Pharmacokinetic-pharmacodynamic assessment of faropenem in a lethal murine Bacillus anthracis inhalation postexposure prophylaxis model.

There are few options for prophylaxis after exposure to Bacillus anthracis, especially in children and women of childbearing potential. Faropenem is a beta-lactam in the penem subclass that is being developed as an oral prodrug, faropenem medoxomil, for the treatment of respiratory tract infections. Faropenem was shown to have in vitro activity against B. anthracis strains that variably express the bla1 beta-lactamase (MIC range,

Is 60 days of ciprofloxacin administration necessary for postexposure prophylaxis for Bacillus anthracis?

Sixty days of ciprofloxacin administration at 500 mg every 12 h is currently recommended for the prophylaxis of inhalational exposure to Bacillus anthracis. We examined Bacillus anthracis (Delta-Sterne strain) in our hollow-fiber infection model. We measured the ciprofloxacin concentrations achieved and the number of organisms present before heat shock (total population) and after heat shock (spore population). We fit a mathematical model to these data. Monte Carlo simulation with differing initial spore burdens (3, 5, and 6.9 log(10) CFU/ml) demonstrated that 35 days of this regimen would completely clear the spore burden in 95% of patients. Durations of 110 days did not achieve 99.9% eradication, irrespective of initial burden, because of between-patient variance in drug pharmacokinetics. Given the absence of person-to-person transmission for Bacillus anthracis, adverse drug effects with long-term ciprofloxacin administration, and the possibility of engendering resistance in bodily flora, shorter prophylaxis duration should be given consideration, along with careful monitoring of all exposed individuals.

Pharmacokinetics-pharmacodynamics of gatifloxacin in a lethal murine Bacillus anthracis inhalation infection model.

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 population pharmacokinetic models for gatifloxacin and simulation to identify dosing regimens with high probabilities of attaining exposures likely to be efficacious in adults and children. In this work, 6- to 8-week-old nonneutropenic female BALB/c mice received aerosol challenges of 50 to 75 50% lethal doses of B. anthracis (Ames strain, for which the gatifloxacin MIC is 0.125 mg/liter). Gatifloxacin was administered at 6- or 8-h intervals beginning 24 h postchallenge for 21 days, and dosing was designed to produce profiles mimicking fractionated concentration-time profiles for humans. Mice were evaluated daily for survival. Hill-type models were fitted to survival data. To identify potentially effective dosing regimens, adult and pediatric population pharmacokinetic models for gatifloxacin and Monte Carlo simulation were used to generate 5,000 individual patient exposure estimates. The ratio of the area under the concentration-time curve from 0 to 24 h (AUC(0-24)) to the MIC of the drug for the organism (AUC(0-24)/MIC ratio) was the PK-PD measure most predictive of survival (R(2) = 0.96). The 50% effective dose (ED(50)) and the ED(90) and ED(99) corresponded to AUC(0-24)/MIC ratios of 11.5, 15.8, and 30, respectively, where the maximum effect was 97% survival. Simulation results indicate that a daily gatifloxacin dose of 400 mg for adults and 10 mg/kg of body weight for children gives a 100% probability of attaining the PK-PD target (ED(99)). Sensitivity analyses suggest that the probability of PK-PD target attainment in adults and children is not affected by increases in MICs for strains of B. anthracis to levels as high as 0.5 mg/liter.