Use of anInVitroPharmacodynamic Model To Derive a Moxifloxacin Regimen That Optimizes Kill ofYersinia pestisand Prevents Emergence of Resistance

Abstract

ABSTRACTYersinia pestis, the causative agent of bubonic, septicemic, and pneumonic plague, is classified as a CDC category A bioterrorism pathogen. Streptomycin and doxycycline are the “gold standards” for the treatment of plague. However, streptomycin is not available in many countries, andY. pestisisolates resistant to streptomycin and doxycycline occur naturally and have been generated in laboratories. Moxifloxacin is a fluoroquinolone antibiotic that demonstrates potent activity againstY. pestisinin vitroand animal infection models. However, the dose and frequency of administration of moxifloxacin that would be predicted to optimize treatment efficacy in humans while preventing the emergence of resistance are unknown. Therefore, dose range and dose fractionation studies for moxifloxacin were conducted forY. pestisin anin vitropharmacodynamic model in which the half-lives of moxifloxacin in human serum were simulated so as to identify the lowest drug exposure and the schedule of administration that are linked with killing ofY. pestisand with the suppression of resistance. In the dose range studies, simulated moxifloxacin regimens of ≥175 mg/day killed drug-susceptible bacteria without resistance amplification. Dose fractionation studies demonstrated that the AUC (area under the concentration-time curve)/MIC ratio predicted kill of drug-susceptibleY. pestis, while theCmax(maximum concentration of the drug in serum)/MIC ratio was linked to resistance prevention. Monte Carlo simulations predicted that moxifloxacin at 400 mg/day would successfully treat human infection due toY. pestisin 99.8% of subjects and would prevent resistance amplification. We conclude that in anin vitropharmacodynamic model, the clinically prescribed moxifloxacin regimen of 400 mg/day is predicted to be highly effective for the treatment ofY. pestisinfections in humans. Studies of moxifloxacin in animal models of plague are warranted.