==== Front PLoS One PLoS One plos PLOS ONE 1932-6203 Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0286088 PONE-D-22-25412 Research Article Biology and Life Sciences Anatomy Body Fluids Blood Platelets Medicine and Health Sciences Anatomy Body Fluids Blood Platelets Biology and Life Sciences Physiology Body Fluids Blood Platelets Biology and Life Sciences Cell Biology Cellular Types Animal Cells Blood Cells Platelets Medicine and Health Sciences Hematology Thrombocytopenia Medicine and Health Sciences Hematology Medicine and Health Sciences Health Care Health Care Facilities Hospitals Intensive Care Units Biology and life sciences Organisms Bacteria Staphylococcus Staphylococcus aureus Methicillin-resistant Staphylococcus aureus Biology and life sciences Microbiology Medical microbiology Microbial pathogens Bacterial pathogens Staphylococcus Staphylococcus aureus Methicillin-resistant Staphylococcus aureus Medicine and health sciences Pathology and laboratory medicine Pathogens Microbial pathogens Bacterial pathogens Staphylococcus Staphylococcus aureus Methicillin-resistant Staphylococcus aureus Medicine and Health Sciences Clinical Medicine Signs and Symptoms Sepsis Biology and Life Sciences Anatomy Renal System Medicine and Health Sciences Anatomy Renal System Medicine and Health Sciences Surgical and Invasive Medical Procedures Blood and Lymphatic System Procedures Stem Cell Transplantation Hematopoietic Stem Cell Transplantation Medicine and Health Sciences Surgical and Invasive Medical Procedures Transplantation Cell Transplantation Stem Cell Transplantation Hematopoietic Stem Cell Transplantation Effect of linezolid on platelet count in critically ill patients with thrombocytopenia Effect of linezolid on platelet count in critically ill patients with thrombocytopenia https://orcid.org/0000-0002-9688-6154 Tatsumi Hiroomi Conceptualization Data curation Investigation Methodology Project administration Writing – original draft * Akatsuka Masayuki Data curation Writing – review & editing https://orcid.org/0000-0002-2361-3227 Kuroda Hiromitsu Data curation Writing – review & editing Kazuma Satoshi Data curation Writing – review & editing Suzuki Shintaro Data curation Masuda Yoshiki Supervision Writing – review & editing Department of Intensive Care Medicine, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan Mayne Elizabeth S. Editor University of Cape Town Faculty of Science, SOUTH AFRICA Competing Interests: Tatsumi H received lecture fees from TSUMURA & CO and industry-academia collaborative research grant from Otsuka Pharmaceutical Factory, Inc. Masuda Y received lecture fees from MSD K.K., Asahi Kasei Pharma Corp. and Japan Blood Product and industry-academia collaborative research grant from JIMRO Co., Ltd. Other authors declare that they have no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials. * E-mail: htatsumi@sapmed.ac.jp 29 6 2023 2023 18 6 e028608813 9 2022 8 5 2023 © 2023 Tatsumi et al 2023 Tatsumi et al https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Introduction Linezolid (LZD) is one of the antibiotics used to treat methicillin-resistant Staphylococcus aureus. In Japan, the dose of LZD is not generally adjusted by renal function or therapeutic drug monitoring and is readily available for critically ill patients. The adverse effects of LZD include pancytopenia, especially thrombocytopenia. We investigated the effect of LZD on platelet counts in critically ill patients with thrombocytopenia during admission to the intensive care unit (ICU). Methods Fifty-five critically ill patients with existing thrombocytopenia (platelet count < 100 ×103 /μL) who received LZD for five days or more during the period from January 2011 to October 2018 were included. Changes in platelet count and frequency of platelet concentrate (PC) transfusion were evaluated retrospectively. Results Mean (± standard error) platelet count prior to initiation of LZD was 47 ± 4 ×103 /uL, which increased significantly to 86 ± 13 ×103 /uL on day 15 (p<0.01). Median [interquartile range] duration of LZD therapy was 9 [8–12] days. Thirty-two patients (58.2%) required PC transfusion in the 15-day study period. The daily rate of PC transfusion decreased from 30.2% on days 1–5 to 18.2% on days 11–15. Similar tendencies were observed in patients with non-hematological and hematological disease. Conclusion Thrombocytopenia in critically ill patients in the ICU did not worsen after initiation of LZD therapy, and may be considered for the treatment of MRSA in this setting. The authors received no specific funding for this work. Data AvailabilityAll relevant data are within the paper and its Supporting Information files. Data Availability All relevant data are within the paper and its Supporting Information files. ==== Body pmcIntroduction Among Gram-positive bacteria, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) are crucial pathogens that cause hospital-acquired infection [1] and are related to high rates of hospital mortality, especially in critically ill patients [2]. Of the antibiotics used for MRSA and VRE, linezolid (LZD) has several features including low molecular weight (337.35 Da), low protein binding rate (31%), large