RESIDENCY RESEARCH PROJECT MANUSCRIPT Evaluating the utility of a weighted-incidence syndromic combination antibiogram on time to appropriate antibiotic therapy in patients with gram-negative bacteremia Dan Zangari Pharmacy Resident Trillium Health Partners 2016 – 2017 Primary Investigator Dan Zangari, HBSc, PharmD Pharmacy Resident Trillium Health Partners – Mississauga Hospital Co-Investigators Rebekah Lee, PharmD, ACPR Emergency Medicine Pharmacist Trillium Health Partners – Credit Valley Hospital Christopher Graham, MD Infectious Diseases Physician Trillium Health Partners – Mississauga Hospital Lilly Yonadam, BScPhm, MScEpi Antimicrobial Stewardship Pharmacist Trillium Health Partners – Mississauga Hospital Joanne Stockford, BScPhm, ACPR Antimicrobial Stewardship Pharmacist Trillium Health Partners – Credit Valley Hospital Project Sites Trillium Health Partners – Mississauga Hospital 100 Queensway Street West Mississauga, ON L5B 1B8 Trillium Health Partners – Credit Valley Hospital 2200 Eglinton Avenue West Mississauga, ON L5M 2N1 ABSTRACT Background: Gram-negative bacteremia (GNB) is associated with mortality rates up to 30%, with even higher rates in patients who receive inappropriate empiric antibiotic therapy. A weighted-incidence syndromic combination antibiogram (WISCA) is a novel hospital- and infection-specific tool which may aid clinicians in choosing appropriate antibiotic therapy. Objectives: The primary objective was to determine whether a WISCA improves time to appropriate antibiotic therapy in patients with GNB initially treated with inappropriate antibiotics. Secondary objectives included changes in the rates of in-hospital mortality, intensive care unit (ICU) admission, days of antibiotic therapy, consumption of antibiotics used for empiric treatment of GNB, and subsequent diagnosis of C. difficile infection (CDI). Methods: A retrospective pre- and post-implementation study was conducted across two campuses of a large Canadian community teaching hospital from December 2016 to March 2017. Adult patients with a positive blood culture for a gram-negative organism treated at either site with at least one dose of an antibiotic were included. Electronic medical records were used to collect data which was analyzed using two-sample t-tests and Chi-square tests. Results: A total of 210 GNB episodes were included in this interim analysis. Inappropriate empiric therapy was defined as not having received an antibiotic to which the organism was susceptible by release of the gram-stain. This subgroup (28.3% of patients), was analyzed in the primary objective which showed no significant difference in time to appropriate antibiotic therapy for patients in the pre-WISCA vs. post-WISCA arms (42.32 vs. 54.91 hours; p=0.25). There were no significant differences in any of the secondary objectives following implementation of the WISCA. Conclusions: Interim results do not show a significant difference in time to appropriate antibiotic therapy for patients with GNB following implementation of a WISCA. Additional data is required to make appropriate conclusions regarding the utility of this tool. INTRODUCTION Gram-negative bacteremia (GNB) is associated with high mortality rates, estimated to be approximately 30%. Mortality rates are even higher rates in patients who receive inappropriate antibiotic therapy1. Rates of antibiotic resistant infections have been escalating, and GNB associated with antibiotic resistant organisms has been linked to negative outcomes2-7. Specifically, patients with GNB infections caused by multi-drug resistant (MDR) pathogens such as Pseudomonas aeruginosa, extended-spectrum beta- lactamase (ESBL) producing organisms, and carbapenemase-producing Enterobacteriaceae (CPE) are more likely to receive inappropriate empiric antibiotic therapy and have higher rates of mortality2. A study by Lautenbach et al. found that ESBL-producing Escherichia coli (E. coli) or Klebsiella pneumonia (K. pneumoniae) infections, although not limited to GNB, were associated with a median time to effective antibiotic therapy of 72 hours. This was compared with a median of 11.5 hours in control cases, as well as significantly increased duration of hospitalization in those patients with infections secondary to resistant organisms8. A Spanish study by Rodriguez-Bano et al. found that in patients with community-onset GNB due to ESBL-producing E. coli, health care exposure, urinary catheter use, and prior antimicrobial exposure were independent risk factors associated with the infection5. Data from a previous study conducted here at Trillium Health Partners (THP) by Lee et al. found that approximately 8.8% of GNB cases studied were attributable to ESBL organisms, and 40.5% were caused by an antibiotic-resistant organism