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

BACKGROUND AND OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Re-evaluation of the current dose advice is necessary. We advocate for a standard dose reduction to 50% after 2 days of standard dosing for all patients with an estimated glomerular filtration of <60 mL/min/1.73 m2. 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.

INTRODUCTION: 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. METHODOLOGY: 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. RESULTS: 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). CONCLUSIONS: 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.

Predictive Modeling of Drug-Related Adverse Events with Real-World Data: A Case Study of Linezolid Hematologic Outcomes.

Electronic health records (EHRs) provide meaningful knowledge of drug-related adverse events (AEs) that are not captured in standard drug development and postmarketing surveillance. Using variables obtained from EHR data in the University of California San Francisco de-identified Clinical Data Warehouse, we aimed to evaluate the potential of machine learning to predict two hematological AEs, thrombocytopenia and anemia, in a cohort of patients treated with linezolid for 3 or more days. Features for model input were extracted at linezolid initiation (index), and outcomes were characterized from index to 14 days post-treatment. Random forest classification (RFC) was used for AE prediction, and reduced feature models were evaluated using cumulative importance (cImp) for feature selection. Grade 3+ thrombocytopenia and anemia occurred in 31% of 2,171 and 56% of 2,170 evaluable patients, respectively. Of the total 53 features, as few as 7 contributed at least 50% cImp, resulting in prediction accuracies of 70% or higher and area under the receiver operating characteristic curves of 0.886 for grade 3+ thrombocytopenia and 0.759 for grade 3+ anemia. Sensitivity analyses in strictly defined patient subgroups revealed similarly high predictive performance in full and reduced feature models. A logistic regression model with the same 50% cImp features showed similar predictive performance as RFC and good concordance with RFC probability predictions after isotonic calibration, adding interpretability. Collectively, this work demonstrates potential for machine learning prediction of AE risk in real-world patients using few variables regularly available in EHRs, which may aid in clinical decision making and/or monitoring.

Linezolid-induced lactic acidosis.

Linezolid is a commonly prescribed antibiotic in clinical practice. Although thrombocytopenia and peripheral neuropathy are frequently encountered following prolonged administration of linezolid, lactic acidosis is a rare adverse drug reaction. We present the case of a patient on linezolid for disseminated multidrug-resistant tuberculosis who presented with vomiting, dyspnoea, hypotension and high anion gap metabolic acidosis. The initial presentation mimicked sepsis syndrome. Ketoacidosis and renal dysfunction were ruled out. There was no history of ingestion of toxins/toxic alcohols. Sepsis was unlikely because extensive radiological and microbiological testing could not identify an infection. Given the possibility of linezolid-induced lactic acidosis (LILA), linezolid was discontinued on admission. The patient's lactic acidosis resolved, and his overall condition improved. A retrospective diagnosis of LILA was thus established. LILA should be considered when patients on linezolid present with lactic acidosis and other causes for the lactic acidosis have been ruled out.

Second-line antituberculosis drug exposure thresholds predictive of adverse events in multidrug-resistant tuberculosis treatment.

OBJECTIVES: This study aimed to investigate the association between drug exposure and adverse events (AEs) during the standardized multidrug-resistant tuberculosis (MDR-TB) treatment, as well as to identify predictive drug exposure thresholds. METHODS: We conducted a prospective, observational multicenter study among participants receiving standardized MDR-TB treatment between 2016 and 2019 in China. AEs were monitored throughout the treatment and their relationships to drug exposure (e.g., the area under the drug concentration-time curve from 0 to 24 h, AUC0-24 h) were analyzed. The thresholds of pharmacokinetic predictors of observed AEs were identified by boosted classification and regression tree (CART) and further evaluated by external validation. RESULTS: Of 197 study participants, 124 (62.9%) had at least one AE, and 15 (7.6%) experienced serious AEs. The association between drug exposure and AEs was observed including bedaquiline, its metabolite M2, moxifloxacin and QTcF prolongation (QTcF >450 ms), linezolid and mitochondrial toxicity, cycloserine and psychiatric AEs. The CART-derived thresholds of AUC0-24 h predictive of the respective AEs were 3.2 mg·h/l (bedaquiline M2); 49.3 mg·h/l (moxifloxacin); 119.3 mg·h/l (linezolid); 718.7 mg·h/l (cycloserine). CONCLUSIONS: This study demonstrated the drug exposure thresholds predictive of AEs for key drugs against MDR-TB treatment. Using the derived thresholds will provide the knowledge base for further randomized clinical trials of dose adjustment to minimize the risk of AEs.

