treatment of infections caused by mdr-gramnegatives: update (literature review)
DESCRIPTION
Journal Watch/Club on the latest articles dealing with multi-drug resistant gramnegativesTRANSCRIPT
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Treatment of infections caused by MDR-Gramnegatives
Literature review
José Ramón Paño Unidad de Enfermedades Infecciosas y Microbiología Clínica
Medicina InternaH.U. La Paz (Madrid)February 19th, 2014
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Methods
Surveillance (RSS feeds)• CID, JID, JAC, AAC, The Lancet Infectious
Diseases, JAMA, NEJM
Period: Jan 2013-Feb 2014
Selection• I have followed my own criteria • Of initially selected articles, some will be commented
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Outline
• Carbapenemase-producing Enterobacteriaceae
• “Weird” combinations for XDR-GNR
• Optimization of AB dosing
• Carbapenem-sparing regimens
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Carbapenemase-producing Enterobacteriaceae
Falagas ME. AAC. 2014;58(2):654–63
• 20 nonrandomized studies comprising 692 patients who received definitive treatment
• 7/20 prospective, 12/20 retrospective and 1 case-control study
• 15/20 CPE (carbapenemase-producing E) and 5/20 CRE (carbapenem-resistant E)
• 14/20 K. pneumoniae as the sole pathogen and 5/20 as the predominant one; E. cloacae sole pathogen in 1/20
• 8/20 BSI was the predominant type of infection (>50%). Pneumonia and UTI prevailed in 12/20
• KPC 8/20 (316); MBL/OXA 5/20 (201)
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CP-K.pneumomiae: Combination therapy
Falagas ME. AAC. 2014;58(2):654–63
Antimicrobial Regimen Number of Patients (Number of Studie)
28d/30d mortality
Tigecycline + colistin
51 patients(4 studies)
0-30%
Tigecycline +colistin
11 patients (VIM)(1 study)
67%
Tigecycline + gentamicin
15 patients(2 studies)
0-50%
Carbapenem +colistin
25 patients(4 studies)
0-67%*
Colistin + gentamicin
30 patients(3 studies)
40-61%
* Highest mortality amongst ICU ant solid-organ transplant
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CP-K. pneumoniae: Monotherapy
Falagas ME. AAC. 2014;58(2):654–63
AntimicrobialRegimen
Number of Patients (Number of Studie)
28d/30d mortality
Carbapenem 29 patients(3 studies)
9-50%
Tigecycline 38 patient(4 studies)
0-53%
Colistin 102 patients(8 studies)
33-57%
Gentamicin 26 patients [19/26 UTI](3 studies)
6.8-80%
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Carbapenemase-producing Enterobacteriaceae
Falagas ME. AAC. 2014;58(2):654–63
Conclusion
• Too much heterogeinity of patients/studies to obtain solid conclusions
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Clin Microbiol Rev. 2012;25(4):682–707
• Pubmed search
• 34 clinical studies: clinical, microbiological and therapeutical data
• 301 patients : 160 KPC y 141 MBL
• Type of infection: 244 BSI; 32 Pneumonia
Carbapenemase-producing Enterobacteriaceae
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Clinical Studies
Tzouvelekis LS et al. Clin Microbiol Rev. 2012;25(4):682–707
Combo (Carb
)
Combo (≠Carb
)
Aminoglyc
Carb Tige
Colistin
Inappropria
te0
10
20
30
40
50
60
Clinical Failure (%)
N=36
N=63
N=21N=36
N=14
N=72N=56
Carbapenemase-producing Enterobacteriaceae
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Tzouvelekis LS et al. Clin Microbiol Rev. 2012;25(4):682–707
• Concordantly with PK/PD, success rate is related to carbapenem MIC
Carbapenemase-producing Enterobacteriaceae
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Principles• Combo for severe infections• Dosing has to be optimized
- Search for highest tolerated dose if feasible
• Most frequently active antimicrobials
- Aminoglycosides- Colistin
- Tigecycline- Fosfomycin
- b-lactams: carbapenem, aztreonam*, 3rd Cephalosporins** * Sólo para MBL sin BLEE asociada
** Sólo para OXA-48 sin BLEE asociada
- If active (infrequent): Quinolones and TMP/SMX are good therapeutic options
Carbapenemase-producing Enterobacteriaceae
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HULP flow-chart for CPE therapy
Moderate-Severe infections: Recomendaciones1st Is b-lactam available?
