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    The Sterilizing Effect of Ertapenem-Clavulanate in a Hollow-Fiber Model of Tuberculosis and Implications on Clinical Dosing.

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    Authors
    van Rijn, Sander P
    Srivastava, Shashikant
    Wessels, Mireille A
    van Soolingen, Dick
    Alffenaar, Jan-Willem C
    Gumbo, Tawanda
    Type
    Article
    Language
    en
    
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    Title
    The Sterilizing Effect of Ertapenem-Clavulanate in a Hollow-Fiber Model of Tuberculosis and Implications on Clinical Dosing.
    Published in
    Antimicrob Agents Chemother 2017, 61(9) pii: e02039-16
    Publiekssamenvatting
    Carbapenems are now being explored for treatment of multidrug-resistant 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 (Emax) 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 (%TMIC). 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 %TMIC of ≥40%. 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.
    DOI
    10.1128/AAC.02039-16
    PMID
    28696238
    URI
    http://hdl.handle.net/10029/620999
    ae974a485f413a2113503eed53cd6c53
    10.1128/AAC.02039-16
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