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Incorporating Rapid Diagnostic Microbiology Testing into Antimicrobial Stewardship M I C H E L L E P E A H O TA , P H A R M D , B C P S Objectives 1. Describe recent advancements in microbiology rapid diagnostic testing 2. Review current literature describing the impact of rapid diagnostic testing on antimicrobial stewardship and patient outcomes 3. Evaluate the incorporation of rapid diagnostics into an antimicrobial stewardship program to identify positive blood cultures Case 1 HPI: MJ is a 68 YO M end stage renal disease (ESRD) on hemodialysis (HD) (MWF) presents to ER from HD clinic after he was noted to have chills, rigors, and a fever of 102.1. In the ER he is lethargic and febrile. The ER sent 2 sets of blood cultures. PMH: ESRD on HD (HD catheter), Diabetes, Hypertension Allergy: penicillin (GI upset) Medications: Insulin glargine, metoprolol, zolpidem prn, docusate, senna Social history: Denies IVDA, no tobacco, no alcohol Case 1 The microbiology lab performed a gram stain and notifies the ER that both sets of MJ’s blood cultures have gram positive cocci in clusters. Which empiric antibiotic should be started? The microbiology lab set up MJ’s blood cultures on the BioFire FilmArray. The team was notified that the patient’s blood cultures are growing Staphylococcus aureus mecA negative. What (if any) changes should be made to MJ’s antibiotic regimen? Antimicrobial Stewardship Program (ASP) ID Physician Clinical Pharmacist Information Systems Specialist Microbiology Epidemiologist Early Antibiotic Administration Septic shock Acute organ dysfunction secondary to documented or suspected infection Major health care issue Effective antimicrobial administration Impact on mortality Timing is important Selection is important Early Antibiotic Administration . Kumar et al., Crit Care Med. 2006 Antibiotic Selection Initial selection should be broad enough to cover all likely pathogens Drug allergies Local susceptibility patterns Comorbidities Patient history Empiric therapy should be tailored to local susceptibility patterns Antimicrobial Exposure De-escalate when causative pathogen has been identified Microbiology Alert of positive culture Organism identification (ID) Antimicrobial susceptibility Traditional Microbiologic Methods for ID De-escalate or escalate therapy Initiate empiric therapy Gram stain Plate culture Set up antimicrobial susceptibilities Incubate Perform biochemical tests/culture based-technique Antimicrobial Susceptibility Definitive therapy Obtain ID Time Required to Deliver Routine Bacterial Culture Results Goff DA, et al. Pharmacother. 2012. Rapid Molecular Identification Methods Rapid methods that can deliver results minutes to a few short hours Several commercially available tests Enable timely antimicrobial optimization “Game changer” Rapid Molecular Identification Methods Polymerase chain reaction (PCR) Multiplex PCR Nanoparticle Probe Technology (Nucleic Acid Extraction and PCR Amplification) Peptide Nucleic Acid Fluorescent In Situ Hybridization Matrix-Assisted Laser Desorption/Ionization Time-of- Flight Mass Spectrometry (MALDI-TOF) MALDI-TOF Matrix-assisted laser desorbtion/ionization time-of-flight mass spectrometry Ability to analyze thousands of samples per day Multiple sources: blood, respiratory, urine, wound Identifies bacteria based on unique protein sequences Ionization and disintegration of target molecule Mass/charge ratio analyzed Mass spectrum provides a profile of the organism compared to those of well-characterized organism in a library Process ~1 hour MALDI-TOF MALDI-TOF Able to reduce time to organism ID by 24-36 hours Can not detect resistance mechanisms Limitation in organism ID at species level Streptococci, Shigella, Propionibacterim Peptide Nucleic Acid Fluorescent In Situ Hybridization PNA-FISH One of the first commercially available rapid diagnostic tests for blood Synthetic oligonucleotide fluorescence-labeled probes Hybridization to species-specific ribosomal RNA Fluorescence is detected using a fluorescence microscope Peptide Nucleic Acid Fluorescent In Situ Hybridization Organism detection S. aureus, coagulase-negative staphylococci (CoNS) Enterococci Gram negative rods (Pseudomonas, Klebsiella, E.coli) Candida (C. albicans, glabrata, C. parapsilosis, C. krusei, C. tropicalis) mecA probe (MRSA) Peptide Nucleic Acid Fluorescent In Situ Hybridization