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 – Hospital

Co-Investigators Rebekah Lee, PharmD, ACPR

Emergency Medicine Pharmacist

Trillium Health Partners – Christopher Graham, MD

Infectious Diseases Physician Trillium Health Partners –

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 when comparing their traditional antibiogram to the WISCA. For example, the susceptibility of E. coli to fluoroquinolones based on their traditional antibiogram was 84%, however in all patients with UTIs, only 62% would have been adequately covered with a fluoroquinolone. This number was even lower for patients with ABIs (37%)11. Randhawa et al. also demonstrated the development of two WISCAs for ventilator- associated pneumonia (VAP) and catheter-related blood stream infection (CRBSI) at Sunnybrook Hospital12. They noted that in comparison to standard practice, use of WISCA antibiotic regimens could have resulted in excess adequate antimicrobial coverage rates of 56% more patients by 12 hours after initial blood cultures, 42% at 24 hours, and 18% at 48 hours12. While these two studies have demonstrated the potential utility of a WISCA, studies of its use in practice are lacking and are necessary to better understand whether this tool would have a meaningful impact on time to appropriate empiric antibiotic therapy.

As part of the Lee et al. study at THP9, a WISCA (Figure 1) was generated from gram- negative blood isolates from patients at the Mississauga Hospital (MH) and Credit Valley Hospital (CVH) and was included at the bottom of gram stain reports for patients with a positive blood culture with a gram-negative bacteria. We conducted a retrospective analysis of patients treated for GNB both prior to and after implementation of this tool at the both THP sites. The aim of our study was to evaluate whether the implementation of this tool significantly improved time to appropriate empiric antibiotic therapy in patients with GNB, specifically in the subset of patients treated initially with inappropriate empiric antibiotic therapy (IEAT). We aimed to reduce the time to appropriate therapy by 12 hours (from a mean of 41.1 hours9) in this patient population through the use of this tool. We also explored a variety of important secondary patient-based outcomes, including the change in the rates of in-hospital mortality, transfer to the ICU within 48 hours of initial blood cultures, total days of antibiotic therapy and the consumption of antibiotics used for empiric treatment of GNB, and subsequent diagnosis of C. difficile infection.

Figure 1. Trillium Health Partners Weighted-Incidence Syndromic Combination Antibiogram

METHODS

Study Design We conducted a pre-implementation and post-implementation study across two community-teaching hospitals at Trillium Health Partners in Mississauga, , Canada. The participating sites included the Mississauga Hospital (827 beds) and the Credit Valley Hospital (382 beds). The study was reviewed and received approval by the institutional research ethics board.

Study Population Adult patients aged 18 years of age and older were included in the study if they were treated in the emergency department or admitted to the MH or CVH and had a positive blood culture for at least one gram-negative organism. Patients included in the study must also have received at least one dose of an antibiotic. Patients were included in the post-implementation data if their blood cultures were drawn after February 2, 2017, the date the WISCA was implemented. An equal number of patients were then included in the study in reverse chronological order, beginning from February 1, 2017. GNB episodes where blood cultures were positive for the same organism within 10 days of the initial positive blood cultures for that patient were excluded. Patients with multiple positive blood cultures for the same organism were included multiple times in the study if the blood cultures were drawn more than 10 days apart. The secondary outcome of in-hospital mortality was documented once for a given patient during each separate admission. Outcomes

The primary outcome was the mean time to appropriate antibiotic therapy in the subset of patients who were initially treated with inappropriate antibiotics. Antibiotic therapy was considered appropriate if all causative organisms demonstrated in vitro susceptibility to the antibiotic therapy administered. Initial therapy was considered inappropriate if an appropriate antibiotic was not administered by the time the gram-stain and WISCA were reported, or if no antibiotics were administered by the time the gram- stain and WISCA were reported. If combination therapy was administered, they were deemed to be appropriate if the causative organism demonstrated in vitro susceptibility to at least one of the antibiotics. For poly-microbial gram-negative infections, therapy was considered appropriate if all infecting organisms demonstrated in vitro susceptibility to the antibiotic therapy administered.

Secondary outcomes included the change in the rate of in-hospital mortality, requirement for ICU admission with 48 hours of cultures being drawn, days of antibiotic therapy, consumption of various antibiotics (3rd-generation cephalosporins, piperacillin- tazobactam, aminoglycosides, fluoroquinolones, and carbapenems), and proportion of patients with a CDI diagnosis, following implementation of the WISCA.

