Antimicrobial Stewardship Certificate Program Antimicrobial Stewardship and Microbiology: Focus on Rapid Diagnostic Tests Karri A. Bauer, PharmD, BCPS (AQ-ID) Specialty Practice Pharmacist Infectious Diseases The Ohio State University Wexner Medical Center 1 Objectives Discuss the various rapid diagnostic technologies Evaluate the use of rapid diagnostic technologies on patient outcomes Determine considerations during the preimplementation, implementation, and postimplementation phases of rapid diagnostic technologies 2 1
Patient Case 62 year old male presented to the ED with cc of night sweats HPI: 3 day history of generalized fatigue, fevers and night sweats and nausea PMH: HTN, HLD, DM2 Physician Exam: Vitals: Temp 102.1 F, HR 110, BP 120/70, RR 20, 98% on RA Blood cultures obtained prior to initiation of vancomycin + piperacillin/tazobactam 3 General Principles Basic Microbiology Direct examination Culture/Gram stain Rapid biochemical tests Antibody and antigen detection Average time to deliver antimicrobial susceptibility testing results to a physician is 40 hours Numerous studies have demonstrated the impact of inappropriate antimicrobial therapy on mortality Kerremans JJ, Verboom P, Stijnen T, et al. Rapid identification and antimicrobial susceptibility testing reduce antibiotic use and accelerate pathogen-directed antibiotic use. J. Antimicrob Chemother 2008;61:428-435. 2
Dilemma with Conventional Methods Day 0 Day 1 Day 2 Day 3 Day 4 Positive Blood Culture Conventional Species ID Blood Draw Gram Stain Conventional Dx Empiric Rx Broad-spectrum Rx Targeted Rx Gram stain provides limited information. Cannot tell the species Culture is too slow Clinicians can t wait an additional 1-3 days to treat the infection Leads to inappropriate and ineffective therapy for some patients and unnecessarily therapy for others Introduction New advances in RDTs provide collaborative opportunities for antimicrobial stewardship programs (ASPs) Enhance functions of clinical microbiology laboratories Provide accurate organism identification Timely antimicrobial susceptibility testing data RDTs benefit the individual patient but also p increase the effectiveness of ASPs 3
Conventional/New Timeline Day 0 Day 1 Day 2 Day 3 Day 4 Positive Blood Culture Conventional Species ID Blood Draw Gram Stain Conventional Dx Empiric Rx Broad-spectrum Rx Targeted Rx Blood Draw Empiric Rx Positive Blood Culture Gram Stain Species ID Targeted Rx Rapid and accurate results on day 1 Supports decisions for appropriate and targeted therapy 1-3 days earlier than conventional methods Rapid Diagnostic Technologies 4
Polymerase Chain Reaction (PCR) Fluorescently labeled probe with primers Amplify target DNA Combines amplification and detection ti into 1 process Roche Molecular System s LightCycler SeptiFast MecA BD GeneOhm s Cdiff assay Cepheid s C. difficile assay Multiplex PCR Fluorescently labeled prove with > 1 set of primers Simultaneous detection of multiple organisms and resistant makers BD GeneOhm s Staph SR assay Cepheid s Xpert MRSA/SA blood culture and C. difficile/epi assays BioFire Diagnostics FilmArray 5
Nanoparticle Probe Nucleic acid extraction and PCR amplification Hybridization of target DNA to capture oligonucleotides on a microarray Signal amplification of hybridized probes provides an automated analysis Nanosphere s Verigene blood culture Grampositive and Gram-negative Verigene Gram Positive Blood Culture (BC-GP) Test Available Test Panels Species Staphylococcus aureus Staphylococcus epidermidis Staphylococcus lugdunensis Streptococcus anginosus Streptococcus agalactiae Streptococcus pneumoniae Streptococcus pyogenes Enterococcus faecalis Genus Staphylococcus spp. Streptococcus spp. Micrococcus spp. Listeria spp. Resistance meca vana vanb Enterococcus faecium 6