Bioisosteric modification of Linezolid identified the potential M. tuberculosis protein synthesis inhibitors to overcome the myelosuppression and serotonergic toxicity associated with Linezolid in the treatment of the multi-drug resistance tuberculosis (MDR-TB).

Linezolid is the first and only oxazolidinone antibacterial drug was approved in the last 35 years. It exhibits bacteriostatic efficacy against M. tuberculosis and is a crucial constituent of the BPaL regimen (Bedaquiline, Pretomanid, and Linezolid), which was authorized by the FDA in 2019 for the treatment of XDR-TB or MDR-TB. Despite its unique mechanism of action, Linezolid carries a considerable risk of toxicity, including myelosuppression and serotonin syndrome (SS), which is caused by inhibition of mitochondrial protein synthesis (MPS) and monoamine oxidase (MAO), respectively. Based on the structure toxicity relationship (STR) of Linezolid, in this work, we used a bioisosteric replacement approach to optimize the structure of Linezolid at the C-ring and/or C-5 position for myelosuppression and serotogenic toxicity. Extensive hierarchical multistep docking, drug likeness prediction, molecular binding interactions analyses, and toxicity assessment identified three promising compounds (3071, 7549 and 9660) as less toxic potential modulators of Mtb EthR protein. Compounds 3071, 7549 and 9660 were having the significant docking score of -12.696 Kcal/mol, -12.681 Kcal/mol and -15.293 Kcal/mol towards the Mtb EthR protein with less MAO-A and B affinity [compound 3071: MAO A (-4.799 Kcal/mol) and MAO B (-6.552 Kcal/mol); compound 7549: MAO A (> -2.00 Kcal/mol) and MAO B (> -2.00 Kcal/mol) and compound 9660: MAO A (> -5.678 Kcal/mol) and MAO B (> -6.537Kcal/mol) and none of them shown the Leukopenia as a side effect due to the Myelosuppression. The MD simulation results and binding free energy estimations correspond well with docking analyses, indicating that the proposed compounds bind and inhibit the EthR protein more effectively than Linezolid. The quantum mechanical and electrical characteristics were evaluated using density functional theory (DFT), which also demonstrated that the proposed compounds are more reactive than Linezolid.Communicated by Ramaswamy H. Sarma.

Model-based dose optimization framework for bedaquiline, pretomanid and linezolid for the treatment of drug-resistant tuberculosis.

AIMS: Bedaquiline, pretomanid and linezolid (BPaL) combination treatment against Mycobacterium tuberculosis is promising, yet safety and adherence concerns exist that motivate exploration of alternative dosing regimens. We developed a mechanistic modelling framework to compare the efficacy of the current and alternative BPaL treatment strategies. METHODS: Pharmacodynamic models for each drug in the BPaL combination treatment were developed using in vitro time-kill data. These models were combined with pharmacokinetic models, incorporating body weight, lesion volume, site-of-action distribution, bacterial susceptibility and pharmacodynamic interactions to assemble the framework. The model was qualified by comparing the simulations against the observed clinical data. Simulations were performed evaluating bedaquiline and linezolid approved (bedaquiline 400 mg once daily [QD] for 14 days followed by 200 mg three times a week, linezolid 1200 mg QD) and alternative dosing regimens (bedaquiline 200 mg QD, linezolid 600 mg QD). RESULTS: The framework adequately described the observed antibacterial activity data in patients following monotherapy for each drug and approved BPaL dosing. The simulations suggested a minor difference in median time to colony forming unit (CFU)-clearance state with the bedaquiline alternative compared to the approved dosing and the linezolid alternative compared to the approved dosing. Median time to non-replicating-clearance state was predicted to be 15 days from the CFU-clearance state. CONCLUSIONS: The model-based simulations suggested that comparable efficacy can be achieved using alternative bedaquiline and linezolid dosing, which may improve safety and adherence in drug-resistant tuberculosis patients. The framework can be utilized to evaluate treatment optimization approaches, including dosing regimen and duration of treatment predictions to eradicate both replicating- and non-replicating bacteria from lung and lesions.

Role for Linezolid in drug sensitive tuberculosis.