distribution volume (40–50 L/kg), and lipophilicity, and therefore excellent tissue migration properties. Among the various anti-MRSA drugs, which include vancomycin (VAN), in Japan the dose of LZD is not generally adjusted based on renal function or therapeutic drug monitoring (TDM). Therefore, LZD is readily available for patients with acute kidney injury (AKI) and those who are receiving continuous renal replacement therapy (CRRT). One of the adverse effects of LZD is pancytopenia, especially thrombocytopenia. Previous studies have shown that the development of LZD-induced thrombocytopenia may be associated with body weight [3–5], baseline platelet level [4, 6–8], prolonged duration of therapy [9, 10], renal function [3, 5, 6, 11, 12] and plasma LZD concentration [4, 8, 11]. Accordingly, an anti-MRSA drug other than LZD is commonly selected for patients with thrombocytopenia, without regard to other causes of thrombocytopenia such as sepsis, disseminated intravascular coagulation (DIC), and myelosuppression. The aim of this study was to investigate the effect of LZD on platelet count in critically ill patients with thrombocytopenia in the intensive care unit (ICU) setting. Patients and methods Study design This retrospective study was performed at the ICU of Sapporo Medical University Hospital (Sapporo, Japan). The study protocol conformed to the ethical guidelines enshrined in the Declaration of Helsinki and was approved by the Research Ethics Committee of Sapporo Medical University (approval No. 302–145). The requirement for informed consent was waived due to the retrospective and observational nature of the study. An information disclosure document about the study was created and made available to the study patients and their families via the website of the hospital’s ICU, guaranteeing the opportunity for study patients and their families to refuse participation. Patients and setting The subjects were critically ill patients in the ICU with thrombocytopenia who received LZD for five days or more during the period from January 2011 to October 2018. Patients with sepsis who are admitted to the ICU often have AKI or undergo CRRT, and when selecting an anti-MRSA drug that requires dose adjustment, it takes time to adjust the blood concentration within the effective range. Because the dose of LZD is not generally adjusted based on renal function or TDM in Japan, we chose LZD for the treatment of MRSA. In this study, thrombocytopenia was defined as a platelet count of less than 100 ×103 /μL at the time of LZD administration. Patients who died due to acute or irreversible progression of the primary disease (Fig 1) within 15 days after the start of LZD administration and those younger than 18 years were excluded. As a general rule, the daily dose of LZD was 600 mg intravenously twice a day, and the timing of LZD discontinuation was decided by physicians and ICU staff at the daily ICU conference. The use of platelet concentrate (PC) transfusion was also decided at the daily ICU conference, with indications including the platelet count, change in the platelet count, presence or absence of bleeding, treatment content such as blood purification therapy, and the necessity of treatment with a high bleeding risk. 10.1371/journal.pone.0286088.g001 Fig 1 Flow chart of patient selection. *Cause of death: Complications after hematopoietic stem cell transplantation: 4 Fulminant hepatitis / acute liver failure: 3 Postresuscitation encephalopathy: 2 Alveolar hemorrhage due to vasculitis: 1 Progression of malignant tumor: 1. Patient characteristics including age and sex, primary disease, reason for ICU admission, change in platelet count from days 1 to 15 after the start of LZD administration, and PC transfusion from days 1 to 15 after the start of LZD administration were evaluated retrospectively. The daily rate of PC transfusion (defined as PC transfused patients divided by the total patients) was calculated over the 15 days and compared among three periods: early period (days 1–5), middle period (days 6–10), and late period (days 11–15). Because the present study was performed retrospectively, daily platelet counts had not been obtained in all patients, and the original data had many missing values. The missing data were mostly after ICU discharge, especially on the first day after PC transfusion, when the platelet count was expected to increase. Therefore, we prepared and evaluated corrected data in which the missing platelet count data were compensated for as the average of the measured values on the previous day and the next day. The patients were divided into two groups: a hematological disease group and a non-hematological disease group (Table 1). In the hematological disease group, thrombocytopenia or pancytopenia occurred due to chemotherapy or hematopoietic stem cell transplantation for the treatment of hematological diseases or malignancies. Change in platelet count during LZD administration was analyzed in each group. 