Research Article: In-vitro Activity of Avermectins against Mycobacterium ulcerans

Date Published: March 5, 2015

Publisher: Public Library of Science

Author(s): Till F. Omansen, Jessica L. Porter, Paul D. R. Johnson, Tjip S. van der Werf, Ymkje Stienstra, Timothy P. Stinear, Christian Johnson.

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.

Partial Text: Buruli ulcer (BU) is a neglected tropical disease that presents as skin nodules, plaques or oedematous lesions that can progress to open ulcers [1]. BU is caused by infection with Mycobacterium ulcerans, a mycobacterium that is related to the causative agents of tuberculosis and leprosy [2]. Most BU patients are children under the age of 15 [3]. The mode of transmission of the disease is not well understood. Superstitious beliefs predominate in rural West Africa, resulting in delayed treatment seeking and stigmatization of patients [4,5]. Mortality associated with BU is low nevertheless morbidity is high. Extensive ulcers frequently lead to lifelong physical disability [6,7].

The current treatment regimen of 8-weeks streptomycin and rifampicin for Buruli ulcer is highly effective but also problematic and promising alternative all-oral treatments are sought [13,14]. Here we have shown that ivermectin and moxidectin were able to inhibit the growth of different M. ulcerans strains at 4–8 μg/ml. These findings are comparable to previous research where MICs of 1–8 μg/ml against M. tuberculosis with ivermectin, selamectin, moxidectin or doramectin were reported [15].



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