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SIDP – Antimicrobial Stewardship Certificate Program Antimicrobial Stewardship and Microbiology: Focus on Rapid Diagnostic Tests

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Antimicrobial Stewardship Certificate Program

Antimicrobial Stewardship and Microbiology: F R id Di ti T tFocus on Rapid Diagnostic Tests

Karri A. Bauer, PharmD, BCPS (AQ-ID)Specialty Practice Pharmacist Infectious DiseasesThe Ohio State University Wexner Medical Center

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Objectives

Discuss the various rapid diagnostic technologiesEvaluate the use of rapid diagnostic technologiesEvaluate the use of rapid diagnostic technologies on patient outcomesDetermine considerations during the preimplementation, implementation, and postimplementation phases of rapid diagnostic technologies

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Patient Case

62 year old male presented to the ED with cc of night sweatsHPI: 3 day history of generalized fatigue feversHPI: 3 day history of generalized fatigue, fevers and night sweats and nauseaPMH: HTN, HLD, DM2Physician Exam:

Vitals: Temp 102.1°F, HR 110, BP 120/70, RR 20, 98% on RA

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98% on RABlood cultures obtained prior to initiation of vancomycin + piperacillin/tazobactam

General Principles

Basic MicrobiologyDirect examinationCulture/Gram stainCulture/Gram stainRapid biochemical testsAntibody and antigen detection

Average time to deliver antimicrobial susceptibility testing results to a physician is 40 hoursNumerous studies have demonstrated the impact of inappropriate antimicrobial therapy on mortality

Kerremans JJ, Verboom P, Stijnen T, et al. Rapid identification and antimicrobial susceptibility testing reduce antibiotic use and accelerate pathogen-directed antibiotic use. J. Antimicrob Chemother 2008;61:428-435.


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Dilemma with Conventional Methods

Day 0 Day 1 Day 2 Day 3 Day 4

Gram stain provides limited information. Cannot tell the species

Empiric Rx Broad-spectrum Rx Targeted Rx

Conventional Dx

PositiveBlood Culture

Gram Stain

Conventional Species ID

Blood Draw

Culture is too slow

Clinicians can’t wait an additional 1-3 days to treat the infectionLeads to inappropriate and ineffective therapy for some patients and unnecessarily therapy for others

Introduction

New advances in RDTs provide collaborative opportunities for antimicrobial stewardship programs (ASPs)programs (ASPs)Enhance functions of clinical microbiology laboratories

Provide accurate organism identification Timely antimicrobial susceptibility testing data

RDTs benefit the individual patient but also pincrease the effectiveness of ASPs


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Day 0 Day 1 Day 2 Day 3 Day 4

Conventional/New Timeline

Empiric Rx Broad-spectrum Rx Targeted Rx

Conventional Dx


Gram Stain

Conventional Species ID

Blood Draw

Positive• Rapid and accurate results on day 1


Blood Draw

Species ID

Targeted RxEmpiric Rx

Gram Stain• Supports decisions for appropriate and

targeted therapy 1-3 days earlier than conventional methods

Rapid Diagnostic Technologies


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Polymerase Chain Reaction (PCR)

Fluorescently labeled probe with primersAmplify target DNA

C bi lifi ti d d t ti i t 1Combines amplification and detection into 1 process

Roche Molecular System’s LightCycler SeptiFastMecABD GeneOhm’s Cdiff assayCepheid’s C. difficile assay

Multiplex PCR

Fluorescently labeled prove with > 1 set of primersSimultaneous detection of multiple organismsSimultaneous detection of multiple organisms and resistant makers

BD GeneOhm’s Staph SR assayCepheid’s Xpert MRSA/SA blood culture and C.difficile/Epi assaysBioFire Diagnostics’ FilmArray


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Nanoparticle Probe

Nucleic acid extraction and PCR amplificationHybridization of target DNA to capture oligonucleotides on a microarrayoligonucleotides on a microarraySignal amplification of hybridized probes provides an automated analysis

Nanosphere’s Verigene blood culture Gram-positive and Gram-negative

Verigene Gram Positive Blood Culture (BC-GP) Test

Available Test Panels

Species GenusSpecies GenusStaphylococcus aureus Staphylococcus spp.

Staphylococcus epidermidis Streptococcus spp.

Staphylococcus lugdunensis Micrococcus spp.

Streptococcus anginosus Listeria spp.

