Demonstrating the protective efficacy of the novel fluoroquinolone finafloxacin against an inhalational exposure to Burkholderia pseudomallei [PublishAheadOfPrint]

Burkholderia pseudomallei is the causative agent of melioidosis, a serious disease endemic in South East Asia and Northern Australia. Antibiotic treatment is lengthy and relapse often occurs. Finafloxacin is a novel fluoroquinolone with increased antibacterial activity in acidic conditions in contrast to other fluoroquinolones which demonstrate reduced activity at lower pH. Therefore finafloxacin may have improved efficacy against B. pseudomallei, which can survive within host cells where the local pH is acidic. In vitro analysis was performed using MICs, MBCs, time kill assays, persister cell assays and macrophage assays. Finafloxacin showed increased bactericidal activity at pH 5 in comparison to pH 7 and ciprofloxacin at pH 5. In vivo studies in BALB/c mice included pharmacokinetic studies to inform an appropriate dosing regimen. Finafloxacin efficacy was evaluated in an inhalational murine model of melioidosis where antibiotic treatment was initiated at 6 or 24 hours post challenge and continued for 14 days, and mice were observed for 63 days. Survival of infected mice following 14 days of treatment was 80%, 60% or 0% for treatment initiated at 6 hours and 60%, 30% or 0 % for treatment initiated at 24 hours for finafloxacin, co-trimoxazole or ciprofloxacin, respectively. In summary, finafloxacin has increased bactericidal activity for B. pseudomallei under acidic conditions in vitro and improves survival in a murine model of melioidosis when compared to ciprofloxacin. Furthermore, finafloxacin improves bacteriological clearance when compared to co-trimoxazole, suggesting it may offer effective post exposure prophylaxis against B. pseudomallei.

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