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GenMark Diagnostics

ePLEX® BLOOD CULTURE IDENTIFICATION (BCID): DESIGNED TO IMPROVE PATIENT CARE AND CLINICAL OUTCOMES

Association for Molecular Pathology (AMP)

November 15, 2017

Agenda

• ePlex: True Sample-to-Answer System & Blood Culture ID solution

• Improving outcomes in bloodstream infections through the

partnership of molecular diagnostics and antimicrobial stewardship

Slides 7-31 developed and presented by:

Dr. Tristan Timbrook, Pharm.D., M.B.A., B.C.P.S.

University of Utah Health

• ePlex BCID analytical and beta customer data review

Product in development. Not available for sale in the U.S. Specifications subject to change.

ePlex®: The True Sample-to-Answer Solution™Designed for the Patient, Optimized for the Lab™

For In Vitro Diagnostic Use.

The Sepsis Challenge Sepsis is common, costly, and deadly… and time is critical in ensuring positive outcomes

1. Sepsis Fact Sheet, World Sepsis Day: www.world-sepsis-day.org.

2. Institut Pasteur, Sepsis/Septicemia: https://www.Pasteur.fr/en/medical-center/disease-sheets/sepsis-septicemia

3. HCUP Statistical briefing #204; National Inpatient Hospital Costs: The Most Expensive Conditions by Payer, 20134. Kumar, et. al., (2006) Crit Care Med, Vol. 34, No. 6

5. IDSA: Better Tests Better Care, The Promise of Next Generation Diagnostics

Sepsis strikes ~30 million people worldwide each year1

Resulting in a death every 3-4 seconds2

Sepsis is the most expensive condition treated in U.S. hospitals, costing ~$18,000 per case3

For every 1 hour delay in effective treatment, mortality increases by up to ~8%4 and 20-30% of patients receive ineffective initial antibiotic therapy5

http://www.world-sepsis-day.org/

https://www.pasteur.fr/en/medical-center/disease-sheets/sepsis-septicemia

The ePlex® Blood Culture Identification Solution Rapid, Comprehensive Identification of Sepsis-causing Organisms

Organism ID & Antibiotic Susceptibility Testing (ID/AST)Blood

Draw Sub-Culturing

Gram

Stain

Conventional Blood Culture(~48-72h+)

t=0 8h 16h 24h 32h 40h 48h 56h 64h 72-96h

Bottle

Culture

ID/

AMR

t=0 8h 10h

ePlex® BCID saves days compared to conventional

methods and is designed to: • Decrease time to appropriate antimicrobial treatment

• Reduce hospital length of stay and overall costs

• Improve antibiotic stewardship and infection control

• Improve patient outcomes


Blood

DrawBottle

Culture

ID = Identification (of bacterial organisms); AMR = Antimicrobial Resistance

*ID + AMR can aid in guiding treatment decisions; subculture and AST may be needed for confirmation, identification of organisms not detected by ePlex BCID panels and susceptibility testing

*

ePlex BCID Designed to be the most comprehensive BCID panels: for rapid, routine ID & resistance gene detection

BCID

PanelPathogen

Targets

Resistance

GenesKey Differentiators

Gram-

Positive

20 4

• Common Blood Culture contaminant organisms to aid in rapidly

ruling out blood culture contamination

• Pan Gram-Negative and Pan Candida targets help to ensure against

missed infections

Gram-

Negative

21 6

• Anaerobes or otherwise difficult to culture organisms

• Important multidrug resistant organisms (MDRO)

• Difficult to treat pathogens or not covered by typical empiric therapy

• Pan Gram-Positive and Pan Candida targets help to ensure against

missed infections

Fungal

Pathogen

16 0

• Common Candida species

• Emerging Candida species that are often fluconazole resistant

• Organisms implicated in neonatal fungemia

• Other emerging fungal pathogens that are often echinocandin or

amphotericin B resistant


IMPROVING OUTCOMES IN BLOODSTREAM INFECTIONS THROUGH THE PARTNERSHIP OF MOLECULAR DIAGNOSTICS AND ANTIMICROBIAL STEWARDSHIP

TRISTAN TIMBROOK,PHARMD,MBA,BCPS

ANTIMICROBIAL STEWARDSHIP PHARMACIST

UNIVERSITY OF UTAH HEALTH

SALT LAKE CITY, UT

[email protected]

DISCLOSURES

• Dr. Timbrook serves on the speakers bureau and as an advisory consultant for

BioFire Diagnostics, LLC and GenMark Diagnostics, Inc.

