Gepotidacin Pharmacokinetics-Pharmacodynamics Against
Escherichia coli
in the One-Compartment and Hollow-Fiber
In Vitro
Infection Model Systems
Gepotidacin is a novel, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action with an in vitro spectrum of activity that includes Escherichia coli . Our objectives herein were the following: 1) to identify the pharmacokinetic-pharmacodynamics (PK-PD) index associated with efficacy for gepotidacin against E. coli ; 2) to determine the magnitude of the above-described PK-PD index associated with various bacterial reduction endpoints for E. coli ; and 3) to characterize the relationship between gepotidacin exposure and on-therapy E. coli resistance amplification. A 24-hour one-compartment in vitro infection model was used to investigate the first two study objectives and a 10-day hollow-fiber in vitro infection model was used to evaluate the third objective. For the dose-fractionation studies (objective 1), in which E. coli NCTC 13441 (gepotidacin MIC, 2 mg/L) was evaluated, free-drug gepotidacin area under the concentration-time curve (AUC) from 0 to 24 h to the MIC (AUC/MIC ratio) was identified as PK-PD index most closely associated with change in bacterial burden ( R 2 = 0.925). For the dose-ranging studies (objective 2), in which four E. coli isolates (gepotidacin MIC range, 1 to 4 mg/L) were studied, the magnitude of the median free-drug gepotidacin AUC/MIC ratio associated with net bacterial stasis and 1- and 2-log 10 CFU reductions for the pooled dataset was 33.9, 43.7, and 60.7, respectively. For the hollow-fiber in vitro infection model studies (objective 3), in which one isolate ( E. coli NCTC 13441 gepotidacin MIC, 2 mg/L) was evaluated, free-drug gepotidacin AUC/MIC ratios 275 and greater were sufficient to suppress on-therapy resistance amplification. Together, the data generated from these studies will be useful to support discrimination among candidate dosing regimens for future clinical study.