Data Collection

Internal reports were generated via the microbiology lab and study author, which isolated patients with positive blood cultures for gram-negative organisms. Data for primary and secondary outcomes were collected using the hospital electronic databases including scanned and electronic patient charts, laboratory values and culture and sensitivity reports. Baseline data was collected with respect to age, gender, comorbidities, community- vs. hospital-acquisition of infection, recent antibiotic use, the gram-negative organisms isolated, presumed source of infection, requirement for ICU admission, total days of antibiotic therapy, antibiotics received, documented CDI, and in-hospital mortality.

Statistical Analysis Continuous variables were expressed as means ± standard deviation and were analyzed using two-sample t-tests. Categorical variables were expressed as proportions (n, %) and were analyzed using Chi-square tests.

RESULTS

Patient Characteristics An interim analysis was conducted in June 2017 with the data available at the time. A total of 244 episodes of gram-negative bacteremia occurring between December 2016 and March 2017 were screened for eligibility for inclusion in the analysis (Figure 2). Thirty-four episodes were excluded, as they did not meet the inclusion criteria of the study. Therefore, 210 episodes of gram-negative bacteremia were included in the analysis of the results. Of these, 105 episodes occurred prior to implementation of the WISCA, and 105 episodes occurred following implementation of the WISCA. The baseline characteristics for patients included in the study are detailed in Table 1. The mean age of patients was 72 years, with 42% female patients in the pre-WISCA group and 47% females in the post-WISCA group. There was more renal disease in the pre-WISCA group and more autoimmune disease and recent antibiotic exposure in the post-WISCA group.

In the pre-defined subgroup of patients treated with IEAT, the mean age was 64 in the pre-WISCA group and 71 in the post-WISCA group, with 48% females in the pre-WISCA group and 58% in the post-WISCA group.

Isolated gram-negative organisms were similar between the two groups except for ESBL organisms, for which there were more in both the overall post-WISCA population and in the IEAT post-WISCA subgroup. Sources of infection were similar when compared between groups except for more reports of genitourinary tract and unknown sources of infection in the IEAT post-WISCA subgroup. There was more inappropriate empiric antibiotic therapy in the post-WISCA group. Figure 2. Study Inclusion Diagram

Table 1. Baseline Characteristics

Primary Outcome

The primary outcome of time to appropriate antibiotic therapy in the subset of patients initially treated with inappropriate empiric antibiotic therapy was 44.3 ± 26.1 hours in the pre-WISCA group compared to 56.3 ± 42.0 hours in the post-WISCA group (P = 0.18, Table 2).

Table 2. Primary Outcome

Secondary Outcomes

The rate of in-hospital mortality was 27.5% in the pre-WISCA group compared to 24.5% in the post-WISCA group (P = 0.63). The rate of ICU admission within 48 hours of initial blood cultures was 9.5% in the pre-WISCA group and 5.7% in the post-WISCA group (P = 0.30). The mean total number of days on antibiotic therapy was 12.6 ± 9.1 in the pre- WISCA group and 13.3 ± 7.9 in the post-WISCA group (P = 0.55). There were no significant differences in exposure empiric antibiotic exposure for any of the pre-specified antimicrobials in the pre-WISCA group compared to the post-WISCA group (39.0% vs. 48.6%, P = 0.16 for 3rd-generation cephalosporins; 1.9% vs. 5.7%, P = 0.15 for aminoglycosides; 18.1% vs. 26.7%, P = 0.14 for carbapenems; 20.0% vs. 17.1%, P = 59 for fluoroquinolones; 51.4% vs. 45.7%, P = 0.41 for piperacillin-tazobactam). The rate of C. difficile infection within 30 days was 2.9% in both the pre-WISCA and post-WISCA groups (P = 0.99).

Table 3. Secondary Outcomes

DISCUSSION

Based on these preliminary results, there was no significant difference in time to appropriate antibiotic therapy in patients with gram-negative bacteremia who were initially treated with inappropriate antibiotics following the implementation of a WISCA. Conversely, there was a non-significant increase in time to appropriate therapy in the post- WISCA group. Although this was only a trend, one possible explanation for this finding includes a higher proportion of patients with bacteremia caused by ESBL organisms in the post-WISCA population (7.4% in the pre-WISCA group vs. 20.7% in the post-WISCA group; P < 0.005). This increase in ESBL-related gram-negative bacteremia was seen not only in the overall study population, but also in the IEAT subgroup analyzed for the primary outcome, although this was also not statistically significant (30.4% vs. 46.2%; P = 0.18). Other explanations for the increased time to appropriate therapy may include lack of physician understanding of the WISCA, changes in rates of other (non-ESBL) antibiotic- resistant organisms, and the lack of adequate data required to detect a significant difference. We included all episodes of gram-negative bacteremia in the analysis of the secondary endpoints, regardless of whether empiric antibiotic therapy was appropriate, to determine the impact of the WISCA on the entire patient population. There were no significant differences in any of the secondary outcomes. As gram-negative bacteremia is associated with a high mortality rate, we hypothesized that improved time to appropriate antibiotic therapy may have an effect on decreasing the mortality rate. We also compared the rates of patients who required admission to the ICU within 48 hours of their initial blood cultures being drawn.