OUTLINE

• Discuss systematic review and meta-analysis of rapid diagnostics in

bloodstream infections

• Review performance of genotypic resistance detection in gram negative

infections, actionability of results, and potential for ePlex BCID

• Beyond identification and resistance detections, highlight the potential clinical

advantage of ePlex BCID in polymicrobial infections

• Background

• Delays in time to effective therapy in bacteremia have been shown to be associated with

increased mortality

• Rapid diagnostic testing (RDT) in bloodstream infections (BSI) have facilitated faster time

to appropriate therapy

• Outcomes with RDT in BSI have not been consistent across all studies

• Objective: Determine overall effect of RDT in BSIs from published literature

Timbrook TT, et al. Clin Infect Dis. 2017;64(1):15-23.

METHODS

• Literature Search

• Searched PubMed, CINAHL, Web of Science, and Embase

• Inception to 31 May 2016 for BSI studies

• Comparing clinical outcomes between mRDT and conventional microbiology

• Outcomes

• Mortality risk, mortality risk in studies with antimicrobial stewardship, mortality risk by organism, time to

effective therapy, and length of stay (LOS)

• Data extraction and Analysis

• Mortality, time to effective therapy, and LOS were assessed using a random-effects model to estimate

either pooled odds ratios (ORs) or weighted mean differences

• All meta-analyses were performed using Review Manager software (The Cochrane Collaboration,

version 5.3)


RESULTS

• Flow diagram of

included studies

• 5,920 patients

included among

31 studies


RESULTS

• Study Characteristics

• Only 6 studies (19.4%) were conducted outside the United States

• The majority of studies included (26 of 31; 83.9%) were designed as pre- and

postintervention quasi-experimental studies at mRDT initiation

• Majority, where reported, among adults (95.2%, 20/21) and academic medical centers

• Gram positive organism studies most abundant (54.8%)


RESULTS

• Lab practices

• Varied greatly among studies

• Technology used, frequency of testing, and reporting process

• Of the 19 studies reporting the frequency of laboratory sample testing

• 5 (26.3%) reported real-time testing

• 10 (52.6%) reported batch testing between 1to 4 times daily

• Of 5 studies with real-time testing, only 2 noted real-time reporting

• Reporting also varied between primary team notification vs nursing


RESULTS

• Antimicrobial Stewardship activities

• ASP facilitating mRDT represented the majority of the data (20 of 31 studies; 64.5%)

• Of the 14 studies reporting ASP notification processes, only half were 24 × 7 real-time

• The remainder had set response hours (eg, 8 AM to 5 PM; Monday–Friday) or once daily

review of results.


RESULTS

• RDT reduced risk of

mortality (OR 0.66, 95%

CI 0.54 – 0.80)

• Subgroup of ASP RDT

significantly decreased

mortality while absence

of ASP did not

• Calculated number

needed to test of 20 to

decrease mortality by 1


RESULTS

• Mortality decreased for gram-

negative and gram-positive

organisms

• No mortality reduction found for

candidemias but sample was small


RESULTS

• Time to effective

therapy

decreased by 5

hours

• Among VRE,

decreased by

27 hours


RESULTS

• Length of stay

decreased by

2.5 days


RDT IN BSI META-ANALYSIS CONCLUSIONS

• For BSIs, RDT was associated with significant decreases in mortality risk in the

presence of a ASP, but not in its absence

• RDT also decreased the time to effective therapy and the length of stay

• RDT should be considered as part of the standard of care in patients with BSIs


FUTURE CONSIDERATIONS AND OPPORTUNITIES

• Real-time testing vs batching

• Real-time stewardship vs intermittent

• Best practices / most effective practices for reporting RDT results

• Doing stewardship, I make one phone call a day to inform clinicians “staph species” per

PCR means CoNS not S. aureus based on our labs preference in reporting practices

DO THE RESULTS OF THE META APPLY TO MY HOSPITAL? IT DEPENDS…

Broadness of

empiric therapy vs

local resistance

Inadequate therapy

• Escalation

opportunities

• Time to effective

therapy

• Mortality benefit

Overly broad therapy

• De-escalation

opportunities

• Time to optimal

therapy

• AE and collateral

damage avoidance

RDT and

stewardship

facilitated

opportunities all

around

WHAT IS THE BENEFIT OF GRAM NEGATIVE RESISTANCE DETECTION?

