Rapid Diagnostic Testing RDT and Antimicrobial Stewardship South

Rapid Diagnostic Testing (RDT) and Antimicrobial Stewardship South Peninsula Hospital

Goals of Rapid Diagnostic Testing (RDT) • Decreases time to identification of pathogen from days to hours • Can distinguish between viral vs bacterial infections • Allows streamlining to appropriate therapy • Facilitate the decision about whether or not to prescribe abx • Prevent the use of unnecessary antibiotics • Facilitates de-escalation • Decreased antimicrobial resistance • Many studies have shown decreased • • . Duration of illness Length of stays Costs 30 -day all cause mortality

Impacts of rapid diagnostic testing in optimizing antimicrobial selection § Source: adapted from Goff, DA et al. (2012) Using rapid diagnostic tests to optimize antimicrobial selection in antimicrobial stewardship programs. Pharmacother 32(8): 677 -687.

Rapid Diagnostic tests Gram-positives, Gram-Negatives, Yeast • PCR (polymerase chain reaction) • Gene. Xpert (Cepheid); Film. Array (Biofire) & others • Turnaround time @60 min • PNA FISH (peptide nucleic acid fluorescence in situ hybridization) • GNR Traffic Light PNA FISH (Advan. Dx), Yeast Traffic Light PNA FISH (Advan. Dx) • Turnaround time @90 min • Nucleic Acid • Verigene (Nanosphere) • Turnaround time @120 – 150 min • MALDI-TOF matrix-assisted laser desorption ionization-time of flight • MALTI Biotyper (Bruker Daltonics); VITEK MS (bio. Merlieux) • Turnaround time 10 -30 min; very expensive; no resistance markers

Bio. Fire Diagnostics Over 20 Years of Innovations 2000 Applied PCR • Bio. Threat Testing • Food Testing 1990 Idaho Technology, Inc. 1996 Molecular Biology Tools • Light. Cycler® Film. Array. TM 2011: Respiratory Panel 2013: Blood Culture Identification Panel 2014: Gastrointestinal Panel

Film. Array: The Fastest Way to Better Results Easy • 2 minutes of hands-on time Fast • Run time of about 1 hour Comprehensive • Tests for a variety of pathogens that cause respiratory, blood, and gastrointestinal infections, as well antimicrobial resistance genes

Film. Array: The Fastest Way to Better Results – Comprehensive – Panels cover a wide range of targets involved in causing respiratory, bloodstream, and gastrointestinal infections Respiratory Panel Blood Culture Identification Panel Gastrointestinal Panel 20 27 22 targets • 3 bacteria • 17 viruses targets • 19 bacteria • 5 yeast • 3 antibiotic resistance genes • 13 bacteria • 5 viruses • 4 parasites

Respiratory Panel (RP) Viruses Adenovirus Coronavirus HKU 1 Coronavirus NL 63 Coronavirus 229 E Coronavirus OC 43 Human Metapneumovirus Human Rhinovirus/Enterovirus Influenza A/H 1 Influenza A/H 3 Influenza A/H 1 -2009 Influenza B FDA-cleared for the first time. Parainfluenza 1 Parainfluenza 2 Parainfluenza 3 Parainfluenza 4 Respiratory Syncytial Virus Bacteria Bordetella pertussis Chlamydophila pneumoniae Mycoplasma pneumoniae

Blood Culture Identification (BCID) Panel Gram+ Bacteria Enterococcus Listeria monocytogenes Staphylococcus S. aureus Streptococcus S. agalactiae S. pyogenes S. pneumoniae Gram- Bacteria Acinetobacter baumannii Haemophilus influenzae Neisseria meningitidis Pseudomonas aeruginosa Enterobacteriaceae Enterobacter cloacae complex Escherichia coli Klebsiella oxytoca Klebsiella pneumoniae Antibiotic Resistance Proteus mec. A – methicillin resistant van A/B – vancomycin resistant Serratia marcescens KPC – carbapenem resistant FDA-cleared for the first time. Yeast Candida albicans Candida glabrata Candida krusei Candida parapsilosis Candida tropicalis

