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

IntroductionBuruli ulcer (BU) is a neglected tropical disease primarily affecting skin and sometimes bone. Standard therapy consists of rifampicin (RIF, once daily) plus clarithromycin (CLA, twice daily) over 8 weeks. Adding amoxicillin-clavulanate (AMX/CLV) may shorten treatment, but predicting treatment success before clinical trial implementation is challenging. AimsTo assess the probability of bacterial eradication following treatment with novel investigational BU regimens over different intervals using a mechanism-based modelling and simulation approach. MethodsIn vitro time-kill assays with RIF, CLA, and AMX/CLV alone and in combination were performed with a range of clinical isolates of Mycobacterium ulcerans. Bactericidal activity was characterized using a bacterial growth dynamics model, including an Emax function to describe the drug effect. Subsequently, clinical trial simulations were performed to evaluate drug disposition and skin penetration in a cohort of virtual subjects, taking into account interindividual variability in pharmacokinetics and pharmacodynamics (n=70/arm). Several regimens, including standard therapy and AMX/CLV-containing combinations with higher RIF doses were assessed. The probability of eradication at 4-8 weeks was assessed across strains with different susceptibility and assuming varying bacterial load at start of treatment. ResultsBeta-lactam containing combinations resulted in higher potency and maximum killing rates relative to the currently recommended regimens. Consequently, regimens containing AMX/CLV with higher RIF doses (20 mg/kg q.d. or 10 mg/kg b.i.d.) outperformed standard therapy, achieving 100% eradication within 4 weeks for baseline loads up to 1,000 CFU/mL across most isolates, except one from China. At higher loads (10,000 CFU/mL), 6 weeks were required. ConclusionsThe use of mechanism-based modelling and clinical trial simulations provides a robust translational framework for the evaluation of novel therapies for neglected diseases, such as BU. Irrespective of differences in bacterial susceptibility, adding AMX/CLV or using RIF-AMX/CLV dual therapy may reduce BU treatment from 8 to 4 weeks.