The potential of liposome-encapsulated ciprofloxacin as a tularemia therapy

Abstract

Liposome-encapsulation has been suggested as method to improve the efficacy of ciprofloxacin against the intracellular pathogen, Francisella tularensis. Early work with a prototype formulation, evaluated for use against the F. tularensis live vaccine strain, showed that a single dose of liposomal ciprofloxacin given by the intranasal or inhalational route could provide protection in a mouse model of pneumonic tularemia. Liposomal ciprofloxacin offered better protection than ciprofloxacin given by the same routes. Liposomal ciprofloxacin has been further developed by Aradigm Corporation for Pseudomonas aeruginosa infections in patients with cystic fibrosis and non-cystic fibrosis bronchiectasis. This advanced development formulation is safe, effective and well tolerated in human clinical trials. Further evaluation of the advanced liposomal ciprofloxacin formulation against the highly virulent F. tularensis Schu S4 strain has shown that aerosolized CFI (Ciprofloxacin encapsulated in liposomes for inhalation) provides significantly better protection than oral ciprofloxacin. Thus, liposomal ciprofloxacin is a promising treatment for tularemia and further research with the aim of enabling licensure under the animal rule is warranted.

Keywords: Francisella tularensis; ciprofloxacin; liposomal; tularemia.

Figure 1

Therapeutic efficacy of a single dose of ciprofloxacin or liposomal ciprofloxacin against murine inhalational F. tularensis LVS and Schu S4 infection. Mice were challenged with F. tularensis LVS by the intranasal route (approximately 1 × 10² CFU at DRDC or 6 × 10⁴ CFU at Dstl) or F. tularensis Schu S4 by the aerosol route (10 CFU retained dose). Treatment was initiated at 72 h post-challenge for LVS infections and 24 h post-challenge in the Schu S4 study. Treatment included 50 mg/kg of oral ciprofloxacin, 50 mg/kg of intranasal ciprofloxacin, 50 mg/kg liposomal ciprofloxacin, or 1 mg/kg lung dose of aerosolized liposomal ciprofloxacin. Graph shows percentage survival at the end of the experiment. LVS (DRDC) data is adapted from Di Ninno et al. (1993) (Intranasal ciprofloxacin and liposomal ciprofloxacin) and Wong et al. (2003) (aerosolized liposomal ciprofloxacin). Schu S4 and LVS (Dstl) data is adapted from Hamblin et al. (2014).