Activity of dalbavancin against Bacillus anthracis in vitro and in a mouse inhalation anthrax model

Abstract

Bacillus anthracis, the causative agent of anthrax, can produce fatal disease when it is inhaled or ingested by humans. Dalbavancin, a novel, semisynthetic lipoglycopeptide, has potent activity, greater than that of vancomycin, against Gram-positive bacteria and a half-life in humans that supports once-weekly dosing. Dalbavancin demonstrated potent in vitro activity against B. anthracis (MIC range, < or =0.03 to 0.5 mg/liter; MIC(50) and MIC(90), 0.06 and 0.25 mg/liter, respectively), which led us to test its efficacy in a murine inhalation anthrax model. The peak concentrations of dalbavancin in mouse plasma after the administration of single intraperitoneal doses of 5 and 20 mg/kg of body weight were 15 and 71 mg/kg, respectively. At 20 mg/kg, the dalbavancin activity was detectable for 6 days after administration (terminal half-life, 53 h), indicating that long intervals between doses were feasible. The mice were challenged with 50 to 100 times the median lethal dose of the Ames strain of B. anthracis, an inoculum that kills untreated animals within 4 days. The efficacy of dalbavancin was 80 to 100%, as determined by the rate of survival at 42 days, when treatment was initiated 24 h postchallenge with regimens of 15 to 120 mg/kg every 36 h (q36h) or 30 to 240 mg/kg every 72 h (q72h). A regimen of ciprofloxacin known to protect 100% of animals was tested in parallel. Delayed dalbavancin treatment (beginning 36 or 48 h postchallenge) with 60 mg/kg q36h or 120 mg/kg q72h still provided 70 to 100% survival. The low MICs and long duration of efficacy in vivo suggest that dalbavancin may have potential as an alternative treatment or for the prophylaxis of B. anthracis infections.

FIG. 1.

Distribution of susceptibilities to dalbavancin and vancomycin for 30 B. anthracis strains. Red bars, dalbavancin; black bars, vancomycin.

FIG. 2.

Pharmacokinetics of dalbavancin in mouse plasma after the administration of two separate single doses (5 or 20 mg/kg) by either the i.v. or the i.p. route. Each point is the mean for three mice.

FIG. 3.

Postexposure survival by use of prophylaxis against anthrax. Dalbavancin treatment was initiated 24 h after challenge. The mice were monitored for survival for 42 days, and there were10 mice per treatment group. (A) Ciprofloxacin at 30 mg/kg q12 (control). (B) Dose range given q36h. Dalbavancin doses versus control, P < 0.001; dalbavancin doses versus ciprofloxacin, P > 0.05. (C) Dose range given q72h. Dalbavancin doses versus control, P < 0.001; dalbavancin doses versus ciprofloxacin, P > 0.05.

FIG. 4.

Efficacy of delayed treatment with dalbavancin against anthrax. Delayed treatment with dalbavancin was compared to treatment with ciprofloxacin at 30 mg/kg q12 initiated at 48 h postchallenge. The mice were monitored for survival for 42 days. 24 PC, 36 PC, and 48 PC, initiation of treatment at 24, 36, and 48 h postchallenge (PC). (A) Ciprofloxacin treatment (n = 4). (B) Treatment with dalbavancin at 60 mg/kg q36. Each cohort had 10 mice at the time of initiation of treatment at 36 h and 48 h postchallenge. (C) Treatment with dalbavancin at 120 mg/kg q72. The numbers of mice in each cohort at the time of initiation of treatment were seven for 36 h postchallenge and six for 48 h postchallenge. Dalbavancin treatments versus controls, P < 0.001; dalbavancin treatments versus ciprofloxacin, P > 0.05.