Streptococcus agalactiae ResistanceStreptococcus pneumoniae mecA

Streptococcus pyogenes vanA

Enterococcus faecalis vanB

Enterococcus faecium


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Verigene Gram Negative Blood Culture (BC-GN) Test

Available Test Panels

Species GenusSpecies GenusEscherichia coli Acinetobacter spp.

Klebsiella pneumoniae Citrobacter spp.

Klebsiella oxytoca Enterobacter spp.

Pseudomonas aeruginosa Proteus spp.

Resistance

CTX-M KPC

NDM VIM

IMP OXA

FilmArray Blood Culture Identification Panel

Available Test PanelsGram-Positive Gram-Negative

Enterococcus Acinetobacter baumannii

Listeria monocytogenes Haemophilus influenzae

Staphylococcus aureus Neisseria meningitidis

Streptococcus agalactiae Pseudomonas aeruginosa

Streptococcus pneumoniae Enterobacter cloacae

Streptococcus pyogenes Escherichia coli

Streptococcus pyogenes Klebsiella oxytoca

Enterococcus faecalis Klebsiella pneumoniae

Enterococcus faecium Proteus spp.

Serratia marcescens


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Peptide Nucleic Acid Fluorescent In Situ Hybridization (PNA FISH)

Synthetic oligonucleotide fluorescence-labeled probesNeutral charge of the synthetic molecule allows rapidNeutral charge of the synthetic molecule allows rapid hybridization to species-specific ribosomal RNAFluorescence is detected using a fluorescence microscopeQuickFISH (AdvanDx)Requires less setup timeq pFaster turnaround time

90 minutes-20 minutes from positive blood cultures

PNA FISH

S. aureus Coagulase-negative staph Negative


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Matrix-Assisted Laser Desorption-Ionization Time-of Flight Mass Spectrometry (MALDI-TOF)

Mass spectrometry results in ionization and disintegration of a target moleculedisintegration of a target moleculeMass/charge ratio of the resulting fragments is analyzed to produce a molecular signature

Provides a profile or fingerprint of the organismAnalyze thousands of samples/day from a variety of sourcesy

R id Di ti T h l i dRapid Diagnostic Technologies andAntimicrobial Stewardship


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Staphylococcus aureus

S. aureus infections constitute a tremendous burdenS aureus bacteremia requires promptS. aureus bacteremia requires prompt microbiological diagnosis and antibiotic administrationVancomycin is often used empirically Use of antistaphylococcal -lactams have demonstrated superior clinical outcomesdemonstrated superior clinical outcomes compared to vancomycin for MSSA infections

Available RDTsOrganism Detection

time, hTechnology Manufacturer Batching CLIA

DesignationTrade Name

SA, CoNS 0.3 PNA QuickFISH AdvanDx No High S.aureus/CoNS PNA QuickFISH

MRSA 0 1 Immunochromatography Alere No Moderate Alere PBP2aMRSA 0.1 Immunochromatography AlereScarborough, Inc.

No Moderate Alere PBP2a Culture Colony Test

S. aureus 0.2 Immunochromatography AlereScarborough, Inc.

No Not rated BinaxNOWS. aureus

MSSA, MRSA

20-26 Chromogenic medium BD No High BBLCHROMagarMRSA II

MRSA 2 PCR Roche Diagnostics

Yes High LightCyclerMRSA

MSSA, 2 Multiplex PCR BD GeneOhm Yes High BD GeneOhmMRSA, CoNS

gStaph SR

MSSA, MRSA, CoNS

1 Multiplex PCR Cepheid No Moderate XpertMRSA/SA BC

S. aureus, S.epidermidis

1 Multiplex Nanosphere No Moderate VerigeneBC-GP

MALDI-TOF MS and FilmArray can also be used.


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mecA Gene Testing and Intervention

Carver PL, Lin S-W, DePestel DD, et al. Impact of mecA gene testing and intervention by infectious diseases clinical pharmacists on time to optimal antimicrobial therapy for Staphylococcus aureus bacteremia at a university hospital. JClin Micro 2008;46:2381-2383.

Drug Therapy for Patients with MSSA Bacteremia

Parta M, Goebel M, Thomas J, et al. Impact of an assay that enables rapid determination of Staphylococcus species and their drug susceptibility on the treatment of patients with positive blood culture results. Infect Control HospEpidemiol 2010;31(10):1043-1048.


