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

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

Open link

Publication date

July 2018

DOI

10.1093/jac/dky096

Publisher

Oxford University Press (OUP)

Abstract

Objectives: The oxazolidinone linezolid is an effective component of drug-resistant TB treatment, but its use is limited by toxicity and the optimumdose is uncertain. Current strategies are not informed by clinical pharmacokinetic (PK)/pharmacodynamic (PD) data; we aimed to address this gap. Methods: We defined linezolid PK/PD targets for efficacy (fAUC(0-24): MIC > 119 mg/L/h) and safety (fC(min)<1.38mg/L). We extracted individual-level linezolid PK data from existing studies on TB patients and performed meta-analysis, producing summary estimates of fAUC(0-24) and fCmin for published doses. Combining these with a published MIC distribution, we performed Monte Carlo simulations of target attainment. Results: The efficacy target was attained...