10.1371/journal.pone.0286088.t001 Table 1 Patient characteristics (January 2011 to October 2018, Sapporo Medical University Hospital). All Non-hematological Hematological (n = 55) (n = 41) (n = 14) Age (y): median [IQR] 69 [62.5–75.5] 73 [66–76] 50 [61.8–75.5] Sex Female: N (%) 16 (29.1) 12 (29.3) 4 (28.6) Male: N (%) 39 (70.9) 29 (70.7) 10 (71.4) Primary disease Non-hematological: N (%) 41 (74.5) Cardiovascular: N (%) 15 (27.3) Gastrointestinal: N (%) 9 (16.4) Hepatobiliary-pancreatic: N (%) 6 (10.9) Respiratory: N (%) 3 (5.5) Head and neck: N (%) 2 (3.6) Orthopedic: N (%) 2 (3.6) Other: N (%) 4 (7.3) Hematological: N (%) 14 (25.5) Acute myeloid leukemia: N (%) 6 (10.9) Acute lymphoblastic leukemia: N (%) 4 (7.3) Myelodysplastic syndromes: N (%) 2 (3.6) Other: N (%) 2 (3.6) APACHE II: median [IQR] 24 [20.5–28] 25 [19–28] 23.5 [21–29.5] SOFA score at ICU admission: median [IQR] 8 [7–10.5] 8 [6–10] 9 [8–10.8] Presumed cause of thrombocytopenia Sepsis: N (%) 26 (47.3) 26 (63.4) 0 Chemotherapy: N (%) 2 (3.6) 1 (2.4) 1 (7.1) Chemotherapy + sepsis: N (%) 11 (20.0) 7 (17.1) 4 (28.6) Hepatic failure: N (%) 1 (1.8) 1 (2.4) 0 Hepatic failure + sepsis: N (%) 4 (7.3) 4 (9.8) 0 Hematopoietic stem cell transplantation: N (%) 4 (7.3) 0 4 (28.6) Hematopoietic stem cell transplantation + sepsis: N (%) 4 (7.3) 0 4 (28.6) Other: N (%) 3 (5.5) 2 (4.9) 1 (7.1) Infection on ICU admission: N (%) 34 (61.8) 25 (61.0) 9 (64.3) DIC on ICU admission: N (%) 26 (47.3) 19 (46.3) 7 (50.0) AKI on ICU admission: N (%) 31 (56.4) 23 (56.1) 8 (57.1) Duration of LZD administration (day): median [IQR] 9 [8–12] 9 [8–12] 10 [7.3–12.8] Administration of CRRT: N (%) 42 (76.4) 32 (78.0) 10 (71.4) Administration of PC transfusion: N (%) 32 (58.2) 19 (46.3) 13 (92.9) Duration of ICU stay (d): median [IQR] 15 [8.5–23.5] 15 [8–22] 16.5 [9.3–23.8] ICU mortality: N (%) 13 (23.6) 8 (19.5) 5 (35.7) 28-day mortality: N (%) 16 (29.1) 9 (22.0) 7 (50.0) Statistical analysis Categorical variables and continuous variables of the patients’ characteristics are presented as the number (%) and median [interquartile range, IQR], respectively. Platelet counts are presented as the mean ± standard error. Serial change in platelet count was assessed using Friedman’s test. When a statistically significant difference was obtained after Friedman’s test, Wilcoxon’s t-test with Bonferroni correction was performed as a post hoc test. Probability values less than 0.05 in a two-sided test were considered statistically significant. Results Patient characteristics Patient characteristics are listed in Table 1. Fifty-five patients were included (Fig 1). LZD was administered as empiric or definitive therapy. Median age was 69 [62.5–75.5] years and 39/55 (70.9%) were male. As indicators of the severity of illness, acute physiology and chronic health evaluation (APACHE) II score and sequential organ failure assessment (SOFA) score were 24 [20.5–28] and 8 [7–10.5], respectively. Infection was diagnosed on admission to the ICU in 34/55 (61.8%), and 26/55 (47.3%) developed DIC on ICU admission. The effects of chemotherapy and hematopoietic stem cell transplantation were also taken into consideration as causes of thrombocytopenia, in addition to the effects of sepsis alone. Among the primary diseases, cardiovascular disease was the most common (27.3%), followed by hematological (25.4%) and gastrointestinal disease (16.4%). Thirty-one patients (56.4%) had AKI on ICU admission and 42 patients (76.4%) needed CRRT while in the ICU. Median duration of LZD administration was 9 [8–12] days and median duration of ICU stay was 15 [8.5–23.5] days. Changes in platelet count and PC transfusion in all patients Changes in mean platelet count are shown for the original and corrected data in Fig 2A and 2B, respectively. The mean (± standard error, SE) platelet count was 47 ± 4 ×103 /μL before LZD administration, which showed a gradual but statistically significant increase over the 15-day period (p < 0.01, in the original and corrected data). Mean (± SE) platelet counts were 86 ± 13 ×103 /μL in the original data and 95 ± 13 ×103 /μL in the corrected data on day 15, which were significantly higher than those before initiation of LZD therapy (p < 0.01 in both the original and corrected data). Thirty-two patients (58.2%) required PC transfusion in the 15 days after starting LZD administration. The daily rates of PC transfusion after starting LZD administration were 30.2%, 20.7%, and 18.2% in the early, middle, and late periods, respectively. 10.1371/journal.pone.0286088.g002 Fig 2 Change in platelet count in all patients (January 2011 to October 2018, Sapporo Medical University Hospital). A. Original data. Platelet count showed a gradual but statistically significant increase (p < 0.01). Platelet count was significantly higher on day 15 than before LZD administration (86 ± 13 ×103 /μL and 47 ± 4 ×103 /μL, respectively; p < 0.01). There were missing values after the 9th day. B. Corrected data. Platelet count showed a gradual but statistically significant increase (p < 0.01). Platelet counts were significantly higher on day 15 than before LZD administration (95 ± 13 ×103 /μL and 47 ± 4 ×103 /μL, respectively; p < 0.01). Changes in platelet count and PC transfusion in the non-hematological disease group Sub-analyses of the 41 patients whose primary disease was non-hematological are shown in Fig 3. Findings in this group were similar to those in all patients even when hematological diseases were excluded. Mean (± SE) platelet count was 56 ± 4 ×103 /μL before LZD administration, and increased gradually over 15 days (p < 0.01 in both the original and corrected data). Mean (± SE) platelet counts were 94 ± 16 ×103 /μL in the original data and 100 ± 15 ×103 /μL in the corrected data on day 15, which were significantly higher than those before initiation of LZD therapy (p = 0.02 and p < 0.01, respectively). Nineteen patients (46.3%) required PC transfusion in the 15 days after starting LZD administration. The daily rates of PC transfusion after starting LZD administration were 17.1%, 8.8%, and 7.3% in the early, middle, and late periods, respectively. 