Finafloxacin Is an Effective Treatment for Inhalational Tularemia and Plague in Mouse Models of Infection

Abstract

Infection with aerosolized Francisella tularensis or Yersinia pestis can lead to lethal disease in humans if treatment is not initiated promptly. Finafloxacin is a novel fluoroquinolone which has demonstrated broad-spectrum activity against a range of bacterial species in vitro, in vivo, and in humans, activity which is superior in acidic, infection-relevant conditions. Human-equivalent doses of finafloxacin or ciprofloxacin were delivered at 24 h (representing prophylaxis) or at 72 or 38 h (representing treatment) postchallenge with F. tularensis or Y. pestis, respectively, in BALB/c mouse models. In addition, a short course of therapy (3 days) was compared to a longer course (7 days). Both therapies provided a high level of protection against both infections when administered at 24 h postchallenge, irrespective of the length of the dosing regimen; however, differences were observed when therapy was delayed. A benefit was demonstrated with finafloxacin compared to ciprofloxacin in both models when therapy was delivered later in the infection. These studies suggest that finafloxacin is an effective alternative therapeutic for the prophylaxis and treatment of inhalational infections with F. tularensis or Y. pestis.

Keywords: finafloxacin; plague; tularemia.

FIG 1

Concentration of F. tularensis in organs before treatment was initiated. Bacterial counts (CFU/g of tissue or CFU/ml bone marrow) were determined in panels of organs at 24 or 72 h postchallenge. (A) Five mice were challenged and euthanized at 24 h postchallenge. (B) Five mice were challenged and euthanized at 72 h postchallenge. LoD, limit of detection.

FIG 2

Percentage survival of mice in each treatment group following challenge with aerosolized F. tularensis. Mice were challenged with a mean retained dose of 272 CFU of F. tularensis by the inhalational route and treated with finafloxacin (23.1 mg/kg) every 8 h by the oral route or ciprofloxacin (30 mg/kg) every 12 h by the i.p. route. Control animals received substances by the oral (vehicle) or i.p. (PBS) route. Regimens were initiated at 24 (A) or 72 (B) hours postchallenge for 3 or 7 days. **, P < 0.01; ****, P < 0.0001.

FIG 3

Clinical scores recorded throughout the study. Mice were challenged with a mean retained dose of 272 CFU of F. tularensis by the inhalational route and treated with finafloxacin (23.1 mg/kg) every 8 h by the oral route or ciprofloxacin (30 mg/kg) every 12 h by the i.p. route. Control animals received substances by the oral (vehicle) or i.p. (PBS) route. Regimens were initiated at 24 or 72 h postchallenge and continued for 3 or 7 days. These are heat maps for each mouse in the study, determined using the clinical scores recorded for each individual mouse, a minimum of twice daily. The lighter the color, the less severe the disease. Gray boxes represent animals that succumbed to infection. The arrows and shaded boxes represent the treatment period.

FIG 4

Concentration of Y. pestis in organs before treatment was initiated. Bacterial counts (CFU/g of tissue or CFU/ml) were determined in panels of organs at 24 or 38 h postchallenge. (A) Five mice were challenged and euthanized at 24 h postchallenge. (B) Five mice were challenged and euthanized at 38 h postchallenge. LoD, limit of detection.

FIG 5

Percentage survival of mice in each treatment group following challenge with aerosolized Y. pestis. Mice were challenged with a mean retained dose of 8.9 × 10³ CFU of Y. pestis by the inhalational route and treated with finafloxacin (23.1 mg/kg) every 8 h by the oral route or ciprofloxacin (30 mg/kg) every 12 h by the i.p. route. Control animals received substances by the oral (vehicle) or i.p. (PBS) route. Regimens were initiated at 24 h postchallenge for 3 or 7 days (A) or at 38 h postchallenge for 3 or 7 days (B).

FIG 6

Clinical scores recorded throughout the study. Mice were challenged with a mean retained dose of 8.9 × 10³ CFU of Y. pestis by the inhalational route and treated with finafloxacin (23.1 mg/kg) every 8 h by the oral route or ciprofloxacin (30 mg/kg) every 12 h by the i.p. route. Control animals received substances by the oral (vehicle) or i.p. (PBS) route. Regimens were initiated at 24 or 38 h postchallenge and continued for 3 or 7 days. These are heat maps for each mouse in the study, determined using the clinical scores recorded for each individual mouse, a minimum of twice daily. The lighter the color, the less severe the disease. Gray boxes represent animals that succumbed to infection. The arrows and shaded boxes represent the treatment period.