Abstract:

Objective: To analyze the influence of linezolid blood concentration on hematological toxicity in drug-resistant tuberculosis patients, as well as to explore other risk factors for hematopoietic toxicity. Methods: A prospective cohort study was conducted in 219 drug-resistant tuberculosis patients, all of them were continuously included and received chemotherapy treatment containing linezolid from January 2019 to February 2021 in Beijing Chest Hospital affiliated to Capital Medical University. Clinical data and blood samples 2 hours after administration were collected. A high performance liquid chromatography-mass spectrometry was used to measure the plasma concentrations of linezolid. The diagnostic value of blood drug concentration (peak concentration) on blood system toxicity was determined by drawing receiver operating characteristic curve (ROC curve), and the optimal diagnostic threshold was also determined. Multivariate logistic regression was used to analyze the influencing factors of blood system toxicity. Results: Among 219 subjects, 92 cases (42.0%) had hematological toxicity, including leukopenia (15.5%, 34/219), anemia (21.5%, 47/219), and thrombocytopenia (27.4%, 60/219), and the other 127 (58.0%) cases did not have any toxic reactions associated with linezolid. The peak plasma concentration of linezolid in patients with hematotoxicity was 17.1 (11.8, 22.8) μg/ml, significantly higher than that of non-occurrence (14.7 (10.4, 18.0) μg/ml)(Z=-3.206, P=0.001). Of patients without hematological toxicity, 29.1% (37/127) had serum albumin of <40 g/L, which was significantly lower than that of those with serum albumin ≥40 g/L (70.9%, 90/127)(χ²=7.998, P=0.005). Based on the ROC curve analysis, the linezolid’s peak concentration had predictive value on blood system toxicity (the area under the curve was 0.627), and 20.7 μg/ml of the linezolid’s peak concentration was the best diagnostic point. The multivariate logistic regression analysis showed that, the risk of hematotoxicity in patients with serum albumin <40 g/L was 2.622 times higher than that in patients with serum albumin ≥40 g/L (OR=2.622, 95%CI:1.344-5.117); the risk of blood system toxicity in patients with the peak plasma concentration of linezolid >20.7 μg/ml was 6.419 times higher than that in patients with the peak blood concentration≤20.7 μg/ml (OR=6.419, 95%CI:2.874-14.337). Conclusion: The proportion of hematological toxicity caused by linezolid is high. It is important to be aware of the possibility of blood system toxicity when administering linezolid to patients with serum albumin <40 g/L and linezolid peak plasma concentration >20.7 μg/ml.

Key words: Tuberculosis, pulmonary, Drug resistance, Antitubercular agents, Drug toxicity, Evaluation studies