Triple oral beta-lactam containing therapy for Buruli ulcer treatment shortening

María Pilar Arenaz-Callao; Rubén González Del Río; Ainhoa Lucía Quintana; Charles J Thompson; Alfonso Mendoza-Losana; Santiago Ramón-García

doi:10.1371/journal.pntd.0007126

Triple oral beta-lactam containing therapy for Buruli ulcer treatment shortening

PLoS Negl Trop Dis. 2019 Jan 28;13(1):e0007126. doi: 10.1371/journal.pntd.0007126. eCollection 2019 Jan.

Authors

María Pilar Arenaz-Callao^{1

2}, Rubén González Del Río², Ainhoa Lucía Quintana³, Charles J Thompson⁴, Alfonso Mendoza-Losana², Santiago Ramón-García^{1

2

3

4}

Affiliations

¹ Research & Development Agency of Aragon (ARAID) Foundation, Zaragoza, Spain.
² Global Health R&D, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
³ Mycobacterial Genetics Group. Department of Microbiology, Preventive Medicine and Public Health. Faculty of Medicine, University of Zaragoza, Zaragoza, Spain.
⁴ Department of Microbiology and Immunology, University of British Columbia, Vancouver, B.C. Canada.

Abstract

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.

Publication types

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

MeSH terms

Administration, Oral
Amoxicillin / pharmacology
Amoxicillin / therapeutic use
Buruli Ulcer / drug therapy*
Buruli Ulcer / microbiology
Clarithromycin / pharmacology
Clarithromycin / therapeutic use
Clavulanic Acid / pharmacology
Clavulanic Acid / therapeutic use
Dose-Response Relationship, Drug
Drug Synergism
Drug Therapy, Combination
Humans
Microbial Sensitivity Tests
Mycobacterium ulcerans / drug effects*
Mycobacterium ulcerans / enzymology
Rifampin / pharmacology
Rifampin / therapeutic use
beta-Lactamase Inhibitors / pharmacology*
beta-Lactamase Inhibitors / therapeutic use
beta-Lactamases / metabolism*

Substances

beta-Lactamase Inhibitors
Clavulanic Acid
Amoxicillin
beta-Lactamases
Clarithromycin
Rifampin

Grants and funding

This work was supported by grants from a People Programme (Marie Skłodowska Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007–2013) under REA agreement No. 291799 (Tres Cantos Open Lab Foundation - COFUND programme), from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 749058, and from the Tres Cantos Open Lab Foundation to SRG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.