Linezolid-induced Thrombocytopenia Research Articles

A nomogram incorporating linezolid and metabolite concentrations for predicting linezolid induced thrombocytopenia in patients with renal impairment

A nomogram to estimate the risk of linezolid-induced thrombocytopenia in patients with renal impairment is not available. The aim of the study is to develop a nomogram for predicting linezolid-induced thrombocytopenia in patients with renal impairment and to investigate the incremental value of PNU-142300 concentration beyond clinical factors and linezolid trough concentration (Cmin) for risk prediction. Logistic regression was used to identify independent risk factors for linezolid-induced thrombocytopenia in patients with renal impairment and nomograms were established. The performance of the nomograms was assessed in terms of area under the receiver operating characteristic curve (AUROC), net reclassification improvement (NRI), integrated discrimination improvement (IDI) , decision curve analysis (DCA) and calibration. Internal validation and external validation of the nomograms were also performed. Four nomograms were created: nomogram A including total bilirubin, creatinine clearance and concomitant mannitol use; nomogram B containing linezolid Cmin additionally; nomogram C containing total bilirubin, concomitant mannitol use, linezolid Cmin, and PNU142300 concentration; nomogram D including total bilirubin, concomitant mannitol use, and PNU142300 concentration. Nomogram C improved the prediction performance than nomogram A (AUROC 0.881 vs. 0.749; NRI 0.290; IDI 0.226) and nomogram B (AUROC 0.881 vs. 0.812; NRI 0.152; IDI 0.130) in the training cohort. DCA analysis showed that nomogram C yielded a greater net benefit. Compared with nomogram A and nomogram B, nomogram C also showed superior discriminatory efficacy, good calibration and clinical usefulness in the external validation cohort. The nomogram containing PNU-142300 concentration and linezolid Cmin had better predictive capability than that containing linezolid Cmin for predicting linezolid-induced thrombocytopenia in patients with renal impairment.

Exploring the impact of baseline platelet count on linezolid-induced thrombocytopenia: a retrospective single-center observation study.

Patients treated with linezolid (LZD) frequently develop thrombocytopenia, and previous studies have identified the risk factors for this condition. However, the relationship between the development of LZD-induced thrombocytopenia and baseline platelet count has varied according to different reports. To explore the relationship between platelet count and the development of LZD-induced thrombocytopenia. Patients who underwent LZD at Hokkaido University Hospital in Japan from September 2008 to March 2023 were included. We collected data on patient characteristics and platelet counts at baseline and during LZD therapy from the electronic medical records. Thrombocytopenia was defined as a decrease in platelet count by 30% or more from baseline, or a platelet level < 100,000/µL. Two hundred and ninety-five patients who received LZD were included in this study, of whom 34.9% developed thrombocytopenia. In the early days of LZD treatment, the thrombocytopenia group showed a nearly 5% decrease in platelet count, while the non-thrombocytopenia group exhibited an increase of over 5%. Additionally, focusing on early onset thrombocytopenia (within 5 days), a baseline platelet count of < 150,000/µL was identified as a risk factor for early thrombocytopenia. Conversely, it was also observed that 24.7% of patients with a baseline platelet count ≥ 150,000/µL still developed early thrombocytopenia. Our findings suggest that while a baseline platelet count of < 150,000/µL is a risk factor for the early onset of thrombocytopenia, vigilant monitoring of platelet counts by clinical pharmacists in the early stages of LZD treatment is essential, regardless of baseline platelet levels.

Risk factors for linezolid - induced haematological toxicity in patients: a retrospective study.

