Effective Antimicrobial Regimens for Use in Humans for Therapy of Bacillus anthracis Infections and Postexposure Prophylaxis

Abstract

Expanded options for treatments directed against pathogens that can be used for bioterrorism are urgently needed. Treatment regimens directed against such pathogens can be identified only by using data derived from in vitro and animal studies. It is crucial that these studies reliably predict the efficacy of proposed treatments in humans. The objective of this study was to identify a levofloxacin treatment regimen that will serve as an effective therapy for Bacillus anthracis infections and postexposure prophylaxis. An in vitro hollow-fiber infection model that replicates the pharmacokinetic profile of levofloxacin observed in humans (half-life [t 1/2 ], 7.5 h) or in animals, such as the mouse or the rhesus monkey (t 1/2 , ϳ2 h), was used to evaluate a proposed indication for levofloxacin (500 mg once daily) for the treatment of Bacillus anthracis infections. The results obtained with the in vitro model served as the basis for the doses and the dose schedules that were evaluated in the mouse inhalational anthrax model. The effects of levofloxacin and ciprofloxacin treatment were compared to those of no treatment (untreated controls). The main outcome measure in the in vitro hollow-fiber infection model was a persistent reduction of culture density (>4 log 10 reduction) and prevention of the emergence of levofloxacin-resistant organisms. In the mouse inhalational anthrax model the main outcome measure was survival. The results indicated that levofloxacin given once daily with simulated human pharmacokinetics effectively sterilized Bacillus anthracis cultures. By using a simulated animal pharmacokinetic profile, a once-daily dosing regimen that provided a human-equivalent exposure failed to sterilize the cultures. Dosing regimens that "partially humanized" levofloxacin exposures within the constraints of animal pharmacokinetics reproduced the antimicrobial efficacy seen with human pharmacokinetics. In a mouse inhalational anthrax model, once-daily dosing was significantly inferior (survival end point) to regimens of dosing every 12 h or every 6 h with identical total daily levofloxacin doses. These results demonstrate the predictive value of the in vitro hollow-fiber infection model with respect to the success or the failure of treatment regimens in animals. Furthermore, the model permits the evaluation of treatment regimens that "humanize" antibiotic exposures in animal models, enhancing the confidence with which animal models may be used to reliably predict the efficacies of proposed antibiotic treatments in humans in situations (e.g., the release of pathogens as agents of bioterrorism or emerging infectious diseases) where human trials cannot be performed. A treatment regimen effective in rhesus monkeys was identified.

Discriminating Virulence Mechanisms amongBacillus anthracisStrains by Using a Murine Subcutaneous Infection Model

“…Pulmonary anthrax in mice is produced by delivering B. anthracis into the lung by aerosolization or by intranasal or intratracheal (i.t.) inoculation (8,9,21,22,29,30). Other routes used for experimental infection are subcutaneous (s.c.) (30,49) and intravenous (i.v.)…”

Impact of Spores on the Comparative Efficacies of Five Antibiotics for Treatment of Bacillus anthracis in an In Vitro Hollow Fiber Pharmacodynamic Model

“…Yet, identification of the antibiotic regimen that kills B. anthracis at the highest rate may improve treatment outcomes for this rapidly progressive, often fatal disease. Moreover, the pharmacokinetics of drugs frequently differ between animals and humans (9,19). Thus, studies in animals may not predict the relative efficacies of clinically prescribed antibiotic regimens in people (9,21).…”

“…The in vitro hollow fiber systems have been described previously (9,11,(22)(23)(24). Bacteria inoculated into the extracapillary space of a hollow fiber cartridge (FiberCell Systems, Inc., Frederick, MD) containing MHB can be exposed to fluctuating concentrations of a drug that simulate the non-protein-bound (free) serum concentrationtime profiles reported for clinically prescribed antibiotic regimens that are used in humans (Fig.…”

“…Yet this information is crucial since the administration of the most rapidly active drug may have a life-saving advantage in patients who are critically ill from disease due to this microbe. Furthermore, since B. anthracis isolates resistant to ciprofloxacin and doxycycline have been described (1,3,5,9,12), identification of additional antimicrobial agents with efficacies against this pathogen is needed.…”

Pharmacokinetic Considerations and Efficacy of Levofloxacin in an Inhalational Anthrax (Postexposure) Rhesus Monkey Model

“…However, challenges arise in designing an effective dosing regimen based on the differences between pharmacokinetic parameters for humans and those for rhesus monkeys. The half-life of levofloxacin in the blood of rhesus monkeys is much shorter (approximately 2 h) than in the blood of humans (approximately 7 h), making the use of the human once-daily (QD) dosing regimen unacceptable (6). Therefore, a novel humanized dosing regimen for levofloxacin designed to simulate human pharmacokinetics was selected and utilized in this inhalation anthrax rhesus monkey study designed to demonstrate the efficacy of levofloxacin for the treatment of inhalational (postexposure) anthrax.…”