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Time to Antibiotic Switch

10

12

3.6

10

4.54

6

8

10

Day

s

PreinterventionPostintervention

p=0.02

p=0.15

2

0

2

MSSA MRSABauer KA, West JE, Balada-Llasat JM, et al. An antimicrobial stewardship program’s impact with rapid polymerase chain reaction methicillin Staphylococcus aureus/S. aureus blood culture in patients with S. aureus bacteremia. ClinInfect Dis 2010;51(9):1074-1080.

RDT and Stewardship Intervention-Hospital Costs

$69,73770 000

80,000

$48,350

30,000

40,000

50,000

60,000

70,000

p=0.02

0

10,000

20,000

Preintervention PostinterventionBauer KA, West JE, Balada-Llasat JM, et al. An antimicrobial stewardship program’s impact with rapid polymerase chain reaction methicillin Staphylococcus aureus/S. aureus blood culture in patients with S. aureus bacteremia. ClinInfect Dis 2010;51(9):1074-1080.


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Coagulase-Negative Staphylococci spp.

Often considered a contaminantMultiple positive blood cultures require therapyClinicians often determine the positive blood cultures to represent contamination

ASP PharmD Interventions for CoNS Using Rapid PCR

Preintervention Postintervention

P

Discontinuation of antistaphyloccalantibiotics, hours

57.7 25.7 0.005

Total antibiotic exposure, days

97.6 54.1 0.011

Infection-related LOS, days

10 5.5 0.018

Infection-related costs $28,973 $20,635 0.144Initiated vancomycin 7 (21%)

Wong JR, Bauer KA, Mangino JE, Goff DA. Antimicrobial stewardship pharmacist interventions for coagulase-negative staphylococci positive blood cultures using rapid polymerase chain reaction. Ann Pharmacother 2012; 46(11): 1484-1490.


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Assessment of PNA FISH CoNS in the Absence of Stewardship Intervention

Holtzman C, Whitney D, Barlam T, et al. Assessment of impact of peptide nucleic acid fluorescence in situhybridization of rapid identification of coagulase-negative staphylococci in the absence of antimicrobial stewardship intervention. J Clin Micro 2011;49(4):1581-1582.

Enterococci spp.

3rd most commonly isolated healthcare-associated organismIntrinsically resistant to many antibioticsMay acquire additional resistant determinantsVRE bacteremia associated with suboptimal patient outcomesEmpiric therapy includes vancomycin, p py y ,daptomycin, or linezolid


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Available RDTs

Organism Detectio Technology Manufactur Batchin CLSI TradeOrganism Detection time, h

Technology Manufacturer

Batching

CLSIDesignation

TradeName

E. faecalis, E. faecium

0.5 PNA QuickFISH AdvanDx No High Enterococcus faecalis/OE PNA QuickFISH

E. faecalis, E. faecium(also detects VRE)

2.5 Multiplex PCR Nanosphere No Moderate Verigene BC-GP

MALDI TOF MS and FilmArray can also be usedMALDI-TOF MS and FilmArray can also be used.

PNA FISH for Enterococcal Bactermia

404550

45%

10152025303540

PreinterventionPostintervention

26%

0 001

p=0.04

05

10

Time to therapy (days) 30-day mortality (%)

1.33.1p<0.001

Forrest GN, Roghmann MC, Toombs LS, et al. Peptide nucleic acid fluorescent in situ hybridization for hospital-acquired enterococcal bacteremia: delivering earlier effective antimicrobial therapy. AntimicrobAgents Chemother 2008;52:3558-3563.


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Gram-Negative Organisms

Top healthcare prioritySuboptimal patient outcomes

I d LOS t lit d h lth tIncreased LOS, mortality, and healthcare costsIncreased number are multidrug-resistantLimited treatment options

Available RDTs

Organism Detection time, h

Technology Manufacturer

Batching

CLSI Designation

Trade Name

E. coli, K. pneumoniae, K.

t P

2.5 Multiplex PCR Nanosphere No Moderate Verigene BC-GN

oxytoca, P.aeruginosa, S. marcescens, Acinetobacterspp., Proteusspp., Citrobacterspp., Enterobacterspp.

E. coli, P. aeruginosa, K. pneumoniae

0.5 PNA QuickFISH AdvanDx No High GNR Traffic Light PNA QuickFISHs

E coli K 1 Multiplex PCR BioFire Yes Moderate FilmArrayE. coli, K.pneumoniae, K. oxytoca, P. aeruginosa, A. baumannii,Enterobacterspp., Proteus spp, S.marcescens, H influenzae, N. meningitidis

1 Multiplex PCR BioFireDiagnostics

Yes Moderate FilmArraySystem and Panels

MALDI-TOF MS can also be used.