This single-center, observational cohort study aimed to investigate the risk factors associated with linezolid-induced hematological toxicity by analyzing the linezolid trough concentration (Cmin) obtained from patients undergoing treatment between January 2020 and December 2021. A total of 111 eligible individuals were included in the study, of which 47 were diagnosed with linezolid-induced thrombocytopenia and 18 were diagnosed with linezolid-induced hemoglobin decrease. Binary logistic regression analysis revealed that creatinine clearance level (Ccr) < 50 mL/min/1.73 m2 (OR, 5.463; 95% CI, 1.249-23.888, p = 0.024) and Cmin > 7 mg/L (OR, 62.660; 95% CI, 14.293-274.708, p = 0.001) were risk factors associated with linezolid-induced thrombocytopenia. Area under the ROC curve for Cmin was 0.955, with a maximum Youden index of 0.837. The corresponding critical value was 6.94 mg/L (sensitivity 91.5%; specificity 92.2%). Ccr < 50 mL/min/1.73 m2 (OR, 7.282; 95% CI, 1.765-30.048, p = 0.006) and Cmin > 7mg/L (OR, 6.364; 95% CI, 1.937-20.910, p = 0.020) were found to be associated with linezolid-induced hemoglobin reduction. The area under the ROC curve for Cmin was 0.755, Youden index was 0.477 at the maximum, and the corresponding critical value was 7.53 mg/L (sensitivity 77.8%; specificity 69.9%). Renal insufficiency is a related risk factor for linezolid-induced hematological toxicity. Patients receiving linezolid treatment should be closely monitored with blood routine and plasma concentration, particularly in patients with moderate or severe renal insufficiency. The plasma trough concentration of linezolid could be a suitable predictor for linezolid-induced thrombocytopenia and anemia.

Therapeutic drug monitoring of linezolid and exploring optimal regimens and a toxicity-related nomogram in elderly patients: a multicentre, prospective, non-interventional study.

The concentrations of linezolid, its optimal regimen and the associated side effects in elderly patients remain unclear. In this multicentre, prospective study, elderly patients receiving linezolid at four tertiary hospitals in Beijing between May 2021 and December 2022 were included. Linezolid concentrations and haematological toxicity were monitored dynamically. Risk factors for linezolid overexposure and moderate-to-severe linezolid-induced thrombocytopenia (M/S LIT) were analysed, and a predictive model of M/S LIT was developed. A total of 860 linezolid concentrations were measured in 313 patients. The median trough concentrations of linezolid were 24.4 (15.3, 35.8) mg/L at 36-72 h and 26.1 (17.0, 38.1) mg/L at 5-10 days (P = 0.132). Severe linezolid exposure was independently associated with age, estimated glomerular filtration rate (eGFR) and the worst SOFA score (SOFA1), and we further recommended dose regimens for elderly patients based on these findings. The incidences of linezolid-induced thrombocytopenia(LIT) and M/S LIT were 73.5% and 47.6%, respectively. M/S LIT was independently correlated with treatment duration, average trough concentration (TDMa), baseline platelet count, eGFR and baseline SOFA score (SOFA0). The developed nomogram predicted M/S LIT with an area under the curve of 0.767 (95% CI 0.715-0.820), a sensitivity of 71.1% and a specificity of 73.2%. Linezolid trough concentrations increased dramatically in the elderly, by about 10 mg/L in patients aged 65-80 years, followed by a further increase of 10 mg/L for every 10 years of age. Therapeutic drug monitoring is recommended in elderly patients receiving linezolid. The developed nomogram may predict M/S LIT and guide dosage adjustments of linezolid. Clinical trial registration number: ChiCTR2100045707.

Rapid Onset and Recovery Linezolid-Induced Thrombocytopenia: A Large-Sample, Single-Center Retrospective Cohort Study

Rapid Onset and Recovery Linezolid-Induced Thrombocytopenia: A Large-Sample, Single-Center Retrospective Cohort Study

Linezolid-Induced Thrombocytopenia in Patients with Renal Impairment: A Case Series, Review and Dose Advice.

Oral linezolid is often used as alternative therapy for intravenous vancomycin. According to the current guidelines, no dose adjustment has to be made in case of renal impairment. Nevertheless, in our hospital we have seen several patients with renal impairment who developed linezolid-induced thrombocytopenia when linezolid was taken in the standard dose. In this case series and review we want to emphasize the necessity of reviewing the Dutch and international guidelines. We describe five cases with renal impairment that developed linezolid-induced thrombocytopenia in our hospital. A PubMed literature review was conducted to identify other cases and find the optimal dosing regimen for these patients. Our cases join a long list of cases and available literature about linezolid-induced thrombocytopenia in patients with renal impairment. Less linezolid-induced thrombocytopenia was found, both in our cases and in the literature, after dose reduction of 50%. High linezolid trough concentrations were associated with a higher risk of linezolid-induced thrombocytopenia. Besides renal impairment, other risk factors for developing linezolid-induced thrombocytopenia were also identified, such as low body weight, high daily dose/kg, higher age, longer duration of therapy, low baseline count, malignity, low-dose aspirin and interacting co-medication. Re-evaluation of the current dose advice is necessary. We advocate for a standard dose reduction to 50% after 2days of standard dosing for all patients with an estimated glomerular filtration of <60mL/min/1.73m2. Besides this, therapeutic drug monitoring and thrombocytes monitoring may be executed weekly when patients have renal impairment or other risk factors for developing linezolid-induced thrombocytopenia.

