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dc.contributor.authorvan Rijn, Sander P
dc.contributor.authorSrivastava, Shashikant
dc.contributor.authorWessels, Mireille A
dc.contributor.authorvan Soolingen, Dick
dc.contributor.authorAlffenaar, Jan-Willem C
dc.contributor.authorGumbo, Tawanda
dc.date.accessioned2018-01-03T13:14:43Z
dc.date.available2018-01-03T13:14:43Z
dc.date.issued2017-09
dc.identifier.citationSterilizing Effect of Ertapenem-Clavulanate in a Hollow-Fiber Model of Tuberculosis and Implications on Clinical Dosing. 2017, 61 (9) Antimicrob. Agents Chemother.en
dc.identifier.issn1098-6596
dc.identifier.pmid28696238
dc.identifier.doi10.1128/AAC.02039-16
dc.identifier.urihttp://hdl.handle.net/10029/620999
dc.description.abstractCarbapenems 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.
dc.language.isoenen
dc.rightsinfo:eu-repo/semantics/closedAccessen
dc.titleThe Sterilizing Effect of Ertapenem-Clavulanate in a Hollow-Fiber Model of Tuberculosis and Implications on Clinical Dosing.en
dc.typeArticleen
dc.identifier.journalAntimicrob Agents Chemother 2017, 61(9) pii: e02039-16en
html.description.abstractCarbapenems 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.


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