding ability to PBPs of
cefiderocol to its antibacterial/bactericidal activity against K. pneumoniae and E. coli compared
to meropenem and ceftazidime, reported that neither porin mutations nor single iron transport
mutations result in clinically relevant increases of cefiderocol MICs, probably due to the active
siderophore transport system and β-lactamase stability [62].
Another in vitro study assessed contribution of chelating ability with iron (III) and the utilization
of iron transporters through the outer membrane to the in vitro activity of cefiderocol against
P. aeruginosa compared to other siderophore compounds (hydroxypyridone-substituted
siderophore monobactams BAL30072, MB-1 and SMC-3176) [61]. The results suggest that
cefiderocol is active against the mutants with multiple transporters with MIC of 2 µg/mL while
other siderophore beta-lactams demonstrated lower activity. Of note, cefiderocol antibacterial
activity was not affected by major efflux pump MexAB-OprM of P. aeruginosa, which is known
to confer multidrug resistance (MDR) [61].
In the latest update of resistance investigations of the SIDERO-WT collection, Ito et al.
reported overall low rates of resistance against cefiderocol (Ito et al., Poster presentation,
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ASM Microbe 2019). The authors followed up with additional characterizations of the mutant
strains identified in the SIDERO-WT-2014 subsample (red box in Table 46 below).
Table 46: Number of cefiderocol non-susceptible isolated in global surveillance studies (MIC ≥8
μg/mL)
Among the 38 isolates tested, 25 strains were Acinetobacter baumannii possessing PER β-
lactamase isolated in Russia (18 isolates), Turkey (6 isolates) and Sweden (1 isolate), and 5
isolates were Klebsiella pneumoniae possessing NDM carbapenemase from Turkey. The
addition of avibactam resulted in a ≥4-fold decrease of cefiderocol MIC to ≤0.5 μg/mL in 33
isolates that did not harbor NDM. Against the 5 isolates containing NDM, the addition of either
DPA or avibactam did not decrease the MIC of cefiderocol, but the addition of both avibactam
and DPA showed ≥8-fold decrease of the MIC to cefiderocol to ≤0.5 μg/mL. In contrast,
meropenem MIC showed ≥64-fold decrease with the addition of DPA alone against these
NDM-producing isolates. Additional testing of a further collection of 46 PER-producing isolates
from IHMA confirmed that 43 had cefiderocol MIC of ≤4 μg/mL.
The authors concluded that the findings suggest that the high MICs observed were unlikely
due to the presence of PER or NDM alone.
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5.4.1.8 Summary Analysis: Expected comparative susceptibility
To determine susceptibility of Gram-negative bacteria to cefiderocol, multinational surveillance
studies (SIDERO) were conducted over four consecutive years (2014 to 2018) using
systematically collected clinical isolates from approximately 100 clinical laboratories in North
American and European countries. A separate multinational surveillance study of Proteeae
clinical isolates was also conducted. The antibacterial activity of cefiderocol was determined
in iron-depleted cation-adjusted Mueller-Hinton broth medium (ID-CAMHB) medium, a method
approved by the Clinical and Laboratory Standards Institute (CLSI). Comparators were tested
in parallel using standard cation- adjusted Mueller-Hinton medium according to CLSI
recommendations.
In February 2020, EUCAST defined a new clinical breakpoint for cefiderocol of 2 μg/mL for P.
Aeruginosa and Enterobacterales. For A. baumanii and S. maltophilia, was proposed
insufficient evidence (IE) refering to PK-PD breakpoints of 2 μg/mL (table below), which were
used for this analysis. For the comparators, EUCAST breakpoint (version 9.0) were used in
the analysis. In the absence of species specific breakpoint, PK/PD breakpoint were applied.
For colistin, PK/PD breakpoint were not available so the analysis considered the
Pseudomonas breakpoint of 2 μg/mL as an arbitrary breakpoint for Stenotrophomonas sp. and
Burkholderia sp.
Table 47: EUCAST breakpoints for cefiderocol
Species Sensitive (≤) Resistant (>)
PK-PD breakpoints 2 μg/mL 2 μg/mL
Enterobacterales 2 μg/mL 2 μg/mL
Pseudomonas Aeruginosa 2 μg/mL 2 μg/mL
Acientobacter baumanii 2 μg/mL 2 μg/mL
Stenotrophomonas maltophilia 2 μg/mL 2 μg/mL
In total and for all infection sites, 20911 isolates were collected between 2013 and 2018 from
11 European countries. Out of the 20911 isolates, Enterobacterales represented 66.5 % of
the pathogens, Acinetobacter spp. 12.7%, Burkholderia sp 0.7 %, Pseudomonas aeruginosa
16.1% and Stenotrophomonas maltophilia 3.9%.
Susceptibility for cefiderocol and the comparators was estimated in different subgroups of
pathogens, suspected MDR/CR infections were defined as pathogens resistant to both
ciprofloxacin and cefepime simultaneously.
Theoretical success in suspected MDR/CR infections was estimated for each antibacterial
agent tested by combining the ECDC Epidemiological data of GN pathogen distribution in
each individual infection site with the susceptibility to each antibacterial agent.
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Table 48 and Table 49 (A-D) below summarize the results of such analyses for four different
infection sites and the respective relevant comparators:
Table 48: Susceptibility to Cefiderocol and comparators in all sites of infections for MDR3
pathogens
Table 49- Theoretical success of antibacterial therapy in Gram‐negative 3MDR pathogens in gastrointestinal site of infections (A) Pneumonia; (B) cUTI; (C) BSI; (D) Gastrointestinal
(A)
(B)
(C)
(D)
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Regardless of the infection sites, cefiderocol demonstrated the highest theoretical success
compared with meropenem, ceftolozane/tazobactam, ceftazidime/avibactam or colistin,for
pre-emptive therapy in suspected MDR/CR infections.
Table 50: Summary table Theoretical percentage of success for Gram‐negative antibacterial
therapy on aerobic Gram‐negative pathogens in different infection type
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5.4.2 Individual study results (PK/PD data, study report S-649266-CPK-004-B)
This section summarizes the methodology, underlying assumptions, and main findings from
extensive population PK/PD modelling efforts for ceficerocol. The full study report of the
PK/PD population model (S-649266-CPK-004-B) is included in the submission.
5.4.2.1 Model description
A population pharmacokinetic (PK) analysis was performed to develop a model using a total
of 3427 plasma concentration data of cefiderocol from the single ascending dose
(SAD)/multiple dose (MAD) study (1203R2111), the renal impairment study (1222R2113), the
phase 2 APEKS-cUTI study (1409R2121), the phase 3 CREDIBLE-CR study (1424R2131),
and the phase 3 APEKS-NP study (1615R2132).
A 3-compartment model was used to describe the plasma concentrations of cefiderocol. The
covariates explored included creatinine clearance calculated by Cockcroft-Gault equation
(CrCL), body weight, age, albumin concentration, aspartate aminotransferase , alanine
aminotransferase, total bilirubin, sex, race, infection (no infection, complicated urinary tract
infection [cUTI] or acute uncomplicated pyelonephritis [AUP] in the phase 2 study, cUTI in the
CREDIBLE-CR study, bloodstream infections/sepsis [BSI/sepsis], either hospital-acquired
pneumonia [HAP]/ventilator-associated pneumonia [VAP]/healthcare-associated pneumonia
[HCAP] in the CREDIBLE-CR study, and HAP/VAP/HCAP in the APEKS-NP study), and
ventilation (with or without mechanical ventilation during PK sampling). CrCL was the most
significant covariate on cefiderocol total clearance (CL), as expected. Observed plasma
cefiderocol concentrations were adequately described by the developed final model.
5.4.2.2 Results
Individual maximum concentration (Cmax), daily area under the concentration-time curve
(AUC) at steady state, percentage of time for which free drug concentration in plasma exceeds
minimum inhibitory concentration (MIC) over dosing interval (%fT>MIC), and the %fT>MIC
with MIC of 4 μg/mL (%fT>4) were predicted using Monte Carlo simulation of 1000 virtual
patients for each infection sites. The ELF concentrations of cefiderocol in patients with
pneumonia were predicted using a developed ELF model based on the ELF concentrations in
20 healthy subjects and 7 ventilated patients with pneumonia. The ELF compartment was
linked with plasma compartment in the population PK model. The
probabilityPTAPTAprobabilityPTA of target attainment for cefiderocol in ELF was also
estimated usingwithwithusingwith Monte-Carlo simulations. A thousand virtual patients with
pneumonia were generated for the simulations [251].
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Probability of target attainment (PTA) were simulated to achieve 75%T>MIC for the different patient population in plasma and in ELF, depending
on the renal function and dose adjustment required.
Table 51: PTA per infectious disease renal function, and dose
Target
fT>MIC
PK variable Infection disease
Renal Function Regimena
MIC (µg/mL)
0.25 0.5 1 2 4 8 16
75% Plasma HAP/VAP/HCAP Augmented 2 g q6h 100 100 100 100 99.7 94.5 60.4
Normal 2 g q8h 100 100 100 99.9 98.9 87.1 43.4
Mild 2 g q8h 100 100 100 100 99.8 97.0 69.7
Moderate 1.5 g q8h 100 100 100 100 99.9 98.7 83.3
Severe 1 g q8h 100 100 100 100 100 99.9 90.7
ESRD 750 mg q12h 100 100 100 100 100 99.6 86.3
BSI/sepsis Augmented 2 g q6h 100 100 100 100 99.4 91.3 49.6
Normal 2 g q8h 100 100 100 99.9 97.3 80.6 32.6
Mild 2 g q8h 100 100 100 99.9 99.6 94.4 57.7
Moderate 1.5 g q8h 100 100 100 100 99.9 98.0 74.8
Severe 1 g q8h 100 100 100 100 100 99.8 84.8
ESRD 750 mg q12h 100 100 100 100 100 99.2 79.2
cUTI/AUP Augmented 2 g q6h 100 100 100 100 99.9 96.9 73.3
Normal 2 g q8h 100 100 100 100 99.6 93.6 56.3
Mild 2 g q8h 100 100 100 100 99.8 98.4 81.2
Moderate 1.5 g q8h 100 100 100 100 100 99.6 90.4
Severe 1 g q8h 100 100 100 100 100 100 95.9
ESRD 750 mg q12h 100 100 100 100 100 100 91.6
ELF HAP/VAP/HCAP Augmented 2 g q6h 100 100 100 99.8 92.1 55.9 11.0
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Normal 2 g q8h 100 100 100 99.6 88.5 45.3 6.8
Mild 2 g q8h 100 100 100 99.8 94.1 62.1 16.2
Moderate 1.5 g q8h 100 100 100 100 96.5 67.6 19.3
Severe 1 g q8h 100 100 100 99.9 98.0 75.4 27.1
ESRD 750 mg q12h 100 100 100 99.9 94.7 64.7 21.9
Augmented: CrCL ≥ 120 mL/min (120 to < 150 = 50%; ≥ 150 = 50%). Normal: CrCL 90 to < 120 mL/min.
Mild: CrCL 60 to < 90 mL/min. Moderate: CrCL 30 to < 60 mL/min. Severe: CrCL 15 to < 30 mL/min. ESRD: CrCL 5 to < 15 mL/min.
PTA for 75% fT>MIC was above 97% for a MIC of 4 mg/L regardless of the site of infection or the renal function. In the ELF, PTA for 75% fT>MIC
was above 88% for a MIC of 4 mg/L confirming the adequacy of the dosing regimen in the different patient populations.
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5.4.3 Retrospective analysis of cefiderocol and comparators by population
PK/PD simulation
A retrospective analysis was performed comparing the probability of target attainment
(PTA) for cefiderocol, ceftolozane/tazobactam and meropenem against
Enterobacterales and Pseudomonas aeruginosa in a representative patient population
at risk of MDR or carbapenem resistant infections. Published pharmacokinetic (PK)
models for meropenem and ceftolozane/tazobactam, and an existing model for
cefiderocol, were used with standard dosage regimens for simulating individual PK
data. The intial list of comparators included ceftazidime/avibactam and colistin, but this
proved not possible to include:
the model implemented for ceftazidime-avibactam could not be appropriately
validated.
the model for colistin, required information about the correlation matrix, and the
nature of the parameter values reported in the original colistin model article,
which was not made available by the original model’s authors.
PTA for clinically relevant pharmacokinetic/pharmacodynamic (PK/PD) targets was
calculated from steady state PK profiles for a range of minimum inhibitory
concentrations (MICs). The calculated PTAs in plasma for the 3 antimicrobials were
above 95% at their respective MIC corresponding to their EUCAST breakpoints
confirming published results. Cumulative fractions of response (CFRs) were also
calculated to estimate using European MIC distributions from the SIDERO surveillance
selected for being resistant to two antibiotic classes (quinolone and cephalosporins)
and thereby representative of a patient population at risk of MDR infections. CFR
analysis was performed on selected European isolates already resistant to cefepime
and ciprofloxacin. In this patient population infected with suspected MDR/CR
pathogens, CFRs were 97.4% and 99.8% for cefiderocol for Enterobacterales and
Pseudomonas spp. respectively. The cumulative fractional responses for cefiderocol
against Enterobacterales and Pseudomonas spp. are considerably higher than seen
for meropenem and ceftolozane-tazobactam. Despite the simulation of high dose,
extended infusion of meropenem CFRs were 91.2% for Enterobacterales but only
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68.4% for Pseudomonas spp. The dose simulated for ceftolozane/tazobactam is also
a high dose applied for the treatment of nosocomial pneumonia however due to the
selected suspected MDR/CR isolates CFRs were only 67.2% for Enterobacterales and
55.2% for Pseudomonas spp.
Table 52. Estimated CFR for MIC distributions corresponding to Enterobacterales and Pseudomonas spp. More simulation results for corresponding PTA, MIC and T>MIC target values are shown in Appendix C. The applied MIC distributions can be seen in Appendix D of the study report.
Cefiderocol Meropenem Ceftolozane-tazobactam*
MIC distribution: Cumulative fraction of response, CFR (%) xxx
Enterobacterales 97.4 91.2 67.2
Pseudomonas spp. 99.8 68.4 55.2
Meaningful comparisons could be made between the performances of the models for
cefiderocol, meropenem and ceftolozane-tazobactam. The simulations showed a
superior performance of cefiderocol against Enterobacterales and Pseudomonas spp
in terms of cumulative fraction of response when compared with meropenem and
ceftolozane/tazobactam (Table 52). It should be noted, though, that the meropenem
model exhibited a very long terminal half-life for the drug in plasma, probably reflecting
that the experimental data originate from a patient population where the majority of the
patients had bloodstream infections.
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5.4.4 Clinical study results (clinical outcomes)
Each section begins with a summary of the results for the respective primary endpoint, followed
by summaries of relevant secondary endpoints in the order shown below. Detailed results (e.g.,
stratifications by pathogen) are provided in 5.4.3 [262, 263]. The section on APEKS-cUTI
contains additional results from a network-meta-analysis.
The Table 53 below summarizes the endpoint analyses requested by EUnetHTA in the scoping
process. In the following sections, the results for each of these endpoints are presented, if
applicable.
EA: early assessment; EOT: end of treatment; TOC: test of cure; FUP: follow up; EOS: end of
study; NR: not relevant; NA: not applicable
Table 53: Endpoint Analysis as per EUnetHTA Request
Study Endpoint/Analysis Available
time points
Stratifi-
cation
by
infection
site
Stratification
by pathogen
Primary
endpoint?
APEKS-
cUTI
Clinical outcome EA, EOT,
TOC, FUP
NA
No. Pathogen
specific data
detailed
results on file
[262]
No
Composite
microbiological
eradication and
cure
EA, EOT,
TOC, and FUP
Yes (at TOC)
Microbiological
eradication
EA, EOT,
TOC, FUP
No
All-cause mortality
at day 14 and 28
NR No
Changes of MIC or
appearance of
resistant bacteria
At EOS
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Network meta-
analysis (NMA)
Clinical Cure
and
microbiological
eradication at
TOC and FU
Not relevant
APEKS-NP Clinical outcome TOC NA
Main
pathogens
No
Microbiological
eradication
EA, EOT,
TOC, FUP
Main
pathogens
No
All-cause
mortality
Day 14, day
28
Yes Yes, day 14
ACM
CREDIBLE-
CR (only
descriptive
results)
Clinical outcome EOT, TOC, FU Yes Main
pathogens
and non-
fermenters
Yes, for
HAP/VAP/HCAP
and BSI/sepsis
Microbiological
eradication
EOT, TOC, FU Yes Yes, for cUTI
All-cause mortality
(part of safety
assessment in
study protocol)
Day 14, day
28, EOS
Yes No
Blue font: primary endpoint
5.4.4.1 APEKs-cUTI
APEKS-cUTI was a Phase 2, multicentre (multinational), double-blind, randomised, active-
controlled, parallel-group study including 452 patients diagnosed with complicated urinary tract
infection [51] Clinicaltrials.gov Record NCT02321800).
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The Figure 29 below summarizes the trial design and displays relevant endpoints.
Figure 29: APEKS-cUTI study design and endpoints
5.4.4.1.1 APEKS-cUTI primary efficacy endpoint: composite clinical
and microbiological response at TOC in the mITT population
Primary efficacy endpoint analysis
In accordance to the FDA guidelines, the primary efficacy endpoint is the composite of clinical
outcome and microbiological outcome at TOC. The response rate for the primary efficacy
endpoint was 72.6% (183/252) of subjects in the cefiderocol group and 54.6% (65/119) of
subjects in the IPM/CS group.
In a post-hoc analysis, the adjusted treatment difference was 18.58% (95% CI; 8.23%, 28.92%)
in favor of cefiderocol (Figure 30) demonstrated superiority; it and met the criterion for
noninferiority at the prespecified 20% and 15% margins (the lower limit of the 95% CI was
8.23% and exceeded both -15% and -20%). In addition, as it exceeded zero, which is
consistent with the superiority of cefiderocol compared with IPM/CS this was further confirmed
to be statistically significant (p=0.0004). Similar results were observed in the sensitivity analysis
(composite clinical and microbiological response in ME population) [51, 236].
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Table 54: Summary for Composite of Clinical and Microbiological Outcome by Time
Point (Microbiological Intent-to-Treat Population)
Figure 30: Primary efficacy results: Composite outcome at TOC in the MITT population
(Clinical and microbiological response)
[a]Treatment difference (cefiderocol minus
imipenem/cilastatin) is the adjusted estimate
of the difference in the responder rate
between the 2 treatment arms, calculated
using a stratified analysis with Cochran-
Mantel-Haenszel weights based on the
stratified factor at baseline (cUTI with or
without pyelonephritis vs acute
uncomplicated pyelonephritis). CI,
confidence interval; MITT, modified intent-to-
treat; TOC, test of cure. Source: Portsmouth,
2018 [51]; Data on file [236]
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Treatment differences by clinical diagnosis were consistent with the treatment difference in the
mITT population, with cefiderocol demonstrating higher efficacy rates than IPM/CS in patients
with cUTI with or without pyelonephritis, and with acute uncomplicated pyelonephritis (Figure
31) [51, 236]. The treatment differences by gender and age were also consistent with the
treatment difference for the primary analysis (Figure 31) [51, 236].
Figure 31: Primary efficacy results: Composite outcome at TOC by predefined subgroups
aTreatment difference (cefiderocol minus imipenem/cilastatin) is the adjusted estimate of the
difference in the responder rate between the 2 treatment arms, calculated using a stratified
analysis with Cochran-Mantel-Haenszel weights based on the stratified factor at baseline (cUTI
with or without pyelonephritis vs acute uncomplicated pyelonephritis); bMITT population
included all patients who received at least one dose of study drug and had a qualifying baseline
Gram-negative uropathogen (≥1×10⁵ CFU/mL). CFU, colony forming units; CI, confidence
interval; cUTI, complicated urinary tract infection; MITT, modified intent-to-treat; NI, non-
inferiority; TOC, test of cure. Source: Portsmouth S, et al. Lancet Infect Dis 2018;18:1319–28.
Composite clinical and microbiological response at TOC across different pathogens
For E. coli and Klebsiella spp. pneumoniae. the most frequently observed pathogens, the
treatment difference between both arms was preserved. The composite of microbiological
eradication and clinical response was higher in the cefiderocol group and the treatment
difference was statistically significant with a treatment difference of 15.53% for E. coli and
25.91% for Klebsiella spp. (Table 55) [51, 236]. Other uropathogens occurred at a low
frequency (in less than 10 patients in at least 1 of the groups) and therefore a statistical
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comparison could not be made for either clinical response or microbiological eradication [51,
236].
Table 55: Composite of Clinical Response and Microbiological Outcome per
Pathogen at TOC (microbiological ITT population)
Pathogen
Percent Response % (n/N) Treatment Difference (95%CI)
Cefiderocol
Imipenem/ Cilastatin
E. coli 74.0 (108/146)
58.4 (45/77)
15.53 (2.42-28.64) *
K. pneumoniae
73.9 (34/46)
48.0 (12/25)
25.91 (2.58-49.25) *
P. aeruginosa
46.7 (7/15)
50.0 (2/4)
-3.33 (NA)
P. mirabilis
69.2 (9/13)
0.0 (0/1) 69.23 (NA)
CI - confidence Interval; NA, not available; * significant difference
Additional detailed stratified results for the primary endpoint by uropathogen are
on file[262, 263].
5.4.4.1.2 APEKS-cUTI secondary endpoint: Clinical Outcome
Clinical Outcome per Subject at EA, EOT, TOC, and FUP
At TOC, clinical response was 89.7% (226/252) of subjects in the cefiderocol group and 87.4%
(104/119) of subjects in the IPM/CS group. At FUP, sustained clinical response was higher in
the cefiderocol group (81.3% [205/252] of subjects) than in the IPM/CS group (72.3% [86/119]
of subjects), with an adjusted treatment difference of 9.02% (95% CI; -0.37%, 18.41%) (Table
56).
Clinical response rates for the ME Population (Table 14.2.5.1.2 of the CSR) were similar to the
Micro-ITT Population, with sustained clinical response at FUP in the cefiderocol group (85.1%
[194/228]) higher than in the IPM/CS group (78.3% [83/106]). Results were otherwise similar
for both treatment groups and assessment time points for this population.
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Table 56: Summary of Clinical Outcomes per Subject by Time Point
(Microbiological Intent-to-Treat Population)
Stratified analyses: Clinical Outcome by Baseline Uropathogens at EA, EOT, TOC, and FUP
The summary of clinical outcome per uropathogen by time point (4 major uropathogens: E.
coli, K. pneumoniae, P. aeruginosa, and P. mirabilis) for the Micro-ITT Population is shown in
Table 57. For each of the major pathogen cefiderocol demonstrated no significant treatment
difference in clinical outcome at any of the assessment time point. Additional detailed stratified
analyses per pathogen and time point are on file [262, 263].
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Table 57: Summary of Clinical Outcome per Uropathogen (E. coli, K. pneumoniae,
P. aeruginosa, and P. mirabilis) by Time Point (Microbiological ITT Population)
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5.4.4.1.3 APEKS-cUTI secondary endpoint: Microbiological outcome
The microbiological eradication rate in the mITT Population (Table 58) was statistically
significantly higher at TOC in the cefiderocol group (73.0% [184/252] of subjects) compared
with the IPM/CS group (56.3% [67/119] of subjects). The adjusted treatment difference of
17.25% (95% CI; 6.92%, 27.58%) in favor of the cefiderocol group was statistically significant
and clinically meaningful. Results for both treatment groups were similar at EA and at EOT.