Association of clinical factors with thrombocytopenia in patients receiving linezolid treatment: a retrospective study.

Linezolid (LZD) plays an important role in the treatment of severe infections caused by Gram-positive bacteria. Thrombocytopenia is regarded as one of the most common side effects of linezolid, which results from the destruction of platelets or myelosuppression. The study aimed to identify the risk factors associated with the development of thrombocytopenia in Vietnamese patients. This retrospective, descriptive cross-sectional study was performed on adult patients who received parenteral LZD therapy (1,200 mg/day) in at least 3 days between January 2020 and June 2021 at a tertiary referral hospital in Vietnam. Thrombocytopenia was defined as either a final platelet count of less than 100 G/L or a 25% decrease in platelet count from baseline. Multivariate logistic regression analysis was applied to predict risk factors associated with LZD-induced thrombocytopenia. In the 208 patients included in the study, the average age was 69 and males accounted for 73.1%. LZD-induced thrombocytopenia occurred in 37% of patients. LZD-induced thrombocytopenia was significantly associated with shock (HR = 8.26, 95% CI 3.82 - 17.84, p < 0.001), baseline creatinine clearance (HR = 1.02, 95% CI [1.01 - 1.03], p = 0.002), and duration of LZD treatment of at least 14 days (HR = 4.45, 95% CI [1.83 - 11.05], p = 0.001). The results showed that thrombocytopenia was fairly common in patients using linezolid. Shock, renal failure, and duration of linezolid therapy of at least 14 days were significant risk factors for the incidence of linezolid-induced thrombocytopenia.

Prediction of risk factors for linezolid-induced thrombocytopenia based on neural network model.

Background: Based on real-world medical data, the artificial neural network model was used to predict the risk factors of linezolid-induced thrombocytopenia to provide a reference for better clinical use of this drug and achieve the timely prevention of adverse reactions. Methods: The artificial neural network algorithm was used to construct the prediction model of the risk factors of linezolid-induced thrombocytopenia and further evaluate the effectiveness of the artificial neural network model compared with the traditional Logistic regression model. Results: A total of 1,837 patients receiving linezolid treatment in a hospital in Xi 'an, Shaanxi Province from 1 January 2011 to 1 January 2021 were recruited. According to the exclusion criteria, 1,273 cases that did not meet the requirements of the study were excluded. A total of 564 valid cases were included in the study, with 89 (15.78%) having thrombocytopenia. The prediction accuracy of the artificial neural network model was 96.32%, and the AUROC was 0.944, which was significantly higher than that of the Logistic regression model, which was 86.14%, and the AUROC was 0.796. In the artificial neural network model, urea, platelet baseline value and serum albumin were among the top three important risk factors. Conclusion: The predictive performance of the artificial neural network model is better than that of the traditional Logistic regression model, and it can well predict the risk factors of linezolid-induced thrombocytopenia.

384. Factors Potentiating the Risk of Linezolid-induced Thrombocytopenia in Patients without Haemato-oncologic Diseases: A Case-control Study

