Objectives: Escherichia coli is the leading bacterial species implicated in intra-abdominal infections. In these infections a high bacterial burden with pre-existing resistant mutants are likely to be encountered and resistance could be amplified with suboptimal dosing. Our objective was to investigate the pharmacodynamics of moxifloxacin against a high inoculum of E. coli using an in vitro hollow fibre infection model (HFIM).
Methods: Three wild-type strains of E. coli (ATCC 25922, MG1655 and EC28044) were studied by exposing approximately 2 x 10(8) cfu/mL (20 mL) to escalating dosing regimens of moxifloxacin (ranging from 30 to 400 mg, once daily). Serial samples were obtained from HFIM over 120 h to enumerate the total and resistant subpopulation. Quinolone resistance-determining regions of gyrA and parC of resistant isolates were sequenced to confirm the mechanism of resistance.
Results: The pre-exposure MIC of the three wild-type strains was 0.0625 mg/L. Simulated moxifloxacin concentration profiles in HFIM were satisfactory (r(2) >or= 0.94). Placebo experiments revealed natural mutants, but no resistance amplification. Regrowth and resistance amplification was observed between 30 mg/day (AUC/MIC = 47) and 80 mg/day dose (AUC/MIC = 117). Sustained bacterial suppression was achieved at >or=120 mg/day dose (AUC/MIC = 180). Point mutations in gyrA (D87G or S83L) were detected in resistant isolates.
Conclusions: Our results suggest that suboptimal dosing may facilitate resistance amplification in a high inoculum of E. coli. The clinical dose of moxifloxacin (400 mg/day) was adequate to suppress resistance development in three wild-type strains. Clinical relevance of these findings warrants further in vivo investigation.