Linezolid Use and Cytopenias in Patients Treated for Multidrug-resistant Tuberculosis Open Access
Graciaa, Daniel (Spring 2021)
Abstract
Background: Treatment of multidrug-resistant (MDR) TB requires long courses of therapy of 6-18 months. Linezolid is an oxazolidinone antibiotic used for MDR-TB treatment; while effective, its use is associated with adverse events including low blood counts (cytopenias) with treatment over 4 weeks. Data on toxicities with long-term use of linezolid and drug pharmacodynamics in TB treatment are limited and are barriers to implementation.
Methods: This was a secondary analysis of a National Institutes of Health (NIH)-funded retrospective cohort study of patients treated for MDR-TB in the country of Georgia from 2015-2017 that collected clinical and laboratory data via medical chart review and patient interview. The standard daily linezolid dose was 600 mg daily. Intensive blood sampling 4-6 weeks after treatment initiation generated serum linezolid trough concentration (Cmin) and area under the curve. Linezolid PK exposure was defined using literature-reported thresholds and receiver operating characteristic curves. Cytopenias were defined using an NIH adverse event (AE) scale with grades of increasing severity from 1-4. Logistic regression was used to estimate odds ratios (OR) and evaluate the relationship between linezolid PK exposure with development and severity of cytopenias.
Results: Among 100 patients enrolled, 80 had linezolid in their baseline regimen; 76 had PK data available. Cytopenia adverse events occurred in 31 (40.8%) for an incidence rate of 53 per 100 person-years. No patients required dose reduction or interruption due to cytopenias. Cytopenias were associated with linezolid PK parameters (OR 5.78 [95% CI 1.08-30.3] for thrombocytopenia with Cmin > 2mg/L) and higher-grade cytopenia AE were associated with higher PK parameters (OR 5.70 [95% CI 1.11-29.2] for thrombocytopenia with Cmin > 2mg/L).
Conclusions: Cytopenias occur frequently with long-term use of linezolid 600 mg/day and are associated with pharmacokinetic parameters early in therapy. However, this dose appears to be well-tolerated as there were no treatment-limiting cytopenia adverse events.
Table of Contents
INTRODUCTION 1
BACKGROUND 2
METHODS 5
RESULTS 10
DISCUSSION 15
REFERENCES 18
TABLES/FIGURES
Table 1. Baseline characteristics 22
Table 2. Treatment characteristics and outcomes 23
Table 3. Laboratory follow up 24
Table 4. Logistic regression analysis of cytopenia adverse events 25
Table 5. Ordinal logistic regression analysis of anemia adverse events 26
Table 6. Ordinal logistic regression analysis of thrombocytopenia adverse events 27
Figure 1. Study population flow diagram 28
Figure 2. Receiver operating characteristic curves 29
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