Pharmacodynamic evidence for tedizolid use in Mycobacterium avium lung disease

TL;DR

Tedizolid shows strong potential for treating Mycobacterium avium lung disease, with optimal dosing identified through pharmacodynamic modeling.

Contribution

The study provides pharmacodynamic evidence for tedizolid dosing in MAC lung disease using multiple clinical isolates.

Findings

Tedizolid reduced MAC bacterial burden by 3.61 log10 CFU/mL at a target AUC0–24/MIC of 155.5.

Doses of 200 and 300 mg/day achieved target exposure in 86% and 93% of virtual patients, respectively.

Abstract

On guideline-based therapy for Mycobacterium avium complex (MAC) lung disease (LD), ∼50%–60% of patients suffer recalcitrant disease. Tedizolid is a promising agent based on the intracellular hollow fibre model of MAC-LD (HFS-MAC) using the MAC laboratory reference isolate (ATCC#700898), with a target exposure 0–24 area under the concentration-time curve (AUC0–24)-to-minimum inhibitory concentration (MIC) of 23.46.

We performed a 28-day study in the HFS-MAC inoculated with five different MAC isolates treated with six daily exposures, using intrapulmonary pharmacokinetics of tedizolid. Data were analysed using inhibitory sigmoid maximal effect (Emax) modelling of bacterial burden versus AUC0–24/MIC. Monte Carlo experiments were implemented to determine the optimal oral tedizolid dose achieving target exposure in lungs of 10,000 virtual patients.

Tedizolid killed the five clinical isolates of MAC with an Emax of 3.61 ± 1.05 log10 CFU/mL below day 0 burden at a target exposure AUC0–24/MIC of 155.5 ± 38.84 (r2 = 0.98). In Monte Carlo experiments, the dose of 200 and 300 mg/day achieved the target exposure in 86% and 93% of patients, respectively.

Based on the reported HFS-MAC studies using multiple clinical isolates of MAC, we propose that tedizolid at 200–300 mg/day should be tested as the backbone of novel combinations to treat MAC-LD.

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