• Approximately 50.6% of empiric regimens for ESBL organisms are

inappropriate and 76.4% for Carbapenemase-producing organisms

• Inadequately treated resistant gram negative infections associated with

higher mortality rates (38.4% vs 27.4%; p=.049)

• A pre-post study using a gram-negative panel with resistance markers among

195 bacteremias noted a 34h decrease in time to effective therapy among

ESBL isolates (41.4h vs 7.3h; p=.04)

Harris P, et al. Int J Antimicrob Agents. 2017;50(5):664-672

Kang C, et al. AAC. 2005;49(2):760-766.

Walker T, et al. JCM. 2016;54(7):1789-96.

GRAM NEGATIVE RESISTANCE IS INCREASING…

• Veterans Affairs data

across 130 facilities and

from 2003-2013

• Increasing non-

susceptibility such as ESBL

E. coli (Right)

Goto M, et al. EID. 2017;23(11):1815-1825.

DOES GRAM NEGATIVE RESISTANCE DETECTION OFFER ACTIONABLE RESULTS IN REAL-WORLD SETTINGS?

• Detroit Medical Center and University of Maryland evaluated the

performance of a gram-negative panel with resistance detection against

automated susceptibility testing

• Evaluation of predictive performance of the panel across a two diverse

hospital settings

• From June 2015-July 2016

Claeys KC, et al. ECCMID 2017.


Organism N Target

Antimicrobial

Resistance

Marker

Sens Spec PPV NPV

E. Coli 384 Ceftriaxone Any 89 99 97 98

K. Pneumoniae 140 Ceftriaxone Any 85 99 97 94

Ertapenem KPC 86 100 100 99

Proteus spp. 57 Ceftriaxone Any 57 100 100 94

Acinetobacter spp. 39 Meropenem OXA 80 93 80 93

P. Aeruginosa 51 Cefepime Any -- -- -- 88

K. Oxytoca 23 Ceftriaxone Any 50 100 100 95

Enterobacter spp. 61 Cefepime Any 33 100 100 97

Citrobacter spp. 10 Cefepime Any -- --- -- 100

Claeys KC, et al. ECCMID 2017.Detroit Medical Center


Organism N Target

Antimicrobial

Resistance

Marker

Sens Spec PPV NPV

E. Coli 106 Ceftriaxone Any 89 99 94 96

K. Pneumoniae 58 Ceftriaxone Any 80 100 100 91

Ertapenem KPC 100 98 83 100

Proteus spp. 12 Ceftriaxone Any -- -- -- 100

Acinetobacter spp. 14 Imipenem OXA 100 100 100 100

P. Aeruginosa 43 Piperacillin-

Tazobactam

Any -- -- -- 65

K. Oxytoca 9 Ceftriaxone Any -- -- -- 100

Enterobacter spp. 33 Cefepime Any 100 100 100 100

Citrobacter spp. 6 Cefepime Any -- -- -- 100

Claeys KC, et al. ECCMID 2017.University of Maryland Medical Center


• With >90% NPV and high PPV, authors noted clinical utility for antimicrobial

stewardship in escalating and de-escalating therapy with the exception of P.

aeruginosa due to the complex resistance mechanisms

• Similar results seen from Rodel et al DMID 2016

• ESBL NPV 93.3, PPV 100

• Gram negative resistance detection is an essential tool for antimicrobial

stewardship to improve patient outcomes

Claeys KC, et al. ECCMID 2017.

WHAT IS THE ADVANTAGE OF EPLEX BCID?

• Beyond advantages in gram-negative resistance detection, ePlex BCID can facilitate

polymicrobial bloodstream infection detection missed by gram-stain directed testing

platforms

• Gram stain directed testing may miss polymicrobial bloodstream infections by not

readily identifying all organism during HPF review

• ePlex BCID has broad inclusivity of gram-positive and gram-negative resistance

genes so resistance gene benefits extend more broadly compared to other RDT

systems

Timbrook T, et al. J Clin Microbiol. 2015;53(7):2371-2373.

