Postexposure Prophylaxis and Treatment of Bacillus anthracis Infections: A Systematic Review and Meta-analyses of Animal Models, 1947-2019

Abstract

Background: Anthrax is endemic to many countries, including the United States. The causative agent, Bacillus anthracis, poses a global bioterrorism threat. Without effective antimicrobial postexposure prophylaxis (PEPAbx) and treatment, the mortality of systemic anthrax is high. To inform clinical guidelines for PEPAbx and treatment of B. anthracis infections in humans, we systematically evaluated animal anthrax treatment model studies.

Methods: We searched for survival outcome data in 9 scientific search engines for articles describing antimicrobial PEPAbx or treatment of anthrax in animals in any language through February 2019. We performed meta-analyses of efficacy of antimicrobial PEPAbx and treatment for each drug or drug combination using random-effects models. Pharmacokinetic/pharmacodynamic relationships were developed for 5 antimicrobials with available pharmacokinetic data. Monte Carlo simulations were used to predict unbound drug exposures in humans.

Results: We synthesized data from 34 peer-reviewed studies with 3262 animals. For PEPAbx and treatment of infection by susceptible B. anthracis, effective monotherapy can be accomplished with fluoroquinolones, tetracyclines, β-lactams (including penicillin, amoxicillin-clavulanate, and imipenem-cilastatin), and lipopeptides or glycopeptides. For naturally occurring strains, unbound drug exposures in humans were predicted to adequately cover the minimal inhibitory concentrations (MICs; those required to inhibit the growth of 50% or 90% of organisms [MIC50 or MIC90]) for ciprofloxacin, levofloxacin, and doxycycline for both the PEPAbx and treatment targets. Dalbavancin covered its MIC50 for PEPAbx.

Conclusions: These animal studies show many reviewed antimicrobials are good choices for PEPAbx or treatment of susceptible B. anthracis strains, and some are also promising options for combating resistant strains. Monte Carlo simulations suggest that oral ciprofloxacin, levofloxacin, and doxycycline are particularly robust choices for PEPAbx or treatment.

Keywords: anthrax; antimicrobial; drug-resistant; postexposure prophylaxis; treatment.

Figure 1.

Comparison of efficacies for specified antimicrobials used for postexposure prophylaxis (A) or treatment (B). A, Odds of survival (with 95% confidence interval [CI]) for postexposure prophylaxis monotherapy studies with specified antimicrobial compared with nontreated controls. B, Odds of survival (with 95% CI) for treatment monotherapy studies with specified antimicrobial compared with nontreated controls.

Figure 2.

Comparison of efficacies for specified antimicrobial combinations for treatment of susceptible or resistant Bacillus anthracis (A) and anthrax meningitis (B). A. Odds of survival (with 95% confidence interval [CI]) for antimicrobial combinations that included ciprofloxacin for treatment of animals infected with either sensitive or resistant strains. B, Odds of survival (with 95% CI) for treatment monotherapy studies using a rabbit model of anthrax meningitis with a susceptible strain with specified antimicrobials compared with nontreated controls. Due to limited data availability and high mortality rates, a control arm from one anthrax meningitis paper was used as a comparison for treatment arms in 2 other papers. The 3 papers were analyzed as if they were 1 paper.

Figure 3.

Monte Carlo simulation results on the probability of pharmacokinetic/pharmacodynamic target attainment plotted against the minimum inhibitory concentration (MIC) for clinically relevant dosage regimens of 5 antimicrobials. The exposure targets for antimicrobial postexposure prophylaxis (PEPAbx) and treatment (Rx) are indicated, with more details in the Supplementary Materials. Abbreviations: d, day; AUC, area under the concentration-time curve; fAUC, area under the unbound plasma concentration-time curve; inf, infinity.