The Fluoroquinolone Finafloxacin Protects BALB/c Mice Against an Intranasal Infection With Francisella tularensis Strain SchuS4

Abstract

The efficacy of the novel fluoroquinolone finafloxacin was evaluated as a potential therapeutic in vitro and in vivo , following an intranasal infection of Francisella tularensis strain SchuS4 in BALB/c mice. We demonstrated that short treatment courses of finafloxacin provide high levels of protection, with a single dose resulting in a significant increase in time to death when compared to ciprofloxacin. In addition, following investigation into the window of opportunity for treatment, we have shown that finafloxacin can provided protection when administered up to 96 h post-challenge. This is particularly encouraging since mice displayed severe signs of disease at this time point. In summary, finafloxacin may be a promising therapy for use in the event of exposure to F. tularensis , perhaps enabling the treatment regimen to be shortened or if therapy is delayed. The efficacy of finafloxacin against other biological threat agents also warrants investigation.

Demonstration of the Broad-Spectrum In Vitro Activity of Finafloxacin against Pathogens of Biodefense Interest

“…The data set detailed in these studies demonstrates that finafloxacin has activity under both acidic and neutral conditions, with enhanced activity of finafloxacin in low-pH environments, where other antibiotics (including ciprofloxacin) have reduced activity. This has been demonstrated for all of the biodefense pathogens of interest and is in agreement with data generated by other groups (7, 8, 10, 11). The improved activity of finafloxacin compared to that of ciprofloxacin (a typical treatment for infections caused by B.…”

“…The availability of formulations of finafloxacin that can be delivered orally and systemically makes finafloxacin a worthy alternative for the treatment of a range of infections. In addition to good safety and efficacy data obtained in patients suffering from complicated urinary tract infections and pyelonephritis, previous studies have also demonstrated efficacy against the biothreat agents Burkholderia pseudomallei and Francisella tularensis in vitro and in vivo (6, 9–11). The aim of this study was to further evaluate the in vitro activity of finafloxacin against larger strain panels of biodefense pathogens.…”

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

“…Finafloxacin provided a protective benefit when compared with ciprofloxacin when where finafloxacin and ciprofloxacin offered 96% and 60% protection (respectively) when delivered for 7 days and initiated at hours post-challenge (35).…”

“…Comparisons from 10 days post-challenge onwards in these mice were not made, as too many mice had succumbed to infection. (38,35). Although the route of infection was different, the LD50 of strain SCHU S4 by both routes is low (<10 CFU) (39,40).…”

“…and orally) resulted in an improved clinical outcome over a 10-day course of ciprofloxacin in a phase 2 trial of complicated urinary tract infections (UTIs) and/or pyelonephritis, and it demonstrated the ability to treat fluoroquinolone-resistant uropathogens ( 31 , 32 ). In addition, in vitro activity has been demonstrated against all of the bacterial agents of biodefence interest, with efficacy demonstrated against inhalational infection with Burkholderia pseudomallei and intranasal infection with F. tularensis in vivo ( 33 – 35 ).…”