In-vitro activity of avermectins against Mycobacterium ulcerans

Till F Omansen; Jessica L Porter; Paul D R Johnson; Tjip S van der Werf; Ymkje Stienstra; Timothy P Stinear

doi:10.1371/journal.pntd.0003549

In-vitro activity of avermectins against Mycobacterium ulcerans

PLoS Negl Trop Dis. 2015 Mar 5;9(3):e0003549. doi: 10.1371/journal.pntd.0003549. eCollection 2015 Mar.

Authors

Till F Omansen¹, Jessica L Porter², Paul D R Johnson³, Tjip S van der Werf⁴, Ymkje Stienstra⁵, Timothy P Stinear²

Affiliations

¹ Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia; University of Groningen, University Medical Center Groningen, Department of Internal Medicine/Infectious Diseases, Groningen, The Netherlands.
² Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia.
³ Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia; Austin Centre for Infection Research (ACIR), Infectious Diseases Department, Austin Health, Heidelberg, Victoria, Australia; Department of Medicine, University of Melbourne, Heidelberg, Victoria, Australia.
⁴ University of Groningen, University Medical Center Groningen, Department of Internal Medicine/Infectious Diseases, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands.
⁵ University of Groningen, University Medical Center Groningen, Department of Internal Medicine/Infectious Diseases, Groningen, The Netherlands.

Abstract

Mycobacterium ulcerans causes Buruli ulcer (BU), a debilitating infection of subcutaneous tissue. There is a WHO-recommended antibiotic treatment requiring an 8-week course of streptomycin and rifampicin. This regime has revolutionized the treatment of BU but there are problems that include reliance on daily streptomycin injections and side effects such as ototoxicity. Trials of all-oral treatments for BU show promise but additional drug combinations that make BU treatment safer and shorter would be welcome. Following on from reports that avermectins have activity against Mycobacterium tuberculosis, we tested the in-vitro efficacy of ivermectin and moxidectin on M. ulcerans. We observed minimum inhibitory concentrations of 4-8 μg/ml and time-kill assays using wild type and bioluminescent M. ulcerans showed a significant dose-dependent reduction in M. ulcerans viability over 8-weeks. A synergistic killing-effect with rifampicin was also observed. Avermectins are well tolerated, widely available and inexpensive. Based on our in vitro findings we suggest that avermectins should be further evaluated for the treatment of BU.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Buruli Ulcer / drug therapy
Ivermectin / analogs & derivatives*
Ivermectin / pharmacology
Microbial Sensitivity Tests
Mycobacterium ulcerans / drug effects*
Mycobacterium ulcerans / growth & development
Rifampin / administration & dosage
Streptomycin / administration & dosage

Substances

Ivermectin
avermectin
Rifampin
Streptomycin

Grants and funding

TPS was supported by a Fellowship from the National Health and Medical Research Council of Australia (GNT1008549, www.nhmrc.gov.au). TFO was supported by the Buruli ulcer Groningen foundation (https://buruli1ulcer2groningen3.wordpress.com/2014/01/26/buruli-ulcer-groningen/). YS was supported by the Netherlands Organisation for Scientific Research (91610074, VENI grant, www.nwo.nl/en/funding). The funders had no role in study design, data collection and analysis, decision to publish or preparations of the manuscript.