Tuberculosis (TB) continues to be a global challenge. Reducing the duration of TB treatment for drug-sensitive TB (DSTB) has direct and distinct advantages. We ventured into the aspect of utilizing linezolid as a pivotal drug in shortening therapy in DSTB. Linezolid has gained prominence as it is faring well in resistant TB management. Only a few studies use the strategy of Linezolid in DS-TB but it seems a lucrative approach, the bactericidal effects have been reported favourably in the studies. There have been concerns about the potential adverse drug effects of Linezolid reported but clinical trials have demonstrated safety and tolerability when administered for shorter periods. If the safety and efficacy of giving Linezolid for a shorter period along with standard drugs for DSTB is established it could lead to newer avenues using Linezolid for shortening the duration of treatment for DSTB as an alternative to treat DSTB.

Comparison of the incidence of nausea and vomiting between linezolid and vancomycin using claims database: a retrospective cohort study.

BACKGROUND: Nausea and vomiting during linezolid therapy have been reported as part of safety analyses in clinical trials. We have previously examined the incidence of vomiting during linezolid therapy (18.1%). A previous study conducted at a single hospital showed low external validity. It is necessary to verify whether these results can be reproduced using generalizable data sources. AIM: To evaluate the incidence of nausea and vomiting during linezolid therapy compared with vancomycin using a Japanese claims database. METHOD: Patients administered linezolid or vancomycin were selected from the database between January 2005 and June 2017. The primary endpoint was the comparison of nausea and vomiting between the linezolid and vancomycin groups. We conducted propensity score matching (PSM) to adjust for patient characteristics. To assess risk factors for nausea and vomiting, logistic regression was conducted as the secondary endpoint. We defined nausea and vomiting as the first prescription of antiemetics during linezolid or vancomycin therapy as a surrogate endpoint. RESULTS: In total, 1215 patients were enrolled. After PSM, the number of patients in the linezolid and vancomycin groups was 241. Nausea and vomiting were observed in 11.2% and 5.0% of patients in the linezolid and vancomycin groups, respectively (p < 0.05). Linezolid administration was extracted as a risk factor for nausea and vomiting (odds ratio, 2.09; 95% confidence interval, 1.02-4.30). CONCLUSION: This study clarified the relationship between linezolid and nausea and vomiting using a Japanese claims database. Further studies are required to elucidate the unknown mechanisms of linezolid-induced nausea and vomiting.

A rare case of hypertensive urgency caused by linezolid was reported: A case report.

RATIONALE: Linezolid itself is rarely reported to cause blood pressure elevation, and it is rare to report that linezolid causes hypertensive urgency. PATIENTS CONCERNS: This case report describes a 38-year-old man who developed acute hypertension after a postoperative foot infection that was treated with linezolid antitherapy. Hypertensive urgency occurred without obvious potential interaction between linezolid and drugs. After receiving appropriate treatment and stopping medication, the patient's blood pressure returned to normal and did not recur. DIAGNOSES: Hypertensive crises occurred during the treatment of linezolid. INTERVENTIONS: After stopping linezolid, the patient's blood pressure gradually returned to normal. OUTCOMES: The patient's blood pressure returned to normal on the 26th day after stopping linezolid, and no abnormal blood pressure was found in the follow-up 2 months after discharge. LESSONS: Linezolid is rarely reported to cause elevated blood pressure, even though it may occur in the absence of obvious drug interactions. Case reported fewer reasons may be for clinicians statistically insignificant or notice, and hypertensive urgency often lead to clinical risk, should be given enough attention to clinical. Pay attention to blood pressure monitoring during use, when there is abnormal increase in blood pressure, should consider adverse drug reactions, give timely discontinuation and give symptomatic treatment.

A Rare Skin Rash: Linezolid-Induced Purpuric Drug Eruption without Vasculitis in a Puerto Rican Man.