10.1371/journal.pone.0286088.g003 Fig 3 Change in platelet count in the non-hematological disease group (January 2011 to October 2018, Sapporo Medical University Hospital). A. Original data. Platelet count showed a gradual but statistically significant increase (p < 0.01). Platelet count was significantly higher on day 15 than before LZD administration (94 ± 16 ×103 /μL and 56 ± 4 ×103 /μL, respectively; p = 0.02). There were missing values after the 9th day. B. Corrected data. Platelet count showed a gradual but statistically significant increase (p < 0.01). Platelet count was significantly higher on day 15 than before LZD administration (100 ± 15 ×103 /μL and 56 ± 4 ×103 /μL, respectively; p < 0.01). Changes in platelet count and PC transfusion in the hematological disease group Sub-analyses of the 14 patients whose primary disease was hematological are shown in Fig 4. A similar tendency was observed even when the primary disease was limited to hematological disease. Mean (± SE) platelet count was 20 ± 2 ×103 /μL before LZD administration and increased gradually over 15 days (p < 0.01 in both the original and corrected data). Mean (± SE) platelet counts were 66 ± 24 ×103 /μL in the original data and 80 ± 26 ×103 /μL in the corrected data on day 15, the latter being significantly higher than that before initiation of LZD therapy (p = 0.04). Thirteen patients (92.9%) required PC transfusion in the 15 days after starting LZD administration. The daily rates of PC transfusion after starting LZD administration were 68.6%, 55.7%, and 50.0% in the early, middle, and late periods, respectively. 10.1371/journal.pone.0286088.g004 Fig 4 Change in platelet count in the hematological disease group (January 2011 to October 2018, Sapporo Medical University Hospital). A. Original data. Platelet count showed a gradual but statistically significant increase (p < 0.01). Platelet count was significantly higher on day 15 than before LZD administration (66 ± 24 ×103 /μL and 20 ± 2 ×103 /μL, respectively; p = 0.08). There were missing values after the 14th day. B. Corrected data. Platelet count showed a gradual but statistically significant increase (p < 0.01). Platelet count was significantly higher on day 15 than before LZD administration (80 ± 26 ×103 /μL and 20 ± 2 ×103 /μL, respectively; p = 0.04). Changes in platelet count in patients without PC transfusion Sub-analysis in 23 patients who did not receive PC transfusion are shown in Fig 5. Mean (± SE) platelet count was 68 ± 5 ×103 /μL before LZD administration, and increased gradually over 7 days and then plateaued (p < 0.01 in both the original and corrected data). Mean (± SE) platelet counts were 125 ± 21 ×103 /μL in the original data and 130 ± 22 ×103 /μL in the corrected data on day 15, which were significantly higher than those before initiation of LZD administration (p = 0.03 and 0.04, respectively). 10.1371/journal.pone.0286088.g005 Fig 5 Change in platelet count in patients without PC transfusion (January 2011 to October 2018, Sapporo Medical University Hospital). A. Original data. Platelet count showed a gradual but statistically significant increase (p < 0.01). Platelet count was significantly higher on day 15 than before LZD administration (125 ± 21×103 /μL and 68 ± 5 ×103 /μL, respectively; p = 0.03). There were missing values after the 9th day. B. Corrected data. Platelet count showed a gradual but statistically significant increase (p < 0.01). Platelet count was significantly higher on day 15 than before LZD administration (130 ± 22 ×103 /μL and 68 ± 5 ×103 /μL, respectively; p = 0.04). Discussion Numerous reports [9, 10, 13, 14] have shown that long-term administration of LZD is associated with thrombocytopenia. In general, LZD-induced thrombocytopenia occurs from 7 days after the start of administration and resolves several days after discontinuation of LZD [2, 6, 13–18]. However, the effect of administration of LZD on platelet count in patients with thrombocytopenia was previously unknown. The present study showed that platelet count increased gradually and that the need for PC transfusion showed a decreasing trend after LZD administration in patients whose platelet count was less than 100 ×103 /μL in the early period of LZD administration. These findings were similar between the hematological and non-hematological disease groups. In the subanalysis of patients without PC transfusion, platelet count increased gradually after LZD administration and plateaued after day 7. Therefore, we consider that LZD does