To the best of our knowledge, this study is the first to demonstrate that patients who received RRT or concurrent fluconazole treatment may have a higher incidence of linezolid-associated thrombocytopenia. In addition, we revealed the real-world situation and the association between clinical risk factors and linezolid-associated thrombocytopenia.
By performing binary logistic regression, RRT, concurrent fluconazole therapy, and longer duration of linezolid were identified as risk factors for linezolid-associated thrombocytopenia.
We discovered that patients who received RRT had a significantly higher risk (with vs. without RRT: 79.2% vs. 44.6%, P = 0.0032) and shorter median time (with vs. without RRT: 8 vs. 15 days, P = 0.0043) to have thrombocytopenia. Our finding was compatible with Hanai et al.’s results, which showed an onset time of 8.5 d in patients undergoing hemodialysis 8. Hirano et al. found that patients with CrCL < 30 mL/min (60.0%) had a significantly higher incidence of thrombocytopenia then those with CrCL > 60 mL/min (26.4%) 5. Moraza et al. and Hanai et al. 8reported similar findings 7. Several studies have revealed that renal function plays a critical role in thrombocytopenia associated with linezolid 5–8,10,12,21. The manufacturer recommends that the pharmacokinetic parameters of the parent drug are not transformed 2, and that no dosage adjustment is needed for renal impairment. However, a higher incidence of thrombocytopenia was noted among our patients who received RRT. Brier et al. concluded that the levels of two primary metabolites (PNU-142586 and PNU-142300) were higher in patients requiring hemodialysis 22. Matsumoto et al. suggested that renal impairment elevated linezolid trough concentration, and higher drug exposure might be related to thrombocytopenia 23. Considering the higher possibility of thrombocytopenia in renal dysfunction, physicians should be aware of the harmful outcomes, although the mechanism of linezolid-associated remains unclear.
The literature reports fluconazole-associated thrombocytopenia limited to several case reports. Pasikhova et al. reported a case of fluconazole-associated agranulocytosis with thrombocytopenia 17. One population-based study enrolled 54,803 users of either fluconazole or itraconazole, and only 1 of 34,220 fluconazole users had thrombocytopenia 24. So far, no interaction between fluconazole and linezolid has been found25. Little information is available regarding the underlying fluconazole and linezolid-associated thrombocytopenia. We suppose that the use of fluconazole may indicate more severe sepsis, and sepsis may be the direct result of thrombocytopenia 26. Therefore, further studies are necessary.
We found that patients treated with linezolid for ≥ 14 d had a relatively higher frequency of thrombocytopenia (duration ≥ 14 d vs. 14 > duration ≥ 5 d: 63.83% vs. 43.14%, P = 0.0403) (results detailed in Supplementary Fig. S2). Our results are compatible with those of other studies. Hirano et al. 5 and Takahashi et al. 13 reported a higher incidence of thrombocytopenia among patients with linezolid duration ≥ 14 d. Choi et al. 11 even suggested an increased odds ratio for linezolid duration ≥ 7 d. Therefore, we suggest monitoring platelet counts for prolonged durations of linezolid administration, especially for those who received RRT.
According to recent studies, the incidence of thrombocytopenia ranged from 16.7–48.4% in adults treated with linezolid 4–13. Kim et al. 10 revealed a 48.3% risk of thrombocytopenia in a cohort of 60 ICU patients, and thrombocytopenia was defined as a platelet count of < 150×109/L or a decrease of at least 50% from the baseline. The relatively higher incidence (53.1%) in our study could have resulted from different disease severities and definitions of thrombocytopenia.
Our data showed that patients with diabetes mellitus had twice the risk of thrombocytopenia. However, this was not significant after adjusting for confounding factors. Diabetic kidney disease, a microvascular complication, frequently leads patients to undergo dialysis or renal transplantation 27. Consequently, a higher proportion of diabetes mellitus in the thrombocytopenic group is anticipated. Regarding the administration route, oral-form linezolid was mostly prescribed for discharge in our study. This could be a possible explanation for the higher ratio of intravenous linezolid in patients with thrombocytopenia. Our results were compatible with the findings of Takahashi et al. 13, which showed that oral linezolid decreased the risk of thrombocytopenia.
However, the mechanism underlying linezolid-associated thrombocytopenia remains unclear. Several mechanisms have been proposed. For instance, immune-mediated thrombocytopenia has been proposed by Bernstein et al. 28. Other theories, including the suppression of platelets release from mature megakaryocytes 29, and Tsuji et al. assumed that the inhibition of the platelet formation was the most common mechanism 30. Many studies reported that the linezolid-associated adverse reactions were related to linezolid trough concentration (Cmin) 31,32. Cojutti et al. 33 monitored patients’ Cmin for dose adjustment at day 3–5 of therapy, and 2–8 mg/L was taken as desired range for Cmin. Peripheral venous blood samples were collected 5 min prior to the subsequent dose. Levels of linezolid were analyzed by a validated HPLC analysis method. However, more studies are necessary to clarify the approach of dose adjustment.
Several clinical factors might also affect platelets, such as a history of surgery and recent transfusions 34. Using radionuclides, the mean life span of transfused platelets in humans was 9.9 ± 0.6 d 35–38. Therefore, we excluded patients who received platelet transfusions ≤ 10 d before initiation of linezolid. Moreover, the material of the dialyzer may cause thrombocytopenia; polysulfone membranes and amounts of polyvinylpyrrolidone are thought to be related to its occurrence, but the exact mechanism remains to be elucidated 39.
Our observational cohort study has several limitations. First, due to the retrospective nature of the study design, we could not make causal inferences. Second, means of monitoring concentrations of linezolid and its metabolites were not available, and it was difficult to evaluate the pharmacokinetic parameters of linezolid in thrombocytopenic patients. Monitoring linezolid Cmin at steady-state condition may be a feasible approach. However, therapeutic drug monitoring of linezolid is in experimental stage, and more studies are warranted.