Pharmacodynamics of moxifloxacin against a high inoculum of Escherichia coli in an in vitro infection model.
OBJECTIVE
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.
Singh
Renu
R
Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX, USA.
Ledesma
Kimberly R
KR
Chang
Kai-Tai
KT
Hou
Jing-Guo
JG
Prince
Randall A
RA
Tam
Vincent H
VH
D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001372:Aza Compounds / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015169:Colony Count, Microbial; D027081:DNA Gyrase / Q000235:genetics; D004252:DNA Mutational Analysis; D027101:DNA Topoisomerase IV / Q000235:genetics; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000187:drug effects*; D004927:Escherichia coli Infections / Q000382:microbiology*; D029968:Escherichia coli Proteins / Q000235:genetics; D024841:Fluoroquinolones; D006801:Humans; D008962:Models, Theoretical; D000077266:Moxifloxacin; D011804:Quinolines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D017422:Sequence Analysis, DNA
D000900:Anti-Bacterial Agents; D001372:Aza Compounds; D029968:Escherichia coli Proteins; D024841:Fluoroquinolones; D011804:Quinolines; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase; D000077266:Moxifloxacin