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Article Dans Une Revue Clinical Infectious Diseases Année : 2022

Increased linezolid plasma concentrations are associated with the development of severe toxicity in MDR-TB treatment.

Johannes Eimer
Mathilde Fréchet-Jachym
  • Fonction : Auteur
Damien Le Dû
  • Fonction : Auteur
Eric Caumes
  • Fonction : Auteur
Najoua El-Helali
  • Fonction : Auteur
Dhiba Marigot-Outtandy
  • Fonction : Auteur
Valérie Pourcher
  • Fonction : Auteur
Christophe Rioux
  • Fonction : Auteur
Yazdan Yazdanpanah
  • Fonction : Auteur
Emmanuel Lecorché
  • Fonction : Auteur
Faiza Mougari
  • Fonction : Auteur
Claire Andrejak
Anne Bourgarit
  • Fonction : Auteur
Elise Klement
  • Fonction : Auteur
Bénédicte Rivoire
  • Fonction : Auteur
Guillaume Thouvenin
  • Fonction : Auteur
Simone Tunesi
  • Fonction : Auteur
Marie Wicky
  • Fonction : Auteur
Marie Jaspard
  • Fonction : Auteur
Corentine Alauzet
  • Fonction : Auteur
Lelia Escaut
  • Fonction : Auteur
Sophie Ellis-Corbet
  • Fonction : Auteur
Christine Bernard
  • Fonction : Auteur
Anne-Laure Roux
  • Fonction : Auteur

Résumé

Abstract Background Treatment of multidrug-resistant (MDR) tuberculosis with linezolid is characterized by high rates of adverse events. Evidence on therapeutic drug monitoring to predict drug toxicity is scarce. This study aimed to evaluate the association of linezolid trough concentrations with severe toxicity. Methods We retrospectively assessed consecutive patients started on linezolid for MDR tuberculosis between 2011 and 2017. The primary outcome was severe mitochondrial toxicity (SMT) due to linezolid, defined as neurotoxicity or myelotoxicity leading to drug discontinuation. The impact of plasma linezolid trough concentrations >2 mg/L was assessed in multivariate Cox proportional hazards models including time-varying covariates. Results SMT occurred in 57 of 146 included patients (39%) at an incidence rate of 0.38 per person-year (95% confidence interval, .30–.49). A maximum linezolid trough concentration >2 mg/L was detected in 52 patients (35.6%), while the mean trough concentration was >2 mg/L in 22 (15%). The adjusted hazard ratio for SMT was 2.35 (95% confidence interval, 1.26–4.38; P = .01) in patients with a mean trough concentration >2 mg/L and 2.63 (1.55–4.47; P < .01) for SMT after the first detection of a trough concentration >2 mg/L. In an exploratory analysis, higher maximum trough concentrations were dose-dependently associated with toxicity, while lowering elevated trough concentrations did not restore baseline risk. Conclusions Linezolid trough concentrations >2 mg/L are strongly associated with the development of severe treatment-emergent toxicity in patients treated for MDR tuberculosis. Pending further prospective evidence, an individual risk-benefit assessment on the continuation of linezolid treatment is warranted in any patient with trough concentrations >2 mg/L.

Domaines

Bactériologie
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Dates et versions

hal-03909796 , version 1 (22-12-2022)

Identifiants

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Johannes Eimer, Mathilde Fréchet-Jachym, Damien Le Dû, Eric Caumes, Najoua El-Helali, et al.. Increased linezolid plasma concentrations are associated with the development of severe toxicity in MDR-TB treatment.. Clinical Infectious Diseases, 2022, ⟨10.1093/cid/ciac485⟩. ⟨hal-03909796⟩
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