THE FAST AND THE SUSCEPTIBLE: RAPID DIAGNOSTICS IN INFECTIOUS - PowerPoint PPT Presentation

THE FAST AND THE SUSCEPTIBLE: RAPID DIAGNOSTICS IN INFECTIOUS DISEASE Brandon Dionne, PharmD, BCPS, AAHIVP Assistant Clinical Professor Northeastern University Clinical Pharmacy Faculty – Infectious Diseases Brigham and Women’s Hospital

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DISCLOSURES  Advisory Board – Roche Diagnostics

OBJECTIVES  Compare the different types of rapid microbiologic diagnostic tests (RDT) available  Explain the utility of RDTs for antimicrobial stewardship efforts  Describe the impact of RDTs on patient outcomes

WHY RAPID DIAGNOSTIC TESTING?  Time to appropriate antimicrobial therapy has a significant effect on morbidity and mortality  Increase in mortality of 7.6% for each hour delay in septic shock  Broad spectrum antibiotics may have collateral damage or may not be the most effective agent  Vancomycin has been shown to be inferior to β -lactam antibiotics for methicillin-susceptible Staphylococcus aureus (MSSA)  Antibiotic use is unnecessary or inappropriate in as many as 30-50% of cases Kumar A, et al. Crit Care M ed. 2006;34:1589-1596. Kim SH, et al. Antimicrob. Agents Chemother. 2008;52(1):192-197. Hecker MT, et al. Arch Intern Med 2003;163:972-978.

ANTIMICROBIAL STEWARDSHIP  Antimicrobial stewardship programs are multidisciplinary  Physician, pharmacist , epidemiologist, clinical microbiologist , infection preventionist, information systems specialist  Goals are to improve outcomes and minimize collateral damage  Secondary goal to lower costs  Prospective audit with feedback is a core strategy  Use of RDTs is suggested for respiratory and blood specimens Dellit TH, et al. Clin Infect Dis . 2007;44(2):159-177. Barlam TF, et al. Clin Infect Dis . 2016;62(10):e51-77

ANTIMICROBIAL DEVELOPMENT VS RESISTANCE 1 = Methicillin-resistant Total # New Antibacterial Agents Staphylococcus aureus (MRSA) 2 = Vancomycin-resistant Enterococci (VRE) 3 = Imipenem-resistant Pseudomonas aeruginosa 4 = Imipenem-resistant Acinetobacter baumanii 5 = Fluconazole-resistant Candida spp. Adapted from Septimus EJ, Owens RC. Clin Infect Dis 2011;53:S8-S14.

CURRENT RDTs  Currently available RDTs use a variety of methods for detection  Differing levels of complexity and turnaround times (TATs)  May be able to detect only a single organism or multiple organisms  Some can detect antimicrobial resistance  May be helpful in targeted therapy and de-escalation

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TIMELINE OF STANDARD DIAGNOSTICS  Basic microbiology  Culture  Gram stain  Colony isolation  Biochemical tests  Identification and susceptibility Goff DA, et al. Pharmacotherapy . 2012;32(8):677–687

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MALDI-TOF MS  Matrix-assisted laser desorption ionization – time of flight (MALDI-TOF) mass spectrometry (MS)  Can identify to either genus or species level  Very fast – 5 minutes to identification  Hardware is expensive  Individual tests are inexpensive http://www.sigmaaldrich.com/technical-documents/articles/biology/custom-dna-oligos-qc-analysis-by-mass-spectrometry.html

MALDI-TOFVS CONVENTIONAL METHODS  Quasi-experimental study of patients with gram negative bacteremia  46 hour reduction in time to de-escalation (p = 0.004)  36.7 hour improvement in time to effective treatment in patients with inactive therapy (p < 0.001)  Reduction in LOS by 2.6 days (p = 0.01) and cost by ~$20,000 (p = 0.009)  Quasi-experimental study of patients with bacteremia or candidemia  Decrease in time to effective antibiotic therapy (20.4 vs 30.1 hours; p = 0.021)  2.8 day decrease in mean LOS (p = 0.07)  Reduction in mortality from 20.3% to 14.5% (p = 0.02) Perez KK, et al. Arch Pathol Lab Med . 2013;137:1247-1254. Huang AM, et al. Clin Infect Dis . 2013;57:1237-1245.