BACKGROUND Cutaneous adverse drug reactions are the skin's response to a systemic exposure to drugs. Linezolid is an oral oxazolidine used to treat methicillin-resistant Staphylococcus aureus infections. Even though it has well-known adverse effects, purpuric cutaneous adverse drug reactions to linezolid have been scarcely described. This report is of a Puerto Rican man in his 80s who developed an extensive purpuric drug eruption secondary to linezolid use. Clinicians should be aware of this phenomenon, since prompt identification and discontinuation of the agent are essential for recovery. CASE REPORT An 89-year-old Puerto Rican man was given oral linezolid therapy for healthcare-associated pneumonia and developed a widespread, purpuric cutaneous eruption 5 days into therapy. His condition prompted immediate discontinuation of the drug. Forty-eight hours after stopping the medication, he visited the Emergency Department. Abdominal punch biopsy revealed a superficial and perivascular lymphocytic infiltrate with dermal eosinophils, a pathologic finding consistent with a purpuric drug eruption. This allowed for a timely diagnosis, exclusion of other mimickers, such as cutaneous vasculitis, and effective management. CONCLUSIONS Cutaneous adverse drug reactions to linezolid have been scarcely reported in the literature. Due to the low incidence of this manifestation, the identification of the causative agent and accompanying treatment may be delayed. Mainstays in therapy are avoidance of the offending agent and treatment with corticosteroids, antihistamines, barrier ointments, and oral analgesics. Primary healthcare providers should be aware of linezolid-induced cutaneous manifestations, diagnostic clues, and treatment options so they can rapidly identify and effectively treat such complications.

Evaluating newly approved drugs in combination regimens for multidrug-resistant tuberculosis with fluoroquinolone resistance (endTB-Q): study protocol for a multi-country randomized controlled trial.

BACKGROUND: Treatment for fluoroquinolone-resistant multidrug-resistant/rifampicin-resistant tuberculosis (pre-XDR TB) often lasts longer than treatment for less resistant strains, yields worse efficacy results, and causes substantial toxicity. The newer anti-tuberculosis drugs, bedaquiline and delamanid, and repurposed drugs clofazimine and linezolid, show great promise for combination in shorter, less-toxic, and effective regimens. To date, there has been no randomized, internally and concurrently controlled trial of a shorter, all-oral regimen comprising these newer and repurposed drugs sufficiently powered to produce results for pre-XDR TB patients. METHODS: endTB-Q is a phase III, multi-country, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of a treatment strategy for patients with pre-XDR TB. Study participants are randomized 2:1 to experimental or control arms, respectively. The experimental arm contains bedaquiline, linezolid, clofazimine, and delamanid. The control comprises the contemporaneous WHO standard of care for pre-XDR TB. Experimental arm duration is determined by a composite of smear microscopy and chest radiographic imaging at baseline and re-evaluated at 6 months using sputum culture results: participants with less extensive disease receive 6 months and participants with more extensive disease receive 9 months of treatment. Randomization is stratified by country and by participant extent-of-TB-disease phenotype defined according to screening/baseline characteristics. Study participation lasts up to 104 weeks post randomization. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 324 participants across 2 arms affords at least 80% power to show the non-inferiority, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per-protocol populations. DISCUSSION: This internally controlled study of shortened treatment for pre-XDR TB will provide urgently needed data and evidence for clinical and policy decision-making around the treatment of pre-XDR TB with a four-drug, all-oral, shortened regimen. TRIAL REGISTRATION: ClinicalTrials.Gov NCT03896685. Registered on 1 April 2018; the record was last updated for study protocol version 4.3 on 17 March 2023.

Effectiveness and safety of regimens containing linezolid for treatment of Mycobacterium abscessus pulmonary Disease.

OBJECTIVE: To evaluate the effectiveness and safety of linezolid-containing regimens for treatment of M. abscessus pulmonary disease. METHODS: The records of 336 patients with M. abscessus pulmonary disease who were admitted to Shanghai Pulmonary Hospital from January 2018 to December 2020 were retrospectively analyzed. A total of 164 patients received a linezolid-containing regimen and 172 controls did not. The effectiveness, safety, antibiotic susceptibility profiles, outcomes, culture conversion, cavity closure, and adverse reactions were compared in these two groups. RESULTS: The two groups had similar treatment success (56.1% vs. 48.8%; P > 0.05), but treatment duration was shorter in the linezolid group (16.0 months [inter-quartile ranges, IQR: 15.0-17.0] vs. 18.0 months [IQR: 16.0-18.0]; P < 0.01). The rates of sputum culture conversion were similar (53.7% vs. 46.5%, P > 0.05), but time to conversion was shorter in the linezolid group (3.5 months [IQR: 2.5-4.4] vs. 5.5 months [IQR: 4.0-6.8]; P < 0.01). The linezolid group had a higher rate of cavity closure (55.2% vs. 28.6%, P < 0.05) and a shorter time to cavity closure (3.5 months [IQR: 2.5-4.4] vs. 5.5 months [IQR: 4.0-6.8]; P < 0.01). Anemia and peripheral neuropathy were more common in the linezolid group (17.7% vs. 1.7%, P < 0.01; 12.8% vs. 0.6%, P < 0.01). CONCLUSIONS: The linezolid and control groups had similar treatment success rates. The linezolid group had a shorter treatment duration, shorter time to sputum culture conversion, and higher rate and shorter time to lung cavity closure. More patients receiving linezolid developed anemia and peripheral neuropathy.