Abstract Background Thrombocytopenia is a major adverse effect of linezolid due to myelosuppression. Many studies assessed factors associated with this effect, but most included patients with haemato-oncologic diseases, which may confound the assessment of thrombocytopenia. Therefore, this study aimed to investigate risk factors for linezolid-induced thrombocytopenia in patients without haemato-oncologic diseases. Methods This was a multicenter retrospective case-control study of adults treated with linezolid 600 mg twice daily for ≥ 3 days. Cases were the patients who developed thrombocytopenia while controls are those who didn't develop it. Exclusion criteria were haemato-oncologic diseases, active COVID-19, active dengue fever, baseline platelet count &amp;lt; 100 × 103/mm3, concurrent therapy with trimethoprim/sulfamethoxazole or valproic acid, platelet transfusion within 7 days before linezolid therapy, and insufficient platelets data. Various factors were assessed for potential association with linezolid-induced thrombocytopenia (defined as drop in platelet count below 100 × 103/mm3). Results 142 patients were included, 31 cases and 111 controls. Patients in both groups had a median age of 62 years and received linezolid for a median of 8 days. Platelet counts significantly dropped in the cases (Figure 1). Figure 2 shows the trend of change in platelet count (the white square indicates the median duration to thrombocytopenia, 8 days). In the univariate analysis, serum creatinine, creatinine clearance, baseline hemoglobin, baseline platelet count, and bacteremia were significantly associated with thrombocytopenia. However, after adjusting for confounders in the multivariate analysis, only low baseline hemoglobin and bacteremia were associated with thrombocytopenia (adjOR = 0.71; 95% CI 0.53-0.95; P = 0.022 and adjOR = 17.02; 95% CI 1.15-251-71; P = 0.039, respectively). Among the cases, those who had a baseline platelet count of &amp;lt; 200 × 103/mm3 developed thrombocytopenia faster as early as 3 days (log-rank P = 0.002; figure 3). Figure 1 Rate of change in platelet count between the cases (thrombocytopenia) and controls (no thrombocytopenia) Figure 2 Trend of platelet counts over 14 days in the cases (thrombocytopenia) and controls (no thrombocytopenia) Figure 3 Kaplan-Meier curve for the development of thrombocytopenia depending on baseline platelet count Conclusion Patients without haemato-oncologic diseases are at risk of linezolid-induced thrombocytopenia. especially those with bacteremia and low hemoglobin level. Patients with low baseline platelet count should be monitored closely early in therapy. Disclosures All Authors: No reported disclosures

One Drug, Different Mechanisms of Side Effects: Linezolid-Induced Thrombocytopenia and Type B Lactic Acidosis

One Drug, Different Mechanisms of Side Effects: Linezolid-Induced Thrombocytopenia and Type B Lactic Acidosis

Effect of Platelet Parameters on Linezolid-Related Thrombocytopenia in Hospitalized Patients.

Linezolid-induced thrombocytopenia incidence varies considerably. Linezolid-related thrombocytopenia in patients has received few studies which have investigated risk factors including platelet parameters except for platelet counts. The study aims to analyze the effect of platelet parameters, including mean platelet volume and platelet large cell ratio, on linezolid-related thrombocytopenia in patients. The effect of platelet parameters on linezolid-related thrombocytopenia was identified by univariate and multivariate logistic regressions. A Kaplan-Meier survival analysis was carried out to compare the survival of patients who developed linezolid-related thrombocytopenia with patients who did not. Thrombocytopenia occurred at a rate of 41.5% (66/159) after linezolid therapy in hospitalized patients. Platelet parameters, including the difference in mean platelet volume (MPV/fL=0.08 (-1.2-0.9)vs-0.5 (-1.5-0.3), (OR, 0.459; P = 0.001), the difference in platelet large cell ratio (PLCR/fL=0.9 (-5.1-6.2)vs-3.8 (-8.6-2.4), (OR, 1.156; P = 0.001), baseline platelet counts (OR, 0.995; P = 0.006) and duration of linezolid therapy≥10d (OR, 1.346; P = 0.007), were significantly associated with linezolid-related thrombocytopenia in hospitalized patients. In addition, other risk factors which also are associated with linezolid-related thrombocytopenia include baseline red blood cells, co-medication with parecoxib and co-medication with caspofungin. Accumulated in-hospital mortality of patients with thrombocytopenia was significantly higher than that of patients without thrombocytopenia during linezolid treatment (19.7% vs 8.6%, P = 0.003). The difference in mean platelet volume, the difference in large platelet ratio, baseline platelet counts and duration of linezolid therapy≥10d significantly affected the development of linezolid-related thrombocytopenia in hospitalized patients.

Bleeding Complications in Vancomycin-Induced Thrombocytopenia: A Real-world Postmarketing Pharmacovigilance Analysis

