Pharmacokinetics of Levofloxacin in Multidrug- and Extensively Drug-Resistant Tuberculosis patients [PublishAheadOfPrint]

Pharmacodynamics are important in treatment of especially multidrug- and extensively resistant tuberculosis (M/XDR-TB). The free area under the concentration time curve in relation to minimal inhibitory concentration (fAUC/MIC) is the most relevant pharmacokinetic (PK)-pharmacodynamic (PD) parameter to predict the efficacy of levofloxacin (LFX). The objective of our study was to assess LFX PK variability in M/XDR-TB patients and its potential consequence for fAUC/MIC ratios. Patients with pulmonary M/XDR-TB received LFX as part of treatment regimen at a dose of 15 mg/kg once daily. Blood samples obtained at steady state before- and 1, 2, 3, 4, 7, and 12 hrs after drug administration were measured by validated a liquid chromatography-tandem mass spectrometry. MIC values of LFX were determined by the agar dilution method on Middlebrook 7H10 and the MGIT960 system. Twenty patients with a mean age of 31 (IQR; 27-35) years were enrolled in this study. The median AUC_0-24h was 98.8 mg/h/L (IQR; 84.8-159.6). The MIC median value for LFX was 0,5 mg/L with a range of 0.25 to 2.0 mg/L and the median fAUC_0-24/MIC ratio was 109.5 (IQR; 48.5-399.4). In four of the 20 patients the value was below the target value of ≥100. When a MIC of 0.25, 0.5, 1.0 and 2.0 mg/L were applicable, 19, 18, 3 and no patients, respectively, had a fAUC/MIC ratio that exceeded 100. We observed a large variability in AUC. A fAUC_0-24/MIC of ≥ 100 was only observed in case MIC values for LFX were 0.25-0.5 mg/L. Dosages exceeding 15mg/kg should be considered for target attainment if exposures are assumed to be safe.

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