Pharmacodynamic evidence for tedizolid use in Mycobacterium avium lung disease

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 (AUC_0-24)-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 (E _max) modelling of bacterial burden versus AUC_0-24/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 E _max of 3.61 ± 1.05 log₁₀ CFU/mL below day 0 burden at a target exposure AUC_0-24/MIC of 155.5 ± 38.84 (r ² = 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.