Triple oral beta-lactam containing therapy for Buruli ulcer treatment shortening
The potential use of clinically approved beta-lactams for Buruli ulcer (BU) treatment was investigated with representative classes analyzed in vitro for activity against Mycobacterium ulcerans. Beta-lactams tested were effective alone and displayed a strong synergistic profile in combination with antibiotics currently used to treat BU, i.e. rifampicin and clarithromycin; this activity was further potentiated in the presence of the beta-lactamase inhibitor clavulanate. In addition, quadruple combinations of rifampicin, clarithromycin, clavulanate and beta-lactams resulted in multiplicative reductions in their minimal inhibitory concentration (MIC) values. The MIC of amoxicillin against a panel of clinical isolates decreased more than 200-fold within this quadruple combination. Amoxicillin/clavulanate formulations are readily available with clinical pedigree, low toxicity, and orally and pediatric available; thus, supporting its potential inclusion as a new anti-BU drug in current combination therapies.
Buruli ulcer (BU) is a chronic debilitating disease of the skin and soft tissue, mainly affecting children and young adults in tropical regions. Before 2004, the only treatment option was surgery; a major breakthrough was the discovery that BU could be cured in most cases with a standard treatment that involved 8 weeks of combination therapy with rifampicin and streptomycin. However, the use of streptomycin is often associated with severe side effects such as ototoxicity, or nephrotoxicity. More recently, a clinical trial demonstrated equipotency of replacing the injectable streptomycin by the clarithromycin, which is orally available and associated with fewer side effects. BU treatment is now moving toward a full orally available treatment of clarithromycin-rifampicin. Although effective and mostly well tolerated, this new treatment is still associated with side effects and only moxifloxacin is additionally recommended by WHO for BU therapy. New drugs are thus needed to increase the number of available treatments, reduce side effects, and improve efficacy with treatments shorter than 8 weeks. In this work, we describe for the first time the potential inclusion of beta-lactams in BU therapy. More specifically, we propose the use of amoxicillin/clavulanate since it is oral, suitable for the treatment of children, and readily available with a long track record of clinical pedigree. Its inclusion in a triple oral therapy complementing current combinatorial rifampicin-clarithromycin treatment has the potential to counteract resistance development and to reduce length of treatment and time to cure.