The sustained microbiological eradication rate at FUP was also higher in the cefiderocol group
(57.1% [144/252] of subjects) compared with the IPM/CS group (43.7% [52/119] of subjects).
The adjusted treatment difference of 13.92% (95% CI; 3.21%, 24.63%) in favor of the
cefiderocol group was statistically significant and clinically meaningful.
Table 58: Summary of Microbiological Outcome per Subject by Time Point
(Microbiological ITT Population)
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Results for both treatment groups showed no significant difference at EA and at EOT. The
sustained microbiological eradication rate at FUP was also statistically significantly higher in
the cefiderocol group (57.1% [144/252] of subjects) compared with the IPM/CS group (43.7%
[52/119] of subjects).
The adjusted treatment difference of 17.83% (95% CI; 7.42%, 28.24%) for the microbiological
eradication rate at TOC between the treatment groups in the ME Population (Table 14.2.2.1.2
of the CSR) was similar to the results in the Micro-ITT Population.
Microbiological Outcome per Uropathogen at EA, EOT, TOC, and FUP
The summary of microbiological outcome per uropathogen by time point (for the 4 most
frequent uropathogens E. coli, K. pneumoniae, P. aeruginosa, and Proteus mirabilis) for the
Micro-ITT Population is shown in Table 59.
Summaries of microbiological outcomes per uropathogen by time point for all uropathogens
and per uropathogen group by time point are on file[262, 263]. For the most frequently
isolatedisolated uropathogens, E. coli and K. pneumoniae, eradication at EA and EOT was not
different between the treatment groups. For E. coli at TOC and FUP an adjusted treatment
difference of 16.77% and 18.10%, respectively, was demonstrated, and this difference is
consistent with the microbiological responses in the overall population. For K. pneumoniae, an
adjusted treatment difference of 23.00% at TOC was observed, followed by a treatment
difference of 6.33% at FUP.
These results demonstrate the microbiological efficacy of cefiderocol, which is consistently
better than IPM/CS for these uropathogens.
Similar responses were seen in the ME Population for both pathogens; however, for K.
pneumoniae, the difference between the 2 treatment groups for sustained eradication at FUP
was minimal (3.13%) [237].
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Table 59: Summary of Microbiological Outcome per Uropathogen (E. coli, K.
pneumoniae, P. aeruginosa, P. mirabilis) by Time Point (Microbiological ITT
Population)
All rights reserved 206
All rights reserved 207
5.4.4.1.4 APEKS-cUTI secondary endpoint: New Infection and
Superinfection during the Study
No new infections were noted. Superinfection, defined as an uropathogen emerging during
study drug therapy, was limited to a single occurrence of E. coli in 1 subject (Subject 143-002)
in the cefiderocol group. The subject had E. coli isolated from the urine at the EA visit (Table
14.2.4.1.1 of the CSR). Of note, this subject had P. aeruginosa alone isolated at baseline and
was treated for 10 days with cefiderocol. The E. coli superinfection was sensitive to
levofloxacin, cefepime, and IPM, and the MIC for cefiderocol was 0.12 μg/mL. Both E. coli and
P. aeruginosa were eradicated at TOC, and P. aeruginosa alone was isolated at FUP.
There were 8.3% (21/252) of subjects in the cefiderocol group and 15.1% (18/119) of subjects
in the IPM/CS group who had new uropathogens that emerged after the EOS drug therapy in
the mITT Population [262, 263]. Numbers of isolates for each pathogen identified and tested
for susceptibility were small (the largest number was for E. coli, with 8 isolates in the cefiderocol
group and 3 isolates in the IPM/CS group); hence no meaningful comparisons or conclusions
could be made.
In conclusion, the cUTI study demonstrated that in a hospitalized population of 448 patients,
with multiple comorbidities and difficult-to-treat infections caused by MDR pathogens sensitive
to imipenem, cefiderocol was non-inferior to a standard-of-care antibacterial comparator,
IPM/CS. Although the study was only designed to demonstrate non-inferiority, the findings of
a post-hoc analysis were consistent with superiority for cefiderocol. The adjusted treatment
difference favored cefiderocol and the lower limit of the 95 % confidence interval exceeded 0.
The absolute difference of 18.58% in the composite primary endpoint was supported across
all analyzed populations and clinical diagnostic groups with cUTI. The magnitude of the
observed treatment differences is considered clinically important. Sensitivity analyses also
showed that cefiderocol had better microbiological efficacy than IPM/CS in predefined
subgroups and in patients infected with E. coli and K. pneumoniae, the most prevalent
uropathogens.
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5.4.4.2 APEKS-cUTI Network Meta-Analysis (NMA)
Feasibility for an NMA was conducted based on APEKS cUTI study (full detailes of the SLR
and feasibility assessment can be found in [227]). The patient populations and most
importantly, the pathogens included in the different trials were similar, enabling a small NMA
to be conducted based on data from a YHEC SLR and feasibility assessment. The following
analyses were conducted using a fixed effects model (frequentist analysis) as well as a
Bayesian analysis:
Microbiological eradication at TOC and at FU visit
Clinical cure at TOC visit and FU visits
Any adverse event
Any ‘drug related’ adverse event
It should be noted that several of the outcomes and timepoints were infeasible due to
insufficient reporting and 100% events (the equivalent of 0 events). Full report of the NMA
analysis are provided as an attachment [264].
Also, the Figure 32 below reflects the maximum network diagram, of which TANGO II study
was then removed because of significant differences the baseline patient population (patients
were included after CR confirmation), therefore preventing the inclusion of TANGO I and ZEUS
trials in the network:
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Figure 32: Maximum Network Chart for Network Meta-analysis
The most extensive network could be constructed for the microbiological eradication secondary
outcome is displayed in Figure 33 below:
Figure 33: Network Diagram for Microbiological Eradication Secondary Outcome
Consistent with the clinical trials results, the results in Figure 34 show a trend favouring
cefiderocol, and there were significant differences in microbiological eradication rates at TOC
between cefiderocol and imipenem/cilastatin and BAT in the frequentist analysis, respectively.
This is due to superior results in the APEKS-cUTI for cefiderocol vs IPM-CIL (73% vs 56%)
compared to Vasquez for CZA vs IPM-CIL (67% vs 63%). The Bayesian analysis (on the right)
is consistent with frequentist analysis, showing the same trends but without reaching statistical
significant difference:
Legends:
BAT: best available therapy C_T: ceftazalone-tazobactam CZA: ceftaz idime-avibactam DOR: doripenem FDC: cefiderocol IPM_CIL: imipenem/cilastatin LVX: levofloxacin
All rights reserved 210
Figure 34: Microbiological Eradication Rates at TOC - Frequentist Analysis
Figure 35: Microbiological Eradication Rates at TOC - Bayesian Analysis
Similar results and trends were obtained for the microbiological eradication at follow-up in a
smaller network.
Clinical cure endpoint was evaluated in a smaller network as shown in Figure 36 below.
Figure 36: Network Diagram for Clinical Cure Outcome
Legends:
BAT: best available therapy C_T: ceftazalone-tazobactam CZA: ceftaz idime-avibactam DOR: doripenem FDC: cefiderocol IPM_CIL: imipenem/cilastatin LVX: levofloxacin
Legends:
BAT: best available therapy C_T: ceftazalone-tazobactam CZA: ceftaz idime-avibactam DOR: doripenem FDC: cefiderocol IPM_CIL: imipenem/cilastatin LVX: levofloxacin
Legends:
BAT: best available therapy C_T: ceftazalone-tazobactam CZA: ceftaz idime-avibactam DOR: doripenem FDC: cefiderocol IPM_CIL: imipenem/cilastatin LVX: levofloxacin
All rights reserved 211
The safety analysis based on “any adverse event” resulted in the largest network (Figure 37):
Figure 37: Clinical cure rates at TOC - Frequentist Analysis
Figure 38: Clinical Cure rate at TOC - Bayesian Analysis
Figure 39: Clinical cure rates at FU - Frequentist Analysis
The results did not show any statistically significant difference in clinical cure rates
at TOC between cefiderocol and comparators both frequentist (Figure 37) and
Bayesian analysis. However, in the analysis for clinical cure in the FU visit, show
Legends:
BAT: best available therapy C_T: ceftazalone-tazobactam CZA: ceftaz idime-avibactam DOR: doripenem FDC: cefiderocol IPM_CIL: imipenem/cilastatin LVX: levofloxacin
Legends:
BAT: best available therapy C_T: ceftazalone-tazobactam CZA: ceftaz idime-avibactam DOR: doripenem FDC: cefiderocol IPM_CIL: imipenem/cilastatin LVX: levofloxacin
Legends:
BAT: best available therapy C_T: ceftazalone-tazobactam CZA: ceftaz idime-avibactam DOR: doripenem FDC: cefiderocol IPM_CIL: imipenem/cilastatin LVX: levofloxacin
All rights reserved 212
a trend favouring cefiderocol, and there were statistically significant differences
in clinical cure rate at FU between cefiderocol and imipenem/cilastatin in the
frequentist analysis (Figure 39). Again.this is due to the superior results in APEKS
cUTI for cefiderocol vs IPM-CIL (81% vs 72%) compared to Vasquez for CZA vs
IPM-CIL (74% vs 67%). The Bayesian analysis (Figure 38) is consistent with
frequentist analysis, showing the same trends but without reaching statistical
significant difference.
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5.4.4.3 APEKs-NP clinical outcomes
The APEKS-NP study compared treatment with cefiderocol against high-dose, prolonged
infusion (HD) meropenem in patients with nosocomial pneumonia caused by suspected MDR
Gram-negative pathogens. 300 patients were randomized 1:1 to cefiderocol or HD
meropenem, a regimen only used in more difficult-to-treat pathogens which optimizes exposure
and efficacy for meropenem (Figure 40).
Figure 40: APEKS-NP study design
The dose of meropenem was increased from the labeled dose of 1 g to 2 g and extended to a
3-hour infusion to optimize the antibacterial activity of meropenem, at the request of regulators.
[265].
5.4.4.3.1 APEKS-NP primary efficacy endpoint: Day-14 ACM
Cefiderocol demonstrated noninferiority to high-dose extended infusion meropenem with
regard to all-cause mortality at Day 14. The all-cause mortality rate was 12.4% (18/145
subjects) for the cefiderocol group and 11.6% (17/146 subjects) for the HDhigh-doseHD
meropenem group, demonstrating the noninferiority of cefiderocol, as the upper limit of the
95% CI was < 12.5% (95% CI: −6.6, 8.2) (Figure 41).
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Figure 41: All-cause Mortality (mITT)
[a] Treatment difference (cefiderocol minus
meropenem) is the adjusted estimate of the
difference in the all-cause mortality rate at Day
14 and Day 28 between the 2 treatment arms
based on Cochran-Mantel Haenszel weights
using APACHE II score (≤ 15 and ≥ 16) as the
stratification factor.; [b] The 95% CI (2-sided)
is based on a stratified analysis using
Cochran-Mantel Haenszel weights using
APACHE II score (≤ 15 and ≥ 16) as the
stratification factor. The CI was calculated
using a normal approximation to the difference
between 2 binomial proportions (Wald method). Source: Data on file [239]
Table 60: Day 14 All-cause Mortality (mITT and ME-PP Populations)
Population Cefiderocol n/N’ (%)
HD Meropenem n/N’ (%)
Total n/N’ (%)
Treatment Differencea
Difference (%) 95% CIb p-value
mITT N = 145 18/145 (12.4)
N = 147 17/146 (11.6)
N = 292 35/291 (12.0)
0.8 (−6.6, 8.2) 0.0020c
0.8321d
ME-PP N = 105 13/105 (12.4)
N = 101 13/100 (13.0)
N = 206 26/205 (12.7)
−0.3 (−9.4, 8.7) nc
mITT excl meropenem resistante
N = 145 9/91 (9.9)
N = 147 10/90 (11.1)
N = 292 19/181 (10.5)
−1.3 (−10.1, 7.5)
nc
APACHE II = Acute Physiology and Chronic Health Evaluation II; CI = confidence interval; CLSI = Clinical and Laboratory Standards Institute; Day 14 ACM = all-cause mortality at Day 14 since first infusion of study drug; excl = excluding; ME-PP = microbiologically-evaluable per-protocol; mITT = modified intent-to-treat; n = number of subjects who died; nc = not calculated; N = number of subjects in the analysis set; N’= number of subjects with known survival status [a] Treatment difference (cefiderocol minus meropenem) is the adjusted estimate of the difference in the all-cause mortality
rate at Day 14 and Day 28 between the 2 treatment arms based on Cochran-Mantel Haenszel weights using APACHE II score (≤ 15 and ≥ 16) as the stratification factor.
[b] The 95% CI (2-sided) is based on a stratified analysis using Cochran-Mantel Haenszel weights using APACHE II score (≤ 15 and ≥ 16) as the stratification factor. The CI was calculated using a normal approximation to the difference between 2 binomial proportions (Wald method).
[c] p-value for non-inferiority hypothesis. [d] p-value for the superiority hypothesis. [e] Meropenem-resistant subjects were those subjects whose baseline Gram-negative pathogens were resistant to
meropenem based on CLSI susceptibility results. Subjects who did not have any susceptibility results available at baseline based on CLSI were not included for this analysis.
Source: Tables 14.2.1.1.1, 14.2.1.1.3, and 14.2.1.1.4
The sensitivity analysis of Day 14 all-cause mortality using the ME-PP population is in support
of the noninferiority finding in the primary efficacy population (Table 60). In a supplementary
analysis of the primary endpoint, in which subjects who were resistant to HD meropenem were
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excluded from the mITT population, Day 14 all-cause mortality was 9.9% in the cefiderocol
group and 11.1% in the HD meropenem group (Table 60).
Subgroup analyses revealed no statistically significant differences between the included
groups (Figure 42).
Figure 42: Primary efficacy results: Day 14 All-cause Mortality by Subgroups
Source: Data on file [239]
5.4.4.3.2 Secondary efficacy endpoints
Rates of microbiological eradication and clinical cure at TOC confirmed the non-inferiority
between the treatments (Table 61). The microbiological eradication at TOC was 47.6%
(59/124) in the cefiderocol group and 48.0% (61/127) in the HD meropenem group, and the
clinical cure at TOC was 64.8% (94/145) in the cefiderocol group and 66.7% (98/147) in the
HD meropenem group.
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Table 61: Secondary Endpoints (mITT Population)
Endpoint
Cefiderocol (N = 145) n/N’ (%)
HD Meropenem (N = 147) n/N’ (%)
Total (N = 292) n/N’ (%)
Treatment Comparison
Difference (%) 95% CI
Microbiological eradication at TOC
59/124 (47.6) 61/127 (48.0)
120/251 (47.8) -1.4 a (-13.5, 10.7) a
Clinical cure at TOC
94/145 (64.8) 98/147 (66.7)
192/292 (65.8) -2.0 a (-12.5, 8.5) a
Day 28 all-cause mortality
30/143 (21.0) 30/146 (20.5)
60/289 (20.8) 0.5b (-8.7, 9.8)b
EOS all-cause mortality
38/142 (26.8) 34/146 (23.3)
72/288 (25.0) 3.6b (-6.3, 13.4)b
APACHE II = Acute Physiology and Chronic Health Evaluation II; CI = confidence interval; EOS = end of study; mITT = modified intent=to-treat; TOC = test of cure [a] Treatment difference (cefiderocol minus meropenem) is the adjusted estimate of the difference in the eradication
rate or cure rate between the 2 treatment arms. The adjusted difference estimates and the 95% CIs (2-sided) were calculated using a stratified analysis with Cochran-Mantel-Haenszel weights based on the stratified factors at baseline, infection type (HABP/VABP/HCABP), and APACHE II score (≤ 15 and ≥ 16).
[b] Treatment difference (cefiderocol minus meropenem) is the adjusted estimate of the difference in the all-cause mortality rate at Day 28 or at the EOS visit between the 2 treatment arms based on Cochran-Mantel Haenszel weights using APACHE II score (≤ 15 and ≥ 16) as the stratification factor. The 95% CI (2-sided) is based on a stratified analysis using Cochran-Mantel Haenszel weights using APACHE II score (≤ 15 and ≥ 16) as the stratification factor. The CI is calculated using a normal approximation to the difference between 2 binomial proportions (Wald method).
Source: Tables 14.2.2.1.1, 14.2.3.1.1, 14.2.1.1.1, and 14.2.4.1.1
Cefiderocol has demonstrated similar all-cause mortality at Day 28, clinical and microbiological
outcomes to HD meropenem (Table 62) [239]. The microbiological eradication at TOC was
47.6% (59/124) in the cefiderocol group and 48.0% (61/127) in the HD meropenem group and
the clinical cure at TOC was 64.8% (94/145) in the cefiderocol group and 66.7% (98/147) in
the HD meropenem group [239]. All-cause mortality at Day 28 and at EOS was also similar
between the treatment groups [239].
Table 62: Secondary Endpoints (mITT Population)
Endpoint
Cefiderocol
(N = 145) n/N’ (%)
HD meropenem
(N = 147)
n/N’ (%)
Microbiological eradication at TOC 59/124 (47.6) 61/127 (48.0)
Clinical cure at TOC 94/145 (64.8) 98/147 (66.7)
Day 28 all-cause mortality 30/143 (21.0) 30/146 (20.5)
EOS all-cause mortality 38/142 (26.8) 34/146 (23.3)
EOS, end of study; TOC, test of cure
Source: Data on file [239]
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Efficacy data across different pathogens
A similar response between cefiderocol and HD meropenem was observed across different
pathogens (Table 63) [239].
Table 63: Clinical and microbiological outcome per baseline pathogen
Cefiderocol (n=145)
HD Meropenem (n=147)
Treatment comparison
Difference (%)
95% CI
Clinical cure at TOC (mITT)
K. pneumoniae 31/48 (64.6) 29/44 (65.9) −1.3 (−20.8, 18.1)
P. aeruginosa 16/24 (66.7) 17/24 (70.8) −4.2 (−30.4, 22.0)
A. baumannii 12/23 (52.2) 14/24 (58.3) −6.2 (−34.5, 22.2)
E. coli 12/19 (63.2) 13/22 (59.1) 4.1 (−25.8, 33.9)
Microbiological eradication at TOC (mITT)
K. pneumoniae 22/48 (45.8) 24/44 (54.5) −8.7 (−29.1, 11.7)
P. aeruginosa 9/24 (37.5) 11/24 (45.8) −8.3 (−36.1, 19.5)
A. baumannii 9/23 (39.1) 8/24 (33.3) 5.8 (−21.7, 33.2)
E. coli 10/19 (52.6) 11/22 (50.0) 2.6 (−28.0, 33.3) HD, high-dose; TOC, test of cure; Source: Data on file [239]
5.4.4.3.3 Efficacy data based on susceptibility to meropenem
In a subgroup analysis including a small sample of patients with meropenem-non-susceptible
Gram-negative pathogens (as per CLSI break point of 8mg/L), post hoc analyses of subjects
with values of > 16 μg/mL, > 32 μg/mL, and > 64 μg/mL, showed a trend of lower mortality in
the cefiderocol group than in the meropenem group at Day 14 and Day 28; however, the
sample sizes are too small to draw definitive conclusions (Figure 43) [239].
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Figure 43: Day 14 and Day 28 all-cause mortality according to MIC for meropenem
HD, high dose; MIC, minimum inhibitory concentration; Source: Data on file [239]
Microbiological and clinical outcomes at TOC in the subgroup of meropenem-nonsusceptible
subjects are shown in Table 64. The meropenem–nonsusceptible subgroup includes
intermediate and resistant categories of susceptibility. At TOC, the microbiological eradication
rate was 40.0% (14/35) in the cefiderocol group and 33.3% (10/30) in the meropenem group,
and the clinical cure rate was 57.1% (20/35) in the cefiderocol group and 56.7% (17/30) in the
meropenem group.
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Table 64: Microbiological and Clinical Outcome for the Meropenem-non-
susceptible Subgroup (mITT Population)
Meropenem-nonsusceptible Status = Yesa
Cefiderocol (N = 145) n/N’ (%)
HD Meropenem (N = 147) n/N’ (%)
Total (N = 292) n/N’ (%)
Treatment Comparisonb
Difference (%) 95% CI (N’ = 35) (N’ = 30) (N’ = 65)
Microbiological eradication at TOC
14 (40.0) 10 (33.3) 24 (36.9) 6.7 (-16.7, 30.1)
Clinical cure at TOC
20 (57.1) 17 (56.7) 37 (56.9) 0.5 (-23.7, 24.6)
CI = confidence interval; CLSI = Clinical and Laboratory Standards Institute; EOS = end of study; mITT = modified intent=to-treat; N’ = number of meropenem-nonsusceptible subjects; TOC = test of cure [a] The meropenem-nonsusceptible status for subjects was Yes if for any baseline Gram-negative pathogens
(including Stenotrophomonas maltophilia) the CLSI results were nonsusceptible to meropenem. Subjects who did not have any susceptibility results available at baseline based on CLSI were not included for this analysis.
[b] Treatment difference is cefiderocol minus meropenem. The 95% CIs (2-sided) of treatment difference were calculated using a normal approximation to the difference between the 2 binomial proportions (Wald method). The CIs for cure rates within a visit with less than 10 subjects in any treatment arm are not presented.
Source: Tables 14.2.2.1.4 and 14.2.3.1.4
When analyzing microbiological eradication rates based on different CLSI MIC for
meropenem in the non-susceptible group, data suggests that cefiderocol retains
microbiological eradication as MIC for meropenem increases, whereas for it HD
meropenem decreased (Figure 44).
Figure 44: Microbiological eradication by MIC at EOT
EOT, end of treatment; HD, high dose; MIC, minimum inhibitory concentration; Source: Data on file [239]
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Feasibility for NMA in nosocomial pneumonia:
A feasibility assessment was carried out for an NMA for APEKS-NP trial. It proved
not to be possible to conduct an NMA, given that the comparator used in APEKS
NP trial (HD meropenem) was not used in other trials alone, and there was no
bridging study. Even though the molecule is the same, this higher dose and
prolonged infusion optimizes efficacy of meropenem. In addition, APEKS NP
included difficult to treat pathogens such as Acinetobacter baumannii, which are
not included in other clinical trials because they are not susceptible to the newer
drugs. For full information on the feasibility assessment please refer to [227].
5.4.4.4 Comparative analysis of estimated success rates considering the European pathogen epidemiology in the population with suspected MDR/CR infections
In the absence of antibiogram, cefiderocol provides the best predicted susceptibility rates and
estimated success rates considering the European pathogen epidemiology
When critically ill patients require immediate treatment in the absence of AST, the likelihood of
treatment success with cefiderocol and comparators can be predicted through a simple
effectiveness model, that projects the clinical trials outcomes in terms of microbiological
eradication and clinical cure for each of antimicrobials, for a scenario where an antimicrobial
prescription is required in the absence of an antibiogram for a suspected MDR pathogen. This
analysis is therefore based on epidemiology (pathogen prevalence estimates for the specific
site of infection, taken from eCDC) and pathogen susceptibility results (taken from the SIDERO
studies, when selecting pathogens already resistant to ciprofloxacin and cefepime), relying on
drug’s ability to achieve effective concentrations to the infections site. This weighed
susceptibility is then overlaid with the individual relevant antimicrobial outcomes in the clinical
trials for each infection site.