¿MBL+ & aztreonam S (no ESBL)?Yes Aztreonam
+ 2nd agentNo
¿Carbapenem MIC (mero)?≤8 Carbapenem
(mero)+ 2nd agent>8
Other 2 agents
- Source- Micro Activity (MIC)
- Toxicity profile/Comorbidity
Respiratory: Coli/Tige/Fosfo/Aminogluc
Intraabdominal: Tige/Coli/Fosfo/Aminogluc
Urinary: Aminogluc/Fosfo/Coli/Tige
Catheter: Coli/Fosfo/aminogluc/Tige
2nd agent priority scale
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Carbapenemase-producing EnterobacteriaceaeDouble carbapenem therapy?
AAC 2013; 57(5):2388-2390
J Antimicrob Chemother. 2014 Feb 11
• Six difficult cases, that cured with double-carbapenem therapy despite very high carbapenem MIC
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Carbapenemase-producing Enterobacteriaceae
Carbapenem efficacy in infections caused by CPE: Is it just an MIC dependent issue? Does the genotype matter?
Antimicrob Agents Chemother. 2013;57(8):3936–40
Antimicrob Agents Chemother. 2013 Dec 30 [ahead of print]
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Carbapenemase-producing Enterobacteriaceae
Antimicrob Agents Chemother. 2013;57(8):3936–40
Antimicrob Agents Chemother. 2013 Dec 30 [ahead of print]
• PK/PD animal model-based studies (neutropenic murine thigh infection models)
• Comparison of several humanized b-lactam regimens against carbapenemase-producing, carbapenemase+ESBL and wild type K. pneumoniae strains (KP454)
Carbapenem efficacy in infections caused by CPE: Is it just an MIC dependent issue? Does the genotype matter?
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Carbapenemase-producing EnterobacteriaceaeCarbapenem efficacy: MIC-dependent issue or genotype (NDM-KPC)
Antimicrob Agents Chemother. 2013;57(8):3936–40
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Change in log10 CFU/ml after 24 h observed in four clinical NDM-1-producing Enterobacteriaceae isolates after treatment with human-simulated doripenem at 2 g every 8 h as a 4-h infusion (black bars) or ertapenem at 1 g every 24 h (white bars)
Carbapenemase-producing EnterobacteriaceaeCarbapenem efficacy: MIC-dependent issue or genotype (NDM-KPC)
Antimicrob Agents Chemother. 2013;57(8):3936–40
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Carbapenemase-producing EnterobacteriaceaeCarbapenem efficacy: MIC-dependent issue or genotype (OXA-48)
Antimicrob Agents Chemother. 2013 Dec 30 [ahead of print]
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Efficacy of human simulated regimens of (A) ceftazidime 2 g IV every 8 h as a 2-h infusion, (B) levofloxacin 500 mg IV every 24 h, (C) doripenem 2 g every 8 h as a 4-h infusion, and (D) ertapenem 1 g every 24 h against a distribution of OXA-48 producing Enterobacteriaceae isolatesa in a neutropenic murine thigh infection model. Error bars represent standard deviations
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Carbapenemase-producing Enterobacteriaceae
Carbapenem efficacy: Is it just an MIC-dependent issue? Does the genotype matter?
Antimicrob Agents Chemother. 2013;57(8):3936–40
Antimicrob Agents Chemother. 2013 Dec 30 [ahead of print]
• Genotype might matter: For the same MIC, Carbapenem seems less active against OXA-48 producing Enterobacteriaceae as compared to NDM/KPC
Conclussions/Further questions
• Does double-carbapenem therapy work for OXA-48-producing Enterobacteriaceae?
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Antimicrob Agents Chemother. 2014;58(2):851–8.
“Weird” combinations for XDR-GNR
• Colistin acts on the A. baumannii outer membrane….
• …enabling glycopeptides access to cell wall targets (from which they are usually excluded)
• Gordon NC. AAC 2010;54(12):5316–22. • Wareham DW JAC 2011;66(5):1047–51.
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Wareham DW JAC 2011;66(5):1047–51.
Without colistin Subinhibitory colistin
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Wareham DW JAC 2011;66(5):1047–51.
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Wareham DW JAC 2011;66(5):1047–51.
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Antimicrob Agents Chemother. 2014;58(2):851–8.
Can Glycopeptide have any role for the treatment of GNR (rationale)?• Colistin acts on the A. baumannii outer membrane….
• …enabling glycopeptides access to cell wall targets (from which they are usually excluded)
• Gordon NC. AAC 2010;54(12):5316–22. • Wareham DW JAC 2011;66(5):1047–51.
• ¿Are these findings applicable to other GNR? • Vidaillac C- AAC. 2012;56(9):4856–61.
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Antimicrob Agents Chemother. 2014;58(2):851–8.
