Finafloxacin, a Novel Fluoroquinolone, Reduces the Clinical Signs of Infection and Pathology in a Mouse Model of Q Fever

Hartley, M. Gill; Norville, Isobel H.; Richards, Mark I.; Barnes, Kay B.; Bewley, Kevin R.; Vipond, Julia; Rayner, Emma; Vente, Andreas; Armstrong, Stuart J.; Harding, Sarah V.

doi:10.3389/fmicb.2021.760698

Cited by 5 publications

(4 citation statements)

References 40 publications

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“…Previous work performed at Dstl has demonstrated broad spectrum in vitro activity of finafloxacin against Francisella tularensis, Yersinia pestis, Coxiella burnetii, Bacillus anthracis, Burkholderia pseudomallei , and Burkholderia mallei ( Barnes et al, 2019a ; Peyrusson et al, 2021 ). In vivo efficacy has also been demonstrated against F. tularensis, Y. pestis, C. burnetii , and B. pseudomallei ( Barnes et al, 2017 , 2019b , 2021 ; Hartley et al, 2021 ). It has been suggested that this is due to the rapid influx of finafloxacin into cells, the accumulation to high levels within the cell, and a slow efflux rate ( Chalhoub et al, 2019 ).…”

Section: Introductionmentioning

confidence: 98%

Investigation of a combination therapy approach for the treatment of melioidosis

et al. 2022

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The efficacy of finafloxacin as a component of a layered defense treatment regimen was determined in vitro and in vivo against an infection with Burkholderia pseudomallei. Doxycycline was down-selected from a panel of antibiotics evaluated in vitro and used in combination with finafloxacin in a Balb/c mouse model of inhalational melioidosis. When treatment was initiated at 24 h post-infection with B. pseudomallei, there were no differences in the level of protection offered by finafloxacin or doxycycline (as monotherapies) when compared to the combination therapy. There was evidence for improved bacterial control in the groups treated with finafloxacin (as monotherapies or in combination with doxycycline) when compared to mice treated with doxycycline. Survival comparisons of finafloxacin and doxycycline (as monotherapies) or in combination initiated at 36 h post-infection indicated that finafloxacin was superior to doxycycline. Doxycycline was also unable to control the levels of bacteria within tissues to the extent that doxycycline and finafloxacin used in combination or finafloxacin (as a sole therapy) could. In summary, finafloxacin is a promising therapy for use in the event of exposure to B. pseudomallei.

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Section: Introductionmentioning

confidence: 98%

Investigation of a combination therapy approach for the treatment of melioidosis

et al. 2022

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“…Therefore, it could be hypothesized that the reduced rate of clearance might impact the development of long-term conditions. Along with slower clearance, we have some evidence of bacteria being trafficked systemically during treatment both in this study with doxycycline and previously with Finafloxacin, another bacteriostatic antibiotic [43]. Despite extending the infection model out to more than 35 days, complete clearance of the infection was not seen in any of the treated groups.…”

Section: Discussionmentioning

confidence: 60%

Evaluation of Alternative Doxycycline Antibiotic Regimes in an Inhalational Murine Model of Q Fever

et al. 2023

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The timing of the initiation of antibiotic treatment has been shown to impact the clinical outcome of many bacterial infections, including Q fever. Delayed, suboptimal or incorrect antibiotic treatment has been shown to result in poor prognosis, resulting in the progression of acute disease to long-term chronic sequalae. Therefore, there is a requirement to identify an optimal, effective therapeutic regimen to treat acute Q fever. In the study, the efficacies of different doxycycline monohydrate regimens (pre-exposure prophylaxis, post-exposure prophylaxis or treatment at symptom onset or resolution) were evaluated in an inhalational murine model of Q fever. Different treatment lengths (7 or 14 days) were also evaluated. Clinical signs and weight loss were monitored during infection and mice were euthanized at different time points to characterize bacterial colonization in the lungs and the dissemination of bacteria to other tissues including the spleen, brain, testes, bone marrow and adipose. Post-exposure prophylaxis or doxycycline treatment starting at symptoms onset reduced clinical signs, and also delayed the systemic clearance of viable bacteria from key tissues. Effective clearance was dependent on the development of an adaptive immune response, but also driven by sufficient bacterial activity to maintain an active immune response. Pre-exposure prophylaxis or post-exposure treatment at the resolution of clinical signs did not improve outcomes. These are the first studies to experimentally evaluate different doxycycline treatment regimens for Q fever and illustrate the need to explore the efficacy of other novel antibiotics.

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“…Finafloxacin has been evaluated in preclinical and clinical studies that have shown that finafloxacin has increased bactericidal activity at infection-relevant acidic pH against intracellular Legionella pneumophila , ciprofloxacin resistant strains of Escherichia coli and Acinetobacter baumannii , and other Gram-negative and Gram-positive bacterial species ( Emrich et al, 2010 ; Higgins et al, 2010 ; Dalhoff et al, 2011 ; Lemaire et al, 2011 ; Stubbings et al, 2011 ; Vente, 2015 ). Furthermore, we have previously demonstrated that finafloxacin has in vitro activity and in vivo efficacy against a range of biothreat pathogens including Yersinia pestis, B. pseudomallei, Francisella tularensis, Bacillus anthracis , and Coxiella burnetii ( Barnes et al, 2017 , 2019 , 2021 ; Hartley et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Efficacy of finafloxacin in a murine model of inhalational glanders

Barnes

Bayliss²,

Davies³

et al. 2022

Front. Microbiol.

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Burkholderia mallei, the causative agent of glanders, is principally a disease of equines, although it can also infect humans and is categorized by the U.S. Centers for Disease Control and Prevention as a category B biological agent. Human cases of glanders are rare and thus there is limited information on treatment. It is therefore recommended that cases are treated with the same therapies as used for melioidosis, which for prophylaxis, is co-trimoxazole (trimethoprim/sulfamethoxazole) or co-amoxiclav (amoxicillin/clavulanic acid). In this study, the fluoroquinolone finafloxacin was compared to co-trimoxazole as a post-exposure prophylactic in a murine model of inhalational glanders. BALB/c mice were exposed to an aerosol of B. mallei followed by treatment with co-trimoxazole or finafloxacin initiated at 24 h post-challenge and continued for 14 days. Survival at the end of the study was 55% or 70% for mice treated with finafloxacin or co-trimoxazole, respectively, however, this difference was not significant. However, finafloxacin was more effective than co-trimoxazole in controlling bacterial load within tissues and demonstrating clearance in the liver, lung and spleen following 14 days of therapy. In summary, finafloxacin should be considered as a promising alternative treatment following exposure to B. mallei.

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Finafloxacin, a Novel Fluoroquinolone, Reduces the Clinical Signs of Infection and Pathology in a Mouse Model of Q Fever

Cited by 5 publications

References 40 publications

Investigation of a combination therapy approach for the treatment of melioidosis

Investigation of a combination therapy approach for the treatment of melioidosis

Evaluation of Alternative Doxycycline Antibiotic Regimes in an Inhalational Murine Model of Q Fever

Efficacy of finafloxacin in a murine model of inhalational glanders

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