GenMark Diagnostics. eplex BLOOD CULTURE IDENTIFICATION (BCID): DESIGNED TO IMPROVE PATIENT CARE AND CLINICAL OUTCOMES

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1 GenMark Diagnostics eplex BLOOD CULTURE IDENTIFICATION (BCID): DESIGNED TO IMPROVE PATIENT CARE AND CLINICAL OUTCOMES Association for Molecular Pathology (AMP) November 15, 2017

2 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.

3 For In Vitro Diagnostic Use. eplex : The True Sample-to-Answer Solution Designed for the Patient, Optimized for the Lab

4 1. Sepsis Fact Sheet, World Sepsis Day: 2. Institut Pasteur, Sepsis/Septicemia: 3. HCUP Statistical briefing #204; National Inpatient Hospital Costs: The Most Expensive Conditions by Payer, Kumar, et. al., (2006) Crit Care Med, Vol. 34, No IDSA: Better Tests Better Care, The Promise of Next Generation Diagnostics The Sepsis Challenge Sepsis is common, costly, and deadly and time is critical in ensuring positive outcomes Sepsis strikes ~30 million people worldwide each year 1 Resulting in a death every 3-4 seconds 2 Sepsis is the most expensive condition treated in U.S. hospitals, costing ~$18,000 per case 3 For every 1 hour delay in effective treatment, mortality increases by up to ~8% 4 and 20-30% of patients receive ineffective initial antibiotic therapy 5

5 The eplex Blood Culture Identification Solution Rapid, Comprehensive Identification of Sepsis-causing Organisms Gram Stain Conventional Blood Culture (~48-72h+) Blood Draw Bottle Culture Sub-Culturing Organism ID & Antibiotic Susceptibility Testing (ID/AST) t=0 8h 16h 24h 32h 40h 48h 56h 64h 72-96h Blood Draw 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 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 Product in development. Not available for sale in the U.S. Specifications subject to change.

6 eplex BCID Designed to be the most comprehensive BCID panels: for rapid, routine ID & resistance gene detection BCID Panel Gram- Positive Pathogen Targets Resistance Genes 20 4 Key Differentiators 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 Fungal Pathogen 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 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.

7 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

8 DISCLOSURES Dr. Timbrook serves on the speakers bureau and as an advisory consultant for BioFire Diagnostics, LLC and GenMark Diagnostics, Inc.

9 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

10 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.

11 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.

12 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.

13 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.

14 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.

15 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.

16 RESULTS RDT reduced risk of mortality (OR 0.66, 95% CI ) 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.

17 RESULTS Mortality decreased for gramnegative 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.

18 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.

19 RESULTS Length of stay decreased by 2.5 days Timbrook TT, et al. Clin Infect Dis. 2017;64(1):15-23.

20 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.

21 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

22 DO THE RESULTS OF THE META APPLY TO MY HOSPITAL? IT DEPENDS Inadequate therapy Escalation opportunities Time to effective therapy Mortality benefit Broadness of empiric therapy vs local resistance Overly broad therapy De-escalation opportunities Time to optimal therapy AE and collateral damage avoidance RDT and stewardship facilitated opportunities all around

23 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): Kang C, et al. AAC. 2005;49(2): Walker T, et al. JCM. 2016;54(7):

24 GRAM NEGATIVE RESISTANCE IS INCREASING Veterans Affairs data across 130 facilities and from Increasing nonsusceptibility such as ESBL E. coli (Right) Goto M, et al. EID. 2017;23(11):

25 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.

26 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 K. Pneumoniae 140 Ceftriaxone Any Ertapenem KPC Proteus spp. 57 Ceftriaxone Any Acinetobacter spp. 39 Meropenem OXA P. Aeruginosa 51 Cefepime Any K. Oxytoca 23 Ceftriaxone Any Enterobacter spp. 61 Cefepime Any Citrobacter spp. 10 Cefepime Any Detroit Medical Center Claeys KC, et al. ECCMID 2017.

27 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 K. Pneumoniae 58 Ceftriaxone Any Ertapenem KPC Proteus spp. 12 Ceftriaxone Any Acinetobacter spp. 14 Imipenem OXA P. Aeruginosa 43 Piperacillin- Tazobactam Any K. Oxytoca 9 Ceftriaxone Any Enterobacter spp. 33 Cefepime Any Citrobacter spp. 6 Cefepime Any University of Maryland Medical Center Claeys KC, et al. ECCMID 2017.

28 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.

29 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):

30 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

31 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

32 ANALYTICAL AND CUSTOMER CLINICAL TESTING SUMMARY

33 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 Strong performance observed in clinical sample testing across all 3 panels *After discordant resolution; Off-panel organisms/samples and samples that were not tested for discordant resolution were removed from analysis Product in development. Not available for sale in the U.S. Specifications subject to change.

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

35 External Clinical Sample Testing Summary Combined data from 4 clinical alpha/beta sites 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.

36 European Customer Evaluation 40 Clinical samples tested, 5 samples were selected by customer site as those with high potential clinical impact 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. Not performed (fungi) Staphylococcus aureus E. coli Enterobacter cloacae Klebsiella oxytoca Klebsiella pneumoniae Candida glabrata Not performed due to alternate molecular result; Retrospectively performed due to pan GN call; Result: Helicobacter pylori E. coli Enterobacter cloacae complex Klebsiella oxytoca Klebsiella pneumoniae Citrobacter species Candida glabrata Staph aureus + pan GN No targets detected on GN reflex test Organisms missed by both alternate molecular method & MALDI Citrobacter miss by MALDI due to similar appearance of isolates on plates MALDI required long subculture Alternate molecular method not inclusive of fungal targets Without eplex GN pathogen would have been missed 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 Product in development. Not available for sale in the U.S. Specifications subject to change.

37 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.