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PNA FISH

Distinguishes P. aeruginosa from E. coli or K.pneumoniae after the recognition of Gram-negative bacilli of positive blood culturesProvides a key opportunity for stewardship programs to deescalate therapy

Combination therapyAntipseudomonal therapy

Integrating Rapid Pathogen Identification and ASP

Length of Stay and Cost Outcomes in Survivors

Outcome Preintervention cohort Intervention cohort POutcome Preintervention cohort Intervention cohort P

Hospital LOS 11.9 ± 9.3 9.3 ± 7.6 .01

Hospital LOS after BSI onset

9.9 ± 7.1 8.1 ± 6.4 .01

ICU LOS 7.3 ± 8.5 6.3 ± 8.7 .05

ICU LOS after BSI onset

6.1 ± 6 4.9 ± 6.7 .09

Total hospital costs

$45,709 ± $61,806 $26,162 ± $28,996 .009

Perez KK, Olsen RJ, Musick WL, et al. Integrating rapid pathogen identification and antimicrobial stewardship significantly decreases hospital costs. Arch Pathol Lab Med 2013;137(9):1247-1254.


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Impact of Rapid Organism Identification Using MALDI-TOF

25 20 30-Day All-Cause Mortality Length of Stay

20.3%

12.7%

5

10

15

20

% o

f Pat

ient

s

14.2

11.4

5

10

15

Day

s

p=0.021 p=0.0661

0

5

Preintervention Intervention 0

Preintervention Intervention

Huang AM, Newton D, Kunapuli A. et al. Impact of rapid organism identification via matrix-assisted laser desorption/ionization time-of-flight combined with antimicrobial stewardship team intervention in adult patients with bacteremia and candidemia. Clin Infect Dis 2013;57(9):1237-1245.

Impact of MALDI-TOF and ASP Intervention in Patients with A. baumannii Infections

9075 77.7

2836.6

2030405060708090

Hou

rs

PreinterventionIntervention

p=<0.01 p=<0.01

01020

Time to effective therapy Time to effective therapy > 0

Wenzler E, Goff DA, Mangino JE, Reed EE, Wehr A, Bauer KA. Impact of rapid identification of Acinetobacterbaumannii via matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) and antimicrobial stewardship intervention in patient with pneumonia and/or bacteremia. European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Barcelona, Spain May 2014.


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Candida spp.

4th most most common cause of nosocomial bloodstream infectionsTime to positive blood culture and speciesTime to positive blood culture and species identification can take several days Increase in the amount of time to effective antifungal therapy and hospital mortality

RDTs for Candida spp.

Rapid diagnostic

Candida species detected

Date test is performed

Sensitivity Specificity

Positive predictive

valuevalueT2Candidaassay

C. albicans, C. parapsilosis, C. krusei, C. glabrata, C. tropicalis

Day of blood culture

98% 98% 91%

MALDI-TOF MS

All Day of yeast identification

94% 100% 94%

PNA-FISH C. albicans, C. parapsilosis, C. glabrata, C. krusei,

Day of yeast identification

98% 98% 99%

C. tropicalis


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T2 Candida Assay

Magnetic resonance (MR)PCR Hybridization of DNA Probe-decorated nanoparticles Nanosphere microclusters p pLarge changes in sample’s T2MR signalIdentifies 5 species of CandidaDirectly from whole blood

Limits of detection-1 CFU/mLRapid results

3 hours3 hours98% positive agreement and 100% negative agreement

Impact of PNA FISH on Mortality and Hospital Costs

Clinical and Economic OutcomesClinical and Economic OutcomesOutcome No PNA FISH PNA FISH P

Time to appropriate therapy, days

6.2 2.3 <0.001

All cause mortality 26.8% 7.7% 0.14

ICU mortality 41.7% 5.9% 0.02

Cost avoidance > $2.2 million/year

Gamage DC, Olson DP, Stickell LH. Significant decreases in mortality and hospital costs after laboratory testing with PNA FISH. In: 51st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL, September 2011.