As we hypothesized that the implementation of a WISCA would reduce time to appropriate antibiotic therapy, we anticipated a decrease in the overall days that patients remained on antibiotics. However, there was no significant difference between the two groups during the analysis of this secondary outcome.

We also sought to measure the changes in rates of several pre-specified antibiotics following implementation of the WISCA. While we appreciate the high mortality rates associated with gram-negative bacteremia and the benefits of rapidly starting appropriate therapy, we found it prudent to ensure the WISCA did not lead prescribers towards unnecessarily broad antibiotic therapy. We also found, based on Lee’s results, that empiric therapy with piperacillin-tazobactam was inadequate in 38% of patients treated on this regimen, as these patients had gram-negative bacteremia caused by an ESBL organism. We anticipated seeing a reduction in the prescribing of piperacillin-tazobactam in the post- WISCA population. While this did occur (51.4% vs. 45.7%, P = 0.41), the difference was not statistically significant. Notably, there was an increase in prescribing of carbapenems in the post-WISCA group (18.1% vs. 26.7%, P = 0.14), although this was not a statistically significant increase. The increased utilization of carbapenems in the post-WISCA population may be associated with the increased rates of gram-negative bacteremia due to ESBL organisms seen, indicating appropriate usage of this class. We further hypothesized that increased exposure of clinicians to the WISCA on the gram-stain reports may unintentionally alter empiric prescribing patterns when suspecting gram-negative bacteremia. While there was an increase in prescribing of aminoglycosides (1.9% vs. 5.7%, P = 0.15) and 3rd-generation cephalosporins (48.6% vs. 39.0%, P = 0.16), along with a decrease in prescribing of piperacillin-tazobactam (as described above), none of these differences were statistically significant.

Finally, we included the rates of C. difficile infection within 30 days of receiving the first dose of antibiotics for an episode of gram-negative bacteremia, to measure whether implementation of a WISCA posed any safety concerns for patients. We anticipated this could potentially be secondary to prescribing of broader-spectrum antibiotics. The rate of C. difficile infection within 30 days was identical in the pre- and post-WISCA groups, with 3 cases in each.

Limitations of our study include not reaching our target sample size, enrolling patients from only one hospital system (both from the same geographical region), and the retrospective design of the study. As our sample size was not reached, our study is therefore underpowered to detect a statistically significant difference in time to appropriate antibiotic therapy, the primary outcome. While we actually saw a non- significant increase in this endpoint following implementation of the WISCA, this result may actually be significant, while the opposite may in fact be true with additional data. We included patients who were admitted to either the Mississauga Hospital or Credit Valley Hospital, both of which are in Mississauga, Ontario. Resistance patterns differ from region to region, and especially between countries. This leaves the potential that a WISCA may be more or less effective in certain regions or areas with different rates of multidrug resistant infections. The retrospective nature of our study is also a limitation, in that we were not able to control for potential confounders. A regression analysis, to control for several of these possible confounders, would ideally be performed in subsequent studies. While the current analysis of these results suggests limited benefit following implementation of this novel tool, it is important to remember that our study was not powered to detect a significant difference in our primary outcome. We suggest incorporating a component of real time decision support, for example between a pharmacist and physician at the time of the WISCA being reported, to optimize the utility of the WISCA on a patient-specific basis. In addition, nearing the completion of this study, our hospital was in the process of setting up and testing a new MALDI-TOF system. Continuing to collect data using the same protocol, alongside this new tool, may present additional complications and potential confounders. We anticipate in its current state, our WISCA may be less impactful with MALDI-TOF analysis available. However, in centres where MALDI- TOF is not available, and in areas where rapid laboratory results are not feasible, a WISCA may prove to be a valuable, relatively inexpensive tool.

CONCLUSION

Interim results do not show a significant difference in time to appropriate antibiotic therapy for patients with gram-negative bacteremia following implementation of a WISCA. Additional real time decision support may be required to facilitate appropriate empiric antibiotic therapy.

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