not cause thrombocytopenia within at least the first 10 days of administration, and may be considered for patients with thrombocytopenia due to infection or hematological disorder. In addition, we observed no leukopenia or erythrocytopenia that could be attributed to LZD in the present patients. We consider that in the present study, the platelet count increased as a result of effective treatment (including LZD administration) in critically ill patients with thrombocytopenia. Administration of LZD may be associated with resolution of infection and recovery from serious illness, resulting in an increase in platelet count. Although thrombocytopenia may occur as a side effect of LZD in some patients, in a greater number of patients with serious illness, improvements due to the efficacy of LZD occurred earlier than the LZD-induced thrombocytopenia. In fact, the median duration of LZD was 9 days in the present study, which was relatively short. We consider that LZD-induced myelosuppression occurred in few patients because the platelet count recovered before LZD-induced thrombocytopenia would be expected to occur, even after administration of LZD. In other words, if early administration of LZD is effective and LZD is discontinued within a short term, thrombocytopenia due to bone marrow suppression caused by LZD may be avoidable. Even in critically ill patients with thrombocytopenia, initiation of LZD may be considered when LZD is necessary to treat serious illness due to MRSA infection. It is well known that AKI is more likely to occur in critically ill patients. As anti-MRSA drugs are generally excreted by the kidneys, the dose of VAN or teicoplanin (which requires TDM) depends on the degree of impairment of renal function. When AKI worsens to the point that CRRT is required, the dosage decisions become more complicated. LZD has a wide safety margin in terms of blood concentration, and LZD dose is not generally adjusted by renal function or TDM in Japan, even in patients with AKI or during CRRT. Therefore, LZD is easy to use as anti-MRSA drug in treatment of critically ill patients. However, renal failure has been reported as a key determinant of whether thrombocytopenia occurs after LZD administration [19]. In fact, more than half of the present patients had AKI on ICU admission, and 76% required CRRT while in the ICU. Moreover, it has been reported that there is an increasing need for dose adjustment due to individual differences in the efficacy and toxicity of LZD [20]. The effect of renal function and CRRT on LZD concentration was not clear in the present patients. However, if TDM becomes common in Japan in the future, the safety and efficacy of LZD could possibly be improved by adjusting the dose of LZD. Despite the rapid effectiveness of LZD due to its pharmacokinetic features, there may be a hesitancy to administer LZD in patients with thrombocytopenia, especially in those with hematological disease. However, the present finding that platelet count was not affected by LZD during a 2-week administration period suggests that LZD could be selected for empiric therapy even in patients with thrombocytopenia. In particular, if LZD administration is discontinued shortly after the causative bacteria is confirmed, it appears that LZD can be administered safely regardless of thrombocytopenia. In the future, it will be necessary to conduct a prospective and multicenter study to clarify the safety of LZD in terms of platelet count in patients with thrombocytopenia. The present study has several limitations. First, this study was a retrospective, single arm, observational study conducted at a single institute. We chose a single arm study design because there were insufficient patients receiving anti-MRSA drugs other than LZD with which to compare data. Second, platelet counts were missing in several of the data sets, which was compensated for by calculating the average of measured values from the previous and subsequent days. Third, the cause of thrombocytopenia before LZD administration was related to several factors, such as infection and administration drugs, and could not be accurately classified. Fourth, it is undeniable that PC transfusion would have resulted in a sustained increase in platelet counts in some patients; however, as the frequency of PC transfusion progressively decreased from the early to late periods, we consider that the platelet count was recovering even during administration of LZD. In addition, LZD treated the underlying infection as the cause of the initial thrombocytopenia in a proportion of the patients. Therefore, in certain patients, both the PC transfusions and the LZD therapy may have led to a gradual increase in platelet count. Conclusion Initiation of LZD therapy did not worsen thrombocytopenia in critically ill patients in the ICU, and may therefore be considered for the treatment of MRSA in this setting. We recommend close monitoring of platelet count and prompt discontinuation of LZD after resolution of the infection. Supporting information S1 File (XLSX) Click here for additional data file. Abbreviations MRSA methicillin-resistant Staphylococcus aureus VRE vancomycin-resistant enterococci LZD linezolid VAN