Verigene Gram Negative Blood Culture (BC-GN) Test Available Test Panels Species Genus Escherichia coli Acinetobacter spp. Klebsiella pneumoniae Citrobacter spp. Klebsiella oxytoca Enterobacter spp. Pseudomonas aeruginosa Proteus spp. Resistance CTX-M KPC NDM VIM IMP OXA FilmArray Blood Culture Identification Panel Available Test Panels Gram-Positive Enterococcus Listeria monocytogenes Staphylococcus aureus Streptococcus agalactiae Streptococcus pneumoniae Streptococcus pyogenes Streptococcus pyogenes Enterococcus faecalis Enterococcus faecium Gram-Negative Acinetobacter baumannii Haemophilus influenzae Neisseria meningitidis Pseudomonas aeruginosa Enterobacter cloacae Escherichia coli Klebsiella oxytoca Klebsiella pneumoniae Proteus spp. Serratia marcescens 7
Peptide Nucleic Acid Fluorescent In Situ Hybridization (PNA FISH) Synthetic oligonucleotide fluorescence-labeled probes Neutral charge of the synthetic molecule allows rapid hybridization to species-specific ribosomal RNA Fluorescence is detected using a fluorescence microscope QuickFISH (AdvanDx) Requires less setup time Faster turnaround time 90 minutes-20 minutes from positive blood cultures PNA FISH S. aureus Coagulase-negative staph Negative 8
Matrix-Assisted Laser Desorption- Ionization Time-of Flight Mass Spectrometry (MALDI-TOF) Mass spectrometry results in ionization and disintegration of a target molecule Mass/charge ratio of the resulting fragments is analyzed to produce a molecular signature Provides a profile or fingerprint of the organism Analyze thousands of samples/day from a variety of sources R id Di ti T h l i d Rapid Diagnostic Technologies and Antimicrobial Stewardship 9
Staphylococcus aureus S. aureus infections constitute a tremendous burden S. aureus bacteremia requires prompt microbiological diagnosis and antibiotic administration Vancomycin is often used empirically Use of antistaphylococcal -lactams have demonstrated superior clinical outcomes compared to vancomycin for MSSA infections Available RDTs Organism Detection time, h Technology Manufacturer Batching CLIA Designation Trade Name SA, CoNS 0.3 PNA QuickFISH AdvanDx No High S.aureus/CoN SPNA QuickFISH MRSA 01 0.1 Immunochromatography Alere No Moderate Alere PBP2a Scarborough, Inc. Culture Colony Test S. aureus 0.2 Immunochromatography Alere Scarborough, Inc. MSSA, MRSA No Not rated BinaxNOW S. aureus 20-26 Chromogenic medium BD No High BBL CHROMagar MRSA II MRSA 2 PCR Roche Diagnostics Yes High LightCycler MRSA g Staph SR MSSA, 2 Multiplex PCR BD GeneOhm Yes High BD GeneOhm MRSA, CoNS MSSA, MRSA, CoNS S. aureus, S. epidermidis 1 Multiplex PCR Cepheid No Moderate Xpert MRSA/SA BC 1 Multiplex Nanosphere No Moderate Verigene BC-GP MALDI-TOF MS and FilmArray can also be used. 10
meca Gene Testing and Intervention Carver PL, Lin S-W, DePestel DD, et al. Impact of meca gene testing and intervention by infectious diseases clinical pharmacists on time to optimal antimicrobial therapy for Staphylococcus aureus bacteremia at a university hospital. Clin Micro 2008;46:2381-2383. J Drug Therapy for Patients with MSSA Bacteremia Parta M, Goebel M, Thomas J, et al. Impact of an assay that enables rapid determination of Staphylococcus species and their drug susceptibility on the treatment of patients with positive blood culture results. Infect Control Hosp Epidemiol 2010;31(10):1043-1048. 11
