Rethinking Linezolid Dosing for Drug-Resistant TB

Rifampicin-resistant tuberculosis (RR-TB) is treated with combinations that include the antibiotic linezolid, but the best dose and duration of linezolid are still uncertain. Bern-Thomas Nyang’wa and colleagues set out to shed light on this problem by building a population pharmacokinetic model for linezolid and testing how drug exposure relates to established targets. The work focused on patients receiving the BPaLM regimen (bedaquiline, pretomanid, linezolid, and moxifloxacin), a recommended combination for RR-TB, and aimed to support dose optimization and the interpretation of efficacy using pharmacokinetic-pharmacodynamic measures. Ninety-four RR-TB patients in the study received linezolid at 600 mg daily for the first 16 weeks, then stepped down to 300 mg daily for a further 8 weeks. Over the 24-week treatment period the team collected plasma samples at multiple time points to measure linezolid concentrations. Using those measurements, the researchers developed a model that describes how linezolid is absorbed, distributed, and eliminated in this patient group, with the goal of informing safer and more effective dosing strategies.

To analyze drug behavior in the body the investigators measured linezolid in plasma using high-performance liquid chromatography-tandem mass spectrometry and performed pharmacokinetic modeling with nlmixr2 in R. A one-compartment model with first-order absorption and elimination and fat-free mass allometric scaling best fit the data. The model estimated a typical clearance of 6.66 L/h and an apparent volume of distribution of 58.8 L. From the observed concentrations, median AUC₀₋₂₄ was 84.34 mg·h/L on 600 mg and 46.36 mg·h/L on 300 mg. Median trough concentrations were 0.71 mg/L at 600 mg and 0.39 mg/L at 300 mg. The team then evaluated probability of target attainment (PTA) against a pharmacodynamic target expressed as fAUC₀₋₂₄/MIC of 119 and found that the 600 mg dose reached that target only for isolates with MICs ≤0.25 mg/L. Despite these modeled shortfalls, randomized controlled trial findings referenced by the authors indicate that stepping down from 600 mg to 300 mg daily maintained efficacy in RR-TB treatment.

The study highlights an important tension between pharmacokinetic-pharmacodynamic targets derived from linezolid monotherapy and outcomes seen when linezolid is used as part of combination regimens like BPaLM. If PK-PD targets do not reflect the beneficial interactions of drugs in combination, they can underestimate real-world efficacy and lead to dosing choices that prioritize exposure numbers over patient outcomes. The authors argue that current PK-PD targets need revision to better match combination therapy results, because their clinical data show maintained efficacy even with lower linezolid exposure after the step-down. Practically, these findings support continued use of BPaLM regimens while aiming to reduce linezolid toxicity risk through dose-reduction strategies. The model and exposure data provide a foundation for future work to optimize linezolid dosing and balance efficacy with safety in RR-TB treatment, but they also caution clinicians and researchers to interpret PTA results in the context of combination therapy rather than monotherapy benchmarks.