vancomycin TDM therapeutic drug monitoring AKI acute kidney injury CRRT continuous renal replacement therapy DIC disseminated intravascular coagulation ICU intensive care unit PC platelet concentrate IQR interquartile range APACHE acute physiology and chronic health evaluation SOFA sequential organ failure assessment SE standard error 10.1371/journal.pone.0286088.r001 Decision Letter 0 Mayne Elizabeth S. Academic Editor © 2023 Elizabeth S. Mayne 2023 Elizabeth S. Mayne https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version0 29 Oct 2022 PONE-D-22-25412Effect of linezolid on platelet count in critically ill patients with thrombocytopeniaPLOS ONE Dear Dr. Tatsumi, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Both reviewers felt that this manuscript was of interest in patients on linezolid. Both reviewers did highlight a number of minor errors. In  addition, there were 2 queries raised by reviewers one - specifically there appears to be a discrepancy between the results presented in the abstract and the results presented in the text and this should be corrected. In addition, the reviewer felt that the exclusion of patients who died before the 15 day window might mask some toxicity. 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We will update your Data Availability statement to reflect the information you provide in your cover letter. 5. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. Additional Editor Comments: Both reviewers felt that this manuscript was of interest in patients on linezolid. Both reviewers did highlight a number of minor errors. In addition, there were 2 queries raised by reviewers one - specifically there appears to be a discrepancy between the results presented in the abstract and the results presented in the text and this should be corrected. In addition, the reviewer felt that the exclusion of patients who died before the 15 day window might mask some toxicity. It is advised that these results are analysed, possibly as a subgroup [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ********** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ********** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: No Reviewer #2: Yes ********** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ********** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: This study assessed serial platelet counts in patients treated with Linezolid who had baseline thrombocytopenia. The study is of interest, as Linezolid may cause thrombocytopenia, which can cause hesitancy among prescribers to use this agent in patients with low platelet counts. The study shows evidence that the use of Linezolid is safe in this setting, but it must be emphasized that this was with supportive platelet transfusions in at least half the patients. It is unfortunate that it was not possible to compare this cohort to a group of patients with MRSA infection and thrombocytopenia who were not treated with Linezolid, as the current findings leave the question of Linezolid’s contribution to the need for platelet transfusion unanswered. In addition, there are a few areas which could be improved as detailed below: 1) In the abstract, it is stated that 58% of patients required PC, but in the Table, it is reported as 49%. Please correct the error wherever it lies. 2) Patients who died within 15 days of Linezolid administration were excluded, which may mask serious deleterious effects of Linezolid therapy. Ideally, these patients should be included in a subanalysis, and their causes of death assessed (were there any death due to serious bleeding for example, and what were their platelet counts on demise). 3) It would be interesting to include a subanalysis on the platelet trajectory in patients who did not receive platelet transfusion. An improvement in the platelet count independently from transfusion would further support the safety of Linezolid in these patients. 4) Parts of the manuscript (particularly the discussion) require English language editing, and there are several minor typographical errors. Please make the tracked changes in the attached Word document. Reviewer #2: A valuable study to begin the discussion on use of LZD in critically ill patients. There are multiple small editorial changes that I have recommended. The discussion needs to be reworked to assist with clarity and readability of points made. ********** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. ​ Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No ********** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. Attachment Submitted filename: PONE-D-22-25412.docx Click here for additional data file. Attachment Submitted filename: Reveiwer Comments.docx Click here for additional data file. 10.1371/journal.pone.0286088.r002 Author response to Decision Letter 0 Submission Version1 26 Jan 2023 Author response to Reviewer #1: Thank you for your detailed and careful review of our original article. We respond to review comments. 1) In the abstract, it is stated that 58% of patients required PC, but in the Table, it is reported as 49%. Please correct the error wherever it lies. The numbers in the Table 1 were wrong. Changed All to 32 in Table 1 and Non-hematological to 19 in Result and Table 1. 