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

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.

Conflict of interest statement

RGdR and AML are employees of GlaxoSmithKline, a producer of the generic drug amoxicillin/clavulanate. All other authors declare no conflicts of interest.

Figures

Fig 1. Synergistic profiles of current anti-BU…
Fig 1. Synergistic profiles of current anti-BU drugs and selected beta-lactams with rifampicin against M. ulcerans ATCC 19423.
Compounds were assayed in two-fold serial dilutions in a checkerboard format. Rifampicin was assayed in the x-axis while other drugs were assayed in the y-axis. RIF, rifampicin; STR, streptomycin; AMK, amikacin; CLA, clarithromycin; MOX, moxifloxacin; CPD, cephradine; CDN, cefdinir; AMX, amoxicillin; FAR, faropenem; MER, meropenem; CLV, clavulanate.
Fig 2. Multiplicative effects of quadruple synergistic…
Fig 2. Multiplicative effects of quadruple synergistic combinations including rifampicin, clarithromycin, clavulanate and different beta-lactams against M. ulcerans ATCC 19423.
The MIC of each compound was compared alone and in the presence of several synergistic combinations at the MOCC (lowest FICI). Clarithromycin is not displayed since it was tested at a fixed 1/8xMIC concentration (MICCLA = 0.5 μg/mL). Clavulanate was tested at a fixed 5 μg/mL concentration. AMX, amoxicillin; CLA, clarithromycin; CLV, clavulanate; FAR, faropenem; MER, meropenem; RIF, rifampicin.
Fig 3. Dose response curves of amoxicillin…
Fig 3. Dose response curves of amoxicillin alone and in combination against M. ulcerans clinical isolates.
Dose response curves of amoxicillin tested: "alone", alone; "Plus CLV", in the presence of clavulanate; "at MOCC plus CLV", in the presence of clavulanate and rifampicin at the MOCC; "at MOCC plus CLV/CLA", in the presence of clavulanate and rifampicin and clarithromycin at the MOCC. Clavulanate was tested at a fixed 5 μg/mL concentration. AMX, amoxicillin; CLA, clarithromycin; CLV, clavulanate.

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