Time to Antibiotic Switch 12 10 10 8 Days 6 4 3.6 p=0.02 p=0.15 4.5 Preintervention Postintervention 2 2 0 MSSA MRSA Bauer KA, West JE, Balada-Llasat JM, et al. An antimicrobial stewardship program s impact with rapid polymerase chain reaction methicillin Staphylococcus aureus/s. aureus blood culture in patients with S. aureus bacteremia. Clin Infect Dis 2010;51(9):1074-1080. RDT and Stewardship Intervention- Hospital Costs 80,000 70,000000 $69,737 60,000 50,000 40,000 30,000 20,000 10,000 0 Preintervention p=0.02 $48,350 Postintervention Bauer KA, West JE, Balada-Llasat JM, et al. An antimicrobial stewardship program s impact with rapid polymerase chain reaction methicillin Staphylococcus aureus/s. aureus blood culture in patients with S. aureus bacteremia. Clin Infect Dis 2010;51(9):1074-1080. 12
Coagulase-Negative Staphylococci spp. Often considered a contaminant Multiple positive blood cultures require therapy Clinicians often determine the positive blood cultures to represent contamination ASP PharmD Interventions for CoNS Using Rapid PCR Discontinuation of antistaphyloccal antibiotics, hours Total antibiotic exposure, days Infection-related LOS, days Preintervention Postinterventio n 57.7 25.7 0.005 97.6 54.1 0.011 10 5.5 0.018 Infection-related costs $28,973 $20,635 0.144 Initiated vancomycin 7 (21%) P Wong JR, Bauer KA, Mangino JE, Goff DA. Antimicrobial stewardship pharmacist interventions for coagulasenegative staphylococci positive blood cultures using rapid polymerase chain reaction. Ann Pharmacother 2012; 46(11): 1484-1490. 13
Assessment of PNA FISH CoNS in the Absence of Stewardship Intervention Holtzman C, Whitney D, Barlam T, et al. Assessment of impact of peptide nucleic acid fluorescence in situ hybridization of rapid identification of coagulase-negative staphylococci in the absence of antimicrobial stewardship intervention. J Clin Micro 2011;49(4):1581-1582. Enterococci spp. 3 rd most commonly isolated healthcareassociated organism Intrinsically resistant to many antibiotics May acquire additional resistant determinants VRE bacteremia associated with suboptimal patient outcomes Empiric therapy includes vancomycin, p py y, daptomycin, or linezolid 14
Available RDTs Organism Detectio Technology Manufactur Batchin CLSI Trade n time, h er g Designation Name E. faecalis, E. faecium E. faecalis, E. faecium (also detects VRE) 0.5 PNA QuickFISH AdvanDx No High Enterococcu s faecalis/oe PNA QuickFISH 2.5 Multiplex PCR Nanosphere No Moderate Verigene BC- GP MALDI-TOF MS and FilmArray can also be used. PNA FISH for Enterococcal Bactermia 50 45 40 35 30 25 20 15 10 5 0 45% p=0.04 26% p<0.001 001 3.1 1.3 Time to therapy (days) 30-day mortality (%) Preintervention Postintervention Forrest GN, Roghmann MC, Toombs LS, et al. Peptide nucleic acid fluorescent in situ hybridization for hospital-acquired enterococcal bacteremia: delivering earlier effective antimicrobial therapy. Antimicrob Agents Chemother 2008;52:3558-3563. 15
Gram-Negative Organisms Top healthcare priority Suboptimal patient outcomes Increased LOS, mortality, and healthcare costs Increased number are multidrug-resistant Limited treatment options Available RDTs Organism E. coli, K. pneumoniae, K. oxytoca, P. aeruginosa, S. marcescens, Acinetobacter spp., Proteus spp., Citrobacter spp., Enterobacter spp. E. coli, P. aeruginosa, K. pneumoniae Detectio n time, h Technology Manufactur er Batchin g CLSI Designation Trade Name 2.5 Multiplex PCR Nanosphere No Moderate Verigene BC- GN 0.5 PNA QuickFISH AdvanDx No High GNR Traffic Light PNA QuickFISHs E. coli, K. 1 Multiplex PCR BioFire Yes Moderate FilmArray pneumoniae, K. oxytoca, P. aeruginosa, A. baumannii, Enterobacter spp., Proteus spp, S. marcescens, H influenzae, N. meningitidis Diagnostics MALDI-TOF MS can also be used. System and Panels 16