2) Patients who died within 15 days of Linezolid administration were excluded, which may mask serious deleterious effects of Linezolid therapy. Ideally, these patients should be included in a subanalysis, and their causes of death assessed (were there any death due to serious bleeding for example, and what were their platelet counts on demise). All death cases within 15 days after the start of LZD were due to acute or irreversible progression of the primary disease. The duration of LZD administration was 7 [6-8] days. Many patients had low platelet counts at the time of death, but because the median duration of LZD administration was 7 days, we determined that the progression of the primary disease had a significant impact. Inserted the following sentence: Patients who died due to acute or irreversible progression of the primary disease within 15 days… And, added the cause of death to Figure legends of Fig. 1. 3) It would be interesting to include a subanalysis on the platelet trajectory in patients who did not receive platelet transfusion. An improvement in the platelet count independently from transfusion would further support the safety of Linezolid in these patients. Sub-analysis in patients who did not receive PC transfusion was added in Result, Fig 5A/5B and Discussion. Similar tendency was observed. 4) Parts of the manuscript (particularly the discussion) require English language editing, and there are several minor typographical errors. Please make the tracked changes in the attached Word document. We confirmed and revised as much as possible. Attachment Submitted filename: Reveiwer Comments with answer.docx Click here for additional data file. 10.1371/journal.pone.0286088.r003 Decision Letter 1 Mayne Elizabeth S. Academic Editor © 2023 Elizabeth S. Mayne 2023 Elizabeth S. Mayne https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version1 23 Feb 2023 PONE-D-22-25412R1Effect of linezolid on platelet count in critically ill patients with thrombocytopeniaPLOS ONE Dear Dr. Tatsumi, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. The reviewer has commented that they made significant edits to improve the quality of the written English but that these were not accepted by the authors. Please can they ensure that all corrections are made prior to resubmission as the quality of the English remains poor. Please submit your revised manuscript by Apr 09 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript:A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Elizabeth S. Mayne, M.D. Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. Additional Editor Comments: The reviewer has commented that they made significant edits to improve the quality of the written English but that these were not accepted by the authors. Please can they ensure that all corrections are made prior to resubmission as the quality of the English remains poor. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed ********** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes ********** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: I Don't Know ********** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: No ********** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: No ********** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The authors have made improvements to the manuscript, and have largely addressed my major concerns. However, the manuscript (particularly the Discussion) requires English language editing to be fit for publication. ********** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No ********** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. 10.1371/journal.pone.0286088.r004 Author response to Decision Letter 1 Submission Version2 25 Mar 2023 I revised the text and had it checked again by a native English speaker. Attachment Submitted filename: Reveiwer Comments with answer.docx Click here for additional data file. 10.1371/journal.pone.0286088.r005 Decision Letter 2 Mayne Elizabeth S. Academic Editor © 2023 Elizabeth S. Mayne 2023 Elizabeth S. Mayne https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version2 9 May 2023 Effect of linezolid on platelet count in critically ill patients with thrombocytopenia PONE-D-22-25412R2 Dear Dr. Tatsumi, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Elizabeth S. Mayne, M.D. Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #3: All comments have been addressed ********** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #3: Yes ********** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: I Don't Know Reviewer #3: Yes ********** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: No Reviewer #3: Yes ********** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #3: Yes ********** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The manuscript has been substantially improved. The authors are to be congratulated on a job well done! Reviewer #3: (No Response) ********** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #3: No ********** 10.1371/journal.pone.0286088.r006 Acceptance letter Mayne Elizabeth S. Academic Editor © 2023 Elizabeth S. Mayne 2023 Elizabeth S. Mayne https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 22 Jun 2023 PONE-D-22-25412R2 Effect of linezolid on platelet count in critically ill patients with thrombocytopenia Dear Dr. Tatsumi: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Elizabeth S. Mayne Academic Editor PLOS ONE ==== Refs References 1 Backx M , Healy B . Serious staphylococcal infections. Clin Med. 2008;8 : 535–538. doi: 10.7861/clinmedicine.8-5-535 18975490 2 Zhang Z , Liang Z , Li H , Chen L , She D . Comparative evaluation of thrombocytopenia in adult patients receiving linezolid or glycopeptides in a respiratory intensive care unit. Exp Ther Med. 2014;7 : 501–507. doi: 10.3892/etm.2013.1437 24396434 3 Natsumoto B , Yokota K , Omata F , Furukawa K . Risk factors for linezolid-associated thrombocytopenia in adult patients. Infection. 