PurposeVancomycin and linezolid are first-line drugs used for the prophylaxis and treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. Vancomycin is well known as the best alternative drug when linezolid-induced thrombocytopenia occurs. However, several cases with vancomycin-induced thrombocytopenia, especially with bleeding complications, have been reported recently, which has attracted attention. The objective of this study is to assess the potential relevance between vancomycin and bleeding complications in thrombocytopenia. MethodsThis is a real-world pharmacovigilance study conducted in October 2022 using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. We performed a disproportional analysis to assess the risk of bleeding complications in vancomycin-induced thrombocytopenia by calculating reporting odds ratios (RORs) and information components (ICs), with a weak signal defined as a lower limit of the IC 95% CI of 0 to 1.5, a middle signal defined as a lower limit of the IC 95% CI of 1.5 to 3.0, and a strong signal defined as a lower limit of the IC 95% CI of >3.0. FindingsThere were 21,854 cases in the FAERS database that listed vancomycin as a suspected drug from quarter 1 of 2004 to quarter 2 of 2022. There were 800 cases of vancomycin-induced thrombocytopenia and 125 cases of bleeding complications in vancomycin-induced thrombocytopenia. Teicoplanin, tigecycline, and vancomycin (3 middle signals) were sequentially less associated with thrombocytopenia than linezolid (strong signal). However, bleeding complications in thrombocytopenia were significant associated with vancomycin (ROR = 9.641; 95% CI, 8.105–11.468; IC = 3.184; 95% CI, 2.929–3.440 [middle signal]), followed by linezolid (ROR = 9.350; 95% CI, 7.318–11.947; IC = 3.106; 95% CI, 2.745–3.466 [middle signal]), teicoplanin (ROR = 6.399; 95% CI, 2.869–14.272; IC = 2.059; 95% CI, 0.881–3.283 [weak signal]), and daptomycin (ROR = 2.784; 95% CI, 1.496–5.180; IC = 1.287; 95% CI, 0.374–2.201 [weak signal]). Tigecycline and daptomycin were the least likely anti-MRSA drug to cause thrombocytopenia (middle signal and weak signal, respectively) and bleeding complications in thrombocytopenia (no signal and weak signal, respectively). Middle signals of bleeding complication in vancomycin-induced thrombocytopenia were found in all group except those <45 to ≥80 years of age (weak signal). ImplicationsBleeding complications in thrombocytopenia were significantly associated with vancomycin use, and the risk was highest among all the anti-MRSA drugs. Physicians should be aware of this possible serious adverse reaction.

Risk factors for thrombocytopenia in patients receiving linezolid therapy: a systematic review and meta-analysis.

The incidence of linezolid-induced thrombocytopenia (LIT) has been reported to vary widely across studies. We performed a meta-analysis to identify the risk factors for thrombocytopenia among patients who received linezolid treatment. The PubMed, Embase and Cochrane Library databases were searched from inception to November 2022 to identify eligible studies. Data on the potential predictors of incidence in LIT were pooled using a random effects model. Sensitivity analyses were performed to determine the robustness of the results when significant heterogeneity was observed. Forty observational studies involving 6454 patients treated with linezolid were included in the analysis. LIT was estimated to occur in 37% of patients. The following important factors were associated with the incidence of LIT: advanced age, body mass index, concurrent renal impairment or liver disease, abnormal laboratory parameters (including white blood cell count, serum creatinine, baseline platelet count, albumin, creatinine clearance rate, and estimated glomerular filtration rate), treatment durationand renal replacement therapy. A variety of risk factors related to the occurrence of LIT were revealed in our analysis. Early identification of these factors could help patients improve clinical outcomes.

Establishment and validation of a risk prediction model incorporating concentrations of linezolid and its metabolite PNU142300 for linezolid-induced thrombocytopenia.

Linezolid-induced thrombocytopenia is the main factor restricting the clinical application of linezolid. To investigate the relationship between PNU-14230 concentration and linezolid-induced thrombocytopenia and further develop and validate a risk model for predicting linezolid-induced thrombocytopenia. A regression model was constructed to predict the occurrence of linezolid-induced thrombocytopenia, and further externally validated. The predictive performance was evaluated by receiver operating characteristic curve and Hosmer-Lemeshow test. Linezolid Cmin and PNU-142300 concentrations were compared for different kidney function groups. The Kaplan-Meier method was used to estimate the difference in cumulative incidence of linezolid-induced thrombocytopenia among different kidney function patients. In the derivation (n = 221) and validation (n = 158) cohorts, 28.5% and 24.1% of critically ill patients developed linezolid-induced thrombocytopenia. Logistic regression analysis indicated that the independent risk factors were linezolid Cmin, PNU-142300 concentration, baseline platelet count, renal insufficiency (RI) and continuous venovenous haemofiltration (CVVH). The AUC for the risk model was 0.901, and the model was good (P = 0.633). The model also showed good discrimination (AUC 0.870) and calibration (P = 0.282) in the external validation cohort. Compared with normal kidney function patients, patients with RI and CVVH had higher linezolid Cmin and PNU-142300 concentrations (P < 0.001) and higher cumulative incidence of linezolid-induced thrombocytopenia (P < 0.001). PNU142300 concentration, as well as linezolid Cmin, might identify patients at risk of linezolid-induced thrombocytopenia. The risk prediction model had good predictive performance for linezolid-induced thrombocytopenia development. Concentrations of linezolid and PNU-142300 accumulated in patients with RI and CVVH.