The Film. Array BCID Panel Provides Faster Results § For use on blood culture bottles that are: – Flagged as positive by a continuously monitoring blood culture instrument – Positive by Gram stain examination – 100 μL sample required The Film. Array Pathogen ID Blood Draw Blood Culture Positive Gram Stain Approximately 1 h Standard Testing 12– 72 h 5 min Pathogen ID Antimicrobial Susceptibility Testing 24– 72 h • In a clinical study, organisms covered by the BCID panel were detected 60% faster than organisms not included in the BCID panel (21. 67 vs 53. 92 hours, respectively)1 BCID=blood culture identification; ID=identification. 1. Altun O et al. J Clin Microbiol. 2013; 51: 4130 -4136.

Gastrointestinal (GI) Panel Bacteria Parasites Campylobacter (jejuni, coli, and upsaliensis) Clostridium difficile (Toxin A/B) Plesiomonas shigelloides Salmonella Vibrio (parahaemolyticus, vulnificus, and cholerae) Vibrio cholerae Yersinia enterocolitica Cryptosporidium Cyclospora cayetanensis Entamoeba histolytica Giardia lamblia Diarrheagenic E. coli/Shigella Enteroaggregative E. coli (EAEC) Enteropathogenic E. coli (EPEC) Enterotoxigenic E. coli (ETEC) Shiga-like toxin-producing E. coli (STEC) E. coli O 157 Shigella/Enteroinvasive E. coli (EIEC) FDA-cleared for the first time. Viruses Adenovirus F 40/41 Astrovirus Norovirus GI/GII Rotavirus A Sapovirus (I, IV, and V)

The Film. Array Panels The Future of Film. Array Meningitis Panel GI Panel BCID Panel Respiratory Panel FDA-Cleared May 2014 Lower Respiratory Panel In development FDA Clearance Anticipated 2015 FDA-Cleared June 2013 FDA-Cleared May 2011 The Film. Array Platform Panels BCID=blood culture identification; GI=gastrointestinal.

Meningitis/Encephalitis Panel: In Development Bacteria Viruses Escherichia coli K 1 Haemophilus influenzae Listeria monocytogenes Neisseria meningitidis Streptococcus agalactiae Streptococcus pneumoniae Cytomegalovirus (CMV) Enterovirus Epstein-Barr virus (EBV) Herpes simplex virus 1 (HSV-1) Herpes simplex virus 2 (HSV-2) Human herpesvirus 6 (HHV-6) Human parechovirus Varicella zoster virus (VZV) Yeast Cryptococcus gattii Cryptococcus neoformans

Taking Out the Guesswork: Easy-to-Interpret Results • The Film. Array software processes the data and creates a positive or negative call for each organism, providing the results in a simple and easy-to-read report

Clinical Benefits: Respiratory Panel (RP)

Clinical and Economic Consequences of Respiratory Infections In the United States 25, 000 1, 026, 476 $40 billion family physician consultations 1 hospitalizations due to upper respiratory tract infections between 1998 and 20062 estimated annual cost of non-influenza– related viral respiratory tract infections 3 1. Heikkinen T, Järvinen A. Lancet. 2003; 361: 51 -59. 2. Christensen KLY et al. Clin Infect Dis. 2009; 49: 1025 -1035. 3. Fendrick AM et al. Arch Intern Med. 2003; 163: 487 -494.

Unmet Needs in Diagnosing and Treating Respiratory Infections Of influenza-positive children 43% were hospitalized within Of outpatients with confirmed RSV infection two days of symptom onset 1. 5% but only received antiviral treatment 1 a specific 3% received diagnosis of RSV infection 2 RSV=respiratory syncytial virus. 1. Poehling KA et al. Pediatrics. 2013; 131(2): 206 -216. 2. Hall CB et al, N Engl J Med. 2009; 360(6): 588 -598.

