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Shorter-course treatment for Mycobacterium ulcerans disease with high-dose rifamycins and clofazimine in a mouse model of Buruli ulcer
Starting in 2004, the standard regimen for treatment of Buruli ulcer (BU) recommended by the World Health Organization has been daily treatment for eight weeks with rifampin (RIF) and streptomycin. Based on recent clinical trials, treatment with an all-oral regimen of RIF and clarithromycin (CLR) ma...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107292/ https://www.ncbi.nlm.nih.gov/pubmed/30102705 http://dx.doi.org/10.1371/journal.pntd.0006728 |
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author | Converse, Paul J. Almeida, Deepak V. Tasneen, Rokeya Saini, Vikram Tyagi, Sandeep Ammerman, Nicole C. Li, Si-Yang Anders, Nicole M. Rudek, Michelle A. Grosset, Jacques H. Nuermberger, Eric L. |
author_facet | Converse, Paul J. Almeida, Deepak V. Tasneen, Rokeya Saini, Vikram Tyagi, Sandeep Ammerman, Nicole C. Li, Si-Yang Anders, Nicole M. Rudek, Michelle A. Grosset, Jacques H. Nuermberger, Eric L. |
author_sort | Converse, Paul J. |
collection | PubMed |
description | Starting in 2004, the standard regimen for treatment of Buruli ulcer (BU) recommended by the World Health Organization has been daily treatment for eight weeks with rifampin (RIF) and streptomycin. Based on recent clinical trials, treatment with an all-oral regimen of RIF and clarithromycin (CLR) may be an effective alternative. With the achievement of an all-oral regimen, a new goal is to find a regimen that can shorten the duration of treatment without compromising efficacy. We recently observed that increasing the dose of RIF from the standard 10 mg/kg dose to 20 or 40 mg/kg, or replacing RIF with the more potent long-acting rifamycin, rifapentine (RPT) at 10 mg/kg or 20 mg/kg increased the bactericidal activity of the RIF+CLR regimen in a mouse model of BU. We also recently showed that replacing CLR with clofazimine(CFZ) at 25 mg/kg may have greater sterilizing activity than the RIF+CLR regimen. Here, we demonstrate that combining high-dose rifamycins with CFZ at a lower dose of 12.5 mg/kg results in similar reductions in swelling, bacterial burden and mycolactone concentrations in mouse footpads compared to the standard regimens and more rapid sterilization of footpads as determined by the proportions of footpads harboring viable bacteria three months after completion of treatment. The potential of these high-dose rifamycin and CFZ combinations to shorten BU treatment to four weeks warrants evaluation in a clinical trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT03474198, NCT01659437 |
format | Online Article Text |
id | pubmed-6107292 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-61072922018-08-30 Shorter-course treatment for Mycobacterium ulcerans disease with high-dose rifamycins and clofazimine in a mouse model of Buruli ulcer Converse, Paul J. Almeida, Deepak V. Tasneen, Rokeya Saini, Vikram Tyagi, Sandeep Ammerman, Nicole C. Li, Si-Yang Anders, Nicole M. Rudek, Michelle A. Grosset, Jacques H. Nuermberger, Eric L. PLoS Negl Trop Dis Research Article Starting in 2004, the standard regimen for treatment of Buruli ulcer (BU) recommended by the World Health Organization has been daily treatment for eight weeks with rifampin (RIF) and streptomycin. Based on recent clinical trials, treatment with an all-oral regimen of RIF and clarithromycin (CLR) may be an effective alternative. With the achievement of an all-oral regimen, a new goal is to find a regimen that can shorten the duration of treatment without compromising efficacy. We recently observed that increasing the dose of RIF from the standard 10 mg/kg dose to 20 or 40 mg/kg, or replacing RIF with the more potent long-acting rifamycin, rifapentine (RPT) at 10 mg/kg or 20 mg/kg increased the bactericidal activity of the RIF+CLR regimen in a mouse model of BU. We also recently showed that replacing CLR with clofazimine(CFZ) at 25 mg/kg may have greater sterilizing activity than the RIF+CLR regimen. Here, we demonstrate that combining high-dose rifamycins with CFZ at a lower dose of 12.5 mg/kg results in similar reductions in swelling, bacterial burden and mycolactone concentrations in mouse footpads compared to the standard regimens and more rapid sterilization of footpads as determined by the proportions of footpads harboring viable bacteria three months after completion of treatment. The potential of these high-dose rifamycin and CFZ combinations to shorten BU treatment to four weeks warrants evaluation in a clinical trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT03474198, NCT01659437 Public Library of Science 2018-08-13 /pmc/articles/PMC6107292/ /pubmed/30102705 http://dx.doi.org/10.1371/journal.pntd.0006728 Text en © 2018 Converse et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Converse, Paul J. Almeida, Deepak V. Tasneen, Rokeya Saini, Vikram Tyagi, Sandeep Ammerman, Nicole C. Li, Si-Yang Anders, Nicole M. Rudek, Michelle A. Grosset, Jacques H. Nuermberger, Eric L. Shorter-course treatment for Mycobacterium ulcerans disease with high-dose rifamycins and clofazimine in a mouse model of Buruli ulcer |
title | Shorter-course treatment for Mycobacterium ulcerans disease with high-dose rifamycins and clofazimine in a mouse model of Buruli ulcer |
title_full | Shorter-course treatment for Mycobacterium ulcerans disease with high-dose rifamycins and clofazimine in a mouse model of Buruli ulcer |
title_fullStr | Shorter-course treatment for Mycobacterium ulcerans disease with high-dose rifamycins and clofazimine in a mouse model of Buruli ulcer |
title_full_unstemmed | Shorter-course treatment for Mycobacterium ulcerans disease with high-dose rifamycins and clofazimine in a mouse model of Buruli ulcer |
title_short | Shorter-course treatment for Mycobacterium ulcerans disease with high-dose rifamycins and clofazimine in a mouse model of Buruli ulcer |
title_sort | shorter-course treatment for mycobacterium ulcerans disease with high-dose rifamycins and clofazimine in a mouse model of buruli ulcer |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107292/ https://www.ncbi.nlm.nih.gov/pubmed/30102705 http://dx.doi.org/10.1371/journal.pntd.0006728 |
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