Pharmacokinetics-Pharmacodynamics of Gatifloxacin in a Lethal Murine-Bacillus anthracis Inhalation Infection Model

Institute for Clinical Pharmacodynamics, Ordway Research Institute, Albany, NY; School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY; William S. Middleton Memorial VA Medical Center, Madison, WI; Emerging Infections and Fungal Pharmacodynamics Laboratory, Ordway Research Institute, Albany NY; United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD

^* To whom correspondence should be addressed. Email: PAmbrose-ICPD{at}OrdwayResearch.org.

	Abstract

We determined the pharmacokinetic-pharmacodynamic (PK-PD) measure most predictive of gatifloxacin efficacy and the magnitude of this measure necessary for survival in a murine-Bacillus anthracis inhalation infection model. We then used gatifloxacin population pharmacokinetic models and simulation to identify dosing regimens with high probabilities of attaining exposures likely efficacious in adults and children. In this work, 6-8 week-old, non-neutropenic, female, BALB/c mice received aerosol challenges of 50-75 LD₅₀ of B. anthracis (Ames strain, gatifloxacin MIC 0.125 mg/L). Gatifloxacin was administered at 6 or 8 hour intervals beginning 24 hours post-challenge for 21 days and dosed in a manner that mimicked fractionated human concentration-time profiles. Mice were evaluated daily for survival. Hill-type models were fit to survival data. To identify potentially effective dosing regimens, adult and pediatric gatifloxacin population pharmacokinetic models and Monte Carlo simulation were used to generate 5,000 individual patient exposure estimates. The ratio of the area under the concentration-time curve at 24 hours to the minimum inhibitory concentration of the drug to the organisms (AUC_0-24:MIC) was the PK-PD measure most predictive of survival (R² = 0.96). The 50, 90, and 99% effective dose (ED₅₀, ED₉₀ and ED₉₉) corresponded to AUC_0-24:MIC ratios of 11.5, 15.8 and 30, respectively, where maximal effect (E_max) was 97% survival. Simulation results indicate that a daily gatifloxacin dose of 400 mg in adults and 10 mg/kg in children results in a 100% probability of PK-PD target attainment (ED₉₉). Sensitivity analyses suggest the probability of PK-PD target attainment is not affected by MIC increases for strains of B. anthracis as high as 0.5 mg/L in adults and children.