1291. PROVE (Retrospective Cefiderocol Chart Review) Study of Real-World Outcomes and Safety in the Treatment of Patients with Gram-negative Bacterial Infections in the US and Europe

Abstract Background Gram-negative bacterial resistance is a global health problem. Limited treatment options exist, especially for carbapenem resistant (CR) pathogens containing metallo-β-lactamases (MBLs) and multidrug resistant non-lactose fermenting bacteria. Cefiderocol (CFDC) retains activity against resistant strains. We describe the objectives, design, and early results of PROVE, a real world retrospective study of CFDC use. Methods PROVE is a multi-center, chart review study of CFDC use for resistant Gram-negative infections (GNI). Cases were eligible if they received ≥ 72 hrs of CFDC. Demographics, comorbidity, pathogen, infection site, and treatment course were assessed. Outcomes included all-cause 14-day and inpatient mortality and length of stay (LOS). Clinical resolution was defined by documentation that clinical signs and/or symptoms had resolved or improved without relapse. Results 24 patients who were treated with CFDC at 2 sites were included to date. Median age was 48 years (Range: 19 - 69 years); 33% were female. The most common comorbidity was diabetes (n=7, 29%). Median total ICU LOS was 36 days. Targeted treatment of documented GNI without preceding failure of prior therapy accounted for 71% of CFDC use. Empirical and salvage treatments accounted for 4% and 25% respectively (Table 1). Median time from admission to 1st CFDC dose was 21 days. Acinetobacter baumannii and Pseudomonas aeruginosa accounted for > 75% of isolates (Fig.1). 92% of patients had CR isolates; > 50% were respiratory. Sensitivity to CFDC was tested in 58% of which 71% were sensitive. All-cause 14-day post-CFDC mortality was 13% (95% CI: 2, 27) and overall hospital mortality 25% (95% CI: 6, 44). Clinical resolution was reached in 54% (95% CI: 33, 76). Median post-CFDC LOS was 40 days. Outcomes were stratified by key covariates (Table 2). Conclusion We present initial data for real world use of CFDC for resistant GNI. Patients were complex with multiple comorbidities, some hospitalized for long periods before their index GNI. Outcomes largely reflect this patient population. Additional data are needed to determine the optimal role of CFDC. PROVE offers an opportunity to see how CFDC is being utilized in various settings as well as a first look at key, real world outcomes. Disclosures Stephen Marcella, MD, MPH, Shionogi, Inc (Employee) Steven Smoke, PharmD, Karius (Advisor or Review Panel member)Shionogi (Scientific Research Study Investigator, Advisor or Review Panel member) Ryan K. Shields, PharmD, MS, Shionogi (Consultant, Research Grant or Support) David van Duin, MD, PhD, Entasis (Advisor or Review Panel member)genentech (Advisor or Review Panel member)Karius (Advisor or Review Panel member)Merck (Grant/Research Support, Advisor or Review Panel member)Pfizer (Consultant, Advisor or Review Panel member)Qpex (Advisor or Review Panel member)Shionogi (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member)Utility (Advisor or Review Panel member)

Background. Gram-negative bacterial resistance is a global health problem. Limited treatment options exist, especially for carbapenem resistant (CR) pathogens containing metallo-β-lactamases (MBLs) and multidrug resistant non-lactose fermenting bacteria. Cefiderocol (CFDC) retains activity against resistant strains. We describe the objectives, design, and early results of PROVE, a real world retrospective study of CFDC use.
Methods. PROVE is a multi-center, chart review study of CFDC use for resistant Gram-negative infections (GNI). Cases were eligible if they received ≥ 72 hrs of CFDC. Demographics, comorbidity, pathogen, infection site, and treatment course were assessed. Outcomes included all-cause 14-day and inpatient mortality and length of stay (LOS). Clinical resolution was defined by documentation that clinical signs and/ or symptoms had resolved or improved without relapse.

Conclusion.
We present initial data for real world use of CFDC for resistant GNI. Patients were complex with multiple comorbidities, some hospitalized for long periods before their index GNI. Outcomes largely reflect this patient population. Additional data are needed to determine the optimal role of CFDC. PROVE offers an opportunity to see how CFDC is being utilized in various settings as well as a first look at key, real world outcomes.
Disclosures Background. Carbapenem-resistant Enterobacterales are considered an urgent threat for patients in healthcare facilities, causing infections with significant morbidity and mortality. Most isolates are multidrug resistant with limited treatment options, so combination therapy is an alternative. Recently, synergy with piperacillin/ tazobactam (P/T) + meropenem (MP) was demonstrated against 7/10 (70%) KPCproducing Escherichia coli and 9/10 (90%) OXA-48-producing K. pneumoniae using time-kill assay (Lawandi et al, 2021). The aim of the present study was to further evaluate the combination of P/T + MP against KPC-producing Enterobacter cloacae, in addition to OXA-producing K. pneumoniae using our rapid ETEST MIC:MIC synergy method.
Conclusion. Using our ETEST MIC:MIC method, the combination of P/T + MP demonstrated synergy or additivity in 5/7 OXA-producing K. pneumoniae and 7/7 KPC-producing E. cloacae, similar to previously published findings showing synergy in 7/10 KPC-producing E. coli and 9/10 OXA-48-producing K. pneumoniae using time-kill assay. Our ETEST synergy method is simple to use and should be evaluated more extensively. Regardless of the method used, results may or may not correlate in an in vivo setting. In vivo studies are needed.
Disclosures. All Authors: No reported disclosures

Session: P-72. Resistance Mechanisms
Background. Increasing resistance among agents commonly prescribed to treat urinary tract infections indicate that new oral agents are urgently needed.
Ceftibuten in combination with VNRX-7145 is under development as an oral treatment for complicated urinary tract infections caused by serine β-lactamase-producing Enterobacterales, including isolates carrying ESBLs and carbapenemases. In vivo,  is cleaved into to the active inhibitor, VNRX-5236. This study assessed the in vitro activity of ceftibuten/VNRX-5236 against 592 isolates of Enterobacterales from urinary tract infections (UTIs) from a 2018-2020 global culture collection.
Methods. MICs of ceftibuten with VNRX-5236 fixed at 4 µg/mL and comparators were determined following CLSI M07-A11 guidelines against 592 Enterobacterales. Isolates were from community and hospital UTI infections collected from 133 sites in 31 countries in 2018-2020. Resistant phenotypes were based on 2021 CLSI breakpoints.

Results
Disclosures