MALDI-TOF MS Advantages Disadvantages  Can identify many different bacteria  High upfront cost and fungi  Requires pure colony  Not specific to a certain specimen  Lysing kits may allow detection directly from positive blood culture  Very easy to set up and quick to run  No susceptibility/resistance information

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PNA FISH  Peptide nuclueic acid fluorescence in situ hybridization  Can detect select gram positive, gram negative, and yeasts in 20 minutes  Reagents selected based on gram stain  Can detect polymicrobial infections

PNA QuickFISH PROCESS http://www.opgen.com/pathogenid/quickfish-products/

YEAST TRAFFIC LIGHT PNA FISH http://www.advandx.com/science/

YEAST PNA FISH VS CONVENTIONAL METHODS  Quasi-experimental study of patients with blood cultures positive for yeast  Decrease in mean time to targeted therapy from 2.3 to 0.6 days (p = 0.0016)  Mean time to species identification of 0.2 vs 4.0 days (p < 0.001)  Cost savings of about $415 per patient  Quasi-experimental study of patients with blood cultures positive for yeast  Decrease in caspofungin DDD from 8.7 to 3.2 in patients with C. albicans (p < 0.05)  Decrease in cost of about $1800 per patient  $1700 after accounting for cost of PNA FISH Heil EL, et al. Am J Health Syst Pharm. 2012;69:1910-1914. Forrest GN, et al . J Clin Microbiol . 2006;44(9):3381-3383.

S. aureus /CoNS PNA QuickFISH http://www.advandx.com/wp-content/uploads/2014/07/ADV-224-Revd-QF-Staph-Brochure-v5.pdf

S. aureus /CoNS PNA FISH VS CONVENTIONAL METHODS  Prospective, randomized, controlled study of patients with blood cultures positive for gram positive cocci in clusters (GPCC)  Reduction in mortality (16.8% vs 7.9%, p = 0.05)  Biggest change in ICU mortality (47.8% vs 9.5%, p = 0.01)  2 day decrease in duration of antimicrobial therapy and length of stay (LOS)  Retrospective cohort of patients with blood cultures positive for CoNS  Use of PNA FISH led to a significant reduction in LOS of 2 days (p < 0.05)  Non-significant difference in defined daily doses  Reduction in total cost of care by about $4000 per patient Ly T, et al. Ther Clin Risk Manag. 2008;4:637-640. Forrest GN, et.al. J Antimicrob Chemother. 2006;58:154-158.

E. faecalis /OE PNA QuickFISH

E. faecalis /OE PNA QuickFISHVS CONVENTIONAL METHODS  Quasi-experimental study of patients with blood cultures positive for gram positive cocci in pairs and chains  3 day reduction in identification of E. faecalis (1.1 vs 4.1 days; p < 0.001)  2.3 day reduction in identification of E. faecium (1.1 vs 3.4 days; p < 0.001)  Decreased time to appropriate therapy from 3.1 to 1.3 days (p < 0.001)  26% vs 45% 30-day mortality (p = 0.04) Forrest GN, et al. Antimicrob Agents Chemother. 2008;52:3558-3563.

GNR TRAFFIC LIGHT PNA QuickFISH http://www.opgen.com/pathogenid/quickfish-products/gram-negative-quickfish/

PNA FISH Advantages Disadvantages  Relatively inexpensive  More hands-on time for micro lab  Quick turnaround directly from  Limited in number of species that can positive blood culture be detected  No susceptibility/resistance data

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PCR  Polymerase chain reaction (PCR) is a type of nucleic acid amplification test (NAAT)  Detects genetic material of pathogen  Multiplex PCR (mPCR) can detect multiple organisms and/or resistance mechanisms https://www.thermofisher.com/ng/en/home/life-science/cloning/cloning-learning-center/invitrogen-school-of-molecular-biology/pcr-education/pcr-reagents-enzymes/pcr-cycling-considerations.html

PCR-BASED RDTs FOR DETECTING STAPHYLOCOCCUS Organism Time T echnology Batch Pure Auto- CLIA Trade Name (h) colony mated Complexity MRSA 2 PCR Yes No Yes High Roche LightCycler MRSA MSSA, MRSA, 2 Multiplex Yes No Yes High BD GeneOhm Staph CoNS PCR SR MSSA, MRSA, 1 Multiplex No No Yes Moderate Cepheid Xpert MRSA/SA CoNS PCR BC MSSA, MRSA 1 Multiplex No No Yes Moderate Cepheid Xpert MRSA/SA PCR SSTI Adapted from Bauer KA, et al. Clin Infect Dis . 2014;59(S3):S134-5145

XPERTVS CONVENTIONAL METHODS  Quasi-experimental study of patients with blood cultures positive for GPCC  55% vs 76% (p < 0.01) of patients without S. aureus bacteremia treated for S. aureus infection  5.2 vs 49.8 hours (p = 0.007) until MRSA treatment switched to MSSA treatment  Quasi-experimental study of patients with S. aureus bacteremia  Mean reduction in time to MSSA treatment of 1.6 d (p = 0.02)  Length of stay reduced by 6.2 days (p = 0.07)  Hospital costs reduced by $21,387 (p = 0.02) Parta M, et al. Infect Control Hosp Epidemiol. 2010;31(10):1043-1048. Bauer KA, et al. Clin Infect Dis. 2010;51(9):1074-1080.