SUMMARY

• RDT, such as ePlex BCID, in bloodstream infections may impact mortality risk

when combined with antimicrobial stewardship

• RDT in BSIs are associated with decreased the time to effective therapy and

the length of stay

• RDT should be considered as part of the standard of care in patients with BSIs

SUMMARY

• Gram-negative resistance is increasing nationally in the United States

• ePlex BCID is designed to provide clinically impactful results for patients with

bloodstream infections

• ePlex BCID offers advantages in gram-negative resistance detection along

with polymicrobial BSI detection

ANALYTICAL AND CUSTOMER CLINICAL TESTING SUMMARY

In-House Clinical Sample Testing Summary

• More than 1300 samples tested across all 3 panels with high concordance*

– GP panel: 96% concordance

– GN panel: 98% concordance

– FP panel: 99% concordance

• ePlex detected several organisms that were missed or called incorrectly by

reference method (culture), as verified by sequencing

• 128 resistance genes detected and verified by qPCR

– 25 mecA and 22 vanA resistance genes

– 81 gram-negative resistance markers; including CTX-M, OXA and KPC

*After discordant resolution; Off-panel organisms/samples and samples that were not tested for discordant resolution were removed from analysis

Strong performance observed in clinical sample testing across all 3 panels


Broad Inclusivity of Blood Culture Bottle Types/Brands

Company Brand Blood Culture Bottle Type

BD BACTEC Plus Aerobic/F

BD BACTEC Standard/10 Aerobic/F

BD BACTEC Standard Anaerobic/F

BD BACTEC Plus Anaerobic/F

BD BACTEC Peds Plus/F

BD BACTEC Lytic/10 Anaerobic/F

BD BACTEC MYCO/F Lytic*

bioMerieux BacT/ ALERT SA

bioMerieux BacT/ ALERT SN

bioMerieux BacT/ALERT MP*

bioMerieux BacT/ ALERT FA Plus

bioMerieux BacT/ ALERT FN Plus

bioMerieux BacT/ ALERT PF Plus

Thermo Scientific VersaTREK REDOX 1 Aerobic

Thermo Scientific VersaTREK REDOX 2 Anaerobic

• A multi-organism mix was tested for

each panel, with multiple replicates for

each of the 15 bottle types*

• 100% detection of all targets was

achieved

• *Myco/F Lytic and MP bottle types were

tested with BCID-FP assay only

• Bottles containing charcoal have not

been tested and are not recommended

for use with ePlex


No restriction on bottle use for clinical study testing; Full representation expected

External Clinical Sample Testing Summary

• 485 samples tested across all 3 panels at 4 clinical alpha/beta sites with

96% concordance (pre-discordant resolution)

– 3% false positives

– 1% false negatives

– Alpha and beta versions of panels: rate of false positives significantly improved in later

versions

• Resistance genes were shown to have high concordance with SOC results

– 74 resistance genes detected including: mecA, vanA, vanB, CTX-M, OXA, KPC and

NDM

– Resolution pending on one discordant sample (NDM/OXA); all others were in

agreement with reference method

High sensitivity and concordance observed across all panels and test sites


Combined data from 4 clinical alpha/beta sites

European Customer Evaluation

Other MDx Panel MALDI (culture) ePlex Result/Action

Not detected Propionibacterium acnes Propionibacterium acnes Faster de-escalation of antibiotics

Not detected Bacteroides fragilis Bacteroides fragilis Faster escalation of antibiotic treatment

E. coli

Enterobacter spp.

E. coli

Enterobacter cloacae

Klebsiella oxytoca

Klebsiella pneumoniae

E. coli

Enterobacter cloacae

complex

Klebsiella oxytoca

Klebsiella pneumoniae

Citrobacter species

Organisms missed by both alternate molecular

method & MALDI

Citrobacter miss by MALDI due to similar

appearance of isolates on plates

Not performed

(fungi)Candida glabrata Candida glabrata

MALDI required long subculture

Alternate molecular method not inclusive of

fungal targets

Staphylococcus

aureus

Not performed due to alternate

molecular result;

Retrospectively performed due

to pan GN call; Result:

Helicobacter pylori

Staph aureus + pan GN

No targets detected on GN

reflex test

Without ePlex GN pathogen would have been

missed

40 Clinical samples tested, 5 samples were selected by customer site as those with high potential clinical impact


In 13% of samples tested ePlex exhibited better results with high clinical impact related to

faster time to adjustment of antibiotic therapy and detection of additional targets

Summary

• The partnership of MDx and antimicrobial

stewardship can improve outcomes in sepsis and

BSI

• ePlex: True Sample-to-Answer System and

BCID solution

– Broad inclusivity across all 3 assays

– Strong analytical and beta testing performance

– Potential clinical impact shown in customer evaluation


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