Carbapenems are now being explored for treatment of multidrugresistant tuberculosis (MDR-TB), especially in conjunction with clavulanate. Clinical use is constrained by the need for multiple parenteral doses per day and the 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 maximum-effect (E max ) modeling was used to identify the relationship between total bacterial burden and the drug exposure and to 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-h dosing interval of ertapenem concentration persisting above MIC (%T MIC ). We performed 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 a %T MIC of Ն40%. We identified an intravenous dosage of 2 g once per day as achieving the target in 96% of patients. An ertapenem susceptibility breakpoint MIC of 2 mg/liter was identified for that dose. An ertapenem dosage of 2 g once daily is the most suitable to be tested in a phase II study of sterilizing effect in MDR-TB patients. KEYWORDS Mycobacterium tuberculosis, ertapenem, hollow-fiber infection model, MDR-TB, pharmacodynamics, pharmacokineticsT he emergence of drug-resistant tuberculosis (TB), especially multidrug-resistant TB (MDR-TB), extensively drug-resistant TB (XDR-TB), and virtually incurable TB (termed totally drug-resistant TB by some), is a global emergency that threatens to undermine many gains of chemotherapy (1-4). As a result, there is currently a four-pronged effort to combat this problem: (i) identification of new small molecules to kill drug-resistant Mycobacterium tuberculosis, (ii) repurposing of antimicrobial drugs not currently used to treat TB into TB therapeutics, (iii) host-directed therapy, and (iv) use of pharmacokinetics/pharmacodynamics (PK/PD) science to optimize efficacy while suppressing emergence of acquired drug resistance (5-8). Carbapenems, extensively used to treat Gram-negative bacteria over the last 30 years, have also been shown to be effective

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