Treatment outcome, recurrence and safety of multidrug-resistant TB treated with low-dose linezolid.

BACKGROUND: Linezolid (LZD) is a key treatment option for patients with multidrug-resistant/rifampicin-resistant TB (MDR/RR-TB). We investigated the long-term treatment outcomes and safety of MDR/RR-TB treatment using low-dose LZD.METHODS: Medical records of patients with MDR/RR-TB treated with LZD ≥4 weeks between 2004 and 2018 at the Asan Medical Center, Seoul, Republic of Korea, were reviewed. Standard-dose and low-dose LZD groups were defined as patients initially administered LZD ≥600 mg/day or 300 mg/day, respectively.RESULTS: Among 94 patients, 65 were included in the low-dose LZD group; mean age was 43.1 ± 15.6 years, 53 (56.4%) were men and 77 (83.7%) were resistant to fluoroquinolone. The low-dose LZD group showed features of less severe disease, such as limited MDR-TB history and less severe radiological findings. There was no difference in treatment outcomes, relapse and safety between groups. In the low-dose LZD group, 54 (83.1%) succeeded treatment, of whom 48 (88.9%) were followed-up for a median of 38 months; there was no recurrence. Adverse drug reactions were reported in 41 (63.1%); peripheral neuropathy was most frequently reported (n = 31, 47.7%), while myelosuppression was reported in 12 (18.5%).CONCLUSION: Low-dose LZD in selected patients with less severe disease is both effective in the long-term and safe for the treatment of MDR/RR-TB.

Efficacy and Safety of Different Antibiotic Therapies for Bone and Joint Infections: A Network Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Although an increasing number of antibiotics are being used to treat bone and joint infections, their specific efficacy remains controversial. Thus, we aimed to systematically compare the efficacy and safety of antibiotic therapies for orthopedic infections. METHODS: PubMed, Embase, The Cochrane Library, and Web of Science databases were searched from inception to April 2022. Two authors independently and rigorously conducted the screening, data extraction, and quality assessment of the relevant studies. All the extracted data were evaluated using traditional metaanalysis and network meta-analysis by STATA SE 16.0. RESULTS: A total of eleven randomized controlled trials (RCTs) involving 1,063 patients were included for data analysis. The analysis results from the NMA indicated that in terms of the clinical effectiveness rate, linezolid (OR: 1.75, 95% CI: 1.01 to 3.02) showed significant efficacy compared to ampicillin/sulbactam. With regard to the microbiological eradication rate, linezolid showed significant efficacy compared to cephalosporins (OR: 8.13, 95% CI: 1.16 to 57.09) and quinolones (OR: 3.51, 95% CI: 1.18 to 10.49). Similar findings were obtained for subgroup populations with diabetic foot infections (DFI). However, linezolid was significantly related to higher adverse events than ampicillin/sulbactam (OR: 3.25, 95% CI: 1.68 to 6.30) and cephalosporins (OR: 18.29, 95% CI: 1.59 to 209.76). CONCLUSION: Linezolid appeared to be the most promising treatment regimen for staphylococcal bone and joint infections. However, due to the overall limited evidence, the research results need further high-quality RCTs for confirmation.

Comparison of Incidence of Hyponatremia between Linezolid and Vancomycin by Propensity Score Matching Analysis.

