Efficacy of Rifampin Plus Clofazimine in a Murine Model of Mycobacterium ulcerans Disease.
Treatment of Buruli ulcer, or Mycobacterium ulcerans disease, has shifted from surgical excision and skin grafting to antibiotic therapy usually with 8 weeks of daily rifampin (RIF) and streptomycin (STR). Although the results have been highly favorable, administration of STR requires intramuscular...
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ftdoajarticles:oai:doaj.org/article:d3a1fd958498456cba69bdab155369a4 2023-05-15T15:18:40+02:00 Efficacy of Rifampin Plus Clofazimine in a Murine Model of Mycobacterium ulcerans Disease. Paul J Converse Sandeep Tyagi Yalan Xing Si-Yang Li Yoshito Kishi John Adamson Eric L Nuermberger Jacques H Grosset 2015-01-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0003823 https://doaj.org/article/d3a1fd958498456cba69bdab155369a4 EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC4714850?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0003823 https://doaj.org/article/d3a1fd958498456cba69bdab155369a4 PLoS Neglected Tropical Diseases, Vol 9, Iss 6, p e0003823 (2015) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2015 ftdoajarticles https://doi.org/10.1371/journal.pntd.0003823 2022-12-31T03:28:56Z Treatment of Buruli ulcer, or Mycobacterium ulcerans disease, has shifted from surgical excision and skin grafting to antibiotic therapy usually with 8 weeks of daily rifampin (RIF) and streptomycin (STR). Although the results have been highly favorable, administration of STR requires intramuscular injection and carries the risk of side effects, such as hearing loss. Therefore, an all-oral, potentially less toxic, treatment regimen has been sought and encouraged by the World Health Organization. A combination of RIF plus clarithromycin (CLR) has been successful in patients first administered RIF+STR for 2 or 4 weeks. Based on evidence of efficacy of clofazimine (CFZ) in humans and mice with tuberculosis, we hypothesized that the combination of RIF+CFZ would be effective against M. ulcerans in the mouse footpad model of M. ulcerans disease because CFZ has similar MIC against M. tuberculosis and M. ulcerans. For comparison, mice were also treated with the gold standard of RIF+STR, the proposed RIF+CLR alternative regimen, or CFZ alone. Treatment was initiated after development of footpad swelling, when the bacterial burden was 4.64±0.14log10 CFU. At week 2 of treatment, the CFU counts had increased in untreated mice, remained essentially unchanged in mice treated with CFZ alone, decreased modestly with either RIF+CLR or RIF+CFZ, and decreased substantially with RIF+STR. At week 4, on the basis of footpad CFU counts, the combination regimens were ranked as follows: RIF+STR>RIF+CLR>RIF+CFZ. At weeks 6 and 8, none of the mice treated with these regimens had detectable CFU. Footpad swelling declined comparably with all of the combination regimens, as did the levels of detectable mycolactone A/B. In mice treated for only 6 weeks and followed up for 24 weeks, there were no relapses in RIF+STR treated mice, one (5%) relapse in RIF+CFZ-treated mice, but >50% in RIF+CLR treated mice. On the basis of these results, RIF+CFZ has potential as a continuation phase regimen for treatment of M. ulcerans disease. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic Rif ENVELOPE(-16.172,-16.172,66.526,66.526) PLOS Neglected Tropical Diseases 9 6 e0003823 |
institution |
Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Paul J Converse Sandeep Tyagi Yalan Xing Si-Yang Li Yoshito Kishi John Adamson Eric L Nuermberger Jacques H Grosset Efficacy of Rifampin Plus Clofazimine in a Murine Model of Mycobacterium ulcerans Disease. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Treatment of Buruli ulcer, or Mycobacterium ulcerans disease, has shifted from surgical excision and skin grafting to antibiotic therapy usually with 8 weeks of daily rifampin (RIF) and streptomycin (STR). Although the results have been highly favorable, administration of STR requires intramuscular injection and carries the risk of side effects, such as hearing loss. Therefore, an all-oral, potentially less toxic, treatment regimen has been sought and encouraged by the World Health Organization. A combination of RIF plus clarithromycin (CLR) has been successful in patients first administered RIF+STR for 2 or 4 weeks. Based on evidence of efficacy of clofazimine (CFZ) in humans and mice with tuberculosis, we hypothesized that the combination of RIF+CFZ would be effective against M. ulcerans in the mouse footpad model of M. ulcerans disease because CFZ has similar MIC against M. tuberculosis and M. ulcerans. For comparison, mice were also treated with the gold standard of RIF+STR, the proposed RIF+CLR alternative regimen, or CFZ alone. Treatment was initiated after development of footpad swelling, when the bacterial burden was 4.64±0.14log10 CFU. At week 2 of treatment, the CFU counts had increased in untreated mice, remained essentially unchanged in mice treated with CFZ alone, decreased modestly with either RIF+CLR or RIF+CFZ, and decreased substantially with RIF+STR. At week 4, on the basis of footpad CFU counts, the combination regimens were ranked as follows: RIF+STR>RIF+CLR>RIF+CFZ. At weeks 6 and 8, none of the mice treated with these regimens had detectable CFU. Footpad swelling declined comparably with all of the combination regimens, as did the levels of detectable mycolactone A/B. In mice treated for only 6 weeks and followed up for 24 weeks, there were no relapses in RIF+STR treated mice, one (5%) relapse in RIF+CFZ-treated mice, but >50% in RIF+CLR treated mice. On the basis of these results, RIF+CFZ has potential as a continuation phase regimen for treatment of M. ulcerans disease. |
format |
Article in Journal/Newspaper |
author |
Paul J Converse Sandeep Tyagi Yalan Xing Si-Yang Li Yoshito Kishi John Adamson Eric L Nuermberger Jacques H Grosset |
author_facet |
Paul J Converse Sandeep Tyagi Yalan Xing Si-Yang Li Yoshito Kishi John Adamson Eric L Nuermberger Jacques H Grosset |
author_sort |
Paul J Converse |
title |
Efficacy of Rifampin Plus Clofazimine in a Murine Model of Mycobacterium ulcerans Disease. |
title_short |
Efficacy of Rifampin Plus Clofazimine in a Murine Model of Mycobacterium ulcerans Disease. |
title_full |
Efficacy of Rifampin Plus Clofazimine in a Murine Model of Mycobacterium ulcerans Disease. |
title_fullStr |
Efficacy of Rifampin Plus Clofazimine in a Murine Model of Mycobacterium ulcerans Disease. |
title_full_unstemmed |
Efficacy of Rifampin Plus Clofazimine in a Murine Model of Mycobacterium ulcerans Disease. |
title_sort |
efficacy of rifampin plus clofazimine in a murine model of mycobacterium ulcerans disease. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2015 |
url |
https://doi.org/10.1371/journal.pntd.0003823 https://doaj.org/article/d3a1fd958498456cba69bdab155369a4 |
long_lat |
ENVELOPE(-16.172,-16.172,66.526,66.526) |
geographic |
Arctic Rif |
geographic_facet |
Arctic Rif |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 9, Iss 6, p e0003823 (2015) |
op_relation |
http://europepmc.org/articles/PMC4714850?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0003823 https://doaj.org/article/d3a1fd958498456cba69bdab155369a4 |
op_doi |
https://doi.org/10.1371/journal.pntd.0003823 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
9 |
container_issue |
6 |
container_start_page |
e0003823 |
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1766348857364447232 |