Testing time 20 minutes - 2 hours Robust clinical experience Limited targets Limited detection of resistance mechanisms Polymerase Chain Reaction PCR Uses fluorescent probe with 2 primers Amplify target DNA Amplification and detection in 1 process Multiplex PCR >1 set of primers Simultaneous detection of multiple organism and resistance patterns Polymerase Chain Reaction (PCR) https://www.youtube.com/watch?v=0HCWmD7Mv8U Nucleic Acid Amplification Utilizes a fluorescently labeled piece of target DNA Use of 2 primers Amplify a piece of target DNA Amplification and detection Nanosphere VerigeneTM BioFire FilmArrayTM Blood culture identification (BCID) panel FilmArray BCID tests for 24 organims Gram positive Gram negative Yeast BioFire FilmArrayTM Micro Organism Gram positive Enterococcus, L. monocytogenes, Staphylococcus, S. aureus, Streptococcus, S. agalactiae, S. pyogenes, S. pneumoniae Gram Negative Acinetobacter baumanni, Haemophilus influenzae, Nisseria meningitidis, Pseudomonas aeruginosa, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, K. pneumoniae, Proteus, Serratia marcescens Yeast Candida albicans, C. glabrata, C. krusei, C. parapsilosis, C. tropicalis Antibiotic resistance genes -mecA – methicillin resistance -vanA/B- vancomycin resistance -KPC- carbapenem resistance Nucleic Acid Amplification Obtain organism ID and some resistance genes Ability to escalate and de-escalate for certain situations Staphylococcus Enterococcus Only able to escalate therapy for gram negatives Only able to detect select organisms – still need traditional micro ID What next? Action to results Decreased time to ID Decreased time to detection of select resistance genes Opportunity to improve patient care Timing S. aureus MRSA vs. MSSA mecA gene encodes for methicillin resistance (PBP-2a) Vancomycin for MRSA Vancomycin less active against MSSA than anti-staph β-lactams Increased failure rates Higher risk of relapse MSSA bacteremia Drug of choice Nafcillin or oxacillin Cefazolin Detection of S. aureus bacteremia with PCR and ASP’s Impact Clinical and economic outcomes Xpert MRSA kit (Cepheid) and GeneXpert realtime-PCR platform: MRSA vs. MSSA Single Center study Compared patients with S. aureus bacteremia Intervention arm: Microlab notified ID pharmacist and treating physician ID pharmacist paged treating physician and communicated lab results and recommendations Targeted therapy Antibiotic optimization Infectious Diseases Consult Bauer, et al. CID 2010. Detection of S. aureus bacteremia with PCR and ASP’s Impact Mean time to switch to optimal antibiotic Results Mean time to switch from empiric vancomycin to β-lactam for MSSA decreased by 1.7 days (P=0.002) LOS 6.2 days shorter (P=0.07) Hospital costs decreased $21,387 less per patient (P=0.02) Bauer, et al. CID 2010. Coagulase-Negative Staphylococcus CoNS Common pathogen associated with hospital- acquired central line infection Commonly isolated as a contaminant from blood culture Bacteremia vs. contamination True bacteremia = treat Contaminant = discontinue antibiotics Impact of ASP Intervention on CoNS Blood Cultures in Conjunction with Rapid Diagnostics Analyzed the impact of rapid diagnostics with MALDI–TOF plus ASP intervention Single center, quasiexperimental study Historical control – CoNS identified by conventional methods Intervention – CoNS blood culture ID’ed vial MALDI in conjunction with ASP intervention Nagel JL, et al, J Clin Microbiol. 2014. Impact of ASP Intervention on CoNS Blood Cultures in Conjunction with Rapid Diagnostics Nagel JL, et al, J Clin Microbiol. 2014. Impact of ASP Intervention on CoNS Blood Cultures in Conjunction with Rapid Diagnostics MALDI ID CoNS quicker than traditional methods (83.4 vs 57 h, P=0.001) Antibiotics No difference in time to effective therapy Decrease in time to optimal therapy (58.7 vs 34.4h, P=0.03) Similar LOS, ICU stay, recurrent bacteremia and hospital readmission Intervention group had lower mortality rate (21.7% vs 3.1%, P=0.023) Decreased duration of inappropriate antibiotic administration with vancomycin and daptomycin (4.4 vs 3 days, P=0.015) Enterococci Enterococcal bacteremia is the 4th most common cause of hospital-acquired bacteremia in the US Most common species E. faecium and E. faecalis Vancomycin resistant enterococci (VRE) Most commonly E. faecium Daptomycin Linezolid Early appropriate antimicrobial therapy has shown to improve patient outcomes in the ICU PNA-FISH and Enterococcus Blood culture with gram positive cocci in chains (GPCC) PNA-FISH E. faecalis Other enterococci (which include E. faecium) No detection Streptococci Use information to guide antimicrobial therapy PNA-FISH for Enterococcal Bacteremia Quasiexperimental study Control group E. faecium and E. faecalis were ID using conventional methods ASP intervened by clinical factors and final susceptibility Intervention Group PNA-FISH ASP intervened at time of PNA-FISH results Forrest GN, et al. Antimicrob Agents Chemother. 