Linezolid Use and Cytopenias in Patients Treated for Multidrug-resistant Tuberculosis Open Access

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

About this Master's Thesis

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School	Laney Graduate School
Department	Clinical Research
Degree	M.S.
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Medicine and Surgery Health Sciences, Public Health Health Sciences, Pharmacology
Keyword	pharmacodynamic cytopenias pharmacokinetic linezolid drug-resistant tuberculosis
Committee Chair / Thesis Advisor	Russell Kempker, MD, MSc, Emory University
Committee Members	Matthew Magee, PhD, MPH, Emory University Sara Auld, MD, MSc, Emory University

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