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Results for cUTI and pneumonia are shown below [266-269].
Table 65: Susceptibility and effectiveness model predicting outcomes for
Cefiderocol versus comparators in UTI
UTI
Susceptibility
*EPI
Microbiological
eradication at TOC (m-
ITT) from clinical trials
Projected Microbiological
eradication at TOC in the
Suspected population
Clinical Cure at
TOC from
clinical trials
Projected Clinical
Cure at TOC in
the Suspected
antimicrobial
cefiderocol 94.28% 73.00%1 68.82% 89.70%1 84.57%
ceftolozane
/tazobactam 63.87% 80.40%2 51.35% 92.00%2 58.76%
ceftazidime
/avibactam 84.79% 77.40%3 65.63% 70.20%3 59.53%
Source: 1-APEKS cUTI trial; 2- EPAR for Zerbaxa [270] ; 3 RECAPTURE [271],
Results from this effectiveness model analysis showed that cefiderocol has a higher predicted
susceptibility rates in the European prevalent Gram-negative bacteria than comparators in
cUTI and higher projected treatment success rates both microbiological eradication and clinical
cure (Table 65). Given the higher susceptibility rates for cefiderocol, these results are generally
consistent with actual results from the APEKS cUTI trial, but not for comparators as the analysis
included pathogens for which they are not susceptible, situation that can occur in the need to
immediate treatment in the absence of an antibiogram.
Table 66: Susceptibility and effectiveness model predicting outcomes for
Cefiderocol versus comparators in Pneumonia
Pneumonia Susceptibility
*EPI
Microbiological
eradication at
TOC (m-ITT) from
clinical trials
Projected Microbiological
eradication at TOC in the
Suspected population
Clinical Cure at
TOC from
clinical trials
Projected
Clinical Cure
at TOC in the
Suspected
antimicrobial
cefiderocol 92.70% 47.60% 44.13% 64.8% 60.07%
meropenem
(MIC>8mg/mL) 58.29% 50.00%1 29.15% 65.1% 37.95%
ceftolozane/tazobactam 47.55% 73.10% 34.76% 54.4% 25.87%
ceftazidime/avibactam 65.27% 54.00% 35.25% 68.8% 44.91%
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Sources for cefiderocol and comparator data: APEKS-NP (1- for meropenem only results of the
subgroup MIC>8mg/mL were considered); EPAR for Zerbaxa [270], Torres 2018 [272], Torres 2019
[273]
Furthermore, for pneumonia, results from this effectiveness model analysis showed that
cefiderocol has a higher predicted susceptibility and higher predicted treatment success rates
from both a clinical and microbiological perspective. These results are generally consistent with
actual results from the APEKS NP clinical trials, but not for comparators as the analysis
included pathogens for which they are not susceptible (Table 66). Even though a similar
breakpoint of 8mg/L was considered for both APEKS NP and susceptibility analysis in SIDERO
studies, the high dose, prolonged infusion meropenem regimen used in APEKS NP trial,
showed to be effective in pathogens with MICs up to 16mg/ml, reason why the results observed
in this effectiveness model and the clinical trial for the meropenem susceptible group are
different.
Such methodologies are required, when ethical considerations limit clinical trials design to
intendedly risk exposing patients to potentially ineffective drugs. Also, since NMAs are based
on the non-inferiority clinical trials results (which excludes non-susceptible pathogens) the
results obtained between the 2 methodologies are therefore understandably different, but
consistent:
the effectiveness model highlights the potential difference in
effectiveness between different drugs, obtained when antimicrobial
prescription is needed in the absence of antibiogram
the NMA reinforces the notion that similar results are obtained
between drugs when comparing effectiveness in similar patient
population with similar pathogen distribution (i.e. pathogen is
sensitive to both drugs, and both drugs reach the infection site in
effective concentrations, which can occur when antibiogram is
available and prescription is targeted).
Also to note that the results of this effectiveness model will vary according with the local
epidemiology, and changes in susceptibility patterns for each of the drugs.
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5.4.4.5 CREDIBLE-CR
The CREDIBLE CR study was a small, descriptive, randomised, open label, descriptive study
conducted to evaluate efficacy in patients with confirmed CR infections for cefiderocol and
BAT, not designed or powered for statistical comparison between arms (Figure 45). The study
included 150 severely ill patients randomised 2:1 between the treatment groups, consistent
with compassionate use cases, with a range of infection sites including nosocomial pneumonia,
cUTI, BSI/sepsis. Many patients had end stage comorbidities and had failed multiple lines of
therapy.
This study, alongside with the compassionate use cases inform the efficacy of cefiderocol in
the population with confirmed CR infection.
Figure 45: CREDIBLE CR study design
5.4.4.5.1 Primary endpoint analysis
Primary endpoint for HAP/VAP/HCAP and BSI/sepsis: clinical cure rate
Primary endpoint for cUTI: microbiological outcome
Results of clinical cure and microbiological eradication were similar between arms in each point
in time, with the highest differences being observed in patients with cUTI and follow-up visit.
One should remeber that this is a descriptive study without any formal comparison, and
furthermore, the number of patients in each group is too small to derive any conclusions other
than that cefiderocol demonstrated activity, from both a clinical and microbiological outcomes,
in all 3 infection sites (Figure 46 and Figure 47) [242].
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Figure 46: Clinical cure by Clinical Diagnosis and time point
BAT, best available therapy; BSI, bloodstream infection; cUTI, complicated urinary tract infection; EOT, end of
treatment; FU, follow-up; HAP, hospital-acquired pneumonia; HCAP, healthcare-associated pneumonia; Micro-
ITT, microbiological intent-to-treat; TOC, time of cure; VAP, ventilator-associated pneumonia; Source: Data on
file [242]
Figure 47: Microbiological eradication by Clinical Diagnosis and time point
BAT, best available therapy; BSI, bloodstream infection; cUTI, complicated urinary tract infection; EOT, end of
treatment; FU, follow-up; HAP, hospital-acquired pneumonia; HCAP, healthcare-associated pneumonia; Micro-
ITT, microbiological intent-to-treat; TOC, time of cure; VAP, ventilator-associated pneumonia; Source: Data on
file [242]
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5.4.4.5.2 Efficacy data across different pathogens
Outcomes by pathogen were broadly similar between the treatment groups. Cefiderocol has
demonstrated efficacy across all main pathogens [242].
Table 67: Clinical cure and microbiological eradication by baseline CR-pathogen
CR Micro-ITT population Cefiderocol (n=80)
BAT (n=38)
Clinical cure 42/80 (52.5)
19/38 (50.0)
CR A. baumannii 16/37 (43.2)
9/17 (52.9)
CR P. aeruginosa 7/12 (58.3) 5/10 (50.0)
CR K. pneumoniae 18/27 (66.7)
6/12 (50.0)
Microbiological eradication 25/80 (31.3)
9/38 (23.7)
CR A. baumannii 10/37 (27.0)
5/17 (29.4)
CR P. aeruginosa 1/12 (8.3) 2/10 (20.0)
CR K. pneumoniae 13/27 (48.1)
3/12 (25.0)
Source: Data on file [242]
Against the most difficult-to-treat pathogens with New Delhi metallo-β-lactamase (NDM),
metallo-betalactamases or porin channels mutations, cefiderocol showed to be an effective
treatment presenting similar or better clinical and microbiological outcomes than BAT. There
were eight NDM producing Enterobacteriaceae in the cefiderocol arm and four in the BAT arm.
Six out of eight patients in cefiderocol arms had a clinical cure and microbiological response.
Of the four in the BAT arm, none responded (Figure 48). There were 14 KPC producers in the
cefiderocol group and seven in the BAT group. The clinical and microbiological responses were
similar between treatment groups (Figure 48). Porin channel mutations were present in 15
pathogens in the cefiderocol group and 9 in the BAT group with similar clinical responses.
Microbiological eradication was demonstrated in seven out of 15 pathogens in cefiderocol arm
and one out of nine in BAT arm (Figure 48). In patients with infections caused by metallo-
betalactamase producing Gram-negative pathogens, cefiderocol demonstrated benefits for
both clinical cure and microbiological responses (Figure 49), but again, numbers are too small
to derive any conclusion.
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Figure 48: Clinical and Microbiological Outcomes at TOC in Enterobacteriaceae by
Carbapenemase or Porin Channel Mutation (CR Micro-ITT Population)
*OMPK35/36-deficient. Only patients with molecular data are included.
Figure 49: Clinical and Microbiological Outcomes in Metallo Β-lactamase
Producing Gram-negative Pathogens (CR Micro-ITT Population)
5.4.4.5.3 CREDIBLE-CR all-cause Mortality Data
Mortality was evaluated as part of safety assessment in the study, however, as per EUnetHTA
request, it is presented within the efficacy outcomes.
An imbalance in mortality favouring the BAT arm was observed at all time points in the study.
Table 68 and Figure 50 includes a summary of death in all subjects and by infection type at
each time point. Twenty-eight-day mortality represents a fixed time point for all patients and is
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a conventional endpoint to assess both safety and efficacy in antibacterial studies. The Day 28
mortality for all subjects (i.e., all infection sites combined) was 24.8% in the cefiderocol group
and 18.4% in the BAT group. This difference was observed in pneumonia and BSI patients,
but not in subjects with cUTI.
Through EOS (Day 49), mortality for all subjects (ie, all infection sites combined) was 33.7%
in the cefiderocol group and 18.4% in the BAT group.
Table 68: Summary for All-cause Mortality in the Study (Intent to treat Population)
Infection Site All-cause Mortality Rate
Cefiderocol (N = 101) n/N (%) 95% CI
BAT (N = 49) n/N (%) 95% CI
All Infection Sites Combined N' = 101 N' = 49
Day 14 19/101 (18.8) (11.7, 27.8) 6/49 (12.2) (4.6, 24.8)
Day 28 25/101 (24.8) (16.7, 34.3) 9/49 (18.4) (8.8, 32.0)
Through EOS 34/101 (33.7) (24.6, 43.8) 9/49 (18.4) (8.8, 32.0)
Figure 50: All-cause Mortality Rates by Type of Infection
BAT, best available therapy; BSI, bloodstream infection; cUTI, complicated urinary tract infection; HAP, hospital-
acquired pneumonia; HCAP, healthcare-associated pneumonia; VAP, ventilator-associated pneumonia;
Source: Data on file [242]
The time stratification analysis of the mortality data show that the imbalance occurs outside
the treatment effective period: 4 deaths occurred in cefiderocol arm only at very early stages
of treatment (up to day 3 when there was an early assessment), and 9 occurred after after
TOC, which are more likely to be associated with the underlying condition of the patient
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Considering the 2:1 randomization, there was no significant difference in mortality rates
between day 4 and 28 (Table 68).
For completion of mortality information, there were 7 subjects in the CREDIBLE-CR study who
died after study completion are provided on file [274]. There were 2 subjects treated with
cefiderocol (Subjects 2AA001 and 3HK002) and 5 subjects treated with best available therapy
(BAT; Subjects 3HN001, 3HJ001, 3HJ004, 3HM003, and 3FG010) who died after study
completion. Neither of the 2 cefiderocol-treated subjects, but 3 of the 5 subjects treated with
BAT (3HN001, 3HJ004, and 3FG010) had Acinetobacter baumannii as a causative pathogen
at baseline.
The population in the CREDIBLE-CR study was designed to be very heterogeneous as it was
a pathogen-focussed study which included subjects with many underlying conditions, different
infection sites and infections due to a variety of Gram-negative pathogens. The study was
relatively small (101 subjects treated with cefiderocol and 49 subjects treated with BAT) and
due to the heterogeneity of the population the treatment groups do not appear to be balanced
for baseline characteristics such as shock (which has a major impact on mortality) in the
subgroup of subjects with A. baumannii infections. It is likely that the mortality imbalance
observed is due to a variety of factors related to baseline imbalances. [275]
When considering baseline pathogens, mortality was lower in cefiderocol-treated subjects than
BAT-treated subjects for the Enterobacteriaceae and the higher mortality was seen for the non-
fermenters. Many subjects had co-infection with multiple non-fermenters (Table 69). The
difference seen in non-fermenters was mostly due to the difference seen with A. baumannii.
The mortality rate for subjects with P. aeruginosa alone without Acinetobacter spp. as a co-
pathogen was the same in each treatment group being 18.2% (2/11 subjects) for cefiderocol
and 18.2% (2/11 subjects) for BAT [50].
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Table 69: Summary for all-cause mortality overall by pathogens subgroup
(Enterobactereacea and non-fermenters)
Source: Response to D90 [276]
In subjects with A. baumannii infection and a history of shock (both shock at baseline and a
history of shock within 31 days of baseline), mortality rates were much higher than in subjects
without a history of shock in both treatment groups [277]. The proportion of subjects with a
history of shock was higher for the cefiderocol group than for the BAT group and so given the
high mortality rates reported for subjects with shock, the increased incidence of a history of
shock in cefiderocol-treated subjects with A. baumannii may provide an explanation for some
of the difference in mortality rates between the treatment groups in the CREDIBLE-CR study
(Table 70).
Table 70: CREDIBLE-CR study: Mortality subgroup Analysis for Subjects with A.
baumannii (safety population)
Subgroup
Cefiderocol (N=39) BAT (N=17)
N’/N (%)
All-cause mortality n/N' (%) N’/N (%)
All-cause mortality n/N' (%)
Overall 39 19/39 (48.7) 17 3/17 (17.6)
Shock within 31 days of baseline
Yes 9/39 (23.1) 7/9 (77.8) 1/17 (5.9) 1/1 (100)
No 30/39 (76.9) 12/30 (40.0) 16/17 (94.1) 2/16 (12.5)
Shock ongoing at baseline
Yes 7/39 (17.9) 6/7 (85.7) 1/17 (5.9) 1/1 (100)
No 32/39 (82.1) 13/32 (40.6) 16/17 (94.1) 2/16 (12.5)
ICU at baseline
Yes 32/39 (82.1) 15/32 (46.9) 8/17 (47.1) 1/8 (12.5)
No 7/39 (17.9) 4/7 (57.1) 9/17 (52.9) 2/9 (22.2)
BAT = best available therapy; ICU = intensive care unit; N = number of subjects with A baumannii.; N’ = number of subjects in subgroup
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5.4.4.5.4 Comparison of CREDIBLE-CR mortality with other studies
Whereas the mortality rate in the cefiderocol group was consistent with previous studies in
similar populations with high levels of A. baumannii infections ([142, 278, 279]), the mortality
rate in the BAT group was substantially lower than expected from previous studies (Figure 51)
[142, 244, 275, 278-283]. The reason for the lower than expected mortality in the BAT group
is not clear but is likely also due to a variety of factors related to baseline imbalances and other
anomalies (such as the low mortality associated with high APACHE II and SOFA scores). The
evidence suggests that the mortality rate in the BAT group was unexpectedly low for the
population randomised and that the mortality in the cefiderocol group was consistent with what
has been reported in previous studies.
Figure 51: Mortality rates comparison across studies
No other factors that indicated disease severity were identified that clearly contributed to the
mortality imbalance seen between treatments [275].
In conclusion, the difference in mortality between treatments in the CREDIBLE-CR study still
cannot be fully explained. However, there are plausible factors contributing to the mortality
difference in this pathogen-focussed study. The 2:1 randomisation, the small study size, and
the heterogeneity of the patient population, particularly the inclusion of multiple infection sites
and diverse comorbidities, means that it was difficult to ensure that treatment groups were
balanced for all baseline factors. Other than a history of shock, and possibly low WBC count,
no individual baseline characteristic has been identified which could clearly be linked to this
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imbalance. A mortality imbalance was not observed in the APEKS-NP study overall, including
in the subset of subjects infected with A. baumannii [276]. The evidence suggests that the
mortality rate in the BAT group was unexpectedly low for the population randomised and that
the mortality in the cefiderocol group was consistent with what has been reported in previous
studies.
5.4.4.6 Compassionate Use
To date, over 200 patients were treated with cefiderocol, worldwide, within compassionate use
programme. Data for 74 patients who have completed therapy is available, of which only 3
positive outcomes are published to date [246-248]. This programme included patients with a
diversity of infections beyond those presented in the clinical trials, with a baseline patient
characteristics consistent with that of CREDIBLE CR as per previously detailed in section 5.3
5.4.4.6.1 Clinical efficacy and safety
Over 60% of the patients receiving cefiderocol survived when no other possible treatment
option were available to them [244]. Of these, 17 died due to their underlying infection, 6 died
for reasons other than the original bacterial infection, and other causes of death remained
unknown [244]. However, none of the observed deaths were considered to be related to
cefiderocol [245]. Cefiderocol has demonstrated a manageable safety profile with the longest
use being more than 90 days in a renal transplant patient where no apparent safety issues
were observed [244].
Table 71: Mortality and serious adverse events
Mortality, n (%) Cefiderocol (n=74)
Overall mortality 27 (36.5)
Overall mortality by pathogen
Acinetobacter baumannii 12/22 (54.5)
Klebsiella pneumoniae 2/7 (28.6)
Burkholderia cenocepacia 4/10 (40)
Pseudomonas aeruginosa 9/31 (29)
Abnormal LFTs 4 (5.4)
Multiple organ failure 6 (8.1)
Acute renal failure 3 (4.1)
Cardiac arrest 2 (2.7)
Sepsis or septic shock 5 (6.8) LFT, liver function test; SAE, serious adverse event; Source: NDA briefing document[244]; Data on file [245]
All rights reserved 232
5.4.4.7 Published case reports
Case reports for three patients from the expanded access program have been
published so far.
A patient was treated successfully for endocarditis due to extensively drug
resistant (XDR) Pseudomonas aeruginosa.(Edgeworth et al., 2019)[246]
A patient with multiple comorbidities and a complicated intra-abdominal infection
(IAI) due to MDR Pseudomonas aeruginosa was released from hospital care
within six weeks of completion of cefiderocol treatment. (Stevens et al.,
2019)[247]
A patient with VAP and BSI caused by XDR Acinetobacter baumannii and
carbapenemase-producing Klebsiella pneumoniae had potentially serious organ
failure from older anti-infectives. Six weeks after cefiderocol administration, chest
X-rays showed complete resolution of infection (Trecarichi et al., 2019)[248]
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5.4.5 Resistance against Cefiderocol
5.4.5.1 In vitro resistance development
Resistance development to Cefiderocol has been investigated using the standard
in vitro experiments to determine the frequency of spontaneous resistance and to
observe the adaptation of pathogens during serial passaging.
Frequency of spontaneous resistance: The frequency of spontaneous resistance
of E. coli, E. cloacae, K. pneumoniae, and P. aeruginosa (8 strains in total) was
determined in the presence of 10 × MIC of cefiderocol. If resistant mutants were
isolated, the in vitro activity of cefiderocol against the mutant strains was
determined and compared to the susceptibility of the parent strains. The
magnitude of the order of frequency of the resistance for cefiderocol was similar
to ceftazidime with a frequency of 10−7 to 10−8 except for P. aeruginosa for which
the frequency ranged from 10−6 to 10−8. Cefiderocol MIC increase was shown to
be associated with the mutation in the upstream region of pvdS (pyoverdine
synthesis gene) and fadD3 (fatty acyl-CoA synthetase) in P. aeruginosa, and
baeS, envZ, ompR (all are 2-component signal transduction gene), and exbD
(biopolymer transport gene) in K. pneumoniae.
Resistance acquisition assay by serial passage: Resistance acquisition was
evaluated for K. pneumoniae, and P. aeruginosa (5 strains in total) by a 10 times
serial passage in two different media. The MIC of cefiderocol increased in general
1 to 4-fold but for one strain up to 8-fold.
Resistance acquisition by using an in vitro pharmacodynamic model: To estimate
the risk of emergence of cefiderocol-resistant mutants during the treatment of
patients, in vitro PD models simulating the free concentration-time curves in
human plasma was used. The simulated concentration-time curves were
determined for a 2-g cefiderocol q8h administration with 3-hour infusion, 2-g/0.5
g CAZ/AVI q8h administration with 2-hour infusion, and 1-g MEPM q8h
administration with 1-hour infusion. Against all 3 strains, cefiderocol showed rapid
bacterial reduction within 4 hours. Regrowth was observed for one strain, but no
growth was observed with a MIC of ≥ 10 mg/L and no resistant colonies to
cefiderocol were detected at the 24- and 72-hour time points.
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5.4.5.2 MIC shifts during therapy
During the clinical studies, 4-fold MIC increases have been observed with both cefiderocol and
the comparators. Table 72 is summarising the MIC shift observed:
Table 72: Summary of MIC shift
APEKS-cUTI APEKS-NP CREDIBLE CR
Cefidero
col
(N=252)
imipene
m/
cilastatin
(N=119)
Cefidero
col
(N=145)
HD
meropenem
(N=147)
Cefiderocol
(N=101)
BAT
(N=49)
Nb patients with 4-
fold MIC increase 7 3 9* 9 15** 5
% patients with 4-
fold MIC increase 2.8% 2.5% 6.2% 6.1% 14.8% 10.2%
*1 subject with postbaseline MIC>4 mg/L**only 3 with postbaseline MIC>4mg/L, in the APEKS-cUTI none of the strains had an
MIC>4 mg/L postbaseline.
In the 3 clinical studies, a similar percentage of subjects with 4-fold MIC increase was observed
in both the cefiderocol and the comparator treatment group. Only in 4 subjects the MIC
observed postbaseline was above the unbound concentration of cefiderocol in plasma of 4
mg/L. Molecular characterisation of the strains with increased MICs is not completed yet.
In conclusion, as for other antibacterial, in vitro resistance development was observed for
cefiderocol similar to ceftazidime. In clinical trials, MIC’s increase was also observed with the
same magnitude in both treatment gourps (ie cefiderocol and comparators). The HD
meropenem was not sufficient to fully repress increase in MICs during treatment of patient with
nosocomial pneumonia.
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Table 73a: Methods of data collection and analysis of Mortality
Study
reference/ID
Endpoint definition Method of analysis
APEKS-NP All-cause mortality at Day 14 since first
infusion of study drug (ACM): All-cause
mortality rate at Day 14 since first infusion of
study drug will be calculated as the proportion
of patients who experienced mortality
regardless of the cause at or before Day 14
since first infusion.
ACM at Day 28: All-cause mortality rate at Day
28 since first infusion of study drug will be
calculated as the proportion of patients who
experienced mortality regardless of the cause
at or before Day 28 since first infusion.
.
ACM by treatment group will be calculated as the proportion of patients who experienced mortality
regardless of the cause at or before Day 14. The adjusted estimates of the difference in ACM at Day
14 between cefiderocol and meropenem will be presented along with 95% confidence intervals (CIs)
based on a stratified analysis using Cochran-Mantel-Haenszel (CMH) weights. The CI will be 2-sided.
Cochran-Mantel-Haenszel weights will be calculated with APACHE II score (≤ 15 and ≥ 16) as the
stratified factor.
Sensitivity analysis for missing Day 14 ACM status will be implemented as follows: subjects with
unknown mortality status at Day 14 in the cefiderocol group will be imputed as “Death” while any
subject with unknown mortality status at Day 14 in the Meropenem arm will be imputed as “Alive “.
