Antimicrobial Stewardship Team Interventions in Patients with Bacteremia Utilizing Rapid Pathogen Identification via Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS) Yi Guo, PharmD Clinical Pharmacy Manager of Infectious Diseases Montefiore Medical Center Albert Einstein College of Medicine Bronx, NY September 2015

Disclosures I have no relevant financial or nonfinancial relationship(s) with the manufacturers of the antimicrobial agents described or reviewed in this presentation

Objectives Describe the Antimicrobial Stewardship Team (AST) activities at Montefiore Medical Center Describe the Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS) Describe the process of integrating MALDI-TOF MS into the Antimicrobial Stewardship Program for patients with bacteremia Outline future directions with MALDI-TOF

Timely Initiation of Antimicrobials Bloodstream infections (BSIs) are associated with high rates of morbidity and mortality among hospitalized patients. Prompt pathogen identification is crucial for optimizing antimicrobial therapy in patients with BSIs Timely initiation of appropriate antibiotics is associated with improved patient outcomes and decreased healthcare expenditures Delays in microbiological identification hinder the ability of clinicians to streaming therapy Vlek A, etal. PLoS One. 2012; 7: e32589. Lodis TP, etal. Clin Infect Dis 2003;36:1418-23.

Conventional vs. MALDI-TOF MS Current standard of identification relies largely on phenotypic testing that is time consuming MALDI-TOF has proven to be a rapid, cost effective, and accurate alternative to conventional identification MALDI-TOF MS was validated and NYS DOH laboratory approval was received January 2014 for use at Montefiore NYS DOH = New York State Department of Health Bizzini A, etal. Clinical Microbiology and Infection. 2010; 16: 1614-1619.

How does MALDI-TOF MS Work? Photos courtesy of Mayo Clinic Medical Laboratories

How does MALDI-TOF MS Work? Photos courtesy of Mayo Clinic Medical Laboratories

Conventional vs. MALDI by Plate/Bottle MALDI by Bottle 0 hrs Growth detected 0-2hrs Gram Stain Subculture to plate 18-24hrs Sufficient colony growth achieved Set up for ID/susceptibilities Prelim ID released if available 24-48hrs Final ID Susceptibilities 0 hrs Growth detected 0-2 hrs Gram Stain Subculture to plate 8-16 hrs Minimal colony growth achieved Final ID by MALDI (or Preliminary ID pending further testing) 24-48hrs Susceptibilities 0 hrs Growth detected 0-2 hrs Gram Stain BC bottle processing for MALDI 3-6 hrs Final identification (or Preliminary ID pending further testing) 24-48hrs Susceptibilities

MALDI TOF + Antimicrobial Stewardship Huang et al.1 Perez et al.2 Type of Pathogen in Blood Bacteria, Yeast Resistant Gram-negative Organisms   Pre-I (n=256) Post-I (n=245) P value Pre-I (n=157) Post-I (n=112) Time to Organism Identification (hour) 84.0 55.9 <0.001 40.9 14.5 Time to Effective Antibiotic Therapy (hour) 30.1 20.4 0.021 89.7 32 Time to Optimal Antibiotic Therapy (hour) 90.3 47.3 80.9 23.2 Duration of ICU stay (day) 14.9 8.3 0.014 16* 10.7** 0.008 Hospital Length of Stay (day) 14.2 11.4 0.066 23.3* 15.3** 0.0001 30-day All Cause-mortality 20.3% 14.5% 21% 8.9% 0.01 Total Average Hospital Costs per Inpatient N/A $78,991 + $90,106* $52,693 + $83,526** 0.002 Abbreviations: Pre-I, pre-intervention; Post-I, post-intervention; ICU, intensive care unit *n=128, **n=103 1. Huang AM, et al. Clin Infect Dis 2013;57(9):1237-45 2. Perez KK, et al. J infect 2014 Sep;69(3):216-25.

Antimicrobial Stewardship Program Formally established in 2009 Covers 4 campuses (Moses, Einstein, Wakefield, CHAM) 1512 beds Antimicrobial stewardship team (AST) consists of: 4 ID attendings (1 pediatric) 4 ID-trained pharmacists (1 pediatric) Activities: ID approval/auditing Making hospital guidelines/protocols Education Research Publication

ASP Strategies by Campus Resources Restrictions* Audit** Highlights Moses ✔✔✔ ✔✔ ER (CAP, Sepsis) Zosyn Time Out Einstein ER ID Consults Abd hyst ppx bundle Wakefield No fellows ✔Modified at 72 hrs ASP-Medicine early interventions CHAM ✔ Peds List Antiviral & antifungal appropriateness, Dosing * Related lists with categories ** Sentri 7 & home grown queries

Daily Workflow Before Implementation of MALDI Microbiology lab notifies primary team physician via phone regarding positive blood culture Time to initiate appropriate antibiotic depends on timing of the phone call and availability of primary team physician AST does not receive notification of all positive blood culture routinely Before Implementation of MALDI Microbiology lab emails positive blood culture reports to AST 3 times a day, 9am-5pm , Monday-Friday A designated ID MD/PharmD will perform chart review and contact primary team physician Recommending: streamlining antibiotics, ID consults, diagnostic work up, etc. After Implementation of MALDI