A Fast and Accurate Diagnosis Can Ensure Appropriate Treatment Uncertain diagnosis is one of the primary reasons that physicians do not prescribe antivirals 1 Timeliness Influenza treatment should be initiated within 48 hours after symptom onset 2 Timely treatment is associated with shorter hospitalizations among critically ill children, faster resolution of illness, less parental work absenteeism, reduced risk of developing otitis media 1 1. Poehling KA et al. Pediatrics. 2013; 131(2): 206 -216. 2. Harper SA et al. Clin Infect Dis. 2009; 48(8): 1003 -1032. Accuracy The choice of influenza antiviral may depend on the viral subtype 2 Accurate diagnosis of the influenza subtype can inform treatment decisions 2

A Fast and Accurate Diagnosis Can Improve Care for Elderly Patients Respiratory infections, such as RSV, HMPV, and influenza are difficult to differentiate in older adults due to similar clinical presentations and seasonal patterns 1 Timeliness Accuracy Timely antiviral treatment can improve patient outcomes and reduce mortality Early use of antivirals is associated with rapid viral clearance, fewer symptoms, reduced progression to pneumonia, and reduced mortality 2 Sensitivity of rapid tests and viral culture is lower among older patients 1 Accurate diagnostic tests are required to verify illnesses that cannot be confirmed by symptoms or current tests HMPV=human metapneumovirus; RSV=respiratory syncytial virus. 1. Widmer K et al. J Infect Dis. 2012; 206: 56 -62. 2. Ison MG. Antiviral Ther. 2007; 12(4 Pt B): 627 -638.

Clinical Benefits of Rapid and Accurate Diagnosis § The Film. Array RP provides rapid and accurate results with a turnaround time of ~1 hour – FDA cleared for use with nasopharyngeal swab samples (300 μL volume required) § Rapid identification of the causative agent of respiratory infections can improve patient management by: § Informing timely and effective antibiotic or antiviral therapy § Preventing secondary spread of infection § Shortening hospital stays RP=respiratory panel. Loeffelholz MJ et al. J Clin Microbiol. 2011; 49(12): 4083 -4088. § Reducing costs of unnecessary tests

A Fast and Accurate Diagnosis Can Reduce Misuse of Antibiotics An accurate diagnosis reduces overprescribing of antibiotics and prevents antibiotic resistance 1 – Each year, over 10, 000 courses of antibiotics are prescribed for viral conditions 2 – An estimated 55% of antibiotic prescriptions for ARTIs are unnecessary 3 Antibiotic Prescriptions for Adults With Nonpneumonic Acute Respiratory Tract Infections, by Diagnosis 3 63% of all patients with an ARTI received an antibiotic, Narrow-Spectrum Antibiotics including 29% who received a narrow-spectrum agent and Broad-Spectrum Antibiotics 34% who received a broad-spectrum agent ARTI=acute respiratory tract infection; URTI=upper respiratory tract infection. 1. Smolinski M et al. Microbial Threats to Health: Emergence, Detection, and Response. Washington, DC: The National Academies Press; 2003. 2. Centers for Disease Control and Prevention. www. cdc. gov/getsmart/campaign-materials/about-campaign. html. Accessed February 21, 2013. 3. Steinman MA et al. JAMA. 2003; 289(6): 719 -725.

Film. Array Can Help Save Money and Generate Revenue § Implementation of Film. Array RP in a core laboratory to provide service 24 hours a day, 7 days a week for respiratory virus diagnosis EMERGENCY ROOM 71% samples collected from emergency departments RP=respiratory panel. Xu M et al. Am J Clin Pathol. 2013; 139: 118 -123. 900 hrs emergency room time saved ~$8, 723, 700– $11, 968, 200 additional revenue

Clinical Benefits: Blood Culture Identification (BCID) Panel

Septicemia: Mortality and Costs • Septicemia remains a leading cause of death in both adults and infants in the United States, and is the leading cause of death in noncardiac ICUs 1, 2 Sepsis 2 Mortality 2 $24. 3 billion 2 >1. 1 million cases annually >40% annual cost ICU=intensive care unit. 1. Heron M. Nat Vit Stat Rep. 2012; 60: 1 -95. 2. Moore LJ, Moore FA. Surg Clin North Am. 2012; 92(6): 1425 -1443.