The estimates of the difference in the ACM at Day 14 between cefiderocol and meropenem will be
presented along with 95% confidence intervals (CIs) (Wald method) if data warrant. If the number of
subjects within a subgroup is less than 10 in any treatment arm, only the difference in the ACM
between the two treatment arms (no CI) will be presented. The CI will be 2-sided. Similar analysis will
also be carried out for Day 28 all-cause mortality.
Analysis for Day 14 ACM will also be performed by excluding subjects who are meropenem resistant
in the mITT analysis population as a supplementary analysis. Subjects who are meropenem resistant
will be determined from central laboratory culture results
Analyses of ACM at Day 14 will be presented for the following subgroups:
Clinical diagnosis, Gender, Race, Age, Region and Baseline clinical characteristics.
ACM rate during treatment and follow-up
period (until EOS)
ACM rate during treatment and follow-up period (until EOS) will be calculated as the proportion of
patients who experienced mortality regardless of the cause at or before EOS since the first infusion.
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If a subject discontinues from the study before this period and survival information was not available,
then the survival status for this endpoint for the subject will be unknown.
All-cause until EOS visit will be analysed in a similar way to the Primary Efficacy endpoint described
CREDIBLE-CR All-cause mortality at Day 14 and Day28 for
HAP/VAP/HCAP and BSI/sepsis.
Survival time (HAP/VAP/HCAP, BSI/sepsis)
All-cause mortality rate with 95% CI at Day 14, Day 28 and overall by treatment group will be
calculated as the proportion of subjects who experienced mortality regardless of the cause at or
before Day 14 and Day 28, respectively. In this analysis, deaths occurring after EOS will not be used
for analysis and any subject who does not have vital status information at Day 14 and 28 will not be
included in the analysis. This analysis will be performed for both CR MITT and ITT Population.
In addition, for CR MITT Population, subgroup analysis regarding all-cause mortality at Day 28 will be
performed. For the survival time up to End of Study (EOS), the survival curve using Kaplan-Meier
method by treatment group will be presented. For the subjects whose vital status is survival at EOS,
the subjects will be treated as right-censored at EOS. For the subjects whose vital status is not
collected or unknown, the subjects will be treated as right-censored at last visit day.
All-cause mortality rate at Day 14, Day 28 and overall including death after EOS will be calculated by
treatment group for ITT population.
EA: Early Assessment, EOT: End of Treatment, TOC: Test of Cure, FUP: Follow-up, MAX
All rights reserved 237
Table 80b: Methods of data collection and analysis of Clinical outcomes
Study
reference/ID
Endpoint definition Method of analysis
APEKS-cUTI Clinical response at EA
Clinical Cure: Resolution or improvement of
baseline signs and symptoms of cUTI at EA or
return to pre-infection baseline if known.
Clinical Failure: No apparent response to
therapy, persistence of signs and/or symptoms
of cUTI infection beyond pre-infection baseline,
or reappearance of signs and/or symptoms, at
or before the EA.
Indeterminate: Lost to follow-up such that a
determination of clinical response (cure,
improvement, or failure) cannot be made.
Clinical response at EOT and TOC
Clinical Cure: Resolution or improvement of
baseline signs and symptoms of cUTI, or return
to pre-infection baseline if known, at EOT and
TOC.
Clinical Failure: No apparent response to
therapy, persistence of signs and/or symptoms
of cUTI infection beyond pre-infection baseline,
or reappearance of signs and/or symptoms, at
or before the EOT and/or TOC visit.
Indeterminate: Lost to follow-up such that a
determination of clinical response (success or
failure) cannot be made.
Subject reported symptoms identified at baseline will be assessed at EA, EOT, TOC, and FUP utilizing
a Structured Subject Interview (see Appendix 3 of the study protocol [237]) that will evaluate whether
the symptom is still present (and if so the degree of that symptom, i.e., mild, moderate, or severe) or
returned to baseline.
Clinical response will be determined by the investigator based upon resolution or improvement of
clinical signs and symptoms of cUTI prior to receiving any potentially effective antibacterial therapy
for cUTI and subject reported symptoms noted in the Structured Subject Interview. Baseline
symptoms associated with anatomic abnormalities that predisposes to cUTI do not need to be
resolved for a consideration of a successful responder.
For the primary analysis, the clinical response will be a dichotomy (cure or failure) based on the
clinical outcome as assessed by the investigator taking into consideration objective data
(temperature, WBC, urinalysis) and patient reported symptoms noted in the Structured Patient
Interview.
The clinical outcome of interest at EA, EOT, and TOC will be the proportion of subjects who have a
clinical outcome of cure. The outcome of interest at FUP will be the proportion of subjects with
sustained clinical cure.
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Clinical response at FUP
Sustained Clinical Cure: All pre-therapy signs
and symptoms of cUTI show no evidence of
recurrence after administration of the last dose
of study drug.
Failure: Patients carried forward from TOC.
Relapse: Signs and/or symptoms of cUTI that
were absent at TOC reappear at the FUP.
Indeterminate: Lost to follow-up such that a
determination of clinical response (success or
failure) cannot be made
APEKS-NP Clinical response
Clinical Cure: Resolution or substantial
improvement of baseline signs and symptoms
of pneumonia, including a reduction in
Sequential Organ Failure Assessment (SOFA)
and Clinical Pulmonary Infection (CPIS) scores,
and improvement or lack of progression of
chest radiographic abnormalities such that no
additional antibacterial therapy is required for
the treatment of current infection at the EA and
EOT visits, and no antibacterial therapy is
required for the treatment of the current
infection at the TOC.
Clinical Failure: No apparent response to
therapy; persistence or worsening of baseline
signs and/or symptoms of pneumonia;
reappearance of signs and/or symptoms of
The clinical outcomes will be assessed by the investigator according to the described criteria at EA,
EOT and TOC.
The clinical response rate at Early Assessment, End of Treatment and Test of Cure will be calculated
as the proportion of subjects who have a clinical outcome of cure. The adjusted estimate of the
difference in the cure rate between the 2 treatment groups will be presented along with the adjusted
95% CIs based on the CMH weights: diagnosis and APACHE II score. In addition, the number and
proportion of subjects having clinical outcome as failure and indeterminate will be summarized by
treatment group.
Results will be presented per Infection site, Pathogen and Non-fermenters
All rights reserved 239
pneumonia; development of new signs and/or
symptoms of pneumonia requiring antibacterial
therapy other than, or in addition to, study
treatment therapy; progression of chest
radiographic abnormalities; or death due to
pneumonia.
Indeterminate: Lost to follow-up such that a
determination of clinical cure/failure cannot be
made.
APEKS-NP Sustained Clinical Cure: Continued resolution
or substantial improvement of baseline signs
and symptoms of pneumonia, such that no
antibacterial therapy has been required for the
treatment of pneumonia in a subject assessed
as cured at TOC.
Relapse: Recurrence of signs and/or
symptoms of pneumonia, appearance of new
signs and/or symptoms of pneumonia, or new
chest radiographic evidence of pneumonia in a
subject assessed as cured at TOC.
Clinical Failure: Clinical failure at TOC will be
carried forward regardless of lost to follow-up.
Indeterminate: Lost to follow-up, such that a
determination of clinical sustained cure/relapse
cannot be made, or subject received additional
antibacterial therapy for the treatment of the
current infection.
The clinical outcome at FU will be assessed by the investigator according to the
described criteria.
The cure rate at FU will be calculated as the proportion of subjects with clinical outcome of sustained
clinical cure. In addition, the number and proportion of subjects having clinical outcome as relapse,
clinical failure and indeterminate will be summarized by treatment group.
The same analysis method as described above for clinical outcome per subject at EA, EOT and TOC
will be performed for the clinical outcome per subject FU.
The outcome will be tabulated for each treatment group. The adjusted estimate of the difference in
the response rate between the 2 treatments arms along with the adjusted 95% CIs based on the CMH
weights will be presented.
CREDIBLE-CR HAP/VAP/HCAP: Efficacy Criteria for Infection Site Specific Clinical Outcomes assessed at EA, EOT, and TOC
All rights reserved 240
● Clinical Cure: Resolution or
substantial improvement of baseline
signs and symptoms of pneumonia
including a reduction in SOFA and
CPIS scores, and improvement or lack
of progression of chest radiographic
abnormalities such that no additional
antibacterial therapy is required for the
treatment of the current infection.
● Clinical Failure: No apparent
response to therapy; persistence or
worsening of baseline signs and/or
symptoms of pneumonia;
reappearance of signs and/or
symptoms of pneumonia;
development of new signs and/or
symptoms of pneumonia requiring
antibacterial therapy other than, or in
addition to, study treatment therapy;
progression of chest radiographic
abnormalities; or death due to
pneumonia.
● Indeterminate: Lost to follow-up such
that a determination of clinical
cure/failure cannot be made.
cUTI
● Clinical Cure: Resolution or
substantial improvement of baseline
The clinical outcomes will be assessed by the investigator according to the described criteria
established for each infection site at EOT and TOC. In case treatment duration is extended beyond
14 days, an additional clinical outcome will be assessed on Day 14.
Sequential Organ Failure Assessment score (SOFA) and its change from baseline will be summarized
by treatment group per infection site at Baseline, EOT, TOC, and FU. Change from baseline will also
be summarized. In addition, SOFA score regardless of primary infection diagnosis will be analysed in
a similar manner.
For the HABP/VABP/HCABP subjects, CPIS at EOT, TOC, and FU will be summarized by treatment
group.
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signs and symptoms of cUTI, or return
to pre-infection baseline if known,
such that no additional antibacterial
therapy is required for the treatment of
the current infection.
● Clinical Failure: No apparent
response to therapy; persistence or
worsening of baseline signs and/or
symptoms of cUTI; or reappearance of
signs and/or symptoms of cUTI;
development of new signs and/or
symptoms of cUTI requiring
antibacterial therapy other than, or in
addition to, study treatment therapy;
or death due to cUTI.
● Indeterminate: Lost to follow-up such
that a determination of clinical
cure/failure cannot be made.
BSI/Sepsis
● Clinical Cure: Resolution or
substantial improvement of baseline
signs and symptoms including a
reduction in SOFA score, such that no
additional antibacterial therapy is
required for the treatment of
BSI/sepsis. Patients with bacteraemia
must have eradication of bacteraemia
caused by the Gram-negative
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pathogen.
● Clinical Failure: No apparent
response to therapy; persistence or
worsening of baseline signs and/or
symptoms, reappearance of signs
and/or symptoms; development of
new signs and/or symptoms requiring
antibacterial therapy other than, or in
addition to, study treatment therapy;
or death due to BSI/sepsis.
● Indeterminate: Lost to follow-up such
that a determination of clinical
cure/failure cannot be made.
CREDIBLE-CR HAP/VAP/HCAP:
● Sustained Clinical Cure: Continued
resolution or substantial improvement
of baseline signs and symptoms of
pneumonia, such that no additional
antibacterial therapy is required for the
treatment of pneumonia in a patient
assessed as cured at TOC.
● Relapse: Recurrence of signs and/or
symptoms of pneumonia, appearance
of new signs and/or symptoms of
pneumonia, or new chest radiographic
evidence of pneumonia in a patient
Efficacy Criteria for Infection Site Specific Clinical Outcomes assessed at FUP will be determined
according to the described criteria above.
All rights reserved 243
assessed as cured at TOC.
● Indeterminate: Lost to follow-up such
that a determination of clinical
sustained cure/relapse cannot be
made, or patient received additional
antibacterial therapy for the treatment
of the current infection.
● Clinical Failure: Clinical failure at
TOC will be carried forward regardless
of lost to follow-up
cUTI
● Sustained Clinical Cure: Continued
resolution or improvement of baseline
signs and symptoms of cUTI, or return
to pre-infection baseline if known, in a
patient assessed as cured at TOC.
● Relapse: Recurrence of signs and/or
symptoms of cUTI, or appearance of
new signs and/or symptoms of cUTI in
a patient assessed as cured at TOC.
● Indeterminate: Lost to follow-up such
that a determination of clinical
sustained cure/relapse cannot be
made, or patient received additional
antibacterial therapy for the treatment
of the current infection.
● Clinical Failure: Clinical failure at
TOC will be carried forward regardless
All rights reserved 244
of lost to follow-up
BSI/Sepsis
● Sustained Clinical Cure: Continued
resolution or substantial improvement
of baseline signs and symptoms
associated with reduction in SOFA
score, such that no additional
antibacterial therapy is required for the
treatment of the patient’s original
BSI/sepsis in a patient assessed as
cured at TOC.
● Relapse: Recurrence of signs and/or
symptoms of BSI/sepsis, or
appearance of new signs and/or
symptoms of the patient’s original
BSI/sepsis in a patient assessed as
cured at TOC.
● Indeterminate: Lost to follow-up such
that a determination of clinical
sustained cure/relapse cannot be
made, or patient received additional
antibacterial therapy for the treatment
of the current infection.
● Clinical Failure: Clinical failure at
TOC will be carried forward regardless
of lost to follow-up
EA: Early Assessment, EOT: End of Treatment, TOC: Test of Cure, FUP: Follow-up, MAX
All rights reserved 245
Table 80c: Methods of data collection and analysis of Composite microbiological eradication and cure
Study
reference/ID
Endpoint definition Method of analysis
APEKS-cUTI Clinical and microbiologic response:
Resolution or improvement of the symptoms of
cUTI present at trial entry (and no new
symptoms) and the demonstration that
bacterial pathogen found at trial entry is
reduced to fewer than 104 CFU/mL on urine
culture at the TOC (microbiological response).
Clinical or microbiologic failure: Symptoms
of cUTI present at trial entry have not
completely resolved or new symptoms have
developed, the subject has died, or the urine
culture taken at the TOC grows greater than or
equal to 104 CFU/mL of the original pathogen
identified at trial entry.
The primary composite efficacy endpoint is based on the outcome (response or failure) for both the
clinical and microbiologic response at TOC.
The composite outcome is a “response” if both the clinical and microbiologic outcome are responses.
Clinical resolution assessed by the investigator will be defined based in part on the graded response
to the structured subject interview about the current status of the subject’s symptoms that had been
recorded at the time of randomization, and the absence of any new symptoms related to the cUTI.
Definition of clinical and microbiological outcome based on possible combinations of microbiological
outcome and clinical outcome is presented below.
At EA, EOT and TOC:
Per Subject Microbiological
Outcome Clinical Outcome
Composite of Clinical and
Microbiological Outcome
Microbiological eradication Clinical cure Response
Microbiological eradication Clinical failure Failure
Microbiological eradication Indeterminate Indeterminate
Microbiological failure Clinical cure Failure
Microbiological failure Clinical failure Failure
Microbiological failure Indeterminate Failure
Indeterminate Clinical cure Indeterminate
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Indeterminate Clinical failure Failure
Indeterminate Indeterminate Indeterminate
At FUP:
Per Subject Microbiological
Outcome Clinical Outcome
Composite of Clinical and
Microbiological Outcome
Sustained eradication Sustained clinical cure Response
Sustained eradication Clinical failure Failure
Sustained eradication Clinical relapse Failure
Sustained eradication Indeterminate Indeterminate
Microbiological failure Sustained clinical cure Failure
Microbiological failure Clinical failure Failure
Microbiological failure Clinical relapse Failure
Microbiological failure Indeterminate Failure
Indeterminate Sustained clinical cure Indeterminate
Indeterminate Clinical failure Failure
Indeterminate Clinical relapse Failure
Indeterminate Indeterminate Indeterminate
CREDIBLE-CR The definition for composite of clinical and
microbiological outcome based on possible
combinations per subject microbiological
outcome and clinical outcome is shown in the
For the composite clinical and microbiological outcome, the outcomes will be summarized and the
response rate with 95% CI at EOT, TOC, and FU will be calculated per infection site by treatment
group as the proportion of subjects who have both clinical cure and microbiological eradication.
All rights reserved 247
tables for EOT and TOC, and in separate tables
for FUP
Clinical and Microbiological Outcome: EOT and TOC
Per Subject Microbiological
Outcome Clinical Outcome
Composite of Clinical and
Microbiological Outcome
Eradication Clinical cure Response
Eradication Clinical failure Failure
Eradication Indeterminate Indeterminate
Persistence Clinical cure Failure
Persistence Clinical failure Failure
Persistence Indeterminate Failure
Indeterminate Clinical cure Indeterminate
Indeterminate Clinical failure Failure
Indeterminate Indeterminate Indeterminate
Composite Outcome: Follow-up
Per Subject Microbiological
Outcome Clinical Outcome
Composite of Clinical and
Microbiological Outcome
Sustained eradication Sustained clinical cure Response
Sustained eradication Clinical failure Failure
Sustained eradication Clinical relapse Failure
Sustained eradication Indeterminate Indeterminate
Persistence Sustained clinical cure Failure
Persistence Clinical failure Failure
Persistence Clinical relapse Failure
All rights reserved 248
Persistence Indeterminate Failure
Recurrence Sustained clinical cure Failure
Recurrence Clinical failure Failure
Recurrence Clinical relapse Failure
Recurrence Indeterminate Failure
Indeterminate Sustained clinical cure Indeterminate
Indeterminate Clinical failure Failure
Indeterminate Clinical relapse Failure
Indeterminate Indeterminate Indeterminate
EA: Early Assessment, EOT: End of Treatment, TOC: Test of Cure, FUP: Follow-up, MAX
All rights reserved 249
Table 80d: Methods of data collection and analysis of Microbiological outcomes
Study
reference/ID
Endpoint definition Method of analysis
APEKS-cUTI Eradication: A urine culture shows the
bacterial uropathogen(s) identified at baseline
at ≥ 105 CFU/mL are reduced to < 104
CFU/mL.
Persistence: A urine culture shows that the
original bacterial uropathogen(s) identified at
baseline at ≥ 105 CFU/mL grows ≥ 104
CFU/mL.
Indeterminate: No urine culture or a urine
culture that cannot be interpreted for any
reason.
An overall per subject microbiological outcome will be determined at EA, EOT, TOC,
and FUP. In addition, per pathogen microbiological outcomes will be determined for baseline
uropathogens. New pathogens that emerge after study therapy is started will also be assessed. Per
subject and per pathogen microbiological outcomes will be assessed only for Gram-negative
uropathogens which are identified with quantitative measurements by the local laboratory and
confirmed by the central microbiology laboratory. If the pathogen is not sent to central microbiology
laboratory, the outcome will be only assessed by the local laboratory.
For the subjects who have Gram-positive uropathogens at baseline, the Gram-positive uropathogens
will be shown in the listing of local microbiological test and not be considered in either per pathogen
microbiological outcome or per subject microbiological outcome.
Subjects who used non-study antibacterial drug therapy with Gram-negative coverage and thus may
have a potential effect on outcome evaluation in patients with cUTI were treated as microbiological
failure at all the following analysis visits after the use of the non-study antibacterial drug therapy
regardless of outcome above.
As shown below, subjects who experience eradication of all baseline Gram-negative uropathogen(s)
at EA, EOT, and TOC will be considered” microbiological eradication” and subjects who experience
persistence of any baseline Gram-negative uropathogen will be considered” microbiological failures”.
Subjects whose experiences are other than above will be considered” indeterminate”.
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The microbiological response rate at EA, EOT and TOC will be calculated as the proportion of subjects
who experience eradication at EA, EOT and TOC respectively by treatment group. The adjusted
estimate of the difference in the response rate between the 2 treatment groups will be presented along
with the 95% CIs based on a stratified analysis using the CMH weights: infection diagnosis
(HABP/VABP/HCABP) and APACHE II score (≤ 15 and ≥ 16). In addition, the number and proportion
of subjects having microbiological outcome as persistence and indeterminate will be summarized by
treatment group.
APEKS-cUTI Sustained Eradication: A urine culture
obtained after documented eradication at
the TOC, up to and including the FUP, shows
that the bacterial uropathogen(s)
identified at baseline at ≥105 CFU/mL remain
<104 CFU/mL.
Assessment of baseline Gram-negative pathogens at FUP includes sustained eradication
At FU, the per subject microbiological outcome for subjects who experience sustained eradication of
all baseline Gram-negative pathogens will be considered as “sustained eradication” and subjects who
experience recurrence of any baseline Gram-negative pathogens will have a per subject
microbiological outcome of “recurrence”. Subjects who show persistence of any baseline Gram-
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• Persistence: A urine culture obtained any time
after TOC, up to and including the FUP, grows
≥104 CFU/mL of the original uropathogen. If
there are no available culture results, the
outcomes for pathogens that persisted at TOC
are carried forward to the FUP.
• Recurrence: A urine culture obtained any time
after documented eradication at the TOC, up to
and including the FUP, grows ≥104 CFU/mL of
the original uropathogen.
negative pathogens will have a per subject microbiological outcome of “persistence”. Subjects whose
experiences are other than above at FU will be considered “indeterminate”.
APEKS-NP Eradication: Absence of the baseline Gram-
negative pathogen from an
appropriate clinical specimen. Presence of
colonizers or contaminants associated
with a baseline pathogen will be associated
with microbiological outcome of
eradication. If it is not possible to obtain an
appropriate clinical culture, and the
subject has a successful clinical outcome; the
response will be presumed as eradication.
The microbiological outcomes by baseline pathogens will be determined according to the described
criteria at EA, EOT and TOC.
Subjects who experience eradication of all baseline Gram-negative
pathogen(s) at EA, EOT and TOC their per subject microbiological outcome
will be considered “eradication” and subjects who experience persistence of any baseline
Gram-negative pathogens, per subject microbiological outcome will be considered
“persistent”.” Subjects whose experiences are other than the above will be considered
“indeterminate.”
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Persistence: Continued presence of the
baseline Gram-negative pathogen from an
appropriate clinical specimen. Persistence at
End of Treatment or Test of Cure will be carried
forward.
Indeterminate: No culture obtained from an
appropriate clinical specimen or if the
microbiological outcome is eradication after
additional antibacterial therapy for the
treatment of the current infection.
The microbiological response rate at EA, EOT and TOC will be calculated as the
proportion of subjects who experience eradication at EA, EOT and TOC respectively by treatment
group. The adjusted estimate of the difference in the response rate between the 2 treatment groups
will be presented along with the 95% CIs based on a stratified analysis using the CMH weights:
infection diagnosis (HABP/VABP/HCABP) and
APACHE II score (≤ 15 and ≥ 16). In addition, the number and proportion of subjects having
microbiological outcome as persistence and indeterminate will be summarized by treatment group.
APEKS-NP Sustained Eradication: Absence of the
baseline Gram-negative pathogen from an
appropriate clinical specimen after TOC.
Presence of colonizers or contaminants
associated with a baseline pathogen will be
associated with microbiological outcome of
sustained eradication. If it is not possible to
obtain an appropriate clinical culture, and the
The microbiological outcomes by baseline pathogens will be determined according to the described
criteria at FU.
At FU, the per subject microbiological outcome for subjects who experience sustained eradication of
all baseline Gram-negative pathogens will be considered as “sustained eradication” and subjects who
experience recurrence of any baseline Gram-negative pathogens will have a per subject
microbiological outcome of “recurrence”. Subjects who show persistence of any baseline Gram-
All rights reserved 253
subject has a successful clinical response after
TOC, the response will be presumed
eradication.
Recurrence: Recurrence of the baseline
Gram-negative pathogen from an appropriate
clinical specimen taken after TOC, and the
TOC culture was negative.
Persistence: Persistence of any baseline
Gram-negative pathogen from an appropriate
specimen.
