Trimethoprim/sulfamethoxazole (co-trimoxazole) prophylaxis is effective against acute murine inhalational melioidosis and glanders

Barnes, Kay B.; Steward, J.; Thwaite, Joanne E.; Lever, Mark S.; Davies, Cheryl M.; Armstrong, Stuart J.; Laws, Thomas R.; Roughley, Neil; Harding, Sarah V.; Atkins, Timothy P.; Simpson, Andrew J. H.; Atkins, Helen S.

doi:10.1016/j.ijantimicag.2013.02.007

Cited by 27 publications

(23 citation statements)

References 21 publications

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“…The dosing regimen for ciprofloxacin was determined using the dose that matched the human AUC, which equates to 30 mg/kg delivered twice daily via intraperitoneal injection (39). The co-trimoxazole dosing regimen was determined by matching the time above MIC from previously generated data (40). …”

Section: Resultsmentioning

confidence: 99%

“…Considering at least one organ from all of the surviving mice treated with co-trimoxazole for 14 days was colonized with B. pseudomallei and chronic infections are known to be established even after 21 days of co-trimoxazole treatment in mice (40), longer treatment regimens may be warranted than are currently recommended (17, 20, 40). Treating for longer with finafloxacin may further improve the results demonstrated in this study.…”

Section: Discussionmentioning

confidence: 99%

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

Barnes

Hamblin

Richards

et al. 2017

Antimicrob Agents Chemother

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Barnes

Hamblin

Richards

et al. 2017

Antimicrob Agents Chemother

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“…While there are several prototypic strains of B. pseudomallei and several studies have been conducted utilizing aerosol delivery2930313233, comparative data to establish commonly accepted strain(s) to study virulence and disease progression has not been done. Primarily, B. pseudomallei strains K96243 and 1026b have been utilized in aerosol studies.…”

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confidence: 99%

Comparative Burkholderia pseudomallei natural history virulence studies using an aerosol murine model of infection

Massey

Yeager

Blumentritt

et al. 2014

Sci Rep

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Melioidosis is an endemic disease caused by the bacterium Burkholderia pseudomallei. Concerns exist regarding B. pseudomallei use as a potential bio-threat agent causing persistent infections and typically manifesting as severe pneumonia capable of causing fatal bacteremia. Development of suitable therapeutics against melioidosis is complicated due to high degree of genetic and phenotypic variability among B. pseudomallei isolates and lack of data establishing commonly accepted strains for comparative studies. Further, the impact of strain variation on virulence, disease presentation, and mortality is not well understood. Therefore, this study evaluate and compare the virulence and disease progression of B. pseudomallei strains K96243 and HBPUB10303a, following aerosol challenge in a standardized BALB/c mouse model of infection. The natural history analysis of disease progression monitored conditions such as weight, body temperature, appearance, activity, bacteremia, organ and tissue colonization (pathological and histological analysis) and immunological responses. This study provides a detailed, direct comparison of infection with different B. pseudomallei strains and set up the basis for a standardized model useful to test different medical countermeasures against Burkholderia species. Further, this protocol serves as a guideline to standardize other bacterial aerosol models of infection or to define biomarkers of infectious processes caused by other intracellular pathogens.

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“…Antibiotics have been tested for efficacy against glanders in rodent models by administering them shortly after infectious challenge (10,19). While such testing may identify antibiotics effective against human disease, this methodology that treats infection before symptoms arise is quite different than what occurs in actual human infection.…”

Section: Discussionmentioning

confidence: 99%

“…While there are no reports demonstrating the therapeutic efficacy of moxifloxacin against glanders in humans, efficacy has been demonstrated in hamsters (22) and in mice challenged by aerosol and treated shortly after infection (S. Demons, unpublished data). Sulfamethoxazole-trimethoprim has been reported to be efficacious against aerosol infection when tested in mice (19). Current recommendations for treating glanders are ceftazidime or meropenem for initial intensive therapy and sulfamethoxazole-trimethoprim or amoxicillin-clavulanic acid for eradication therapy (23).…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Postexposure Therapy against Glanders in Mice

Waag

2015

Antimicrob Agents Chemother

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Burkholderia mallei, the causative agent of glanders, is a CDC Tier 1 Select Agent for which there is no preventive vaccine and antibiotic therapy is difficult. In this study, we show that a combination of vaccination using killed cellular vaccine and therapy using moxifloxacin, azithromycin, or sulfamethoxazole-trimethoprim can protect BALB/c mice from lethal infection even when given 5 days after infectious challenge. Vaccination only, or antibiotic therapy only, was not efficacious. Although antibiotics evaluated experimentally can protect when given before or 1 day after challenge, this time course is not realistic in the cases of natural infection or biological attack, when the patient seeks treatment after symptoms develop or after a biological attack has been confirmed and the agent has been identified. Antibiotics can be efficacious after a prolonged interval between exposure and treatment, but only if the animals were previously vaccinated.

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Trimethoprim/sulfamethoxazole (co-trimoxazole) prophylaxis is effective against acute murine inhalational melioidosis and glanders

Cited by 27 publications

References 21 publications

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

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

Comparative Burkholderia pseudomallei natural history virulence studies using an aerosol murine model of infection

Efficacy of Postexposure Therapy against Glanders in Mice

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