Dose optimisation of linezolid in critically ill patients based on a population pharmacokinetic model: A two-centre prospective interventional study

ObjectivesThis study evaluated the intervention effect of clinical pharmacist-mediated optimisation of a linezolid regimen using a population pharmacokinetic (PPK) model. MethodsPatients treated with linezolid in two medical centres from January 2020 to June 2021 were retrospectively included in the control group; those treated from July 2021 to June 2022 were prospectively enrolled in the intervention group. Clinical pharmacists optimised the dosage regimen according to a published linezolid PPK model in the intervention group. An interrupted times series approach was used to analyse the data. The incidence of linezolid-induced thrombocytopenia (LIT), target attainment of pharmacokinetic/pharmacodynamic parameters and other adverse drug reactions (ADRs) were compared between the two groups. ResultsIn total, 77 and 103 patients were enrolled in the control and intervention groups, respectively. The intervention group had a lower incidence of LIT and other ADRs than the control group (10.7% vs. 23.4%, P = 0.002; 1.0% vs. 7.8%, P = 0.027). The intervention group exhibited a considerably lower trough concentration (Cmin) and area under the concentration–time curve/MIC ratio (AUC24/MIC) (P = 0.001 and P < 0.001). Cmin and AUC24/MIC rates within the target range were substantially higher in the intervention group (49.6% vs. 20.0%, adjusted P < 0.05; 48.1% vs. 25.6%, adjusted P < 0.05). ConclusionInterventions by clinical pharmacists reduced the incidence of LIT and other ADRs. Implementation of model-informed precision dosing (MIPD) for linezolid markedly increased the Cmin and AUC24/MIC rates within the target range. We recommend MIPD-guided linezolid dose reduction for patients with renal impairment.

Use of Japanese big data from electronic medical records to investigate risk factors and identify their high-risk combinations for linezolid-induced thrombocytopenia.

Thrombocytopenia is a major event associated with linezolid (LZD) therapy. Factors affecting LZD-induced thrombocytopenia (LIT) have been reported in previous studies. However, several issues pertaining to LIT have not yet been clarified. In the present study, we used Japanese big data to investigate associated factors and their high-risk combinations that influence LIT. Patients administered LZD between May 2006 and October 2020 were included in this study. LIT was defined as either a 30% or more reduction from the baseline platelets or platelet values of < 100,000/µL. We evaluated factors affecting LIT and combinations of factors that alter LIT risk according to a decision tree (DT) analysis, a typical machine learning method. We successfully enrolled 1399 patients and LIT occurred in 44.7% of the patients (n = 626). We classified the laboratory data on renal function, LZD duration, age, and body weight (BW) into smaller categories. The results of multivariate analysis showed that prolonged LZD therapy, BW < 45kg, estimated glomerular filtration rate (eGFR) < 30mL/min/1.73 m2, and dialysis were risk factors for LIT. The DT analysis revealed that the highest risk was a combination of LZD duration ≥ 14days and eGFR < 30mL/min/1.73 m2. The present study extracted four risk factors and identified high-risk combinations for LIT. Patients with these risk factors should be closely monitored.

Identifying and Targeting Prediction of the PI3K-AKT Signaling Pathway in Drug-Induced Thrombocytopenia in Infected Patients Receiving Linezolid Therapy: A Network Pharmacology-Based Analysis.

The pharmacological mechanisms underlying the adverse effects of linezolid on thrombocytopenia have not been conclusively determined. This network pharmacology study aimed at investigating the potential pharmacological mechanisms of linezolid-induced adverse reactions in thrombocytopenia. In this study, target genes for linezolid and thrombocytopenia were compared and analyzed. Overlapping thrombocytopenia-associated targets and predicted targets of linezolid were imported to establish protein-protein interaction networks. Gene Ontology and the Kyoto Encyclopedia of Genes and Genome pathway enrichment analyses were performed to determine the enriched biological terms and pathways. The mechanisms involved in linezolid-induced thrombocytopenia were established to be associated with various biological processes, including T cell activation, peptidyl serine modification, and peptidyl serine phosphorylation. The top five relevant protein targets were obtained, including ALB, AKT1, EGFR, IL6, and MTOR. Enrichment analysis showed that the targets of linezolid were positively correlated with T cell activation responses. The mechanism of action of linezolid was positively correlated with the PI3K-AKT signaling pathway and negatively correlated with the Ras signaling pathway. We identified the important protein targets and signaling pathways involved in linezolid-induced thrombocytopenia in anti-infection therapy, providing new information for subsequent studies on the pathogenesis of drug-induced thrombocytopenia and potential therapeutic strategies for rational use of linezolid in clinical settings.

