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Linezolid pharmacokinetics in MDR-TB: a systematic review, meta-analysis and Monte Carlo simulation

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James Millard, Henry Pertinez, Laura Bonnett, Eva Maria Model, Véronique Dartois, John L Johnson, Maxine Caws, Simon Tiberi, Mathieu Bolhuis, Jan-Willem C Alffenaar, Geraint Davies, Derek James Sloan

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Abstract

Objectives The oxazolidinone linezolid is an effective component of drug - resistant TB treatment, but use is limited by toxicity and the optimum dose is uncertain . Current strategies are not informed by clinical pharmacokinetic/pharmacodynamic (PK/PD) data, we aimed to aimed to address this gap. Methods We defined linezolid PK/PD targets for efficacy; free area under the time - concentration curve: minimum inhibitory concentration ratio (ƒAUC0-24:M IC) >119m g/L/hr and safety; free minimum concentration (Cmin) <1.38mg/L . We extracted individual - level linezolid PK data from existing studies on TB patients and performed meta - analysis; producing summary estimates of ƒAUC0-24 and ƒCmin for published doses . Combining these with a published MIC distribution, we performed Monte Carlo simulations of target attainment. Results The efficacy target was attained in all simulated individuals at 300mg q12h and 600mg q12h , but only 20.7% missed the safety target at 300mg q12h versus 98.5% at 600mg q12h . Although suggesting 300mg q12h should be used preferentially, these data were reliant on a single centre . Efficacy and safety targets were missed by 41.0% and 24.2% respectively at 300mg q24h , and 44.5% and 27.5% at 600mg q24h . However, the confounding effect of between study heterogeneity on target attainment for q24h regimens was considerable. Conclusions 300mg q12h linezolid dosing may retain the efficacy of the 600mg q12h licensed dosing with improved safety. Data to evaluate commonly used 300mg q24h and 600mg q24h doses is limited. Comprehensive, prospectively obtained PK/PD data for linezolid doses in drug - resistant TB treatment are required.
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Original languageEnglish
Pages (from-to)1755-1762
Number of pages8
JournalJournal of Antimicrobial Chemotherapy
Volume73
Issue number7
Early online date23 Mar 2018
DOIs
Publication statusE-pub ahead of print - 23 Mar 2018

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