PNA FISH Distinguishes P. aeruginosa from E. coli or K. pneumoniae after the recognition of Gramnegative bacilli of positive blood cultures Provides a key opportunity for stewardship programs to deescalate therapy Combination therapy Antipseudomonal therapy Integrating Rapid Pathogen Identification and ASP Length of Stay and Cost Outcomes in Survivors Outcome Preintervention cohort Intervention cohort P Hospital LOS 11.9 ± 9.3 9.3 ± 7.6.01 Hospital LOS after BSI onset 9.9 ± 7.1 8.1 ± 6.4.01 ICU LOS 7.3 ± 8.5 6.3 ± 8.7.05 ICU LOS after BSI onset Total hospital costs 6.1 ± 6 4.9 ± 6.7.09 $45,709 ± $61,806 $26,162 ± $28,996.009 Perez KK, Olsen RJ, Musick WL, et al. Integrating rapid pathogen identification and antimicrobial stewardship significantly decreases hospital costs. Arch Pathol Lab Med 2013;137(9):1247-1254. 17
Impact of Rapid Organism Identification Using MALDI-TOF % of Patients 25 30-Day All-Cause Mortality 20 20.3% 20 15 15 10 5 p=0.021 12.7% Days 10 5 14.2 Length of Stay p=0.0661 11.4 0 Preintervention Intervention 0 Preintervention Intervention Huang AM, Newton D, Kunapuli A. et al. Impact of rapid organism identification via matrix-assisted laser desorption/ionization time-of-flight combined with antimicrobial stewardship team intervention in adult patients with bacteremia and candidemia. Clin Infect Dis 2013;57(9):1237-1245. Impact of MALDI-TOF and ASP Intervention in Patients with A. baumannii Infections Hours 90 80 70 60 50 40 30 20 10 0 75 77.7 p=<0.01 p=<0.01 36.6 28 Time to effective therapy Time to effective therapy > 0 Preintervention Intervention Wenzler E, Goff DA, Mangino JE, Reed EE, Wehr A, Bauer KA. Impact of rapid identification of Acinetobacter baumannii via matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) and antimicrobial stewardship intervention in patient with pneumonia and/or bacteremia. European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Barcelona, Spain May 2014. 18
Candida spp. 4 th most most common cause of nosocomial bloodstream infections Time to positive blood culture and species identification can take several days Increase in the amount of time to effective antifungal therapy and hospital mortality RDTs for Candida spp. Rapid diagnostic T2Candida assay Candida species detected C. albicans, C. parapsilosis, C. krusei, C. glabrata, C. tropicalis MALDI-TOF All MS PNA-FISH C. albicans, C. parapsilosis, C. glabrata, C. krusei, C. tropicalis Date test is performed Day of blood culture Day of yeast identification Day of yeast identification Sensitivity Specificit y Positive predictive value 98% 98% 91% 94% 100% 94% 98% 98% 99% 19
T2 Candida Assay Magnetic resonance (MR) PCR Hybridization of DNA Probe-decorated nanoparticles Nanosphere microclusters Large changes in sample s T2MR signal Identifies 5 species of Candida Directly from whole blood Limits of detection-1 CFU/mL Rapid results 3 hours 98% positive agreement and 100% negative agreement Impact of PNA FISH on Mortality and Hospital Costs Clinical and Economic Outcomes Outcome No PNA FISH PNA FISH P Time to appropriate 6.2 2.3 <0.001 therapy, days All cause mortality 26.8% 7.7% 0.14 ICU mortality 41.7% 5.9% 0.02 Cost avoidance > $2.2 million/year Gamage DC, Olson DP, Stickell LH. Significant decreases in mortality and hospital costs after laboratory testing with PNA FISH. In: 51 st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL, September 2011. 20