Development and validation of a risk prediction model for linezolid-induced thrombocytopenia in elderly patients

ObjectivesLinezolid is the first oxazolidinone antimicrobial agent developed for treating multi-drug-resistant gram-positive bacterial infections. The study aimed to investigate the risk factors of linezolid (LI)-induced thrombocytopenia (LI-TP) and to develop...

Initial trough concentration may be beneficial in preventing linezolid-induced thrombocytopenia

We assessed whether prospective therapeutic drug monitoring to optimise the therapeutic range could prevent linezolid-induced thrombocytopenia. This prospective interventional study was conducted from September 2017 to October 2020 among 37 adult patients receiving linezolid. Patients were administered one of the following two initial dosages: 600 mg twice or once daily for patients with a creatinine clearance rate of ≥50 or <50 mL/min, respectively. Linezolid dosage adjustment was performed on days 3–5 based on the trough concentration. The serum linezolid levels in 22 and 15 patients were within and above the therapeutic range (2–7 µg/mL), respectively. The incidence of thrombocytopenia was significantly lower among patients whose linezolid levels were within the therapeutic range (4.5%;1/22) than in those whose levels were above the therapeutic range (80%; 12/15). It is important to maintain the linezolid level within the therapeutic range at the first therapeutic drug monitoring to prevent thrombocytopenia.

A Regression Model to Predict Linezolid Induced Thrombocytopenia in Neonatal Sepsis Patients: A Ten-Year Retrospective Cohort Study.

Background: Linezolid-induced thrombocytopenia (LIT) is the main factor limiting the clinical application of linezolid (LZD). The incidence and risk factors of LIT in neonatal patients were possibly different from other populations based on pathophysiological characteristics. The purpose of this study was to establish a regression model for predicting LIT in neonatal sepsis patients. Methods: We retrospectively included 518 patients and divided them into the LIT group and the non-LIT group. A logistic regression analysis was used to analyze the factors related to LIT, and a regression model was established. A receiver operating characteristic (ROC) curve was drawn to evaluate the model’s predictive value. We prospectively collected 39 patients’ data to validate the model and evaluate the effect of LZD pharmacokinetics on LIT. Results: Among the 518 patients, 103 patients (19.9%) developed LIT. The Kaplan–Meier plot revealed that the overall median time from the initiation of LZD treatment to the onset of LIT in preterm infants was much shorter when compared with term infants [10 (6, 12) vs. 13 (9.75, 16.5), p = 0.004]. Multiple logistic regression analysis indicated that the independent risk factors of LIT were lower weight at medication, younger gestational ages, late-onset sepsis, necrotizing enterocolitis, mechanical ventilation, longer durations of LZD treatment, and lower baseline of platelet level. We established the above seven-variable prediction regression model and calculated the predictive probability. The ROC curve showed that the predicted probability of combined body weight, gestational age, duration of LZD treatment, and baseline of platelet had better sensitivity (84.4%), specificity (74.2%), and maximum AUC (AUC = 0.873). LIT occurred in 9 out of 39 patients (23.1%), and the accuracies of positive and negative predictions of LIT were 88.9 and 76.7%, respectively. Compared with the non-LIT patients, the LIT patients had higher trough concentration [11.49 (6.86, 15.13) vs. 5.51 (2.80, 11.61) mg/L; p = 0.028] but lower apparent volume of distribution (Vd) [0.778 (0.687, 1.421) vs. 1.322 (1.099, 1.610) L; p = 0.010]. Conclusion: The incidence of LIT was high in neonatal sepsis patients, especially in preterm infants. LIT occurred earlier in preterm infants than in term infants. The regression model of seven variables had a high predictive value for predicting LIT. LIT was correlated with higher trough concentration and lower Vd.