Demonstrating the Protective Efficacy of the Novel Fluoroquinolone Finafloxacin against an Inhalational Exposure to Burkholderia pseudomallei

Abstract

Burkholderia pseudomallei is the causative agent of melioidosis, a serious disease endemic in Southeast 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 a 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, minimal bactericidal concentrations (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 h postchallenge and continued for 14 days, and mice were observed for 63 days. The survival of infected mice following 14 days of treatment was 80%, 60% or 0% for treatments initiated at 6 h and 60%, 30% or 0% for treatments initiated at 24 h 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 compared with those for ciprofloxacin. Furthermore, finafloxacin improves bacteriological clearance compared with that of co-trimoxazole, suggesting it may offer an effective postexposure prophylaxis against B. pseudomallei.

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

“…Ciprofloxacin was shown to be bacteriostatic at both pHs. Although finafloxacin did not show superior activity in a time kill assay at pH 6 when compared to pH 7, it was able to rapidly kill bacteria (almost 3 logs in 4 h), a finding previously reported for B. pseudomallei (Barnes et al, 2017). This result correlates well with other published work with finafloxacin and other bacterial species in vitro (Higgins et al, 2010; Lemaire et al, 2011).…”

“…An intravenous preparation of ciprofloxacin (Ciproxin 2 mg/ml) was purchased from Bayer (Basingstoke, United Kingdom). Dosing regimens were determined using pharmacokinetic data generated from previous studies (Barnes et al, 2017; Hamblin et al, 2017).…”

“…Efficacy in these trials was determined according to guidelines published by the FDA regarding the development of drugs for the treatment of complicated urinary tract infections (FDA, 2018 guidelines). Recently, we have shown that the oral formulation of finafloxacin has utility in treating infection with the biothreat agent Burkholderia pseudomallei in a BALB/c mouse model of melioidosis (Barnes et al, 2017). It has been suggested that this superior efficacy at infection-relevant pH (in addition to its activity at neutral pH) is due to ability to maintain activity and not be affected by efflux (Randall et al, 2017).…”

An in situ high-throughput screen identifies inhibitors of intracellular Burkholderia pseudomallei with therapeutic efficacy

“…In comparison to ciprofloxacin, significantly increased potency of BFX was observed during intracellular but not extracellular growth, suggesting an ability to achieve higher concentrations of active compound in mammalian cells. If true, further study is warranted to determine if this is due to enhanced membrane permeability, a lower isoelectric point and increased activity in acidic compartments such as the phagolysosome (60, 61), or some other mechanism. A comprehensive assessment of BFX’s spectrum of activity, particularly against other intracellular pathogens such as Shigella and Salmonella , may be informative and clinically relevant in this regard.…”

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

“…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.…”