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
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
Product in development. Not available for sale in the U.S. Specifications subject to change.
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
Product in development. Not available for sale in the U.S. Specifications subject to change.
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
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)
Timbrook TT, et al. Clin Infect Dis. 2017;64(1):15-23.
RESULTS
• Flow diagram of
included studies
• 5,920 patients
included among
31 studies
Timbrook TT, et al. Clin Infect Dis. 2017;64(1):15-23.
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%)
Timbrook TT, et al. Clin Infect Dis. 2017;64(1):15-23.
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
Timbrook TT, et al. Clin Infect Dis. 2017;64(1):15-23.
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.
Timbrook TT, et al. Clin Infect Dis. 2017;64(1):15-23.
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
Timbrook TT, et al. Clin Infect Dis. 2017;64(1):15-23.
RESULTS
• Mortality decreased for gram-
negative and gram-positive
organisms
• No mortality reduction found for
candidemias but sample was small
Timbrook TT, et al. Clin Infect Dis. 2017;64(1):15-23.
RESULTS
• Time to effective
therapy
decreased by 5
hours
• Among VRE,
decreased by
27 hours
Timbrook TT, et al. Clin Infect Dis. 2017;64(1):15-23.
RESULTS
• Length of stay
decreased by
2.5 days
Timbrook TT, et al. Clin Infect Dis. 2017;64(1):15-23.
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
Timbrook TT, et al. Clin Infect Dis. 2017;64(1):15-23.
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.
DOES GRAM NEGATIVE RESISTANCE DETECTION OFFER ACTIONABLE RESULTS IN REAL-WORLD SETTINGS?
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
DOES GRAM NEGATIVE RESISTANCE DETECTION OFFER ACTIONABLE RESULTS IN REAL-WORLD SETTINGS?
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
DOES GRAM NEGATIVE RESISTANCE DETECTION OFFER ACTIONABLE RESULTS IN REAL-WORLD SETTINGS?
• 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
Product in development. Not available for sale in the U.S. Specifications subject to change.
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
Product in development. Not available for sale in the U.S. Specifications subject to change.
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
Product in development. Not available for sale in the U.S. Specifications subject to change.
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
Product in development. Not available for sale in the U.S. Specifications subject to change.
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
Product in development. Not available for sale in the U.S. Specifications subject to change.