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 Nuermberger

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere01478-18
JournalAntimicrobial Agents and Chemotherapy
Volume63
Issue number2
DOIs
StatePublished - Feb 1 2019

Fingerprint

rifapentine
Rifamycins
Mycobacterium ulcerans
Rifampin
Buruli Ulcer
Clarithromycin
Streptomycin
Therapeutics
Social Stigma
Soft Tissue Infections
Tuberculosis
Body Weight
Clinical Trials
Costs and Cost Analysis
Skin
Injections

Keywords

  • Buruli ulcer
  • Clarithromycin
  • High-dose rifamycins
  • Mycobacterium ulcerans
  • Rifampin
  • Rifapentine

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

High-dose rifamycins enable shorter oral treatment in a murine model of mycobacterium ulcerans disease. / Omansen, Till F.; Almeida, Deepak; Converse, Paul J.; Li, Si Yang; Lee, Jin; Stienstra, Ymkje; van der Werf, Tjip; Grosset, Jacques H.; Nuermberger, Eric.

In: Antimicrobial Agents and Chemotherapy, Vol. 63, No. 2, e01478-18, 01.02.2019.

Research output: Contribution to journalArticle

Omansen, TF, Almeida, D, Converse, PJ, Li, SY, Lee, J, Stienstra, Y, van der Werf, T, Grosset, JH & Nuermberger, E 2019, 'High-dose rifamycins enable shorter oral treatment in a murine model of mycobacterium ulcerans disease', Antimicrobial Agents and Chemotherapy, vol. 63, no. 2, e01478-18. https://doi.org/10.1128/AAC.01478-18
Omansen, Till F. ; Almeida, Deepak ; Converse, Paul J. ; Li, Si Yang ; Lee, Jin ; Stienstra, Ymkje ; van der Werf, Tjip ; Grosset, Jacques H. ; Nuermberger, Eric. / High-dose rifamycins enable shorter oral treatment in a murine model of mycobacterium ulcerans disease. In: Antimicrobial Agents and Chemotherapy. 2019 ; Vol. 63, No. 2.
@article{ec41f2929588457abcd26864d4631118,
title = "High-dose rifamycins enable shorter oral treatment in a murine model of mycobacterium ulcerans disease",
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.",
keywords = "Buruli ulcer, Clarithromycin, High-dose rifamycins, Mycobacterium ulcerans, Rifampin, Rifapentine",
author = "Omansen, {Till F.} and Deepak Almeida and Converse, {Paul J.} and Li, {Si Yang} and Jin Lee and Ymkje Stienstra and {van der Werf}, Tjip and Grosset, {Jacques H.} and Eric Nuermberger",
year = "2019",
month = "2",
day = "1",
doi = "10.1128/AAC.01478-18",
language = "English (US)",
volume = "63",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "0066-4804",
publisher = "American Society for Microbiology",
number = "2",

}

TY - JOUR

T1 - High-dose rifamycins enable shorter oral treatment in a murine model of mycobacterium ulcerans disease

AU - Omansen, Till F.

AU - Almeida, Deepak

AU - Converse, Paul J.

AU - Li, Si Yang

AU - Lee, Jin

AU - Stienstra, Ymkje

AU - van der Werf, Tjip

AU - Grosset, Jacques H.

AU - Nuermberger, Eric

PY - 2019/2/1

Y1 - 2019/2/1

N2 - 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.

AB - 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.

KW - Buruli ulcer

KW - Clarithromycin

KW - High-dose rifamycins

KW - Mycobacterium ulcerans

KW - Rifampin

KW - Rifapentine

UR - http://www.scopus.com/inward/record.url?scp=85060777698&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85060777698&partnerID=8YFLogxK

U2 - 10.1128/AAC.01478-18

DO - 10.1128/AAC.01478-18

M3 - Article

VL - 63

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 0066-4804

IS - 2

M1 - e01478-18

ER -