Objective Analyze early outcomes of MALDI + ASP activities in bacteremic patients

Methods Study design: Pre-post interventional observational study Time frame: March-April 2013 vs. March-April 2014 Inclusion criteria: Age >18 (Moses, Einstein, Wakefield) 1st episode of bacteremia with gram-negative organism or S. aureus Exclusion criteria: Age <18 Death or discharge within 24 hours of blood culture (BC) collection Repeat episodes of bacteremia Yeast Statistical analysis: Description of whole population and by cohort. Outcomes analyzed by Mann-Whitney U-test where applicable. Statistics performed utilizing STATA 13.0 software. p≤ 0.05 denotes significance

Outcome Measures Process measures Time to organism identification Time to streamlined susceptible regimen Time to ID consultation Patient outcomes Time to microbiologic clearance Mortality Length of Stay (LOS)

Definitions Time to Organism Identification (Org ID) = Organism identification date/time – BC collected date/time (in hours) Time to Streamlined Susceptible Regimen = Date/time of most narrow, directed, susceptible antibiotics as determined by ASP team – BC collected date/time (in hours) Time to ID consultation Date/time of initial ID evaluation – BC collected date/time (in hours) Time to Microbiological Clearance Date/time first negative blood culture (separated by at least 4 hours from initial blood culture) – BC collected date/time (in hours) Mortality = Death during same hospitalization LOS= Discharge date/time – BC collected (in days)

Results: Flow Chart of Participants Preintervention Group March-April 2013 (n=445) Included in Preliminary Analysis (n= 209) Excluded: CoNS (n=80) Other GP (n=127) Deceased/ER DC/Outpatient (n=16) Yeast (n=11) GN (n=2) Intervention Group March-April 2014 (n=365) Included in Preliminary Analysis (n= 183) (Plate=130, Bottle=53) Excluded: CoNS (n=61) Other GP (n=62) Deceased/ER DC/Outpatient (n=59)

Results: Basic Demographics Mar-April 2013 (n=209) Mar-April 2014 (n=183) Significance Female (%) 54% 50% NS Age (median years) 67 58 Origin (%) Community 40 35 Healthcare 60 65 Severity of illness (%) None-Sepsis 11 10 Sepsis 44 52 Severe Sepsis 29 23 Septic Shock 17 15 % isolated identified by MALDI n/a >95%

Results: Distribution of Organisms Number of Isolates Percent

Results: Process Measures March-April 2013 (n=209) March-April 2014 (n=183) P value Gram Negative Organism (n=153) (n=135) Time to Org ID (hours*) 51.9 29.6 <0.001 Time to Streamlined Susceptible Regimen (hours*) 68.5 56.2 NS Time to ID Consultation (hours*) 34.1 16.2 0.02 S. aureus (n=56) (n=48) 44.5 <0.005 69.2 58.6 Time to ID consultation (hours*) 32.9 12.6 *Reported in median hours

Results: Patient Outcomes March-April 2013 (n=209) March-April 2014 (n=183) P value Gram Negative Organism (n=153) (n=135) Unadjusted mortality (%) 16.3 9.6 NS Time to microbiological clearance (hours*t) 47.3 54.2 Length of Stay (days*) 8.9 8.2 S.aureus (n=56) (n=48) 21.4 10.4 75.3 65.0 9.1 10.8 * reported in median hours/days t data under review, adjusted analysis in progress

Results: Preliminary Outcomes for Severe Sepsis/Shock March-April 2013 (n=96) March-April 2014 (n=69) Gram Negative Organism and/or S. aureus Time to Org ID (hours) 51.8 31.8 Time to Streamlined Susceptible Regimen (hours) 74.2 58.1 Time to ID consultation (hours) 35.1 16.3 Time to microbiological clearance (hours) 69.2 55.9 Unadjusted mortality (%) 23.9 18.8 Length of Stay (days) 10.6 10.1

Perception/Acceptability

Lessons Learned Implementing new technology takes time and planning Requires multidisciplinary effort Cultural barriers to overcome (empiric prescribing, early consultation for S. aureus) Laboratory and AST cost approximately 3-5 additional hours of effort per day Structured intervention with susceptibility follow up

Future Directions Expanding cohort to include all organisms Collect data over longer period of time MALDI-TOF paired with earlier susceptibilities Intermediate rapid testing for ESBL/KPC/MRSA Cost savings analysis Formal statistical analysis including multi-variable regressions and adjustment for severity of illness (chronic and acute)

Acknowledgements Stewardship Team Belinda Ostrowsky, MD, MPH Iona Munjal, MD Priya Nori, MD Connie Park, MD Yi Guo, PharmD Philip Chung, PharmD Julie Williamson, PharmD Statistician Rafael Ruiz, PhD Microbiology Lab Michael Levi, ScD Wendy Szymczak, PhD Philip Gialanella Hitesh Patel Myrna Intal Frank Cardenas

Antimicrobial Stewardship Team and Microbiology Leadership