Indeterminate: No culture obtained from an
appropriate clinical specimen or if the
microbiological outcome is eradication after the
subject received additional antibacterial
therapy for the treatment of the current
infection.
negative pathogens will have a per subject microbiological outcome of “persistence”. Subjects whose
experiences are other than above at FU will be considered “indeterminate”.
The microbiologic response rate at FU will be calculated as the proportion of subjects who experience
sustained eradication of all baseline Gram-negative pathogens after
documented eradication at the TOC.
The same analysis method as described above for microbiological outcome per subject at EA, EOT
and TOC will be performed for the microbiologic outcome per subject at FU. The outcome will be
tabulated for each treatment group. The adjusted estimate of the difference in the response rate
between the 2 treatments arms along with the adjusted 95% CIs based on the CMH weights will be
presented.
CREDIBLE-CR HAP/VAP/HCAP
● Eradication: Absence of the baseline
Gram-negative pathogen from an
appropriate clinical specimen. If it is
not possible to obtain an appropriate
clinical culture and the patient has a
The microbiological outcomes by baseline pathogen will be determined by the sponsor according to
the described criteria established for each infection site at EA, EOT, and TOC. In case treatment
duration is extended beyond 14 days, an additional microbiological outcome will be assessed on Day
14. An overall per-subject microbiological outcome will also be determined based on the individual
microbiological outcomes for each baseline pathogen. Emergent (i.e., non-baseline) pathogens are
considered separately, and do not affect the per-subject microbiological outcome.
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successful clinical outcome, the
response will be presumed as
eradication.
● Persistence: Continued presence of
the baseline Gram-negative pathogen
from an appropriate clinical specimen.
● Indeterminate: No culture obtained
from an appropriate clinical specimen
or additional antibacterial therapy for
the treatment of the current infection.
cUTI
● Eradication: A urine culture shows
the baseline Gram-negative
uropathogen found at entry at ≥ 105
CFU/mL are reduced to < 104
CFU/mL.
● Persistence: A urine culture shows
that the baseline Gram-negative
uropathogen found at entry at ≥ 105
CFU/mL grows ≥ 104 CFU/mL.
● Indeterminate: No urine culture
obtained or additional antibacterial
therapy for the treatment of the current
infection.
BSI/Sepsis
● Eradication: Absence of the baseline
Gram-negative pathogen from a blood
Subjects who experience eradication of all baseline Gram-negative pathogens at EOT and TOC will
be considered “Eradication” and subjects who experience persistence of any baseline Gram-negative
pathogen will be considered “persistence.” Subjects whose experiences are other than above will be
considered “indeterminate.” At FU, subjects who experience sustained eradication of all baseline
Gram-negative pathogens after documented eradication at the TOC will be considered “sustained
eradication” and subjects who experience eradication at TOC, but recurrence of any baseline Gram-
negative pathogen will be considered as” recurrence”, and subjects who are considered as
“persistence” at TOC will be “persistence.” Subjects whose experiences are other than above will be
considered “indeterminate.” (see Table below)
Visit Per Subject Microbiological
Outcome Definition
EOT, TOC Eradication Eradication of all baseline Gram-negative
pathogens
Persistence Persistence of any baseline Gram-negative
pathogens
Indeterminate Other than those above
FU Sustained eradication Sustained eradication of all baseline Gram-
negative pathogens after documented
eradication at the TOC
Persistence Persistence of any baseline Gram- at the TOC
Recurrence Recurrence of any baseline Gram-negative
pathogens for subject’s eradication at the TOC
Indeterminate Other than those above
EOT = End of Treatment; FU = Follow-up; TOC = Test of Cure
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culture and/or other primary source.
● Persistence: Continued presence of
the baseline Gram-negative pathogen
from a blood culture or other primary
source.
● Indeterminate: No culture obtained
or additional antibacterial therapy for
the treatment of the current infection.
HAP/VAP/HCAP
● Sustained Eradication: Absence of
the baseline Gram-negative pathogen
from an appropriate clinical specimen
after TOC. If it is not possible to obtain
an appropriate clinical culture and the
patient has a successful clinical
response after TOC, the response will
be presumed eradication.
● Recurrence: Recurrence of the
baseline Gram-negative pathogen
from an appropriate clinical specimen
taken after TOC and the TOC culture
is negative.
● Indeterminate: No culture obtained
from an appropriate clinical specimen
or patient received additional
antibacterial therapy for the treatment
of the current infection.
The microbiological outcomes by baseline pathogen will be determined according to the described
criteria established for each infection site at FUP.
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● Persistence: Persistence at TOC will
be carried forward.
cUTI
● Sustained Eradication: A culture
taken any time after documented
eradication at TOC, and a urine
culture obtained at FUP shows that
the baseline uropathogen found at
entry at ≥105 CFU/mL remains < 104
CFU/mL.
● Recurrence: A culture taken any time
after documented eradication at TOC,
up to and including FUP that grows
the baseline uropathogen
≥ 104 CFU/mL
● Indeterminate: No urine culture or
patient received additional
antibacterial therapy for the treatment
of the current infection.
● Persistence: Persistence at TOC will
be carried forward.
BSI/Sepsis
● Sustained Eradication: Absence of
the baseline Gram-negative pathogen
from a blood culture or other primary
source after TOC.
● Recurrence: Recurrence of the
baseline Gram-negative pathogen
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from a blood culture or other primary
source after TOC and the TOC culture
is negative.
● Indeterminate: No culture or patient
received additional antibacterial
therapy for the treatment of the current
infection.
● Persistence: Persistence at TOC will
be carried forward.
CREDIBLE-CR New Pathogens
● Superinfection: The identification
from an appropriate clinical specimen
of a new pathogen from the original
infection site. This new pathogen
must be associated with new or
persisting signs and symptoms of
infection.
● New Infection: The identification from
an appropriate clinical specimen of a
new pathogen from an infection site
different from the original infection
site. This new pathogen must be
associated with new or persisting
signs and symptoms of infection.
New pathogens that emerge on or after Day 3 will be categorized as either superinfection or new
infection as follows: Superinfection and new infection will be listed by Gram-negative pathogen and
the others.
EA: Early Assessment, EOT: End of Treatment, TOC: Test of Cure, FUP: Follow-up, MAX
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Table 80e: Methods of data collection and analysis of Susceptibility rates
Study
reference/ID
Endpoint definition Method of analysis
SIDERO-WT
SIDERO-CR
Minimum inhibitory concentrations (MICs) of
cefiderocol, cefepime, ceftazidime-avibactam,
ceftolozane-tazobactam, ciprofloxacin, colistin,
and meropenem, were determined by broth
microdilution.
The range and concentration of each antimicrobial agent tested is listed below:
SIDERO-WT
SIDERO-CR
Percent susceptibility (%) calculation Percent susceptibility (%) was calculated according to CLSI interpretive criteria where available, and
the FDA interpretive criteria for ceftazidime-avibactam. In the absence of any CLSI or FDA
breakpoints for colistin tested against Enterobacteriaceae, the EUCAST
susceptible breakpoint of ≤2 μg/mL was applied.
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5.5 Individual study results (safety outcomes)
1. Describe the relevant endpoints, including the definition of the endpoint and methods of
analysis (Table 94).
Endpoints are described in Dossier Table 94.
2. For the technology, and the comparator, tabulate the total number of adverse events,
frequency of occurrence (as a %), absolute and relative risk and 95% CI reported in each of
the clinical studies. Categorise the adverse events by frequency, severity and system organ
class.
This section summarizes the safety outcomes in the overall sample, based on regulatory documents,
followed by the reporting of results of safety assessments in each clinical study.
5.5.1 Overall safety results: pooled analysis and individual studies: APEKS-cUTI,
APEKS-NP, and CREDIBLE CR
The cefiderocol clinical development program to date includes information from 6 completed clinical
pharmacology studies, a completed Phase 2 study, two Phase 3 studies and cases of compassionate
Table 81 summarises the dose and exposure of patients to cefiderocol within the clinical trials, where
nearly half the patients are from APEKS cUTI that per protocol design had a maximum treatment
duration of 14 days. As so, the vast majority of patients were treated with cefiderocol between 7 to 14
days for cUTI. APEKS NP and CREDIBLE presented longer treatment durations; 52 patients receivd
treatment with cefiderocol between 14 and 22 days (mostly coming from CREDIBLE CR study).
Table 81: Dose and Duration of Exposure to cefiderocol* (Number of Patients by Indication)
*
Source: EU Risk Managing Plan for Fetcroja [284]; cUTI dose was given over 1 hour; CREDIBLE-CR and APEKS NP dose was given over
3 hours
Duration
of
exposure
(days)
cUTI study (Dose
2g cefiderocol 3
times daily (every
8 hours)
for 7-14 days)
CREDIBLE-CR study
(Dose 2g cefiderocol 3
times daily (every 8 hours)
for 7-14 days (may be
extended up to 21 days))
APEKS NP Study
(Dose 2g cefiderocol 3
times daily (every 8
hours) for 7-14 days (may
be extended up to 21
days))
Total (Dose 2g
cefiderocol 3 times
daily)
<5 8 8 14 30
5 to <7 10 7 4 21
7 to ≤14 277 61 97 435
>14 to
≤21 5 16 31
52
>21 0 9 2 11
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Table 82 summarizes treatment-related adverse events for each trial and for the total patient
population studied. An additional detailed summary of all treatment-emergent adverse events is on
file[262, 263].
Pooled adverse event analyses there overall less treatment emergent adverse events with cefiderocol
(344/549 [67.1%]) vs comparators (252/347 [72.6%]). The most common adverse reactions for
cefiderocol were diarrhoea (8.2%), constipation (4.6%), pyrexia (4.0%) and UTI (4.7%).
In the total sample, 56/549 (10.2%) patients treated with cefiderocol experienced treatment related
AEs and 45/347 (13.0%) patients treated with comparators.
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Table 82: Subjects with Treatment Related Adverse Events by System Organ Class and Preferred Term (All Phase II/III Studies) Safety Population
cUTI Study CREDIBLE-CR Study APEKS NP Study All Studies System Organ Class - Preferred Term
Cefiderocol N=300 n (%)
Imipenem/Cilastatin N=148 n (%)
Cefiderocol N=101 n (%)
BAT N=49 n (%)
Cefiderocol N=148 n (%)
Meropenem N=150 n (%)
Cefiderocol N=549 n (%)
Comparator N=347 n (%)
Subjects with any Treatment Related AEs 27 (9.0) 17 (11.5) 15 (14.9) 11 (22.4) 14 (9.5) 17 (11.3) 56 (10.2) 45 (13.0) Blood and lymphatic system disorders 0 0 0 0 0 2 (1.3) 0 2 (0.6) - Disseminated intravascular coagulation 0 0 0 0 0 1 (0.7) 0 1 (0.3) - Thrombocytopenia 0 0 0 0 0 1 (0.7) 0 1 (0.3) Cardiac disorders 0 1 (0.7) 0 0 0 0 0 1 (0.3) - Tachycardia 0 1 (0.7) 0 0 0 0 0 1 (0.3) Ear and labyrinth disorders 0 0 0 0 1 (0.7) 0 1 (0.2) 0 - Ear discomfort 0 0 0 0 1 (0.7) 0 1 (0.2) 0 Gastrointestinal disorders 9 (3.0) 5 (3.4) 4 (4.0) 1 (2.0) 3 (2.0) 5 (3.3) 16 (2.9) 11 (3.2) - Diarrhoea 4 (1.3) 3 (2.0) 2 (2.0) 0 3 (2.0) 5 (3.3) 9 (1.6) 8 (2.3) - Nausea 3 (1.0) 1 (0.7) 0 0 0 0 3 (0.5) 1 (0.3) - Vomiting 1 (0.3) 1 (0.7) 0 1 (2.0) 0 0 1 (0.2) 2 (0.6) - Abdominal pain upper 1 (0.3) 0 0 0 0 0 1 (0.2) 0 - Ascites 0 0 1 (1.0) 0 0 0 1 (0.2) 0 - Constipation 1 (0.3) 0 0 0 0 0 1 (0.2) 0 - Dry mouth 1 (0.3) 0 0 0 0 0 1 (0.2) 0 - Stomatitis 1 (0.3) 0 0 0 0 0 1 (0.2) 0 - Upper gastrointestinal haemorrhage 0 0 1 (1.0) 0 0 0 1 (0.2) 0 - Lip oedema 0 1 (0.7) 0 0 0 0 0 1 (0.3) General disorders and administration site conditions
5 (1.7) 0 2 (2.0) 0 0 2 (1.3) 7 (1.3) 2 (0.6)
- Oedema peripheral 2 (0.7) 0 0 0 0 0 2 (0.4) 0
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cUTI Study CREDIBLE-CR Study APEKS NP Study All Studies System Organ Class - Preferred Term
Cefiderocol N=300 n (%)
Imipenem/Cilastatin N=148 n (%)
Cefiderocol N=101 n (%)
BAT N=49 n (%)
Cefiderocol N=148 n (%)
Meropenem N=150 n (%)
Cefiderocol N=549 n (%)
Comparator N=347 n (%)
- Infusion site pain 2 (0.7) 0 0 0 0 0 2 (0.4) 0 - Feeling hot 1 (0.3) 0 0 0 0 0 1 (0.2) 0 - Oedema 0 0 1 (1.0) 0 0 0 1 (0.2) 0 - Pyrexia 0 0 1 (1.0) 0 0 0 1 (0.2) 0 - Infusion site erythema 1 (0.3) 0 0 0 0 0 1 (0.2) 0 - Hyperthermia 0 0 0 0 0 1 (0.7) 0 1 (0.3) - Multiple organ dysfunction syndrome 0 0 0 0 0 1 (0.7) 0 1 (0.3) Hepatobiliary disorders 0 1 (0.7) 0 0 1 (0.7) 1 (0.7) 1 (0.2) 2 (0.6) - Hepatic failure 0 0 0 0 1 (0.7) 0 1 (0.2) 0 - Hepatic function abnormal 0 1 (0.7) 0 0 0 0 0 1 (0.3) - Hepatocellular injury 0 0 0 0 0 1 (0.7) 0 1 (0.3) Immune system disorders 1 (0.3) 0 0 1 (2.0) 0 0 1 (0.2) 1 (0.3) - Drug hypersensitivity 1 (0.3) 0 0 0 0 0 1 (0.2) 0 - Anaphylactic reaction 0 0 0 1 (2.0) 0 0 0 1 (0.3) Infections and infestations 4 (1.3) 6 (4.1) 2 (2.0) 2 (4.1) 3 (2.0) 6 (4.0) 9 (1.6) 14 (4.0) - Clostridium difficile colitis 1 (0.3) 4 (2.7) 1 (1.0) 0 0 0 2 (0.4) 4 (1.2) - Oral candidiasis 1 (0.3) 0 0 0 1 (0.7) 0 2 (0.4) 0 - Candiduria 2 (0.7) 0 0 0 0 0 2 (0.4) 0 - Clostridium difficile infection 0 0 0 0 1 (0.7) 2 (1.3) 1 (0.2) 2 (0.6) - Pseudomembranous colitis 0 0 1 (1.0) 1 (2.0) 0 0 1 (0.2) 1 (0.3) - Sepsis 0 0 0 1 (2.0) 1 (0.7) 0 1 (0.2) 1 (0.3) - Fungal infection 0 1 (0.7) 0 0 0 0 0 1 (0.3) - Septic shock 0 0 0 1 (2.0) 0 0 0 1 (0.3) - Systemic candida 0 0 0 0 0 1 (0.7) 0 1 (0.3) - Vaginal infection 0 1 (0.7) 0 0 0 0 0 1 (0.3) - Urinary tract infection fungal 0 0 0 0 0 1 (0.7) 0 1 (0.3) - Pseudomonas infection 0 0 0 0 0 1 (0.7) 0 1 (0.3)
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cUTI Study CREDIBLE-CR Study APEKS NP Study All Studies System Organ Class - Preferred Term
Cefiderocol N=300 n (%)
Imipenem/Cilastatin N=148 n (%)
Cefiderocol N=101 n (%)
BAT N=49 n (%)
Cefiderocol N=148 n (%)
Meropenem N=150 n (%)
Cefiderocol N=549 n (%)
Comparator N=347 n (%)
- Candida infection 0 0 0 0 0 1 (0.7) 0 1 (0.3) Investigations 5 (1.7) 2 (1.4) 8 (7.9) 2 (4.1) 4 (2.7) 4 (2.7) 17 (3.1) 8 (2.3) - Alanine aminotransferase increased 1 (0.3) 0 3 (3.0) 0 2 (1.4) 1 (0.7) 6 (1.1) 1 (0.3) - Gamma-glutamyltransferase increased 4 (1.3) 1 (0.7) 0 0 2 (1.4) 0 6 (1.1) 1 (0.3) - Aspartate aminotransferase increased 0 0 3 (3.0) 0 2 (1.4) 1 (0.7) 5 (0.9) 1 (0.3) - Transaminases increased 0 0 1 (1.0) 0 1 (0.7) 0 2 (0.4) 0 - Liver function test increased 0 0 2 (2.0) 0 0 0 2 (0.4) 0 - Hepatic enzyme increased 1 (0.3) 0 0 1 (2.0) 0 2 (1.3) 1 (0.2) 3 (0.9) - Blood creatinine increased 0 1 (0.7) 1 (1.0) 0 0 0 1 (0.2) 1 (0.3) - Blood pressure increased 0 0 1 (1.0) 0 0 0 1 (0.2) 0 - Blood creatine increased 0 0 0 1 (2.0) 0 0 0 1 (0.3) - Blood alkaline phosphatase increased 0 1 (0.7) 0 0 0 0 0 1 (0.3) Metabolism and nutrition disorders 0 0 1 (1.0) 1 (2.0) 0 0 1 (0.2) 1 (0.3) - Hypokalaemia 0 0 1 (1.0) 0 0 0 1 (0.2) 0 - Metabolic acidosis 0 0 0 1 (2.0) 0 0 0 1 (0.3) Musculoskeletal and connective tissue disorders 1 (0.3) 0 0 0 0 0 1 (0.2) 0 - Myalgia 1 (0.3) 0 0 0 0 0 1 (0.2) 0 Nervous system disorders 1 (0.3) 4 (2.7) 1 (1.0) 1 (2.0) 3 (2.0) 0 5 (0.9) 5 (1.4) - Dysgeusia 1 (0.3) 1 (0.7) 1 (1.0) 0 0 0 2 (0.4) 1 (0.3) - Headache 0 3 (2.0) 0 0 1 (0.7) 0 1 (0.2) 3 (0.9) - Dizziness 0 0 0 0 1 (0.7) 0 1 (0.2) 0 - Paraesthesia 0 0 0 0 1 (0.7) 0 1 (0.2) 0 - Status epilepticus 0 0 0 1 (2.0) 0 0 0 1 (0.3) Psychiatric disorders 0 0 0 0 1 (0.7) 0 1 (0.2) 0 - Confusional state 0 0 0 0 1 (0.7) 0 1 (0.2) 0 Renal and urinary disorders 0 0 0 5 (10.2) 0 0 0 5 (1.4) - Acute kidney injury 0 0 0 4 (8.2) 0 0 0 4 (1.2)
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cUTI Study CREDIBLE-CR Study APEKS NP Study All Studies System Organ Class - Preferred Term
Cefiderocol N=300 n (%)
Imipenem/Cilastatin N=148 n (%)
Cefiderocol N=101 n (%)
BAT N=49 n (%)
Cefiderocol N=148 n (%)
Meropenem N=150 n (%)
Cefiderocol N=549 n (%)
Comparator N=347 n (%)
- Renal disorder 0 0 0 1 (2.0) 0 0 0 1 (0.3) Reproductive system and breast disorders 0 0 0 0 0 1 (0.7) 0 1 (0.3) - Vulvovaginal pruritus 0 0 0 0 0 1 (0.7) 0 1 (0.3) Respiratory, thoracic and mediastinal disorders 0 0 1 (1.0) 1 (2.0) 2 (1.4) 0 3 (0.5) 1 (0.3) - Pleural effusion 0 0 1 (1.0) 0 1 (0.7) 0 2 (0.4) 0 - Acute respiratory failure 0 0 0 0 1 (0.7) 0 1 (0.2) 0 - Asthma 0 0 0 0 1 (0.7) 0 1 (0.2) 0 - Respiratory arrest 0 0 0 1 (2.0) 0 0 0 1 (0.3) Skin and subcutaneous tissue disorders 3 (1.0) 0 2 (2.0) 0 2 (1.4) 1 (0.7) 7 (1.3) 1 (0.3) - Rash 0 0 1 (1.0) 0 1 (0.7) 0 2 (0.4) 0 - Pruritus 1 (0.3) 0 0 0 0 1 (0.7) 1 (0.2) 1 (0.3) - Drug eruption 0 0 1 (1.0) 0 0 0 1 (0.2) 0 - Erythema 1 (0.3) 0 0 0 0 0 1 (0.2) 0 - Palmar erythema 0 0 0 0 1 (0.7) 0 1 (0.2) 0 - Rash maculo-papular 1 (0.3) 0 0 0 0 0 1 (0.2) 0 Vascular disorders 0 0 1 (1.0) 0 0 0 1 (0.2) 0 - Hypertension 0 0 1 (1.0) 0 0 0 1 (0.2) 0
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BAT = best available therapy; INC = increase from baseline; PT-INR = prothrombin time-international normalized ratio;
ULN = upper limit of normal; Percentage is calculated using N’ as the denominator, where N’ is the number of subjects with valid postbaseline measurements.
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5.5.2 Safety analyses by clinical trial
5.5.2.1 APEKS cUTI
Cefiderocol was generally safe and well-tolerated in the cUTI study, with a safety profile
consistent with other cephalosporin antibacterials. Adverse events (AEs) and serious adverse
events (SAEs) were comparable between the cefiderocol and imipenem groups. The safety
profile of cefiderocol supports its use in cUTI.
5.5.2.1.1 Extent of Exposure
Safety Analysis Population
Of 452 subjects randomized, 448 received at least 1 dose of the study drugs and were included
in the Safety Population (99.0% [300/303] of subjects in the cefiderocol group and 99.3%
[148/149] of subjects in the IPM/CS group) (Table 82). Of the subjects in the Safety Population,
93.4% (283/303) of randomized subjects in the cefiderocol group and 92.6% (138/149) of
randomized subjects in the IPM/CS group completed the study.
Subjects were excluded from the Safety Population for no study drug infusion (1.0% [3/303]
of subjects in the cefiderocol group and 0.7% [1/149] of subjects in the IPM/CS group). Study
blind was broken for 4 subjects. All four were unblinded before the database was locked to
evaluate potential suspected unexpected serious adverse reactions.
Duration of Study Treatment
The duration of treatment exposure in the Safety Population is shown in Table 83. Treatment
duration was similar between the treatment groups and consistent with the ITT and Micro-ITT
populations. A similar percentage of subjects received less than 5 days of treatment (2.7% in
both treatment groups). A median of 9.0 days of treatment for both groups suggests the
majority of subjects received an adequate duration of therapy, and no differences between the
treatment groups were observed.
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Table 83: Summary of duration of exposure (safety population)
5.5.2.1.2 Brief Summary of Adverse Events
Incidence rates for AEs, treatment-related AEs, and SAEs were numerically lower in the
cefiderocol group compared with the IPM/CS group in the Safety Population (Table 84).
Adverse events and SAEs related to study drug are referred to as “treatment-related” in the
tables.