which was resistant to at least one of the following: a third-generation cephalosporin, fluoroquinolones, piperacillin-tazobactam or carbapenems9. The results of the study showed that mean time to appropriate antibiotic therapy, defined as administration of an antibiotic to which the causative organism was shown to be susceptible to in vitro, was significantly delayed in patients with GNB attributable to antibiotic-resistant organisms (16.9 vs. 1.8 hours, p<0.001). Importantly, the authors found that 19.1% of patients with GNB were treated with inappropriate empiric antibiotic therapy9. Patients with antibiotic-resistant GNB were more likely to receive inappropriate empiric antibiotic therapy (41.1 vs. 3.2%, p<0.001), and time to reach appropriate therapy in the subgroup of patients initially treated with inappropriate therapy was significantly longer (41.1 vs. 1.4 hours, p<0.001). Other studies have also documented the relationship between inappropriate empiric antibiotic therapy for GNB and negative outcomes. Rodriguez et al. found that in patients with community-onset ESBL E. coli GNB, inappropriate empiric antibiotics was associated with increased mortality (adjusted OR 3.0, p=0.007)5. Qureshi et al. conducted a study in patients with GNB due to ESBL or CPE organisms and concluded that inadequate empiric antibiotic therapy was an independent risk factor for increased 28-day mortality rates (OR, 2.26; 95% CI, 1.18–4.34)10. Zilberberg et al. conducted a retrospective cohort study in intensive care unit (ICU) patients with severe sepsis/septic shock associated with GNB and showed the in-hospital mortality rate to be 29.2%2. They defined initial appropriate antibiotic therapy (IAAT) as exposure to an antibiotic with in vitro susceptibility to identified pathogens within 24 hours of infection onset. Nonsurvivors were three times more likely to have received non-IAAT (43.4% vs. 14.6%, p<0.001). Using multiple logistic regression models, they found that receiving non-IAAT was the strongest predictor of in-hospital mortality (adjusted OR 3.87; 95% CI, 2.77–5.41, p<0.0001)2. A retrospective cohort study by Micek et al. in ICU patients with severe sepsis or septic shock associated with GNB found that 31.3% of patients received non-IAAT, and this was associated with significantly higher in-hospital mortality rates (51.7 vs. 36.4%, p<0.001)3. They also published a subsequent study in 2011 showing that in-hospital mortality was 43.6% for patients with GNB due to P. aeruginosa, Acinetobacter species, or Enterobacteriaceae and that 15.3% of patients received an antibiotic to which the causative pathogen was resistant. They also noted that patients with GNB caused by a pathogen with antibiotic resistance was associated with higher in-hospital mortality rates than those with infections secondary to pathogens with no resistance (63.4 vs. 40.0%, p<0.001)4. A retrospective Korean study by Kang et al. in patients with antibiotic-resistant GNB was conducted to determine the effects of non-IAAT on 30-day mortality rates found 52.8% of patients received non-IAAT, and mortality rates were higher in this group compared to patients treated with IAAT (38.4 vs. 27.4%, p=0.049)1. Currently, there are no guidelines with recommendations for optimal empiric treatment of GNB infections. For many clinicians, especially those with little experience in treating these infections and those in areas with a high prevalence of resistant gram- negative organisms, additional tools and recommendations are needed to aid in optimizing therapy. Traditional antibiograms may be of some utility for choosing antibiotics when speciation is known but sensitivity results are not yet available, however they do not help clinicians choose empiric antibiotic therapy. A newer type of antibiogram, a weighted-incidence syndromic combination antibiogram (WISCA) was first described by Hebert et al. in 201211. A WISCA is a hospital- specific antibiogram generated using historical culture and sensitivity results for a given infection over a specified period of time. This data is then used to provide clinicians with historical susceptibility information for both individual and combinations of various antibiotics for that specific type of infection, as opposed to a specific organism. Thus, a WISCA may prove more beneficial than a traditional antibiogram, especially in situations where a specific infection is suspected but speciation of the organism is not known, for infections that are typically poly-microbial, and when treating infections where antibiotic- resistant bacteria are common. Hebert et al. developed WISCAs for urinary tract infections (UTIs) and abdominal biliary infections (ABIs)11. They demonstrated significant differences in susceptibility rates of antibiotics