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: (i) to identify the pharmacokinetic-pharmacodynamic (PK-PD) index associated with the efficacy of gepotidacin against E. coli; (ii) to determine the magnitude of the above-described PK-PD index associated with various bacterial reduction end-points for E. coli; and (iii) to characterize the relationship between gepotidacin exposure and on-therapy E. coli resistance amplification. A 24-h 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 i) in which E. coli NCTC 13441 (gepotidacin MIC, 2 mg/liter) was evaluated, gepotidacin free-drug area under the concentrationtime curve (AUC) from 0 to 24 h to the MIC (AUC/MIC ratio) was identified as the PK-PD index most closely associated with change in bacterial burden (r(2) = 0.925). For the dose-ranging studies (objective ii), in which four E. coli isolates (gepotidacin MIC range, 1 to 4 mg/liter) were studied, the magnitude of the median gepotidacin free-drug AUC/MIC ratio associated with net bacterial stasis and 1- and 2-log(10) CFU reductions for the pooled data set was 33.9, 43.7, and 60.7, respectively. For the hollow-fiber in vitro infection model studies (objective iii), in which one isolate (E. coli NCTC 13441; gepotidacin MIC, 2 mg/liter) was evaluated, gepotidacin free-drug AUC/MIC ratios of 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.

Automated summary

The study aimed to determine the efficacy of gepotidacin against E. coli and its relationship with pharmacokinetic-pharmacodynamic (PK-PD) indexes, as well as to characterize the relationship between gepotidacin exposure and E. coli resistance amplification. Results showed that the gepotidacin free-drug AUC/MIC ratio was closely associated with changes in bacterial burden, and different AUC/MIC values were able to suppress E. coli growth and resistance development.