Prediction of response to Buruli ulcer treatment shortening with novel beta-lactam-containing antimicrobial combinations.

Abstract

Whilst rifampicin (RIF, q.d.) plus clarithromycin (CLA, b.i.d.) for 8 weeks is an effective treatment for Buruli ulcer (BU), this prolonged regimen presents challenges for adherence, particularly in community-based settings. Using a mechanism-based modelling and simulation framework, informed by In vitro bactericidal activity data, this study aimed to predict whether adding amoxicillin-clavulanate (AMX/CLV) could shorten BU treatment. In vitro time-kill data for RIF, CLA, and AMX/CLV, alone and in combination, against Mycobacterium ulcerans isolates were analysed using a nonlinear mixed-effects approach. Clinical trial simulations (n=70/arm) then assessed bacterial eradication times for standard therapy versus AMX/CLV-containing regimens, including higher RIF doses, while accounting for population pharmacokinetic variability and drug skin penetration. In vitro time-kill analyses showed that, excluding isolate ITM070290, AMX/CLV-containing combinations provide comparable or superior potency and faster killing rates than the standard of care. Clinical trial simulations predicted these regimens can reliably achieve bacterial eradication within 4 and 6 weeks for moderate and high bacterial loads, respectively, with only one exception requiring over 8 weeks in high-burden scenarios. Incorporating AMX/CLV alongside optimized RIF doses shows strong potential to shorten BU treatment from 8 weeks down to 4-6 weeks, supporting its ongoing evaluation in clinical trials.