Linezolid Exposure Is Associated with Cytopenias in Patients Treated for Multidrug-Resistant Tuberculosis

Area of Science:

• Pharmacology and Infectious Diseases
• Clinical Pharmacology
• Tuberculosis Research

Background:

• Linezolid is crucial for treating multidrug-resistant tuberculosis (MDR-TB).
• Concerns about linezolid's toxicity, particularly cytopenias after 4 weeks, limit its use.
• Limited data exist on long-term linezolid toxicities and pharmacodynamics in MDR-TB patients.

Purpose of the Study:

• To analyze the relationship between linezolid exposure and cytopenias in MDR-TB patients.
• To evaluate the incidence and characteristics of cytopenias during long-term linezolid therapy.
• To assess the need for dose adjustments or interruptions due to adverse events.

Main Methods:

• Secondary analysis of a prospective cohort study in Georgia (2015-2017).
• Pharmacokinetic (PK) analysis of linezolid trough concentration (Cmin) and AUC0-24 at 4-6 weeks.
• Cytopenias defined by NIH AE scale; logistic regression used to assess PK-toxicity association.

Main Results:

• Cytopenias occurred in 39.5% of 76 patients, with an incidence rate of 46 per 100 person-years.
• Median linezolid therapy duration was 526 days.
• Cytopenias were associated with higher linezolid exposure (Cmin > 2 mg/L, AUC0-24 > 160 mg·h/L) but did not necessitate treatment interruption.

Conclusions:

• Frequent cytopenias are observed with long-term linezolid (600 mg/day) treatment for MDR-TB.
• Linezolid exposure parameters (Cmin, AUC0-24) correlate with cytopenias.
• Despite frequent occurrence, cytopenias did not require dose reduction or interruption in this cohort.