The sterilizing effect of ertapenem-clavulanate in a hollow fiber model of tuberculosis and implications on clinical dosing [PublishAheadOfPrint]

Carbapenems are now being explored for treatment of multi-drug resistant tuberculosis (MDR-TB), especially in conjunction with clavulanate. Clinical use is constrained by the need for multiple parenteral doses per day, and lack of knowledge of the optimal dose for sterilizing effect. Our objective was to identify the ertapenem exposure associated with optimal sterilizing effect and then design a once a day dose for clinical use. We utilized the hollow fiber system model of tuberculosis in a 28-day exposure-response study of 8 different ertapenem doses in combination with clavulanate. The systems were sampled at predetermined time-points to verify the concentration-time profile and identify the total bacterial burden. Inhibitory sigmoid E_max modeling was used to identify the relationship between total bacterial burden and the drug exposure, and identify optimal exposures. Contrary to the literature, ertapenem-clavulanate combination demonstrated good microbial kill and sterilizing effect. In a dose-fractionation hollow fiber study, efficacy was linked to percentage of the 24 hour dosing interval of ertapenem concentration persisting above MIC (%T_MIC). We performed a 10,000 MDR-TB patient computer-aided clinical trial simulations, based on Monte Carlo methods, to identify the doses and schedule that would achieve or exceed %T_MIC ≥40%. We identified an intravenous dose of 2 grams once per day as achieving the target in 96% of patients. An ertapenem susceptibility breakpoint MIC 2 mg/L was identified for that dose. An ertapenem dose of 2g once daily is the most suitable to be tested in a phase II study of sterilizing effect in MDR-TB patients.

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