Liposome encapsulation of ciprofloxacin improves protection against highly virulent Francisella tularensis strain Schu S4

Abstract

Liposome-encapsulated ciprofloxacin for inhalation (CFI) was investigated as a putative postexposure therapeutic for two strains of Francisella tularensis. The efficacies of oral ciprofloxacin and intranasally instilled CFI could not be distinguished in a mouse model of infection with the F. tularensis live vaccine strain (LVS), where a single dose of either formulation offered full protection against a lethal challenge. However, mouse studies with the more virulent Schu S4 strain of F. tularensis demonstrated that a higher level of protection against a lethal aerosol infection is provided by CFI than by oral ciprofloxacin. In addition, using this infection model, it was possible to discriminate the efficacy of intranasally instilled CFI from that of aerosolized CFI, with aerosolized CFI providing full protection after just a single dose. The improved efficacy of CFI compared to oral ciprofloxacin is likely due to the high sustained concentrations of ciprofloxacin in the lung. In summary, CFI may be a promising therapy, perhaps enabling the prophylactic regimen to be shortened, for use in the event of a deliberate release of F. tularensis. The prophylactic efficacy of CFI against other biological warfare (BW) threat agents also warrants investigation.

FIG 1

Therapeutic efficacies of oral ciprofloxacin and intranasal CFI against an inhalational F. tularensis LVS infection in mice. Groups of 5 BALB/c mice were challenged with F. tularensis LVS via the intranasal (I/N) route and treated at 72 h (solid lines) or 96 h (dotted lines) postchallenge with a single 50-mg/kg dose of oral ciprofloxacin (diamonds), intranasal CFI (circles), or PBS (squares) delivered by the intranasal route. (A) Survival of mice. Only mice treated with PBS succumbed to the infection. (B) Clinical scores of mice. Mice were scored on the extent of piloerection, hunching, eye problems, and locomotion, with scores of 0, 1, and 2 specified for each category. (C) Weight change of mice over the course of the experiment. There were no significant differences in weight between mice dosed with oral ciprofloxacin or intranasally instilled CFI.

FIG 2

Therapeutic efficacies of oral ciprofloxacin, intranasal CFI, and aerosolized CFI against inhalational F. tularensis Schu S4 infection in mice. Groups of 12 BALB/c mice were challenged with F. tularensis Schu S4 via the aerosol route and treated at 24 h postchallenge with 50 mg/kg of oral ciprofloxacin (diamonds line), 50 mg/kg of intranasal CFI (circles, solid lines), a 1-mg/kg lung dose of aerosolized CFI (circles, dashed lines), or PBS (squares) delivered by the intranasal route. Graphs show the survival of mice treated with a single dose of antibiotic (A), 3 days of therapy (B), or 5 days of therapy (C). Asterisks indicate significant differences in survival (**, P < 0.005).