Community Hospital Experienced with PNA FISH Length of stay (LOS) costs Daily LOS cost per patient LOS cost savings/patient t Patients with LOS Reduction C. glabrata All yeast $2,607 $33,891 11 $2,607 $15,642 21 Total LOS cost savings $372,801 $328,482 C. albicans/c. glabrata $7,790 $7,790 PNA FISH Costs Net benefit to hospital per patient $34,261 $15,769 Net benefit to hospital per day $2,635 $2,628 Annual net benefit e to hospital $196,633 $172,774 Length of time between yeast detection in blood culture and identification to the species level was decreased significantly (p=0.001) For patients with candidemia caused by C. glabrata, LOS decreased significantly (p=0.008) and significant difference in time to appropriate antifungal therapy (p=0.03) Rush T, Verma P. Do rapid results with the C. albicans/c. glabrata PNA FISH assay have an impact on patient management? A community hospital experience. In: 111 th Annual ASM Meeting, New Orleans, LA 21-24 May 2011:2563. Candidemia-Time to Positivity 162 patients with candidemia 58 ± 17 years Average time to yeast identification 2.22 ± 13days 1.3 Average time to start antifungal therapy 3.5 ± 2.1 days Candida Species Time to Positivity Days (mean ± SD) C. albicans 1.7 ± 1.0 C. glabrata 2.6 ± 1.5 C. tropicals 1.4 ± 1.1 C. parapsilosis 2.2 ± 0.89 Aitken SL, Beyda ND, Shah DN, et al. Clinical practice patterns in hospitalized patients at risk for invasive candidiasis: role of antifungal stewardship programs in the era of rapid diagnostics. Annals of Pharmacotherapy 2014;48(6): 683-690. 21
Time to Antifungal Initiation- Comparison of RDTs erapy Days to initiation of th 4 3.5 3 2.5 2 1.5 1 0.5 0 0.6±0.2 2.5±1.4 2.6±1.3 T2Candida MALDI TOF MS PNA FISH Rapid Diagnostic Test Use of T2Candida on the day of the blood culture resulted in 3136 to 6078 fewer doses of echinocandins annually per 5000 patients Aitken SL, Beyda ND, Shah DN, et al. Clinical practice patterns in hospitalized patients at risk for invasive candidiasis: role of antifungal stewardship programs in the era of rapid diagnostics. Annals of Pharmacotherapy 2014;48(6): 683-690. Clostridium difficile Increasingly challenging infection Increases in severity of disease, clinical failure, and recurrences Epidemiology has changed NAP1/BI/027 22
Available RDTs Detection time, h Technolog y Manufacturer Batching Automate d CLSI Designation Trade Name 1 LAMP Meridian Yes Yes Moderate Illumigene Bioscience C. difficile 2 PCR BD GeneOhm Yes Yes Not rated BD GeneOhm Cdiff Assay 0.5 Multiplex PCR 0 5 utpe PCR Cepheid No Yes Moderate Xpert C. difficile 0.75 Multiplex Cepheid e No Yes Moderate Xpert 3 PCR Gen-Probe Prodesse C. difficile/ep i Yes Yes Not rated ProGastro Cd Assay Important Considerations PCR technology is more sensitive Rate of positive tests can more than double Important t to educate medical staff and hospital administration Implement strict criteria for testing > 3 unformed watery stools in a 24-hour period Formed stool rejected unless lab notified of ileus Samples should not be sent as test of cure 23
Preimplementation DO YOUR HOMEWORK-BEST DATA IS YOUR OWN DATA Organisms Prevalence Problematic Reportable Timing of results Real-time Batch Sensitivity/specificity Purchase/lease Physical space Complexity Resources for clinical and economic outcomes Implementation Education Timing Real time Batch Communication of results Pharmacist/physician resources Pharmacist/physician role Intervention documentation/acceptance rate 24
Postimplementation Workflow Education Documentation/Justification Time to effective/optimal therapy Time to discontinuation or de-escalation Time to ID consult Repeat blood cultures 30-day readmission Length of stay Hospital cost of infection Hospital cost Conclusions Collaboration between microbiology and stewardship will continue to grow Innovative technology Game of speed Microbiologist and stewardship justification Clinically and economically 25