Linezolid trough concentrations greater than 2 mg/L strongly linked to drug toxicity in MDR TB

France: Linezolid trough concentrations greater than 2 mg/L are strongly linked to the development of complicated treatment-associated toxicity in patients treated for multidrug-resistant tuberculosis (MDR-TB), says an article published in Clinical Infectious Diseases.

Linezolid treatment of multidrug-resistant TB is associated with a significant risk of side effects. There is little evidence on therapeutic medication monitoring to anticipate drug toxicity. As a result, Johannes Eimer and colleagues conducted this study to assess the relationship between linezolid trough concentrations and severe toxicity.

Researchers analyzed consecutive individuals who began using linezolid for MDR-TB between 2011 and 2017. The primary endpoint was severe mitochondrial toxicity (SMT) caused by linezolid, which was defined as neurotoxicity or myelotoxicity that required medication withdrawal. The effect of plasma linezolid trough concentrations greater than 2 mg/L was studied using multivariate Cox proportional hazards models with time-varying variables.

The key findings of this study were as follows:

1. SMT occurred in 57 of the 146 patients (39%) with an incidence rate of 0.38 per person-year.

2. In 52 patients (35.6 %), the highest linezolid trough concentration was greater than >2 mg/L, whereas the mean trough concentration was greater than >2 mg/L in 22 individuals (15% ).

3. SMT had an adjusted hazard ratio of 2.35 in patients with a mean trough concentration more than >2 mg/L and 2.63 after the first detection of a trough concentration greater than >2 mg/L.

4. Greater total trough concentrations were dose-dependently related to toxicity in an exploratory study, but reducing increased trough concentrations did not reinstate baseline risk.

In conclusion, this study clearly shows a link between Linezolid trough concentrations greater than 2 mg/L and the development of severe treatment-emergent toxicity in MDR-TB patients. In the absence of additional prospective data, an individual risk-benefit analysis on the continuation of linezolid treatment is necessary in any patient with trough concentrations of more than 2 mg/L.

Reference:

Eimer, J., Fréchet-Jachym, M., Le Dû, D., Caumes, E., El-Helali, N., Marigot-Outtandy, D., Mechai, F., Peytavin, G., Pourcher, V., Rioux, C., Yazdanpanah, Y., Robert, J., & Guglielmetti, L. (2022). Increased linezolid plasma concentrations are associated with the development of severe toxicity in MDR-TB treatment. In Clinical Infectious Diseases. Oxford University Press (OUP). https://doi.org/10.1093/cid/ciac485