1095. Pharmacokinetics-Pharmacodynamics Evaluation of Tebipenem Pivoxil Hydrobromide Using the 10-Day Hollow-Fiber In Vitro Infection Model

Abstract Background Tebipenem pivoxil hydrobromide, an orally bioavailable prodrug of tebipenem, is currently in development for the treatment of complicated urinary tract infections. The spectrum of tebipenem activity against Enterobacterales is consistent with intravenous carbapenems such as ertapenem and meropenem including extended spectrum beta-lactamase (ESBL) and AmpC producing organisms. The goal of these studies was to determine the tebipenem exposure required to prevent on-therapy resistance and to evaluate the tebipenem regimen utilized in the recent Phase 3 clinical trial. Methods Three Escherichia coli clinical isolates (ESBL +, Sequence Type -131) (tebipenem MIC = 0.008 to 0.03 mg/L) were subjected to concentration-time profiles simulating free-drug plasma concentrations after oral administration of tebipenem regimens in a hollow-fiber in vitro infection model. Dose-ranging studies were completed using two isolates at an initial burden of 108 CFU/mL and with exposures for tebipenem regimens ranging from 4.69 to 1200 mg administered every eight hours (q8h). An additional isolate was subjected to only the tebipenem 600 mg q8h regimen evaluated in the Phase 3 trial. Samples were collected for the enumeration of bacterial burdens and evaluation of the simulated pharmacokinetic profile. Each sample for bacterial enumeration was suspended onto drug-free and tebipenem-supplemented agar plates in order to observe the density of the total- and drug-resistant subpopulations over the 10-day period. Results A full dose response, ranging from treatment failure to reductions in bacterial burden from baseline, were observed in the dose-ranging studies for the two E. coli isolates. Tebipenem consistently lowered bacterial burdens below that of the initial inoculum at a dose of 600 mg q8h for all three E. coli isolates. Amplification of resistance was observed intermittently for all regimens, but was never equal to that of the total population at the 600 mg q8h clinical dose. Tebipenem MIC values for isolates collected from the drug-supplemented agar ranged from 0.06 to 0.25 mg/L, representing four two-fold dilutions from baseline. Conclusion These data support the selection of tebipenem dosing regimens that minimize the potential for on-therapy drug-resistance amplification. Disclosures Brian D. VanScoy, B.S., 3-V Biosciences (Grant/Research Support)Achogen (Grant/Research Support)Amplyx Pharmaceuticals, Inc. (Grant/Research Support)Arixa Pharmaceuticals (Grant/Research Support)Arsanis Inc. (Grant/Research Support)B. Braun Medical Inc. (Grant/Research Support)Basilea Pharmaceutica (Grant/Research Support)BLC USA (Grant/Research Support)Boston Pharmaceuticals (Grant/Research Support)Bravos Biosciences, LLC (Grant/Research Support)Cidara Therapeutics Inc. 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