Table 84: Summary of treatment-emergent adverse events (safety population)
Safety Event Cefiderocol (N=300)
n (%)
Imipenem/cilastatin (N=148)
n (%)
Any AE 122 (41.0%) 76 (51.0%)
Any drug-related AEa 27 (8.7%) 17 (11.5%)
Discontinuation due to AEb 5 (1.7%) 3 (2.0%)
Any SAEs 14 (4.7%) 12 (8.1%)
Deathsc 1 (0.3%) 0 (0%)
[a] Considered treatment-related by the investigator; [b] SAEs for cefiderocol: C. difficile, hypersensitivity (itching), increased
hepatic enzymes, diarrhea; [c] Death due to cardiac arrest considered unrelated to study drug by investigator.
AE - adverse event; SAE - serious adverse event; Source: Portsmouth, 2018[51]
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Discontinuations due to AEs were reported for 1.7% (5/300) of subjects in the cefiderocol
group compared with 2.0% (3/148) of subjects in the IPM/CS group.
One death due to cardiorespiratory arrest was observed in the cefiderocol treatment group;
however, this SAE was considered not related to the study drug by both the investigator and
the sponsor [51, 236].
5.5.2.1.3 Incidence of Adverse Events
Adverse events were most frequently reported in the gastrointestinal disorders SOC as shown
in Table 82. Of the AEs reported in at least 2% of subjects, diarrhea, hypertension,
constipation, infusion site pain, headache, nausea, hypokalemia, insomnia, renal cyst, infusion
site erythema, abdominal pain upper, cardiac failure, C. difficile colitis, and vaginal infection
were seen less frequently in the cefiderocol group than in the IPM/CS group (Table 82).
Cough and vomiting were reported more frequently in the cefiderocol group than in the IPM/CS
group. Cough was reported in 2.3% (7/300) of subjects in the cefiderocol group compared with
0.7% (1/148) of subjects in the IPM/CS group. Of note, cough was mild in severity in 5 of 7
subjects and moderate in 2 of 7 subjects in the cefiderocol group, and the single incidence of
cough in the IPM/CS group was mild. There were no reports of severe cough. Vomiting was
reported in 2.0% (6/300) of subjects in the cefiderocol group compared with 1.4% (2/148) of
subjects in the IPM/CS group (all mild in severity). There were no other notable differences
between the treatment groups.
The incidence rate of treatment-related AEs (considered treatment-related by the investigator)
was 9.0% (27/300) of subjects in the cefiderocol group and 11.5% (17/148) of subjects in the
IPM/CS group (Table 82).
5.5.2.1.4 Severity of Adverse Events
The percentage of subjects with mild AEs was approximately the same for each treatment:
25.7% (77/300) of subjects in the cefiderocol group and 24.3% (36/148) of subjects in the
IPM/CS group. However, a lower percentage of subjects in the cefiderocol group had
moderate AEs (13.0% [39/300] of subjects) compared with the IPM/CS group (23.6% [35/148]
of subjects) and severe AEs (2.0% [6/300] of subjects in the cefiderocol group compared with
3.4% [5/148] of subjects in the IPM/CS group) (Table 85).
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Table 85: Number (%) of subjects with adverse events by maximum severity (safety population)
5.5.2.1.5 Relationship
9.0% (27/300) of subjects had AEs reported as related to treatment in the cefiderocol group
and 11.5% (17/148) of subjects in the IPM/CS group (Table 82).
5.5.2.1.6 Other Serious Adverse Events
Serious adverse events were reported in 4.7% (14/300) of subjects in the cefiderocol group
and 8.1% (12/148) of subjects in the IPM/CS group (Table 86). The most frequently reported
SAE was C. difficile colitis (0.7% [3/448] of subjects in the total population), with 0.3% (1/300)
of subjects in the cefiderocol group and 1.4% (2/148) of subjects in the IPM/CS group. The
SAEs of C. difficile colitis in 1 subject in the cefiderocol group (0.3% [1/300]) and in 1 of the 2
subjects in the IPM/CS group (0.7% [1/148]) were considered by the investigator to be
treatment related (Table 87).
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Table 86: Number (percent) of subjects with serious adverse events (SAEs) by organ class and
preferred term (safety population)
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Table 87: Number (%) of subjects with treatment-related serious adverse events (SAEs)
5.5.2.2 APEKS cUTI NMA safety analysis
The safety NMA analysis was only possible to be performed for All AEs and Treatment related
AEs. Results for both endpoints are presented in this section. Full information on the feasibility
assessment and NMA analysis can be found in [227] and [285].
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Figure 52: Network Diagram for Safety Analysis
Results for both safety analysis were non-significant, except for the results observed in the
APEKS cUTI vs Imipenem/cilastatin in the frequentist analysis for all AEs (Figure 53 to Figure
55)
Figure 53: Safety Analysis for All Adverse Events - Frequentist Analysis
Figure 54: Network for safety analysis for Treatment related AEs
Figure 55: safety analysis for Treatment related AEs – Frequentist analysis
Legends:
BAT: best available therapy C_T: ceftazalone-tazobactam CZA: ceftaz idime-avibactam DOR: doripenem FDC: cefiderocol IPM_CIL: imipenem/cilastatin LVX: levofloxacin
Legends:
BAT: best available therapy C_T: ceftazalone-tazobactam CZA: ceftaz idime-avibactam DOR: doripenem FDC: cefiderocol IPM_CIL: imipenem/cilastatin LVX: levofloxacin
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5.5.2.3 APEKs-NP: SAFETY
5.5.2.3.1 Extent of Exposure
Of the 300 randomised subjects, 298 received at least one dose of study drug and were
included in the safety population: 148 subjects in the cefiderocol group (2 g q8h, 3-hour
infusion, or equivalent renally adjusted dose) and 150 in the HD meropenem group (2 g q8h,
3-hour infusion, or equivalent renally adjusted dose). The median (range) duration of treatment
was 10.0 (2-22) days in the cefiderocol group and 8.5 (1-22) days in the HD meropenem group
[238]. Most subjects in both treatment groups had 7-14 days of exposure (65.5% [97/148] and
73.3% [110/150] in cefiderocol and HD meropenem groups, respectively).
Adverse events occurred in 87.8% (130/148) of subjects in the cefiderocol group and 86.0%
(129/150) of the HD meropenem group (Table 88). SAEs occurred in 36.5% (54/148) of
subjects in the cefiderocol group and 30.0% (45/150) in the meropenem group.
Adverse events leading to death occurred in 26.4% (39/148) of subjects in the cefiderocol
group and 23.3% (35/150) in the meropenem group. Treatment-related AEs, treatment-related
SAEs, discontinuations due to AEs, and discontinuations due to treatment-related AEs differed
between treatment groups by < 2%.
Table 88: Overview of Treatment-emergent Adverse Events (Safety Population)
Adverse Event Category
Cefiderocol
(N = 148)
HD Meropenem
(N = 150) Difference of
Proportion
(95% CI)
Subjects
n (%)
# of
events
Subjects
n (%)
# of
events
TEAEs 130 (87.8) 582 129 (86.0) 537 1.8 (-5.8, 9.5)
Treatment-related TEAEs 14 (9.5) 24 17 (11.3) 22 -1.9 (-8.8, 5.1)
TEAEs leading to death 39 (26.4) 49 35 (23.3) 50 3.0 (-6.8, 12.8)
Treatment-emergent SAEs 54 (36.5) 102 45 (30.0) 96 6.5 (-4.2, 17.2)
Treatment-related SAEs 3 (2.0) 6 5 (3.3) 6 -1.3 (-5.0, 2.4)
Discontinuation due to TEAEs 12 (8.1) 18 14 (9.3) 19 -1.2 (-7.6, 5.2)
Discontinuation due to
treatment-related TEAEs
2 (1.4) 4 2 (1.3) 3 0.0 (-2.6, 2.6)
CI = confidence interval; TEAEs = treatment emergent adverse events; SAEs = serious adverse events; Percentage was calculated using the number of subjects in the column heading as the denominator. Adverse events that started on or after the first dose date of the study drug and up to ‘End of Study’ were defined as treatment-emergent. Confidence intervals were calculated using the Wilson score method. Source: APEKS-NP Study Synopsis[238]
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Adverse events with the highest frequency in the cefiderocol group (urinary tract infection
[15.5%], hypokalemia [10.8%], diarrhea [8.8%], and anemia [8.1%]) were also the most
frequent AEs in the high-dose meropenem group (hypokalemia [15.3%], urinary tract infection
[10.7%], diarrhea [8.7%], and anemia [8.0%]) [262, 263].
5.5.2.3.2 Overview of TEAEs
Most subjects in the cefiderocol group and meropenem group experienced at least 1 TEAE
(87.8% [130/148] and 86.0% [129/150], respectively) (Table 88). SAEs were reported in 36.5%
(54/148) in the cefiderocol group and 30.0% (45/150) in the meropenem group. Overall,
treatment-related TEAEs and SAEs, TEAEs leading to death and discontinuation were
reported with similar frequency in the two treatment groups.
5.5.2.3.3 Common TEAEs
The most commonly reported TEAEs (i.e. TEAEs reported in ≥5% of subjects in either
treatment group) are summarised by PT in Table 119-9. All TEAEs are reported by SOC and
PT in a safety data on file[262, 263]. The most commonly reported TEAEs were from the
following SOCs:
Infections and Infestations: in 40.5% (60/148) and 35.3% (53/150) of subjects in
the cefiderocol and meropenem groups, respectively
Metabolism and nutrition disorders: in 29.1% (43/148) and 31.3% (47/150) of
subjects in the cefiderocol and meropenem groups, respectively.
Specifically, the most common TEAEs were urinary tract infection in the cefiderocol group (in
15.5% [23/148] of subjects compared with 10.7% [16/150] in the meropenem group) and
hypokalaemia in the meropenem group (in 15.3% [23/150] of subjects compared with 10.8%
[16/148] in the cefiderocol group). Most TEAEs were reported with similar frequency in the two
treatment groups. TEAEs reported more frequently (>4% difference between treatment
groups) in the cefiderocol group than in the meropenem group were: urinary tract infection (in
15.5% [23/148] vs. 10.7% [16/150] of subjects) and hypomagnesaemia (in 5.4% [8/148] vs.
0.7% [1/150] of subjects). TEAEs reported less frequently in the cefiderocol group than in the
meropenem group (>4% difference between treatment groups) were: hypokalaemia (in 10.8%
[16/148] vs. 15.3% [23/150] of subjects), hepatic enzyme increased, hyponatraemia and
decubitus ulcer (each in 2.7% [4/148] vs. 6.7% [10/150] of subjects), and hypotension (in 1.4%
[2/148] vs. 6.7% [10/150] of subjects).
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5.5.2.3.4 TEAEs by severity
Overall, the proportions of subjects experiencing mild, moderate or severe TEAEs was 23.5%
(70/298), 29.5% (88/298) and 33.9% (101/298), respectively. The incidence of severe TEAEs
was 37.8% (56/148) in the cefiderocol group compared with 30.0% (45/150) in the high-dose
meropenem group.
5.5.2.3.5 Severe TEAEs
The most common severe TEAEs were: cardiac arrest was reported in 4.7% (7/148) in the
cefiderocol group and 3.3% (5/150) in the high-dose meropenem group, and pneumonia, was
reported in 4.7% (7/148) and 2.0% (3/150), respectively; brain oedema was reported in 0.7%
(1/148) subjects in the cefiderocol group compared with 3.3% (5/150) in the meropenem
group.Treatment-related TEAEs
Treatment-related TEAEs are presented by SOC and PT in Table 86. Overall, the incidence
of treatment-related TEAEs was 9.5% (14/148) in the cefiderocol group and 11.3% (17/150)
in the meropenem group. The most common treatment-related TEAE was diarrhoea, reported
for 2.0% (3/148) subjects in the cefiderocol group compared with 3.3% (5/150) subjects in the
meropenem group.
All treatment-related TEAEs associated with increases in liver enzyme in the cefiderocol group
were transient and resolved or were resolving during the study. Overall, the majority of
treatment-related TEAEs were either mild (n=15) or moderate (n=20), while 11 were severe.
5.5.2.3.6 Deaths
The primary objective of this study was to compare all-cause mortality between the 2 groups
at Day 14 after start of study drug therapy in the mITT population. All-cause mortality rates for
the mITT population are reported in the efficacy section.
5.5.2.3.7 Other SAEs
All SAEs reported during the study are presented by SOC and PT on file [238]. Overall, the
frequency of SAEs was 36.5% (54/148) in the cefiderocol group compared with 30.0%
(45/150) in the meropenem group. Overall, the most common SAE was cardiac arrest,
reported in 4.7% (7/148) in the cefiderocol group compared with 3.3% (5/150) in the
meropenem group.
Overall, treatment-related SAEs were reported in 2.0% (3/148) in the cefiderocol group
compared with 3.3% (5/150) in the meropenem group [238].
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Table 89 – Number (percent) of subjects with serious adverse events (SAEs) by organ class and preferred term (safety population)
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5.5.2.3.8 TEAEs leading to study treatment discontinuation
All TEAEs leading to study treatment discontinuation are presented by SOC and PT in Table
119-13. TEAEs leading to study treatment discontinuation were reported for 8.1% (12/148) in
the cefiderocol group and 9.3% (14/150) in the meropenem group. Alanine aminotransferase
increased was the most frequently reported TEAE leading to discontinuation, in 2/148 (1.4%)
subjects in the cefiderocol group. Hepatic enzymes increased was reported in no subjects in
the cefiderocol group and 5/150 (3.3%) in the HD meropenem group. All other TEAEs leading
to discontinuation were reported at most in 1 subject in either treatment group.
5.5.2.3.9 Conclusions for APEKS-NP Study
Overall, the types and frequency of TEAEs for cefiderocol were generally similar to high-dose
meropenem and consistent with safety profile of cephalosporin class of antibacterials.
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5.5.2.4 CREDIBLE-CR
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
5.5.2.4.1 Treatment-Emergent Adverse Events
Over 90% of the subjects in each treatment group had at least 1 adverse event (Table 90).
The incidence of treatment-related adverse events was 14.9% in the cefiderocol group and
22.4% in the BAT group. The incidence of adverse events with an outcome of death by the
end of the study was 33.7% in the cefiderocol group and 18.4% in the BAT group. Of note,
none of the deaths in the cefiderocol group were considered related to study treatment by
either the investigator or Shionogi. The percentage of reported serious adverse events was
49.5% in the cefiderocol group and 46.9% in the BAT group. Overall, 6 subjects experienced
treatment-related serious adverse events (1 in the cefiderocol group and 5 in the BAT group).
The percentage of discontinuations due to adverse events was 9.9% in the cefiderocol group
and 6.1% in the BAT group.
Table 90: Overview of Treatment-emergent Adverse Events (Safety Population)
Cefiderocol (N = 101)
BAT (N = 49)
Adverse Event Category Subjects n (%)
Events n'
Subjects n (%)
Events n'
AEs 92 (91.1) 634 47 (95.9) 311 Treatment-related AEs 15 (14.9) 27 11 (22.4) 16 Death 34 (33.7) 45 9 (18.4) 14 SAEs 50 (49.5) 92 23 (46.9) 36 Treatment-related SAEs 1 (1.0) 1 5 (10.2) 7 Discontinuation due to AEs 10 (9.9) 12 3 (6.1) 3 Discontinuation due to treatment-related AEs
3 (3.0) 3 2 (4.1) 2
AEs = adverse events; BAT = best available therapy; SAEs = serious adverse events
Percentage is calculated using the number of subjects in the column heading as the denominator. Adverse events that started
after the first dose of the study drug and up to End of Study visit are defined as treatment-emergent. One subject received
cefiderocol after completion of BAT; this subject is included under BAT in this table. Source: CREDIBLE-CR Final Study Summary
[243]
Treatment-emergent Adverse Events Reported in Either Treatment Group
The most frequently (> 10% of subjects in either arm) reported adverse events were diarrhea,
pyrexia, septic shock, and vomiting. Adverse events reported more frequently (> 5% difference
between the treatment groups) in the cefiderocol group than in the BAT group were diarrhea,
alanine aminotransferase increased, aspartate aminotransferase increased, pleural effusion,
and chest pain. Adverse events reported less frequently (> 5% difference between the
treatment groups) in the cefiderocol group than in the BAT group were hypokalemia,
hyperkalemia, rash, and depression.
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Transient elevations in liver enzymes due to cefiderocol cannot be excluded; however, like
other cephalosporins, the elevations are reversible after discontinuing the study drug, and
none have resulted in serious hepatotoxicity.
All 6 chest pain cases were in the cefiderocol group and were reviewed. The majority of the
events of chest pain were considered to be noncardiovascular in nature and not related to
cefiderocol. Most of the remaining adverse events occurred at a low frequency, suggesting
manifestations of the subjects’ underlying disease. Overall, no safety signals related to
cefiderocol use were observed.
5.5.2.4.2 Treatment-related Adverse Events
Overall there were 15 (14.9%) of patients with treatment related AEs in the cefiderocol arm
and 11 (22.4%) in the BAT arm.
Diarrhea (2.0%), liver function test abnormal (2.0%), alanine aminotransferase increased
(3.0%), and aspartate aminotransferase increased (3.0%) were the most frequently reported
treatment-related treatment-emergent adverse events in the cefiderocol group, while acute
kidney injury (8.2%) was the most frequently reported treatment-related treatment-emergent
adverse event in the BAT group.
Only 1 (1%; increase in transaminases) in cefiderocol arm and 5 (10.2%) in the BAT arm were
considered serious (1 anaphilactic reaction; 1 septic shock; 1 metabolic acidosis; 1 status
epilepticus; 2 acute renal failure; and 1 respiratory arrest). The higher incidence of treatment-
related SAE in the BAT group was due to use of antibacterials with known renal toxicity in BAT
group. In the BAT group, 5 SAEs of renal impairment (acute kidney injury and renal disorder)
considered related to colistin and tobramycin were reported.
Table 91: Subjects with Treatment-related Adverse Events by Preferred Term (Safety Population)
Preferred Term
Cefiderocol (N = 101) n (%)
BAT (N = 49) n (%)
Subjects with treatment-related AEs 15 (14.9) 11 (22.4) Alanine aminotransferase increased 3 (3.0) 0 Aspartate aminotransferase increased 3 (3.0) 0 Diarrhoea 2 (2.0) 0 Liver function test abnormal 2 (2.0) 0
Ascites 1 (1.0) 0 Blood creatinine increased 1 (1.0) 0 Blood pressure increased 1 (1.0) 0 Clostridium difficile colitis 1 (1.0) 0 Drug eruption 1 (1.0) 0 Dysgeusia 1 (1.0) 0 Hypertension 1 (1.0) 0 Hypokalaemia 1 (1.0) 0 Oedema 1 (1.0) 0 Pleural effusion 1 (1.0) 0
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Preferred Term
Cefiderocol (N = 101) n (%)
BAT (N = 49) n (%)
Pseudomembranous colitis 1 (1.0) 1 (2.0) Pyrexia 1 (1.0) 0 Rash 1 (1.0) 0 Transaminases increased 1 (1.0) 0 Upper gastrointestinal haemorrhage 1 (1.0) 0 Acute kidney injury 0 4 (8.2)
Anaphylactic reaction 0 1 (2.0) Blood creatine increased 0 1 (2.0) Hepatic enzyme increased 0 1 (2.0) Metabolic acidosis 0 1 (2.0) Renal disorder 0 1 (2.0) Respiratory arrest 0 1 (2.0) Sepsis 0 1 (2.0) Septic shock 0 1 (2.0) Status epilepticus 0 1 (2.0) Vomiting 0 1 (2.0)
AEs = adverse events; BAT = best available therapy
Percentage was calculated using the number of subjects in the column heading as the denominator. Adverse events that started
after the first dose of the study drug and up to End of Study visit were defined as treatment-emergent. Although a subject may
have had 2 or more adverse events, the subject was counted only once within a System Organ Class category. The same subject
may have contributed to 2 or more Preferred Terms in the same System Organ Class category. One subject received cefiderocol
after completion of BAT; this subject is included under BAT in this table. The most frequently reported treatment-related treatment-
emergent adverse events are shown in bold. Source: CREDIBLE-CR Final Study Summary [243]
5.5.2.4.3 Serious Adverse Events
Septic shock was the most frequently reported serious adverse event in both the cefiderocol
(11.9%; 12/101 subjects) and BAT (12.2%; 6/49 subjects) groups (Table 92).
Table 92: Subjects with Serious Adverse Events by System Organ Class and Preferred Term
(Safety Population)
System Organ Class Preferred Term
Cefiderocol (N = 101) n (%)
BAT (N = 49) n (%)
Subjects with SAEs 50 (49.5) 23 (46.9) Blood and lymphatic system disorders 1 (1.0) 1 (2.0) Anaemia 0 1 (2.0) Febrile neutropenia 1 (1.0) 0 Cardiac disorders 6 (5.9) 4 (8.2) Bradycardia 1 (1.0) 1 (2.0) Cardiac arrest 4 (4.0) 2 (4.1) Cardiac failure congestive 1 (1.0) 0 Myocardial infarction 1 (1.0) 0 Pulseless electrical activity 0 1 (2.0) Gastrointestinal disorders 5 (5.0) 0 Abdominal pain 1 (1.0) 0 Abdominal pain upper 1 (1.0) 0 Gastrointestinal haemorrhage 1 (1.0) 0 Intestinal ischaemia 1 (1.0) 0 Lower gastrointestinal haemorrhage 1 (1.0) 0 Pancreatitis 1 (1.0) 0 Small intestinal obstruction 1 (1.0) 0 General disorders and administration site conditions 7 (6.9) 3 (6.1) Chills 1 (1.0) 0 General physical health deterioration 0 1 (2.0) Multi-organ failure 2 (2.0) 2 (4.1) Pyrexia 3 (3.0) 0
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System Organ Class Preferred Term
Cefiderocol (N = 101) n (%)
BAT (N = 49) n (%)
Sudden death 1 (1.0) 0 Hepatobiliary disorders 3 (3.0) 0 Chronic hepatic failure 1 (1.0) 0 Hepatic failure 1 (1.0) 0 Hepatitis 1 (1.0) 0 Immune system disorders 0 1 (2.0) Anaphylactic reaction 0 1 (2.0) Infections and infestations 29 (28.7) 11 (22.4) Bacteraemia 3 (3.0) 0 Bacterial infection 1 (1.0) 0 Device related infection 0 1 (2.0) Empyema 1 (1.0) 1 (2.0) Endocarditis 0 1 (2.0) Enterococcal bacteraemia 1 (1.0) 0 Enterococcal infection 2 (2.0) 0 Meningitis 0 1 (2.0) Necrotising fasciitis 0 1 (2.0) Osteomyelitis 1 (1.0) 0 Osteomyelitis acute 0 1 (2.0) Pneumonia 5 (5.0) 1 (2.0) Pneumonia bacterial 1 (1.0) 0 Renal abscess 1 (1.0) 0 Sepsis 3 (3.0) 0 Septic shock 12 (11.9) 6 (12.2)
Systemic candida 1 (1.0) 0 Urinary tract infection 1 (1.0) 0 Urosepsis 1 (1.0) 0 Investigations 5 (5.0) 3 (6.1) Liver function test abnormal 4 (4.0) 3 (6.1) Transaminases increased 1 (1.0) 0 Metabolism and nutrition disorders 3 (3.0) 1 (2.0) Hyponatraemia 1 (1.0) 0 Metabolic acidosis 2 (2.0) 1 (2.0) Neoplasms benign, malignant and unspecified (incl cysts and polyps)
1 (1.0) 0
Lung neoplasm malignant 1 (1.0) 0 Nervous system disorders 3 (3.0) 2 (4.1) Dizziness 1 (1.0) 0 Hypoaesthesia 1 (1.0) 0 Neurological decompensation 1 (1.0) 0 Paraesthesia 1 (1.0) 0 Quadriplegia 0 1 (2.0) Status epilepticus 0 1 (2.0) Renal and urinary disorders 6 (5.9) 2 (4.1) Acute kidney injury 3 (3.0) 2 (4.1) Anuria 1 (1.0) 0 Nephrolithiasis 1 (1.0) 0 Oliguria 2 (2.0) 0 Respiratory, thoracic and mediastinal disorders 7 (6.9) 2 (4.1) Acute respiratory failure 1 (1.0) 1 (2.0) Chronic obstructive pulmonary disease 1 (1.0) 0 Obstructive airways disorder 1 (1.0) 0 Pneumonia aspiration 2 (2.0) 0 Respiratory arrest 0 1 (2.0) Respiratory failure 2 (2.0) 0 Vascular disorders 2 (2.0) 2 (4.1) Hypotension 2 (2.0) 1 (2.0) Shock 1 (1.0) 1 (2.0)
BAT = best available therapy; SAEs = serious adverse events
Percentage was calculated using the number of subjects in the column heading as the denominator. Adverse events that started
after the first dose of the study drug and up to End of Study visit were defined as treatment-emergent. Although a subject may
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have had 2 or more adverse events, the subject was counted only once within a System Organ Class category. The same subject
may have contributed to 2 or more Preferred Terms in the same System Organ Class category.