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Community Hospital Experienced with PNA FISH

C. glabrata All yeastLength of stay (LOS) costs• Daily LOS cost per patient

LOS t i / ti t$2,607

$33 891$2,607

$15 642• LOS cost savings/patient• Patients with LOS Reduction

$33,89111

$15,64221

Total LOS cost savings $372,801 $328,482

C. albicans/C. glabrataPNA FISH Costs

$7,790 $7,790

Net benefit to hospital per patient $34,261 $15,769

Net benefit to hospital per day $2,635 $2,628

Annual net benefit to hospital $196,633 $172,774ua et be e t to osp ta $ 96,633 $ ,

• Length of time between yeast detection in blood culture and identification to the species level was decreased significantly (p=0.001)

• For patients with candidemia caused by C. glabrata, LOS decreased significantly (p=0.008) and significant difference in time to appropriate antifungal therapy (p=0.03)

Rush T, Verma P. Do rapid results with the C. albicans/C. glabrata PNA FISH assay have an impact on patient management? A community hospital experience. In: 111th Annual ASM Meeting, New Orleans, LA 21-24 May 2011:2563.

Candidemia-Time to Positivity

162 patients with candidemia58 ± 17 yearsAverage time to yeast identification 2 2 ± 1 3 daysAverage time to yeast identification 2.2 ± 1.3 daysAverage time to start antifungal therapy 3.5 ± 2.1 days

Candida Species Time to PositivityDays (mean ± SD)

C. albicans 1.7 ± 1.0C glabrata 2 6 ± 1 5C. glabrata 2.6 ± 1.5C. tropicals 1.4 ± 1.1C. parapsilosis 2.2 ± 0.89

Aitken SL, Beyda ND, Shah DN, et al. Clinical practice patterns in hospitalized patients at risk for invasive candidiasis: role of antifungal stewardship programs in the era of rapid diagnostics. Annals of Pharmacotherapy2014;48(6): 683-690.


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Time to Antifungal Initiation-Comparison of RDTs

33.5

4 er

apy

0.6±0.2

2.5±1.4 2.6±1.3

00.5

1 1.5

2 2.5

3

Day

s to

initi

atio

n of

th

0 T2Candida MALDI TOF MS PNA FISH

D

Rapid Diagnostic Test Use of T2Candida on the day of the blood culture resulted in 3136 to 6078 fewer doses of echinocandins annually per 5000 patients

Aitken SL, Beyda ND, Shah DN, et al. Clinical practice patterns in hospitalized patients at risk for invasive candidiasis: role of antifungal stewardship programs in the era of rapid diagnostics. Annals of Pharmacotherapy2014;48(6): 683-690.

Clostridium difficile

Increasingly challenging infection Increases in severity of disease, clinical failure, and recurrencesand recurrences

Epidemiology has changedNAP1/BI/027


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Available RDTs

Detectiontime, h

Technology

Manufacturer Batching Automated

CLSIDesignation

Trade Name

1 LAMP Meridian Yes Yes Moderate Illumigene1 LAMP Meridian Bioscience

Yes Yes Moderate IllumigeneC. difficile

2 PCR BD GeneOhm Yes Yes Not rated BD GeneOhmCdiffAssay

0.5 MultiplexPCR

Cepheid No Yes Moderate XpertC. difficile

0.75 Multiplex Cepheid No Yes Moderate Xpert0 5 u t p ePCR

Cep e d o es ode ate pe tC.difficile/Epi

3 PCR Gen-Probe Prodesse

Yes Yes Not rated ProGastroCd Assay

Important Considerations

PCR technology is more sensitiveRate of positive tests can more than double

I t t t d t di l t ff d h it lImportant to educate medical staff and hospital administrationImplement strict criteria for testing

> 3 unformed watery stools in a 24-hour periodFormed stool rejected unless lab notified of ileusSamples should not be sent as test of curep


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Preimplementation

DO YOUR HOMEWORK-BEST DATA IS YOUR OWN DATAOrganisms

PrevalenceProblematicReportable

Timing of resultsReal-timeBatch

Sensitivity/specificityPurchase/leasePhysical spaceComplexityResources for clinical and economic outcomes

Implementation

EducationTimingTiming

Real timeBatch

Communication of resultsPharmacist/physician resourcesPharmacist/physician rolePharmacist/physician roleIntervention documentation/acceptance rate


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Postimplementation

WorkflowEducationDocumentation/Justification

Time to effective/optimal therapyTime to discontinuation or de-escalationTime to ID consultRepeat blood cultures30-day readmissionyLength of stayHospital cost of infectionHospital cost

Conclusions

Collaboration between microbiology and stewardship will continue to growI ti t h lInnovative technology

Game of speedMicrobiologist and stewardship justification

Clinically and economically

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