2014;42 : 1007–1012. doi: 10.1007/s15010-014-0674-5 25119433 4 Dong HY , Xie J , Chen LH , Wang TT , Zhao YR , Dong YL . Therapeutic drug monitoring and receiver operating characteristic curve prediction may reduce the development of linezolid-associated thrombocytopenia in critically ill patients. Eur J Clin Microbiol Infect Dis. 2014;33 : 1029–1035. doi: 10.1007/s10096-013-2041-3 24515096 5 Tsuji Y , Holford NHG , Kasai H , Ogami C , Heo YA , Higashi Y , et al . Population pharmacokinetics and pharmacodynamics of linezolid-induced thrombocytopenia in hospitalized patients. Br J Clin Pharmacol. 2017;83 : 1758–7172. doi: 10.1111/bcp.13262 28186644 6 Kaya Kılıç E , Bulut C , Sönmezer MÇ , Ozel Ö , Ataman Hatipoğlu Ç , Tuncer Ertem G , et al . Risk factors for linezolid-associated thrombocytopenia and negative effect of carbapenem combination. J Infect Dev Ctries. 2019;13 : 886–891. doi: 10.3855/jidc.10859 32084018 7 Choi GW , Lee JY , Chang MJ , Kim YK , Cho Y , Yu YM , et al . Risk factors for linezolid‐induced thrombocytopenia in patients without haemato-oncologic diseases. Basic Clin Pharmacol Toxicol. 2019;124 : 228–234. doi: 10.1111/bcpt.13123 30171804 8 Cazavet J , Bounes FV , Ruiz S , Seguin T , Crognier L , Rouget A , et al . Risk factor analysis for linezolid-associated thrombocytopenia in critically ill patients. Eur J Clin Microbiol Infect Dis. 2020;39 : 527–538. doi: 10.1007/s10096-019-03754-1 31853741 9 Hirano R , Sakamoto Y , Tachibana N , Ohnishi M . Retrospective analysis of the risk factors for linezolid-induced thrombocytopenia in adult Japanese patients. Int J Clin Pharm. 2014;36 : 795–799. doi: 10.1007/s11096-014-9961-6 24913359 10 Ichie T , Suzuki D , Yasui K , Takahashi H , Matsuda M , Hayashi H , et al . The association between risk factors and time of onset for thrombocytopenia in Japanese patients receiving linezolid therapy: a retrospective analysis. J Clin Pharm Ther. 2015;40 : 279–284. doi: 10.1111/jcpt.12260 25732525 11 Nukui Y , Hatakeyama S , Okamoto K , Yamamoto T , Hisaka A , Suzuki H , et al . High plasma linezolid concentration and impaired renal function affect development of linezolid-induced thrombocytopenia. J Antimicrob Chemother. 2013;68 : 2128–2133. doi: 10.1093/jac/dkt133 23625638 12 Kim HS , Lee E , Cho YJ , Lee YJ , Rhie SJ . Linezolid-induced thrombocytopenia increases mortality risk in intensive care unit patients, a 10 year retrospective study. J Clin Pharm Ther. 2019;44 : 84–90.30243033 13 Attassi K , Hershberger E , Alam R , Zervos MJ . Thrombocytopenia associated with linezolid therapy. Clin Infect Dis. 2002;34 : 695–698. doi: 10.1086/338403 11803505 14 Takahashi Y , Takesue Y , Nakajima K , Ichiki K , Tsuchida T , Tatsumi S , et al . Risk factors associated with the development of thrombocytopenia in patients who received linezolid therapy. J Infect Chemother. 2011;17 : 382–387. doi: 10.1007/s10156-010-0182-1 21127934 15 Orrick JJ , Johns T , Janelle J , Ramphal R . Thrombocytopenia secondary to linezolid administration: what is the risk? Clin Infect Dis. 2002;35 : 348‑349. doi: 10.1086/341310 12115111 16 Rubinstein E , Isturiz R , Standiford HC , Smith LG , Oliphant TH , Cammarata S , et al . Worldwide assessment of linezolid’s clinical safety and tolerability: comparator‑controlled phase III studies. Antimicrob Agents Chemother. 2003;47 : 1824‑1831. doi: 10.1128/AAC.47.6.1824-1831.2003 12760854 17 Bi LQ , Zhou J , Huang M , Zhou SM . Efficacy of linezolid on gram-positive bacterial infection in elderly patients and the risk factors associated with thrombocytopenia. Pak J Med Sci. 2013;29 : 837–842. doi: 10.12669/pjms.293.2925 24353639 18 Hanai Y , Matsuo K , Ogawa M , Higashi A , Kimura I , Hirayama S , et al . A retrospective study of the risk factors for linezolid-induced thrombocytopenia and anemia. J Infect Chemother. 2016;22 : 536–542. doi: 10.1016/j.jiac.2016.05.003 27321773 19 Crass RL , Cojutti PG , Pai MP , Pea F . Reappraisal of linezolid dosing in renal impairment to improve safety. Antimicrob Agents Chemother. 2019;63 : e00605–19. doi: 10.1128/AAC.00605-19 31109977 20 Rao GG , Konicki R , Cattaneo D , Alffenaar JW , Marriott DJE , Neely M , IATDMCT Antimicrobial Scientific Committee. Therapeutic drug monitoring can improve linezolid dosing regimens in current clinical practice: A review of linezolid pharmacokinetics and pharmacodynamics. Ther Drug Monit. 2020;42 : 83–92. doi: 10.1097/FTD.0000000000000710 31652190