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Experimental Therapeutics

High-Dose Rifamycins Enable Shorter Oral Treatment in a Murine Model of Mycobacterium ulcerans Disease

Till F. Omansen, Deepak Almeida, Paul J. Converse, Si-Yang Li, Jin Lee, Ymkje Stienstra, Tjip van der Werf, Jacques H. Grosset, Eric L. Nuermberger
Till F. Omansen
Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USAInfectious Diseases Unit, Department of Internal Medicine, University of Groningen, Groningen, The Netherlands
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Deepak Almeida
Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
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Paul J. Converse
Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
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Si-Yang Li
Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
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Jin Lee
Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
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Ymkje Stienstra
Infectious Diseases Unit, Department of Internal Medicine, University of Groningen, Groningen, The Netherlands
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Tjip van der Werf
Infectious Diseases Unit, Department of Internal Medicine, University of Groningen, Groningen, The NetherlandsDepartment of Pulmonary Diseases and Tuberculosis, University of Groningen, Groningen, The Netherlands
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Jacques H. Grosset
Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
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Eric L. Nuermberger
Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
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DOI: 10.1128/AAC.01478-18
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ABSTRACT

Buruli ulcer (BU), caused by Mycobacterium ulcerans, is a neglected tropical skin and soft tissue infection that is associated with disability and social stigma. The mainstay of BU treatment is an 8-week course of rifampin (RIF) at 10 mg/kg of body weight and 150 mg/kg streptomycin (STR). Recently, the injectable STR has been shown to be replaceable with oral clarithromycin (CLR) for smaller lesions for the last 4 weeks of treatment. A shorter, all-oral, highly efficient regimen for BU is needed, as the long treatment duration and indirect costs currently burden patients and health systems. Increasing the dose of RIF or replacing it with the more potent rifamycin drug rifapentine (RPT) could provide such a regimen. Here, we performed a dose-ranging experiment of RIF and RPT in combination with CLR over 4 weeks of treatment in a mouse model of M. ulcerans disease. A clear dose-dependent effect of RIF on both clinical and microbiological outcomes was found, with no ceiling effect observed with tested doses up to 40 mg/kg. RPT-containing regimens were more effective on M. ulcerans. All RPT-containing regimens achieved culture negativity after only 4 weeks, while only the regimen with the highest RIF dose (40 mg/kg) did so. We conclude that there is dose-dependent efficacy of both RIF and RPT and that a ceiling effect is not reached with the current standard regimen used in the clinic. A regimen based on higher rifamycin doses than are currently being evaluated against tuberculosis in clinical trials could shorten and improve therapy of Buruli ulcer.

FOOTNOTES

    • Received 16 August 2018.
    • Returned for modification 24 September 2018.
    • Accepted 6 November 2018.
    • Accepted manuscript posted online 19 November 2018.
  • Supplemental material for this article may be found at https://doi.org/10.1128/AAC.01478-18.

  • Copyright © 2019 American Society for Microbiology.

All Rights Reserved.

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High-Dose Rifamycins Enable Shorter Oral Treatment in a Murine Model of Mycobacterium ulcerans Disease
Till F. Omansen, Deepak Almeida, Paul J. Converse, Si-Yang Li, Jin Lee, Ymkje Stienstra, Tjip van der Werf, Jacques H. Grosset, Eric L. Nuermberger
Antimicrobial Agents and Chemotherapy Jan 2019, 63 (2) e01478-18; DOI: 10.1128/AAC.01478-18

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High-Dose Rifamycins Enable Shorter Oral Treatment in a Murine Model of Mycobacterium ulcerans Disease
Till F. Omansen, Deepak Almeida, Paul J. Converse, Si-Yang Li, Jin Lee, Ymkje Stienstra, Tjip van der Werf, Jacques H. Grosset, Eric L. Nuermberger
Antimicrobial Agents and Chemotherapy Jan 2019, 63 (2) e01478-18; DOI: 10.1128/AAC.01478-18
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KEYWORDS

Buruli ulcer
Mycobacterium ulcerans
clarithromycin
high-dose rifamycins
rifampin
rifapentine

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