Design• Multicenter (3) observational retrospective study
Patients• Cohort of critically ill patients receiving colistin (Jan´10-Jan´11)
Statistical analysis
• Early deaths after onset of colistin (<5 days) were excluded
Aim• To evaluate the frequency of colistin + glycopeptide combination• To determine the impact of this combo on outcome
• Risk factors for 30 day mortality: Cox regression
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Antimicrob Agents Chemother. 2014;58(2):851–8.
Results• 184 (166 GNR) patients received a colistin-based regimen (20% empirically)
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Antimicrob Agents Chemother. 2014;58(2):851–8.
Results (ii)
Text: 68 (41%)??
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Results (iii)
Text: 68 (41%)??
Antimicrob Agents Chemother. 2014;58(2):851–8.
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Results (iii)
Antimicrob Agents Chemother. 2014;58(2):851–8.
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Conclusions
Antimicrob Agents Chemother. 2014;58(2):851–8.
• Colistin-Glycopeptide is a frequently used antimicrobial combination among critically-ill infected patients.
• Colistin-Glycopeptide Combo for ≥5 days was a factor independently associated with better outcomes among all the patients and among those with only MDR A. baumannii infection
• Is this effect logistic regression magic?: Prospective, randomized studies are needed
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Clin Infect Dis. 2013;57(3):349–58
“Weird” combinations for XDR-GNR
At last, a randomized clinical trial for the therapy of XDR-MO!!!
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Li J. Clin Infect Dis 2007; 45:594–8
Rationale
A) In vitro sinergy
• Giamarellos-Bourboulis EJ. Diagn Microbiol Infect Dis 2001; 40:117–20
• Tripodi M-F. Int J Antimicrob Agents 2007; 30:537–40
• Li J. Clin Infect Dis 2007; 45:594–8
“Weird” combinations for XDR-GNR
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Li J. Clin Infect Dis 2007; 45:594–8
Rationale
A) In vitro sinergy
“Weird” combinations for XDR-GNR
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Rationale
A) In vitro sinergy
B) Experimental studies in animals• Pantopoulou A. Int J Antimicrob Agents 2007; 29:51–5
• Pachon-Ibanez ME. Antimicrob Agents Chemother 2010; 54: 1165–72
- Of note: Strains were rifampin-”susceptible” (CMI 4-16)
- Two different animal models, involving A. baumannii…
- …showing benefits with colistin-rifampin combination
C) Clinical Studies• Petrosillo N. Clin Microbiol Infect 2005; 11:682–3
• Bassetti M JAC 2008; 61:417–20
- High response rates with colistin+rifampin combo
“Weird” combinations for XDR-GNR
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Durante-Mangoni Clin Infect Dis. 2013;57(3):349–58
Design• Multicenter (5) open-label RCT
Hypothesis• Addition of rifampin to colistin 30-d mortality (compared w/colistin [monoRx]
Patients• Critically ill patients with microbiologic evidence of a life-threatening
nosocomial infection due to XDR* AB (*only susceptible to colistin)HAP, VAP, BSI, Complicated intrabdominal infections
Therapeutic arms• Intervention arm: Colistin 2MU TID* + Rifampin 600mg BID (10-21 days) • Control arm: Colistin 2MU TID* (10-21 days)
Sample Size• Expected 30-d mortality in control group: 60%• Expected 30-d mortality in intervention group: 40% Sample size: 207• a (two-tail) 0.05; Power 0.8
“Weird” combinations for XDR-GNR
*No loading dose. Low maintenance dose
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Durante-Mangoni Clin Infect Dis. 2013;57(3):349–58
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Durante-Mangoni Clin Infect Dis. 2013;57(3):349–58
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Durante-Mangoni Clin Infect Dis. 2013;57(3):349–58
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Clin Infect Dis. 2013;57(3):359–61
• Colistin-Rifampin did NOT show any clinically significant benefit in the clinical trials
• Would you devote money/time in further clinical trials using this combo????
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Optimization of AB dosing
Bauer KA. AAC. 201;57(7):2907–12
Design• Non randomized before (20´ bolus)-after (4 h extended infusion)
intervention [cefepime 2g TID]
Patients• Consecutive patients with cefepime-susceptible (MIC ≤ 8mcg/mL)
Pseudomonas bacteremia or pneumonia between 2008 and 2011
• …receiving ≥at least 48h of cefepime within 72h of + blood cultures
• Exclusion criteria: administration of other b-lactam concomitantly with cefepime
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Optimization of AB dosing
Bauer KA. AAC. 201;57(7):2907–12
Results
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Optimization of AB dosing
Bauer KA. AAC. 201;57(7):2907–12
Results
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Optimization of AB dosingResults
30-day mortality• Bolus infusion (20%) vs Extended infusion (3%); p= 0.03
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Optimization of AB dosing
Discussion
Were both populations comparable?
