In-vitro Activity of Avermectins against Mycobacterium ulcerans

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.

Vaccine-specific immune responses againstMycobacterium ulceransinfection in a low-dose murine challenge model

“…We reasoned that because BU patients were likely to be initially infected with a low bacterial inoculum (10, 11, 59) we could use this model to test the protective efficacy of responses induced by the ER + R 4 Pam 2 Cys vaccine. This model features the use of a bioluminescent strain of M. ulcerans (10, 60) and its infectious characteristics are summarised in Fig. 2.…”

“…Escherichia coli ClearColi©BL21 (DE3) containing the plasmid, pJexpress-ER (strain TPS847) was grown at 37°C in Luria-Bertani (LB) broth (Difco, Becton Dickinson, MD, USA) supplemented with 100 µg/ml ampicillin (Sigma-Aldrich, USA) to express the enoyl reductase (ER) protein (57). Log-phase bioluminescent Mycobacterium ulcerans (strain JKD8049 containing integrated plasmid pMV306 hsp:lux G13) (10, 60) was grown at 30°C in 7H9 broth or 7H10 agar (Middlebrook, Becton Dickinson, MD, USA) supplemented with oleic acid, albumin, dextrose and catalase growth supplement (OADC) (Middlebrook, Becton Dickinson, MD, USA), 0.5% glycerol (v/v) and 25 µg/ml kanamycin (Sigma-Aldrich, USA). M. bovis BCG (strain ‘Danish 1331’) used for vaccinations was grown at 37°C in 7H9 broth or 7H10 agar supplemented with OADC.…”

Antibiotic complications during the treatment of Mycobacterium ulcerans disease in Australian patients

“…Furthermore, the safety and effectiveness of alternative agents with demonstrated effectiveness against M . ulcerans , such as bedaqueline, clofazamine and avermectins, could be explored to determine if their use may reduce treatment toxicity without compromising effectiveness.…”

Ivermectin: enigmatic multifaceted ‘wonder’ drug continues to surprise and exceed expectations

“…[102][103][104] Unfortunately, the potential use of ivermectin for tuberculosis treatment is doubtful due to possible neurotoxicity at high dosage levels. Ivermectin was also reported to be bactericidal against M. ulcerans, 105 although other researchers found no significant activity against this bacterium. 106…”