Challenges in Diagnosing Sepsis Early signs of sepsis are nonspecific and often missed, resulting in delays in treatment. 1 In a survey of 917 physicians, only 27% were able to correctly recognize sepsis. 2 Correct answers for each diagnosis (%) 100 80 60 40 20 0 SIRS Infection Sepsis Severe sepsis Septic shock SIRS=systemic inflammatory response syndrome. 1. Moore LJ et al. Surg Clin N Am. 2012; 92(6): 1425 -1443. 2. Assunção M et al. J Crit Care. 2010; 25(4): 545 -552. 25

Unmet Needs in Treating Sepsis 58% A retrospective cohort analysis of 760 patients with severe sepsis 1 In , therapy was delayed 31% received inappropriate antibiotic treatment 42% had resistance to the antibiotic administered Patients who progress to septic shock have a 7. 6% increase in mortality every 1. Shorr AF et al. Crit Care Med. 2011; 39(1): 46 -51. 2. Kumar A et al. Crit Care Med. 2006; 34(6): 1589 -1596. hour while not on appropriate therapy. 2

A Fast Diagnosis Can Ensure Timely Treatment, Which May Reduce Mortality Rate of Sepsis, Severe Sepsis, and Septic Shock 1 70 50 40 30 Mortality rate (%) 60 61% 42% 26% 20 10 0 Timely treatment is essential to prevent the progression of sepsis to septic shock and reduce mortality 1 -3 Infection/sepsis Severe sepsis 1. Alberti C et al, for the European Sepsis Study Group. Am J Respir Crit Care Med. 2005; 171(5): 461 -468. 2. Shorr AF et al. Crit Care Med. 2011; 39(1): 46 -51. 3. Moore LJ et al. Surg Clin North Am. 2012; 92(6): 1425 -1443. Septic shock

Mortality Rate in Septic Patients Cumulative mortality (%) 40 Mortality Rates for 29, 273 Patients by Blood Culture Result and Type of Bacteremia 1 Polymicrobial or fungemia Gram-positive Gram-negative Blood culture negative 30 20 10 0 0 30 60 90 Days of admission 120 150 180 Septic patients with polymicrobial infections have the highest mortality. 1 Polymicrobial infections have been detected in 41. 5% of HA infections, 28. 6% of CA infections, and 33. 8% of ICU-acquired infections. 2 CA=community-acquired; HA=hospital-acquired; ICU=intensive care unit. 1. Sogaard M et al. BMC Infectious Diseases. 2011; 11: 139. 2. Alberti C et al. Intensive Care Med. 2002; 28(2): 108 -121. 28

Clinical Benefits: The Film. Array Gastrointestinal (GI) Panel

Gastrointestinal Infections: Mortality and Costs § 211– 375 million episodes of diarrheal illness occur in the United States annually, resulting in: 73, 000 physician consultations $6 billion 1, 800, 000 3, 100 hospitalizations deaths Guerrant RL et al. Clin Infect Dis. 2001; 32: 331 -351. spent on medical care and lost productivity

Film. Array GI Panel: Potential Patient and Provider Benefits § § Rapid diagnosis of the causative agent of GI infections and appropriate treatment decisions can improve patient outcomes and decrease healthcare costs 1, 2 The Film. Array GI panel is easy to use, and provides rapid and accurate results in ~1 hour 3 Provider Provides more comprehensive testing 4 Informs improved quality of care 2 Guides appropriate follow-up 3 1. 2. 3. 4. Patient Fast results 3 Comprehensive coverage 3 Accurate pathogen identification 3 Shortened illness 1 Shorter hospital visits 2 Reduced morbidity 1 Prevents secondary transmission 1 Guerrant RL et al. Clin Infect Dis. 2001; 32: 334 -351. Nanosphere. Enteric Pathogens Test. www. nanosphere. us/products/enteric-pathogens-test. Accessed February 10, 2014. Film. Array GI [Instruction Booklet]. Salt Lake City, UT: Bio. Fire Diagnostics, LLC. Buss SN et al. J Clin Microbiol. 2013; 51: 3909.