Bauer KA. AAC. 201;57(7):2907–12
• BSI: 28 (bolus) vs 18 (extended infusion)• Is “pneumonia” really a pneumonia?
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Further insight on how to improve colistin dosing
Clinical Infectious Diseases. 2014;58(1):139–41.
Letter to the Editor written by the promoters of the “First International Conference on Polymyxins” (Prato, Italy, May 2-4th, 2013)
There is need to be aware of confusing terminology used in articles published in journals
• IU vs mg (colistin base activity)• 1.000.000 IU = 30 mg CBA
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Contains comprehensive information on colistin
Nice PK/PD blog
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Further insight on how to improve colistin dosing
JAC. 2013;68(10):2311–7
• HPLC and elemental analysis of vials of 4 brands from 3 continents
• PK analysis (CMS and formed colistin) in rats after iv administration
• As CMS is an inactive prodrug, the use of microbiological assays to standardize antibacterial activity in vitro may not reflect the exposure to formed colistin in vivo
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JAC. 2013;68(10):2311–7
RP-HPLC profiles at 214 nm for (a) blank control, (b) colistin and 4 marketed products (c-f)
• ¾ brands had very similar chromatographic profiles• Multiplicity of peaks mixture of different derivatives
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JAC. 2013;68(10):2311–7
PK profile
Colismethate (CMS) Colistin
• The were significant differences in the AUC0-180min among different products suggesting differences in the conversion of CMS to colistin
• The plasma concentration – time profiles of CMS were generally consistent among all four products
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• In vitro studies demonstrate excellent susceptibility of AmpC β-lactamase–producing organisms to cefepime. In addition it seems to be a poor AmpC inducer
Tamma PD Clin Infect Dis. 2013;57(6):781–8
Carbapenem-sparing regimens
Rationale
Hypothesis• “Cefepime is a valuable therapeutic option for infections caused by AmpC producing
Enterobacteriaceae”
• Infections caused by AmpC β-lactamase–producing organisms can successfully be treated with carbapenems
• AmpC β- lactamases can be expressed at levels either by induction or selection for derepressed mutants in the presence of 3rd generation ceph and, thus, should be avoided
• In vitro studies also suggest that an inoculum effect exists and that cefepime may be a less reliable agent for the treat- ment of high inoculum infections
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Tamma PD Clin Infect Dis. 2013;57(6):781–8
Carbapenem-sparing regimensDesign• Single-center (Johns Hopkins) retrospective cohort observational study (2010-12)
Patients• Patients with BSI, Pneumonia or intrabdominal infection in which…• Enterobacter* spp, Citrobacter* or Serratia* were isolated…• having received cefepime or carbapenem for at least 72h
*If AmpC was not phenotypically detected by any of the following methods, patient were excluded: a) cefotetan–boronic acid disk tests and b) cefotetan-cloxacillin Etest strips
Outcome variable• Primary: 30-day mortality• Secondary: Length of hospital stay (LOS) since 1st + culture
Propensity score matching• Propensity score methods were used to ensure similarity of the 2 groups (age,
microorganism, LOS til 1st culture, severity, ICU, source control)
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Tamma PD Clin Infect Dis. 2013;57(6):781–8
Carbapenem-sparing regimensResults
Frequency of AmpC: Enterobacter (38%); Serratia (15%); Citrobacter spp (1%)
• Propensity score matching yielded 32 matched pairs
• Patients receiving meropenem had higher risk of MDRO colonization, comorbidity and immune-supression
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Tamma PD Clin Infect Dis. 2013;57(6):781–8
Carbapenem-sparing regimensResults
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Tamma PD Clin Infect Dis. 2013;57(6):781–8
Carbapenem-sparing regimensResults
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Tamma PD Clin Infect Dis. 2013;57(6):781–8
Carbapenem-sparing regimens
Discussion
Has this study enough power to proof the non-inferiority of cefepime vs meropenem?
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Carbapenem-sparing regimensRetamar P. AAC 2013;57(7):3402–4
Design• Single-center (HVM) prospective cohort observational study
Patients• Patients with ESBL-producing monomicrbial E. coli bacteremia• …who received empirically Pip/Tazo within 24h of blood culture
Outcome variable• Primary: 30-day mortality
Analysis• Considering MIC
High MIC (≥16)Intermediate MIC (4-8)Low MIC (≤2)
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Carbapenem-sparing regimens
Retamar P. AAC 2013;57(7):3402–4
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Tamma PD Clin Infect Dis. 2013;57(6):781–8
Carbapenem-sparing regimens
Discussion
How do these findings should influence empiric therapy? Should they?