One subject received cefiderocol after completion of BAT; this subject is included under BAT in this table.
Source: CREDIBLE-CR Final Study Summary [243]
5.5.2.4.4 Adverse Events Leading to Death
Adverse events leading to death are summarized in the efficacy section (5.4.5 and the
summary study report [243]) There were 20.6% (21/102) of patients in the cefiderocol group
and 6.3% (3/48) of patients in the BAT group with deaths classified in the SOC of Infections
and Infestations. After reviewing the details for each individual patient, this imbalance in
mortality between the treatment groups was not considered a safety issue, considering the
complicated comorbidities and difficult-to-treat infections in this patient population. As per
request of EUnetHTA, mortality data is included in the efficacy section.
5.5.2.4.5 Discussion
Limitations to Detect Adverse Reactions in Clinical Trial Development Programmes
The limitations on adverse drug reactions (ADR) detection are based on the information in
Table 93 for patients with Gram-negative infections (including complicated urinary tract
infection) and considering patients with at least 7 days of treatment with cefiderocol. In addition
to the differences in adverse event reporting which occur in open label vs double-blind studies,
the study populations in the three studies are very different, with the cUTI study subjects more
clinically stable than those in the APEKS NP and CREDIBLE-CR studies.
Table 93: Limitations to detect adverse events in clinical trial programmes
Source: EU Risk Management Plan [284]
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Table 94: Methods of data collection and analysis of AE, TEAE and SAE
Study
reference/ID
Endpoint definition Method of analysis
APEKs-cUTI
APEKs-NP
CREDIBLE-CR
Adverse Events (AE) or
Treatment-emergent Adverse
Events (TEAE)
An AE was defined as any
untoward medical occurrence in
a subject administered a
pharmaceutical product
(including investigational drug)
during a clinical investigation. An
AE could therefore be any
unfavourable and unintended
sign (including an abnormal
laboratory finding), symptom,
unplanned procedure, or disease
temporally associated with the
use of an investigational product,
whether considered related to
the investigational product.
The severity of an event was graded according to the
following definitions:
• Mild: A finding, or symptom was minor and did not
interfere with usual daily activities
• Moderate: The event was discomfort and caused
interference with usual daily activity or affected clinical
status
• Severe: The event caused interruption of the subject's
usual daily activities or had a clinically significant effect
The relationship of an event to the study drug was
determined according to the following criteria:
– Related: An AE that can be reasonably
explained that the study drug caused the AE.
For example, the occurrence of the AE cannot
be explained by other causative factors, but
can be explained by pharmacological effect of
the study drug, such as a similar event had
been reported previously, or
increasing/decreasing the dose affects the
occurrence or seriousness of the AE, etc.
Not Related: An AE that cannot be reasonably
explained that the study drug caused the AE
Unless otherwise noted, the summary of AEs will be
performed for events of treatment emergent.
An expected treatment-related AE was any AE that was
consistent with the current Investigator's Brochure for
cefiderocol.
Expectedness
A treatment-related AE is considered expected if it is
listed in Expected Adverse Reactions in Section
“Undesirable Effects” of “SUMMARY OF DATA AND
GUIDANCE FOR INVESTIGATORS” in the current
investigator's brochure for cefiderocol. The expected
adverse reactions of comparators will be those found in
the EMA SmPC. The expected adverse reactions of
linezolid will be those found in the local SmPC.
Expectedness will be assessed by the sponsor.
Clinical Laboratory Adverse Events
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For any abnormal laboratory test results (haematology,
blood chemistry, or urinalysis) or other safety
assessments (e.g., physical examination, vital signs)
that are worsening from baseline or occur thereafter in
the course of the study, the investigator or sub-
investigator will consider whether these results are
clinically significant. Abnormal laboratory test results are
defined as values outside the reference range. Any test
results which are clinically significant at the discretion of
the investigator or sub investigator are to be recorded
as AEs. If an abnormal laboratory finding is associated
with disease or organ toxicity, the investigator should
report only the disease or organ toxicity as AEs. These
AEs should also be assessed as to whether they meet
the definition of seriousness and reported accordingly.
The investigator or sub-investigator will consider test
results to be clinically significant in the following
circumstances:
Test result leads to any of the outcomes
included in the definition of an SAE.
Test result leads to discontinuation from the
study.
Test result leads to a concomitant drug
treatment or other therapy.
Test result requiring additional diagnostic
testing or other medical intervention.
Test result meeting the management criteria
for liver function abnormalities identified in the
Appendix 6 of the statistical analysis plan
(SAP).
Liver Abnormalities
Management and Discontinuation Criteria for Abnormal
Liver Function tests have been designed to ensure
subject safety and evaluate liver event aetiology. The
investigator or sub-investigator must review study
subject laboratory results as they become available to
identify if any values meet the criteria in Appendix 6.
When any test result meets the management criteria for
liver function abnormalities, the results of further
assessments and required FUP.
Serious Adverse Events (SAE)
An SAE is defined by regulation
as any AE occurring at any dose
The severity of a SAE was graded to the listed criteria.
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that results in any of the following
outcomes:
Death
Life-threatening
condition
Hospitalization or
prolongation of existing
hospitalization for
treatment
Persistent or significant
disability/incapacity
Congenital
anomaly/birth defect
Other medically
important condition
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5.6 Conclusions
1. Provide a general interpretation of the evidence base considering the benefits
associated with the technology relative to those of the comparators.
Cefiderocol is an innovative siderophore cephalosporin antibacterial with a unique molecular
structure designed to provide high stability to carbapenemases and use bacteria’s own
mechanism of iron uptake. Both these attributes enable cefiderocol to overcome three main
mechanisms of beta-lactam bacterial resistance (degradation by β-lactamase enzymes, porin
channel mutations, and overexpression of efflux pumps), which is translated in a wide activity
spectrum against aerobic Gram-negative pathogens, including the MDR and WHO critically
important carbapenem resistant strains of Enterobactereacea, A. baumanii and P. aeruginosa,
as well as intrinsically CR S. maltophilia. MDR pathogens are difficult to treat, have limited
treatment options, and no existing treatment provides both comprehensive coverage and good
safety profile. Cefiderocol therefore constitutes an effective and safe treatment option for
patients with serious infections in the presence of world-wide growing resistances.
MDR infections, including those resistant to carbapenems, primarily occur in vulnerable
hospitalised patients. The treatment of MDR-GNB infections in critically ill patients presents
many challenges are associated with poorer outcomes including increased mortality,
increased length of stay and healthcare resource utilization, compared to non-resistant
pathogens. Since an effective treatment should be administered as soon as possible,
resistance to many antimicrobial classes almost invariably reduces the probability of adequate
empirical coverage, with possible unfavorable consequences in terms of increased mortality,
length of stay and healthcare reseource utilization.
In this light, readily available patient’s medical history and updated information about the local
microbiological epidemiology remain critical for defining the baseline risk of MDR-GNB
infections and firmly guiding empirical treatment choices, with the aim of avoiding both
undertreatment and overtreatment. Treatment of severe MDR-GNB infections in critically ill
patients requires a expert and complex clinical reasoning, taking into account the peculiar
characteristics of the target population, but also the need for adequate empirical coverage and
the more andmore specific enzyme-level activity of novel antimicrobials with respect to the
different resistance mechanisms of MDR-GNB.
Due to the urgent need to develop new treatments based on the underlying pathogens rather
than the infection site, the EMA label is expected to authorize cefiderocol to be used for
treatment of infections due to aerobic Gram-negative organisms in adults with limited
treatment options
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Assessment of the effectiveness of cefiderocol is based on the integration of in vitro, PK/PD
and clinical data. Large susceptibility studies have confirmed cefiderocol wider Gram-negative
spectrum, and being a more potent antimicrobial agent than comparators. It’s very favourable
minimum inhibitory concentrations (MICs) have been shown to correlate well with in vivo
efficacy and randomized clinical trials in patients with cUTI, nosocomial pneumonia, and BSI
have provided confirmation of the efficacy and safety of cefiderocol in key target patient
populations. These reflect the label and are pathogen focused, not restricted to any specific
site of infection and supports the use of cefiderocol in two types of patients:
Hospitalised patients with suspected (but prior laboratory confirmation) MDR/CR
infection who are critically ill and require immediate antibacterial treatment that
provides full cover against CR pathogens and potential resistant mechanisms, to
avoid the risk of rapid clinical deterioration (with the option to de-escalate to a more
targeted treatment when the pathogen and susceptibility profile is subsequently
confirmed).
Hospitalised patients where CR infection has been confirmed and cefiderocol is
best option based on pathogen susceptibility information and/or where other
treatment choices are inappropriate (efficacy, contra-indication or
tolerability).Conclusions based on the in-vitro surveillance, PK/PD data and clinical
data
Cefiderocol is a time-dependent cephalosporin. Preclinical studies showed that cefiderocol
has linear pharmacokinetics, primarily urinary excretion, an elimination half-life of 2–3 hours,
and a protein binding of 58% in human plasma. The probability of a target attainment at ≥75%
of the dosing interval during which the free drug concentration exceeds the minimum inhibitory
concentration (ƒT/MIC) for bacterial strains with an MIC of ≤4 μg/mL was greater than 90% at
the therapeutic dose of 2 g over 3-hour infusion every 8 hours in most patients.
Only renal function markers were found to be influential covariates for the pharmacokinetics
of cefiderocol for patients with altered renal function. Dose adjustment is recommended for
patients with impaired and augmented renal function.
The potent activity of cefiderocol was confirmed in an extensive series of in vitro studies,
against clinical isolates from surveillance studies, and in animal infection models. The
SIDERO-WT study showed ccefiderocol to have activity against 99.5% of Gram-negative
isolates at a MIC of 4 mg/L, while the SIDERO-CR study, which only includes CR isolates,
showed cefiderocol to have potent in vitro activity at a MIC of 4 mg/L against 96.2% of isolates
of carbapenem-non-susceptible pathogens including all of the WHO priority pathogens and
Stenotrophomonas maltophilia. In both studies, cefiderocol was found to give wider Gram-
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negative coverage, and to be a more potent in vitro antibacterial agent than comparators. The
results confirm cefiderocol overcomes multiple mechanisms or resistance and to be stable
against the 4 known classes of β-lactamases, including serine carbapenemases, with potency
which is equal to or greater than comparators.
An improved in vitro potency in addition to a well-characterized favorable PK/PD profile are
crucial to achieve both adequate exposure to the antibacterial over the MIC for the pathogen,
and clinical cure in patients infected with drug-resistant pathogens [52]. Therefore, clinical
studies in antimicrobials, provide only supportive safety and efficacy evidence to the pivotal
in-vitro and PK/PD data. Furthermore, in the context of antibacterial resistance, the standard
clinical trial approach aiming at demonstrating superiority over existing treatments is not
feasible. Treatment options for MDR infections do not allow a superiority trial and it would be
unethical to wihthold effective treatment to pateints in such trials [52]. Hence, clinical trials
have an important role to confirm clinical efficacy, but a limited role in providing comparative
evidence outside the trial, as only pathogens that fall within the in-vitro spectrum of the tested
treatments and comparators are included in the study. This is particularly relevant for
antimicrobial treatment selection in the absence of antibiogram.
The clinical evidence to support the use of cefiderocol is based on 2 randomised, double
blinded clinical trials, and 1 descriptive open-label study. Data from an NMA, an effectiveness
model and compassionate use cases complement the body of confirmatory clinical data.
Low likelihood of in treatment development of resistance against cefiderocol was
demonstrated by the fact that only very few and moderate increases in the cefiderocol MIC
were seen over the treatment course, usually requiring more than 1 simultaneous mutation to
increase the MIC. Cefiderocol also presents low likelihood of generating cross resistance,
given that the main resistant pathway identified in in vitro studies was related with the
siderophore ion uptake.
5.6.1 Evidence to support use of cefiderocol in patients with infections by suspected MDR/CR pathogens:
SIDERO WT provides evidence to support the use of cefiderocol in the group of critically ill
patients with infections suspected to be caused by a MDR pathogen, who require immediate
treatment. These patients would benefit from the availability of an additional effective antibiotic
treatment providing full cover against carbapenem-resistant pathogens while pathogen
susceptibility is being confirmed.
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The SIDERO-WT study tested the in-vitro antibacterial activity of cefiderocol against Gram-
negative bacteria [29]. A total of 30,459 clinical isolates of Gram-negative bacilli were
systematically collected from USA, Canada, and 11 European countries between 2014 and
2017. Cefiderocol demonstrated activity against 99.5% of Gram-negative isolates at a MIC of
4 mg/L. Isolates were less susceptible to the comparators including colistin (95.5%),
ceftazidime-avibacatam (90.2%) and ceftolozane-tazobactam (84.3%).
In a retrospective analysis comparing the probability of target attainment (PTA) for cefiderocol,
ceftolozane/tazobactam and meropenem against Enterobacterales and Pseudomonas
aeruginosa in a representative patient population at risk of MDR or carbapenem resistant
infections, the cumulative fractions of response (CFRs) calculated using European MIC
distributions from the SIDERO surveillance for cefiderocol against Enterobacterales and
Pseudomonas spp. are considerably higher than seen for meropenem and ceftolozane-
tazobactam.
In patients with infections suspected to be caused by MDR/CR pathogens, clinical trials
only provide limited comparative evidence regarding the efficacy of new antibacterials. This is
because trials must include only pathogens for which the tested agents and comparators are
effective, as it would be unethical to knowingly allow patients to have ineffective treatment. In
this setting, standard NMAs also provide little information, as they never account for pathogens
not susceptible to the treatment regimens included in the network. A comparison of efficacy
against all relevant comparators can only be obtained from in-vitro surveillance studies. Hence
approaches integrating all available evidence from in vitro, PK/PD and clinical data (such as
effectiveness models), are the necessary to predict susceptibility rates and clinical
effectiveness rates.
APEKS-cUTI compared cefiderocol with imipenem/cilastatin (IPM/CS) in cUTI caused by
Gram-negative MDR pathogens in hospitalized adults. The study was designed to
demonstrate non-inferiority, with the primary efficacy endpoint being the composite of clinical
response and microbiological response at TOC. 73% of patients in the cefiderocol group
achieved the primary endpoint, vs only 55 % of patients in the IPM/CS group, with an adjusted
treatment difference of 18.6% (95 % CI: 8.2, 28.9). A further post-hoc analysis confirmed
superiority in favour of cefiderocol.
Given the similarority of patients and pathogens included in across trials, a NMA was
conducted to compare the result of APEKS cUTI with relevant comparator studies. Results
showed no statistically significant difference between the APEKS cUTI result and results from
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studies of ceftazidime/avibactam and ceftolozane/tazobactam conducted in a similar
population with a similar pathogen distribution.
The APEKS-NP study compared treatment with cefiderocol against high-dose and prolonged
infusion (HD) meropenem in patients with nosocomial pneumonia caused by MDR Gram-
negative pathogens. Cefiderocol met the primary endpoint of non-inferiority in ACM at day 14
versus HD meropenem (12.4% vs 11.6%; (95 % CI: -6.6, 8.2)). APEKS-NP used an improved
meropenem regimen (both high dose and prolonged infusion time) to optimize its exposure
and efficacy. This meant that a NMA was not possible because previously published
meropenem studies had used a lower dose of meropenem.
The results of the two randomized, double-blind APEKS trials combined provide highly reliable
and clinically relevant evidence to support the use of cefiderocol in patients with suspected
MDR pathogens with limited treatment options.
Furthermore, in an analysis incorporating European pathogen epidemiology and susceptibility
data, cefiderocol provides the best predicted susceptibility rates and estimated clinical and
microbiological success rates regardless of the infection site, in the absence of an antibiogram
for the critically ill patients with suspected MDR pathogen infection requiring immediate
treatment.
Combining these results and clinical data in an effectiveness model, show that cefiderocol has
a greater likelihood of achieving microbiological eradication and clinical cure, in the patients
with suspected MDR/CR infections than relevant comparators across for cUTI and
pneumonia. In the absence of antibiogram, cefiderocol provides an effective option for treating
critically ill, hospitalised patients where CR infection is suspected and time to effective
treatment must be as short as possible, increasing the likelihood of providing an initial
appropriate therapy and potentially avoiding worse morbidity and mortality outcomes
associated with delayed effective therapy.
5.6.2 Evidence to support use of cefiderocol in patients with infections by confirmed CR pathogens:
Data from the SIDERO-CR study indicate that cefiderocol maintains high activity in the
presence of beta-lactamases, carbapenemases, and strains with porin channel mutations or
efflux-pump overexpression. Patients with confirmed MDR/CR infections, for whom the
antibiogram indicates susceptibility for cefiderocol thus gain an additional treatment option
with equal or higher susceptibility than comparators.
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In the SIDERO-CR-2014-2016 study [30], which was a global study of 52 countries, focusing
only on CR isolates, cefiderocol demonstrated potent in vitro activity at a MIC of 4 mg/L against
96.4% of isolates of carbapenem-nonsusceptible pathogens including all of the WHO priority
pathogens and Stenotrophomas maltophilia. Cefiderocol was found to provide a wider Gram-
negative coverage, and more potent in vitro antimicrobial activity than comparators including
ceftazidime/avibactam (39.8%), ceftolozane/tazobactam (37%), and colistin (91.5%).
Clinical trials can provide more reliable information regarding comparative efficacy when the
pathogens have confirmed or expected susceptibility to both drugs. This is consistent with
prescription based on AST results, which occurs in patients with confirmed CR infections. In
this setting, Network meta-analysis (NMA) if feasible provide additional reliable information of
comparative effectiveness.
Evidence of clinical efficacy of cefiderocol in patients with a confirmed CR infection comes
from three sources; the APEKS NP study, the CREDIBLE CR study and the cefiderocol
compassionate use programme:
In a small subgroup of patients participating in the APEKS-NP that was non-susceptible to
meropenem considering a breakpoint of 8mg/L (MIC), similar results in terms of mortality,
clinical and microbiological outcomes were achieved between arms. However, when looking
into the stratification for pathogens with MIC >16 mg/mL, patients on cefiderocol had reduced
mortality and higher clinical cure rates. The HD prolonged infusion meropenem regimen in this
trial, increased exposure in terms of time and concentration to the infection site, increasing
the likelihood of effectiveness, even on pathogens with MIC up to 16mg/mL.
The CREDIBLE CR study was a small, randomised, open label, descriptive, exploratory, study
conducted to evaluate efficacy in patients with confirmed CR infections given cefiderocol or
BAT. The study was not designed or powered for statistical comparison between arms. The
study included 150 severely ill patients, consistent with compassionate use cases, with a
range of infection sites including nosocomial pneumonia, cUTI, BSI/sepsis. Many patients had
end stage comorbidities and had failed multiple lines of therapy. Cefiderocol and BAT were
shown to be effective in terms of clinical and microbiological outcomes in these patients,
particularly for cefiderocol also showing clinical and microbiological efficacy regardless of
carbapenemases present in the pathogen causing the infection. However, there were marked
clinically relevant differences in some baseline characteristics and pathogen distribution of the
cefiderocol and BAT arms. An imbalance in mortality was observed in the cefiderocol arm
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compared to BAT (18/49 vs 5/25), which was not considered to be related with safety signals.
No deaths were found to be causally associated with cefiderocol through assessment by the
investigator and two independent committees. No single factor that would explain the
imbalance was identified. Small patient numbers and multiple confounders preclude definitive
conclusions. Additional analyses revealed that mortality in the treatment arm was similar to
other studies in the context, while the BAT arm performed better than all reported studies,
particularly for non-fermenters. The reasons for this are not understood.
Compassionate use program: More than 200 patients were treated with cefiderocol within the
compassionate use programme around the world, demonstrating the unmet medical need.
Confirmed information on 74 patients who have completed treatment in the compassionate
use program showed that over 60% of the severely ill patients infected with CR Gram-negative
pathogens survived when no other treatment option was available to them.
The overall mortality across the compassionate use programs and CREDIBLE CR was similar,
36.5% and 33.7% respectively, supporting the notion that the population recruited into the
CREDIBLE-CR trial, included severely ill patients with a very poor prognosis, similar to those
applying for compassionate use and other similar studies reported on literature.
5.6.3 Quality of Life
Patients with these severe nosocomial infections are frequently treated in ICU units, often
unconscious, and on many occasions require ventilation (intubation), preventing investigation
of patient-reported outcomes. Because the most severely ill patients cannot complete
questionnaires, this can lead to systematic under-reporting QoL data of the most severe
courses of illness. The fact that these patients are hospitalised already has decrimental impact
on their quality of life. The ward in the hospital also impacts the patient’s quality of life (i.e
patients on ICU or isolation, are expected to have lower quality of life compared to general
ward), although this may be correlated with the severity of the infection and underlying
condition. All these factors make investigating quality of life in antimicrobial clinical trials
difficult and infrequent. The microbiological outcomes and mortality have thus been deemed
to be most relevant, also by regulators. No PROs are, therefore, reported in the dossier.
However, any therapy that resolves the infection and/or reduces length of hospitalization is
expected to improve patient’s quality of life.
5.6.4 Comparators
The in vitro data and combination of the in vitro, PK/PD, and clinical data show that cefiderocol
outperforms all relevant comparators with regard to the likelihood of obtaining microbiological
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eradication in the population with suspected MDR/CR infections. While clinical evidence is
restricted to a limited number of comparators that were deemed to be relevant in the specific
context by regulators, an NMA in the cUTI indication and the additional in vitro data reveal
favourable outcomes of cefiderocol compared with all relevant available treatments (Table
95).
Table 95 - Comparator overview
Population Comparator Data source Result (cefiderocol vs. comparator)
Suspected MDR/CR
High dose Meropenem SIDERO WT surveillance
Broader coverage of Gram-negative, aerobic pathogens. Lower MIC value and preserved efficacy in the presence of carbapenemases.