2008. PNA-FISH and Enterococcus PNA-FISH ID E. faecalis 3 days and E. faecium 2.3 days earlier than conventional methods (P<0.001) Reduction in time to initiating effective therapy (1.3 vs 3.1 days, P<0.001) Decreased 30 day mortality (26% vs 45%) PNA-FISH in conjunction with ASP treatment algorithm decreased time to appropriate empiric therapy Forrest GN, et al. Antimicrob Agents Chemother. 2008. Integrating Rapid Diagnostics and ASP to Improve Outcomes in Patients with Gram-Negative Bacteremia Impact of rapid ID (MALDI-TOF) and susceptibility testing coupled with ASP on patients with resistant gramnegative bacteremia Control group: conventional ID and susceptibility Intervention group: MALDI ID Simultaneous set up for susceptibility testing Results sent to ASP ASP contacted team to discuss results and provide evidence based recommendations when appropriate Perez KK. J Infect. 2014. Integrating Rapid Diagnostics and ASP to Improve Outcomes in Patients with Gram-Negative Bacteremia MALDI reduced time to ID (40.9±15.1 h to 14.5±12.3 h, P<0.001) Susceptibility testing (46.7±12.9 h to 29.3±14.7, P<0.001) Decreased time to optimal antibiotics (80.9±63 h to 23.2 ±19.9 h, P<0.001) Decreased LOS Decreased mortality Decreased hospital costs $26,298 per each bacteremic patient Perez KK. J Infect. 2014. Timeline Comparison Perez KK. J Infect. 2014. Rapid Diagnostic Testing in Conjunction with ASP Case 1 HPI: MJ is a 68 YO M end stage renal disease (ESRD) on hemodialysis (HD) (MWF) presents to ER from HD clinic after he was noted to have chills, rigors, and a fever of 102.1. In the ER he is lethargic and febrile. The ER sent 2 sets of blood cultures. PMH: ESRD on HD (HD catheter), Diabetes, Hypertension Allergy: penicillin (GI upset) Medications: Insulin glargine, metoprolol, docusate, senna, zolpidem prn Social history: Denies IVDA, no tobacco, no alcohol Case 1 The microbiology lab performed a gram stain and notifies the ER that both sets of MJ’s blood cultures have gram positive cocci in clusters. Which empiric antibiotic should be started? The microbiology lab set up MJ’s blood cultures on the BioFire FilmArray™. The team was notified that the patient’s blood cultures are growing Staphylococcus aureus mecA gene negative What (if any) changes should be made to MJ’s antibiotic regimen? Case 1 The microbiology lab performed a gram stain and notifies the ER that both sets of MJ’s blood cultures have gram positive cocci in clusters. Which antibiotic is most appropriate to start given the available information? a) Cefazolin b) Vancomycin c) Linezolid d) Cephalexin Case 1 The microbiology lab performed a gram stain and notifies the ER that both sets of MJ’s blood cultures have gram positive cocci in clusters. Which antibiotic is most appropriate to start given the available information? a) Cefazolin b) Vancomycin c) Linezolid d) Cephalexin Case 1 The microbiology lab set up MJ’s blood cultures on the BioFire FilmArray™. The team was notified that the patient’s blood cultures are growing Staphylococcus aureus mecA gene negative Which antibiotic is most appropriate for MJ’s infection? a) Cefazolin b) Vancomycin c) Linezolid d) Cephalexin e) Daptomycin Case 1 The microbiology lab set up MJ’s blood cultures on the BioFire FilmArray™. The team was notified that the patient’s blood cultures are growing Staphylococcus aureus mecA gene negative Which antibiotic is most appropriate for MJ’s infection? a) Cefazolin b) Vancomycin c) Linezolid d) Cephalexin e) Daptomycin Case 2 LT is a 30 YO M with no significant PMH presents to the ER with fevers, SOB, and productive cough. PMH: depression Allergies: ciprofloxacin (hives/urticaria) Social History: denies IVDA, +EtOH, no tobacco Medications: sertraline CXR: patchy airspace opacities concerning for pneumonia The ER sent 2 sets of blood and sputum cultures and started IV azithromycin