RDT Intervention Examples • GI Panel • Pt on cipro & metronidazole for diarrhea; Rapid GI panel showed STEC – shiga like toxin producing E coli • • • STEC should not be treated with abx as it can precipitate hemolytic uremic syndrome Abx d/c’ed Several pts being treated with metronidazole for presumed C diff diarrhea; Rapid GI panel showed campylobacter • • Abx changed to levofloxacin 33 yo up here from Seattle visiting parents w diffuse watery diarrhea; thought she had gotten sick from kombucha tea at our Saturday market; Rapid GI panel showed vibrio species (not vibreo cholerae) • • Kachemak Bay oysters ? ? ? On interview the pt remembered she had eaten raw oysters in Seattle just prior to travel

RDT Intervention Examples • Blood culture • Vanco started empirically for ? ? sepsis; Rapid blood culture does not detect methicillin resistance • • Vanco d/c’ed; 2014 after implementation of ASP, BUT prior to Film. Array vanco use decreased by 7% Vanco use decreased by 20% in 2014 after implementation of Film. Array IV Rx abuser w hx of endocarditis empirically started on vanco based on hx • • Rapid blood culture ID’ed MRSA and Candida parapsilosis Fluconazole started; being able to identify the candida species aides in selection of antifungal; parapsilosis less susceptible to eichonocandins (micafungin)

RDT Intervention Examples • Strep rapid screen (illumigene) • 16 yo in the ED w severe pharyngitis; WBC 23; pt allergic PCN; MD thinks Grp A strep, so pt started on CFZ • • Rapid strep negative Fusobacterium 2 x as likely to cause pharyngitis in this age group Abx changed to clindamycin IV Intervention took place prior to patient even getting out of the ED to the floor • C diff rapid screen (GI Panel or illumigene) • Rapid C diff results used many times to either start treatment or discontinue empiric tx

RDT Intervention Examples • Pt on 6 wk daptomycin IV daily as OP for hardware infection; g+ cocci; pt had been on multiple abx • Propionibacterium acnes finally grew; slow growing g+ anaerobe; most labs don’t keep plates long enough for it to grow; gaining notoriety for causing hardware infections • Pt changed to ceftriaxone 2 g IV daily • Hospital cost savings $21, 000 vs $500 over the course of tx

Practical Notes • Utility & cost-effectiveness is dependent on clinician’s reacting to data • • These tests are of little value if the results are not acted on quickly Success depends on a close relationship between lab & pharmacy • All rapid test results, culture data (preliminary & final) printed to pharmacy printer • RPh contacts provider with suggestions for appropriate abx • SPHs antimicrobial stewardship program has been in place since January, 2014 • Medical staff very receptive to RPh recommendations and now frequently initiate contact with RPh for suggestions

Practical Notes • • SPH antimicrobial stewardship program started January 2014 with one RPh • # interventions, abx cost/inpt day, & abx burden all statistically significantly improved compared to no ASP 2015 a second trained RPh involved; Jan – Jun impact: • • • Interventions increased by 72% (p<0. 02) Antibiotic cost savings/inpt day increased by 64% (p<0. 02) Overall antimicrobial burden decreased by 4. 2% (p<0. 02) • No Clinical Decision Support System (CDSS) • Procalcitonin • • • Thera. Doc, Sentri 7, Med. Mined, Vigilanz Use computer algorithms to target potential antimicrobial interventions SPH is small so all done manually Medical staff so receptive to our suggestions we feel our timing is perfect for implementing procalcitonin testing Investigating cost

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