APEKS-NP RCT
Non-inferior with regard to mortality (primary outcome) and all clinical and microbiological secondary outcomes.
High dose Meropenem Ceftalozane-tazobactam, Ceftazidime-avibactam
Integrated epidemiology and in-vitro data analysis
Cefiderocol presents higher weighed susceptibility rates in cUTI, pneumonia, BSI, and gastrointestinal samples vs comparators
High dose Meropenem Ceftalozane-tazobactam, Ceftazidime-avibactam
Effectiveness model integrating epidemiology, in-vitro data and clinical data
Cefiderocol presents higher likelihood of clinical and microbiological effectiveness in pneumonia and cUTI vs comparators.
Imipenem/Cilastatin APEKS-cUTI RCT
Non-inferior to comparator, but proven superiority in a post-hoc analysis, on the primary endpoint of combined microbiological eradication / clinical cure at TOC, and secondary endpoint microbiological eradication at TOC.
Ceftalozane-tazobactam, ceftazidime-avibactam, doripenem, imipenem/cilastatin
network meta-analysis for cUTI
In similar patient populations with similar pathogen distribution across different trials, and consistent with APEKS-cUTI there was statistical significant difference in microbiological eradication at TOC vs Imipenem/cilastatin, but in all other endpoints there was no statistically significant difference, including clinical cure rates and adverse events
Ceftolozane/tazobactam SIDERO WT surveillance
Lower MIC90 (0.25 vs. 8 for Pseudomonas, 0.25 vs. 32 for
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Acinetobacter, 1 vs. 64 for Enterobacteriaceae)6 Higher % isolates susceptible to cefiderocol
Ceftazidime/avibactam SIDERO WT surveillance
Same MIC90 for Enterobacteriaceae (1 vs. 1), otherwise superiority of cefiderocol Higher % isolates susceptible to cefiderocol
Confirmed CR
Colistin-based (combination) regimens (most relevant for for A. Baumanii, S. maltophilia, pathogens with metallobeta-lactamases)
SIDERO CR surveillance
Higher % isolates susceptible to cefiderocol; Similar in-vitro efficacy. Colistin is known to have severe side effects, especially kidney toxicity. Resistances against colistin have been reported to increase in epidemiological studies.
Ceftolozane/tazobactam (most relevant for P. aeruginosa, except pathogens with metallobeta-lactamases)
SIDERO CR surveillance
Higher percent susceptibility for cefiderocol against Acinetobacter and Pseudomonas across all included countries (MEM-NS pathogens)7
Ceftazidime/avibactam (most relevant for Enterobacterales, except pathogens with metallobeta-lactamases)
SIDERO CR surveillance
Higher percent susceptibility for cefiderocol against Acinetobacter and Pseudomonas across all included countries (MEM-NS pathogens)
Best available therapy (BAT), predominantly (combination) regimens (most relevant for A. Baumanii, S. maltophilia, pathogens with metallobeta-lactamases)
CREDIBLE-CR Descriptive results only. Evidence of eradication of resistant pathogens. Numerical, non-significant disadvantage with regard to mortality for cefiderocol compared to BAT.
2. Provide a general interpretation of the evidence base considering the harms
associated with the technology relative to those of the comparators.
The presented data demonstrate that cefiderocol has a similar safety profile compared to other
cephalosporins.
Pre-clinical studies showed that single and multiple doses of cefiderocol tested were well
tolerated in both healthy subjects and those with renal impairment. Furthermore, neither QT
interval prolongation nor drug–drug interaction via organic anion transporters was
demonstrated in healthy subjects.
The clinical safety for cefiderocol was established in the three randomised clinical trials,
including 549 treated patients, and showed a similar profile compared to other cephalosporins.
6 Longshaw et al., 2019 ID Week 7 Sato et al. 2019 ID Week
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Pooled adverse event analyses showed that there were overall less treatment emergent
adverse events with cefiderocol (344/549 [67.1%]) vs comparators (252/347 [72.6%]), as well
as less treatment related AEs, (56/549 [10.2%]) with cefiderocol vs compartors (45/347
[13.0%]).
The large APEKS trials with active comparators showed that TEAEs and treatment-related
TAEs were overall balanced between arms. In APEKS-NP, adverse events were experienced
by most subjects in both treatment groups with SAE rates being slightly higher in the
cefiderocol group (36.5%) than in in the meropenem group (30%). In the APEKS-cUTI trial,
serious adverse events (SAE) occurred less in cefiderocol-treated patients than in IPM/CS-
treated patients (5% vs 8%).
In the confirmed carbapenem-resistant CREDIBLE-CR trial, the cefiderocol group had lower
incidence of AEs and treatment-related AEs, but imbalance in mortality, SAEs and
discontinuation due to AEs, compared with BAT was observed. The incidence of treatment-
related AEs leading to discontinuation was similar between treatment groups. A blinded
adjudication committee concluded that none of the deaths was due to a drug-related AE.
The SPC details all potential risks associated with drug interactions or potential harms with
drug use in special categories of patients.
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5.7 Strengths and limitations
1. Summarise the internal validity of the evidence base, considering the study quality, the
validity of the endpoints used as well as the overall level of evidence. Include a
statement about the consistency of the results in the evidence base.
5.7.1 Risk of bias assessment
Unlike therapeutic areas, in vitro studies are key sources of data to substantiate clinical use
of the antibacterials. Traditionally this falls outside the scope of bias assessment, as
theoretically the risk of bias is considered minimal. In this case, same isolates were tested for
all comparators, the methodology used was based on standard defined methods, and data
was reported. The manufacturer provided the study protocol, and several publications for this
assessment; thus, the possibility of selective outcome reporting is regarded as low.
In summary, robustness of the study is ensured through large number of isolate samples,
testing same sample for all comparators. The study shows high internal validity with low risk
of bias.
In addition to the in vitro and PK/PD data, the evidence base in the population with suspected
MDR/difficult-to-treat infections is amended by two RCTs, the APEKS cUTI and APEKS NP
trials. Both studies were multicentre, multinational, double-blind, randomized, active-controlled
studies.
APEKS-cUTI was a Multicentre, Double-blind, Randomized, Clinical Study to Assess the
Efficacy and Safety of Intravenous S-649266 (Cefiderocol) in Complicated Urinary Tract
Infections with or without Pyelonephritis or Acute Uncomplicated Pyelonephritis Caused by
Gram-Negative Pathogens in Hospitalized Adults in Comparison with Intravenous
Imipenem/Cilastatin. Randomization was stratified according to the patient’s clinical diagnosis,
(cUTI with or without pyelonephritis and AUP) and region (North America, European Union,
Russia, and Japan plus the rest of world). Randomization used a computer-generated
randomization list (IXRS® provider), an interactive web or voice response system
(IWRS/IVRS) was used to assign a total of 450 patients to identification numbers for which
treatment has already been randomly assigned. Patients and investigator, site personnel, the
sponsor, and the sponsor’s designees involved in blinded monitoring, data management, or
other aspects of the study were blinded to treatment assignment. The site pharmacist or
qualified designee who prepared the intravenous infusion solution was the only study site
personnel with the identification of the study drug assignments for that site. Generation of
randomization sequence and allocation concealment are considered adequate for this
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study. Performance and detection bias were minimized through the described blinding and
alignment of infusion duration. mITT population proportions were comparable in both arms
with 252/300 for cefiderocol and 119/148 for IPM/CS thus reducing the likelihood of attrition
bias. The main study publication (Portsmouth et al 2018) reported primary outcome
(composite outcome at TOC) by predefined subgroups and microbiological and clinical
secondary outcomes at the predefined time points EA, EOT, TOC, FU as well as any AE,
treatment-related AEs, SAEs, AEs leading to discontinuation, deaths and AEs in at least 2%
of patients in either treatment group. The manufacturer provided the study protocol, SAP, CSR
and study synopsis for this assessment; thus, the possibility of selective outcome reporting
is regarded as low.
In summary, robustness of the study is ensured through randomization and stratification,
blinding and large number of patients. The study shows high internal validity with low risk of
bias at the study level.
APEKS-NP was a Phase 3, Multicentre, Randomized, Double-blind, Parallel-group, Clinical
Study of Cefiderocol Compared with Meropenem for the Treatment of Hospital-acquired
Bacterial Pneumonia, Ventilator-associated Bacterial Pneumonia, or Healthcare-associated
Bacterial Pneumonia Caused by Gram-negative Pathogens. Treatments were randomized to
subject identification numbers by the interactive response technology (IRT) provider in a 1:1
fashion to cefiderocol or meropenem. An IRT was used to assign a total of 300 subjects to
identification numbers for which treatment has already been randomly assigned.
Randomization was performed by the stratified randomization method using their infection
type (HABP, VABP, and HCABP) and APACHE II score (≤ 15 and ≥ 16) as allocation factors.
Linezolid infusion did not require blinding and was labelled with the study number, subject’s
identification number, and infusion rate and drug name. Patients and investigator, site
personnel, the sponsor, and the sponsor’s designees involved in blinded monitoring, data
management, or other aspects of the study were blinded to treatment assignment. The site
pharmacist or qualified designee who prepared the intravenous infusion solution was the only
study site personnel with the identification of the study drug assignments for that site.
Generation of randomization sequence and allocation concealment are considered
adequate for this study. Performance and detection bias were minimized through the
described blinding and alignment of infusion duration. mITT population proportions were
comparable in both arms with 145/148 for cefiderocol and 147/150 for high dose meropenem,
equally the microbiologically-evaluable Per-protocol (ME-PP) population was balanced (105
for cefiderocol and 101 for high dose meropenem), thus reducing the likelihood of attrition
bias. Results of the study have been presented in an international clinical conference, but
have not yet been published as a manuscript and no results have been posted at
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clicnitrials.gov yet, however, the manufacturer provided the study protocol, SAP, and in the
absence of available CSR at the date of EUnetHTA submission, the manufacturer also
provided study synopsis and all the documentation submitted to EMA for this assessment thus
possibility of selective outcome reporting is regarded as low.
Thus, robustness of the study is ensured through randomization and stratification, blinding
and large number of patients. The study shows high internal validity with low risk of bias at
study level.
CREDIBLE-CR was a Multicentre, Randomized, Open-label Clinical Study of S-649266 or
Best Available Therapy for the Treatment of Severe Infections Caused by Carbapenem-
resistant Gram-negative Pathogens.
The study is a small descriptive study, with no inferential analysis planned. The treatments
were randomized to subject identification numbers by the IXRS® provider in a 2:1 fashion, i.e.
to cefiderocol and BAT, respectively. An interactive web or voice response system
(IWRS/IVRS) was used to assign patients to identification numbers for which treatment has
already been randomly assigned. Randomization was performed by the stochastic
minimization method using the infection site (HAP/VAP/HCAP, cUTI, and BSI/sepsis),
APACHE II score (≤15 and ≥16), and region (N. America, S. America, Europe, and Asia-
Pacific) as allocation factors, but did not account for pathogen stratification or other clinically
relevant factors. To avoid deterministic allocation based on the ongoing allocation results,
probabilistic allocation was incorporated [Pocock SJ, Simon R. Sequential Treatment
Assignment with Balancing for Prognostic Factors in the Controlled Clinical Trial. Biometrics
1975; 31: 103-15.]. Planned proportions were approximately 50% with HAP/VAP/HCAP; cUTI
no more than 30% and the remainder of patients were enrolled under the BSI/sepsis
diagnosis. The randomization ratio of patients between treatment groups based on clinical
diagnosis was maintained through the allocation factor of clinical diagnosis at the time of
randomization. BAT was the standard of care for CR infections at each enrolling study site
and could include up to three antibiotics with Gram-negative coverage used in combination.
The comparator BAT could not be defined in the protocol and BAT was determined by the site
investigator based on the assessment of the patient’s clinical condition and had to be
determined by the investigator prior to randomization. The dosage of BAT was adjusted
according to the local country-specific label. De-escalation of BAT was allowed. Concomitant
antibiotics were allowed if the patients had a confirmed/suspected Gram-positive or anaerobic
co-infection (e.g., vancomycin, daptomycin, linezolid, clindamycin, or metronidazole).
Performance and detection bias cannot be ruled out due to the open-label design. mITT
population proportions were comparable in both arms and populations were balanced
reducing the likelihood of attrition bias. Results of the study have not been published yet and
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no results have been posted at clinitrials.gov yet but have been presented to FDA for an
Advisory Committee Meeting and made publicly available in the briefing book. Furthermore,
the manufacturer provided the study protocol, SAP, results summary and in the absence of
available CSR at the date of EUnetHTA submission, the manufacturer also provided study
synopsis and all the documentation submitted to EMA, for this assessment thus possibility of
selective outcome reporting is regarded as low.
In summary, the CREDIBLE-CR study is a small open-label, randomized, multinational,
parallel-group, Phase 3 clinical trial designed as descriptive study. Through its open-label
design, small number of patients and non-inferential design, the study shows unclear internal
validity and high risk of bias at study level.
Table 96: Risk of bias on study level – Randomized trials with cefiderocol
Study
Ad
eq
uate
ge
nera
tio
n o
f
ran
do
miz
ati
on
seq
ue
nce
Ad
eq
uate
allo
cati
on
co
nc
ealm
en
t
Blinding
Rep
ort
ing
of
ind
ivid
ua
l
ou
tco
mes i
nd
ep
en
de
nt
of
resu
lts
No
oth
er
asp
ects
of
bia
s
Ris
k o
f b
ias o
n s
tud
y
level
Pati
en
t
Tre
ati
ng
Sta
ff
<yes/no/
unclear>
<yes/no/
unclear>
<yes/no/
unclear>
<yes/no/
unclear>
<yes/no/
unclear>
<yes/no/
unclear> <high/low>
RCTs
APEKS NP yes yes yes yes yes yes low
APEKS cUTI yes yes yes yes yes yes low
Descriptive Trial
CREDIBLE CR yes no no no yes* no+ high
*Results of the study have not been published yet and no results have been posted at clicnitrials.gov yet. The manufacturer
provided the study protocol, SAP, CSR and study synopsis for this assessment thus possibility of selective outcome reporting is
regarded as low. +Several unbalances detected after study conclusion
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5.7.2 Discussion
Unlike other therapeutic areas, the evaluation of an antimicrobial relies on the combined
consideration of in vitro, PK/PD and clinical data. This is because of the primary importance
of confirming pathogen susceptibility, and theoretically, if the pathogen is susceptible to the
antimicrobial and it has adequate exposure in the infection site, the antibacterial therapy
should be effective. The main evidence supporting efficacy of cefiderocol against a wide range
of Gram-negative, aerobic pathogens thus comes from several large in-vitro surveillance
studies, which were further confirmed by independent national studies in five European
countries (Germany, Italy, Greece, Switzerland, UK). PK/PD studies showed that cefiderocol
could reach target tissues in adequate concentrations at the recommended dosing regimen.
Clinical trials served to confirm efficacy predicted based on the in vitro and PK/PD results.
In vitro testing was performed in iron-depleted broth, a standardized methodology that has
been independently validated and approved. In vitro testing results are critical for clinical
decision making, and the low MIC values reported from the studies together with the
favourable PK/PD data indicate that cefiderocol is likely to will demonstrate clinical activity
against the target Gram-negative, aerobic pathogens regardless of the infection site.
A clinical study in healthy volunteers [8] showed that the penetration ratio of cefiderocol into
ELF was comparable with that of ceftazidime in critically ill patients (0.229 based on free
plasma using a protein unbound fraction of 0.9).
The fraction of time during the dosing interval where free concentration exceeded the MIC
(fT>MIC) for a PD target was reported to be 75%. PK/PD modelling confirmed that with
probabilities of 97% in plasma and 88% in ELF free cefiderocol concentration of 4 mg/L could
be achieved using the recommended dosing regimen. Outcomes of the APEKS-NP trial, which
focused on pneumonia, lent further support to cefiderocol’s adequate penetration into lung
tissues.
In general, clinical trials can only provide very limited evidence regarding the efficacy of new
antibiotics in a real-world population of patients with suspected MDR/CR-resistant pathogens,
because trials must focus on pathogens for which the tested agents are effective; otherwise,
they would be un-ethical. Because trials thus focus on pathogens that fall within the in vitro
spectrum of the tested treatments and comparators, it is difficult to conduct network-meta-
analyses based on these trials. Since each trial excludes patients for which a poor outcome
for the candidate treatment is expected, meta-analysis will only provide answers about the
8 https://academic.oup.com/jac/article/74/7/1971/5435733
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efficacy of the treatment in patients with susceptible pathogens, but it cannot tell which
treatment would have the best chances of success in an overall, un-tested population. Such
results can only be obtained from in vitro surveillance studies. This implies that the clinical trial
programs for antibiotics have an important role to confirm clinical efficacy, but a limited role in
providing comparative evidence.
Formal risk-of-bias assessments performed for this dossier showed that the internal validity of
the clinical trials differed in the two target populations:
In the population with infections that were suspected to be MDR/CR the
randomized and double-blinded APEKS trials provided strong evidence for non-
inferiority of cefiderocol compared to respective treatment options when the
pathogens are susceptible to both cefiderocol and comparator, and also confirmed
the potential benefit of a wider pathogen Gram-negative coverage vs comparators.
o The non-inferiority designs were necessary due to the fact that it would be
unethical to withhold effective treatments from the comparator group.
o The results are not only relevant for today’s use of antibiotics in the clinic, but
also for a future in which resistances are projected to increase further and there
will be many patients who would need new, effective treatment options, such
as cefiderocol. In such a future scenario, cefiderocol treatment would expected
to be superior compared to treatment with ineffective agents due to pan-
resistant pathogens.
The clinical results in the confirmed carbapenem-resistant populations show
lower levels of internal validity, while the compassionate use program illustrates
the relevance in the current treatment landscape.
o Patients with carbapenem non-susceptible pathogens in the APEKS-NP study
were treated as effectively with cefiderocol as with higher-dosage meropenem.
Due to the increase in dosage, meropenem maintained its efficacy in this group,
leading to similar treatment results in both groups. Numerical evidence showed
that cefiderocol maintained activity in high MIC (>16) to meropenem-non-
susceptible infections.
o The CREDIBLE-CR trial was a small, randomised, non-blinded, non-inferential,
exploratory descriptive study to start to gain experience in patients with
confirmed CR infections, severe often end-stage comorbidities, often after
failing multiple lines of therapy (i.e., salvage therapy context). No stratification
was made for pathogen or presence of terminal disease (e.g., disseminated
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cancers, end-stage organ failure). Given the small number of patients included
in the trial, there are differences in the baseline characteristics of the treatment
arms (older, more severe renal impairment in cefiderocol arm).
o The 74 compassionate use studies included open-label treatment of patients
who had received other lines of treatment. The requests for cefiderocol
treatment indicate the urgent clinical need for additional treatment options.
Initial results from these cases confirm that cefiderocol shows clinical activity in
severely ill patients with very limited options.
2. Provide a brief statement of the relevance of the evidence base to the scope of the
assessment.
Overall, the level of evidence supporting cefiderocol treatment is higher in the suspected
resistant population than in the confirmed CR populations, due to the robustness of the APEKS
studies ensured through blinding, randomization, large number of patients, and adequate
control group. The systematic evaluations show high internal validity with low risk of bias at
study level and thus stronger confirmatory clinical results from the APEKS trials.
Population and Comparators: The presented results present the most relevant evidence base
for the assessment of cefiderocol. The most relevant comparators in line with current
regulatory recommendations were considered in in vitro studies and appropriate comparators
reflected in the comparator arms of the clinical trials. As with all antibiotic therapies for patients
with Gram-negative aerobic infections suspected to be MDR/CR/difficult-to-treat or confirmed
CR-resistant, the patient populations included in the trials had a high unmet medical need.
The trial populations in APEKS (cUTI and NP) trials and CREDIBLE-CR study represented
patients eligible for treatment also observed in clinical practice. Complicated urinary tract
infections, nosocomial pneumonia and sepsis are the most common infections observed with
Gram-negative aerobic MDR/CR/difficult-to-treat pathogens.
In line with ethical standards, most effective comparators (IMP/CS and HD meropenem) were
chosen for the APEKS studies. Following good stewardship practice and at request of EMA
BAT was decided to be appropriate to be administered in CREDIBLE-CR study.
Outcomes and timing: Standard outcomes for antibiotic treatment such as clinical and
microbiological outcomes as well as composite clinical and microbiological endpoints and
microbiological and clinical response per-pathogen and per-patient at different time points
(early assessment, end of treatment (EOT), test of cure (TOC), follow-up (FUP)) were
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collected in the respective trials. Clinical endpoints were in line with site of infections and
severity of disease:
For cUTI the primary efficacy endpoint was the composite of clinical response and
microbiological response at the test of cure (TOC).
For nosocomial pneumonia (HAP/VAP/CAP) the primary outcome was all-cause
mortality at day 14.
For HAP/VAP/CAP and bloodstream infections/sepsis in CREDIBLE CR study primary
endpoint was clinical cure at TOC, for cUTI it was microbiological outcomes at TOC.
All of these endpoints are main outcomes routinely assessed for antimicrobial studies
according to current regulatory standards. All endpoints considered in the trials adequately
measure relevant outcomes and follow established practice. Quality of life could not be
assessed for the stated reasons.
A full clinical assessment of cefiderocol’s value needs to consider several important pieces of
contextual information:
Delays in appropriate antibiotic therapy lead to worse clinical outcomes. This means
that an additional treatment that can target pathogens with a high unmet need can lead
to more effective early treatment and improved clinical outcomes.
Resistance rates are increasing. A dramatic slump in the development of new antibiotic
treatments in the past two decades lead to lack of treatment options for current and
future resistances.
o New treatments that show non-inferiority with all available treatments can turn
out to become life-saving last-resort options in the future, when more and more
pathogens have become resistant to the existing options.
o In addition to the static assessment of the current treatment landscape, a
dynamic assessment that includes future trends is necessary to fully
understand the current and future benefit of new antibiotic treatments.
Overall, the evidence provided in this dossier supports the clinical benefit of cefiderocol as an
additional treatment option for patients with Gram-negative, aerobic infections with limited
treatment options. As is true for all antibiotics, clinical use of cefiderocol will be based on the
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integration of in vitro susceptibility data, hospital-wide antibiograms, monitoring resistance
trends, and individual patient needs.
Within the expected pathogen based indication, it is proposed that cefiderocol offers most
value in two clinical scenarios:
Hospitalised patients with suspected MDR/CR infection who are at risk of rapid
deterioration and require antibiotic treatment that provides full cover against
carbapenem-resistant pathogens in the period while pathogen susceptibility is being
confirmed.
Hospitalised patients with a confirmed MDR/CR infection where existing treatment
options are inappropriate because of pathogen susceptibility, contraindications or poor
tolerability
Given the growing threat from MDR/CR infection and the limitations of currently available
treatment options both populations have a high unmet medical need. Advances in fast
diagnostics will allow clinicians to make decisions about effective treatment options earlier and
earlier. The recent advent of several new treatment options, together with such early
diagnostics holds promise to improve outcomes for critically ill patients and slow down the
further spread of resistant pathogens. Economic evaluations of antibiotics based on these
clinical data will need to take the full spectrum of benefits into account (e.g., enablement of
chemotherapy, high-risk surgeries).
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APPENDICES AND ATTACHMENTS
Please see separate file attached with submission dossier
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