and ceftriaxone for CAP Case 2 The lab performed a gram stain and notifies the ER that 1 blood culture bottle has gram positive cocci in clusters on gram stain The ER added vancomycin to LT’s antibiotic regimen Case 2 LT is admitted to the observation unit LT is clinically stable, SOB and cough resolving Temp 98.9, HR 65 BMP, BP 132/80 WBC 12 Blood cultures: 1 out of 2 sets growing Coagulase negative Staphylococcus (from anaerobic bottle only), repeat blood cultures are negative Sputum culture: rejected due to poor sample collection Case 2 Given the available information, what is the most appropriate action? a) Continue vancomycin IV for 14 days, goal trough 15-20 mg/L b) Discontinue vancomycin and narrow to cefazolin for 14 days c) Discontinue vancomycin and discharge patient on oral course of antibiotics for CAP d) Discontinue vancomycin and start daptomycin since CoNS is likely vancomycin resistant Case 2 Given the available information, what is the most appropriate action? a) Continue vancomycin IV for 14 days, goal trough 15-20 b) Discontinue vancomycin and narrow to cefazolin for 14 days c) Discontinue vancomycin and discharge patient on oral course of antibiotics for CAP d) Discontinue vancomycin and start daptomycin since CoNS is likely vancomycin resistant Thomas Jefferson University Hospital Large academic medical center 951 acute care beds 45,131 admissions per year Wide range of clinical specialties Microbiology Lab Services 3 hospital campuses Over 10,000 specimens per month ~4,000 blood specimens per month Thomas Jefferson University Hospital Antimicrobial stewardship program Prospective audit with feedback and intervention ICU stewardship rounds Treatment guideline development Infectious Diseases Subcommittee Members include pharmacists, ID physicians, and microbiologist Drug policy Guidelines Rapid Diagnostic Testing at TJUH MALDI-TOF Direct from blood Urine Sputum Tissue Biofire FilmArray Direct from blood Rapid Diagnostic Testing at TJUH Workflow Result notification Empiric antimicrobial selection for bacteremia guideline ASP intervention Documentation Rapid Diagnostic Testing at TJUH Lab notifies team of + gram stain Lab performs ID on rapid diagnostic technology Lab sends ASP ID results as well as notifies team of ID ASP reviews results and if appropriate contacts team to provide intervention Follow up and documentation TJUH Future Directives Bacteremia bundles Data collection Outcomes research Economic impact evaluation Conclusion Timely administration of optimal antimicrobial therapy is essential to improving patient outcomes Rapid diagnostic testing in conjunction with ASP efforts have demonstrated positive results New technologies in combination with ASP will likely continue to demonstrate improvements in antimicrobial use and patient care References 1. 2. 3. 4. 5. 6. 7. 8. Dellit T, Owens R, McGowan J, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for Developing an Institutional Program to Enhance Antimicrobial Stewardship. CID. 2007;44:159-77. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006; 34:1589-96. Goff DA, Jankowski C, Tenover FC. Using rapid diagnostic tests to optimize antimicrobial selection in antimicrobial stewardship programs. Pharmacother. 2012;32(8):677-87. Bauer KA, West JE, Balada-Llasat JM, et al. An antimicrobial stewardship program’s impact with rapid polymerase chain reaction methicillin-resistant Satphylococcus aureus/S. aureus blood culture test in patients with S. aureus bacteremia. Clin Infect Dis. 2010;51:10174-80. Nagel JL, Huang AM, Kunapuli A, et al. Impact of antimicrobial stewardship intervention on Coagulase-Negative Staphylococcus Blood Cultures in Conjunction with Rapid Diagnostic Testing. J Clin Microbiol. 2014;52(8):2849-54. Forrest GN, Roghmann MC, Toombs LS, et al. Peptide nucleic acid fluorescent in situ hybridiazation for hospitalaquired enterococcal bacteremia: delivering earlier effective antimicrobial therapy. Antimicrob Agents Chemother. 2008; 52:3558-63. Perez KK, Olsen RJ, Musick WL, et al. Integrating rapid pathogen identification and antimicrobial stewardship improves outcomes in patients with antibiotic resistant gram-negative bacteremia. Wong JR, Bauer KA, Mangino JE, et al. Antimicrobials tewardship pharmacist interventions for coagulase-negative staphylococcus positive blood cultures using rapid polymerase chain reaction. Ann Pharmacother. 2012;46:1484-90.