Several cases of severe hyponatremia induced by linezolid (LZD) were reported. However, severe infections could also cause hyponatremia by increasing vasopressin secretion. To prove that hyponatremia is associated with LZD rather than infection, we compared the incidence and risk of developing hyponatremia between patients receiving LZD and those receiving vancomycin (VCM). A retrospective, single-center, observational cohort study was conducted in patients aged 18 years or older who received intravenous LZD or VCM for 7 d or longer. Hyponatremia was defined as serum sodium level lower than 134 mEq/L and more than 5% decrease from baseline after treatment initiation. The incidence and risk of developing hyponatremia were analyzed between LZD and VCM groups using chi-square test. Four hundred and fifty patients who satisfied the selection criteria were divided into LZD (n = 97) and VCM groups (n = 353). Significant differences in patient characteristics between LZD and VCM groups were observed before propensity score matching, but no significant differences were found after matching. LZD group showed a significantly higher incidence and risk of developing hyponatremia compared to VCM group both before (LZD: 16.5%, VCM: 5.4%; p < 0.001, odds ratio 3.472 [95% confidence interval (CI) 1.711-7.048]) and after (LZD: 17.8%, VCM: 5.5%; p = 0.020, odds ratio 3.738 [95% CI 1.157-12.076]) propensity score matching. In conclusion, propensity score analyses suggest that the risk of hyponatremia associated with LZD is approximately 3.7-fold higher than that associated with VCM, regardless of patient background.

Prevalence of potential drug-drug interactions among intensive care unit patients receiving linezolid: a cross-sectional study.

OBJECTIVE: Linezolid is commonly used in intensive care units (ICU) but has the potential to interact with other drugs. This study aimed to evaluate the prevalence of potential drug-drug interactions in ICU patients receiving linezolid. PATIENTS AND METHODS: Data of ICU patients receiving linezolid were extracted and included in the Hospital Prescription Analysis Program of China, and the risk of potential drug-drug interactions between concomitant drugs and linezolid was evaluated using the Lexicomp database. RESULTS: A total of 3,712 ICU patients from 59 hospitals were included in the analysis, and patients received an average of 17 concomitant drugs. A total of 67.9% of patients had potential drug-drug interactions. Patients receiving concomitant drugs with risk ratings of "X", "D", and "C" categories were 20.8%, 30.4%, and 35.1%, respectively. Opioids were the most frequently prescribed drug class with drug-drug interactions (DDIs) in the "X" category, whereas butorphanol, metoclopramide, and sufentanil were the most contraindicated concomitant drugs. CONCLUSIONS: ICU patients receiving linezolid have a high prevalence of potential drug-drug interactions, and efforts should be made to better recognize and manage this risk.

[Translated article] Influence of augmented renal clearance in the lower incidence of linezolid-related haematological toxicity.

OBJECTIVES: Linezolid is an oxazolidin commonly related to the development of haematological toxicity, being renal clearance the major factor involved in the drug clearance. The aim of this study is to evaluate the influence of increased filtration rates in the incidence of linezolid-induced haematological toxicity by comparing augmented renal clearance (ARC) patients versus normal renal function patients. MATERIAL AND METHODS: A retrospective, observational study was conducted on hospitalized patients treated with linezolid for 5 days or more during 2014-2019 period. Patients with a filtration rate of ≥130 mL/min versus reference patients (60-90 mL/min) were compared. Haematological toxicity was defined as a decrease of 25% in platelets, of 25% in haemoglobin, and/or 50% in neutrophils from baseline. Toxicity relevance was classified according to Common Terminology Criteria for Adverse Events v5. Incidence of haematological toxicity between groups was studied by chi-square and Fisher test. Furthermore, percentage diminution of all 3 parameters was calculated and compared by Mann-Whitney test and treatment interruption and transfusion requirements were registered. RESULTS: 30 ARC patients and 38 reference patients were included. Haematological toxicity was observed in 16.66% of ARC patients vs 44.74% of reference patients (P=.014); thrombocytopenia in 13.33% vs 36.84% (P=.051), anaemia in 3.3% vs 10.52% (P=.374) and neutropenia in 10% vs 23.68% (P=.204). Median percentage of platelets decrease in ARC patients was -10.36 (-193.33-62.03) vs 2.68 (-163.16-82.71) in reference patients (P=.333), while haemoglobin decrease was 2.50 (-12.12-25.93) vs 9.09 (-17.72-30.63) (P=.047) and neutrophils decrease was 9.14 (-73.91-76.47) vs 27.33 (-86.66-90.90) (P=.093). 10.5% of normal renal function patients reported at least 1 adverse event grade 3 or superior while 2.6% of them interrupted treatment and 5.2% had transfusion requirements. No major events or interruptions were reported in ARC patients. CONCLUSION: Our findings suggest a lower incidence and clinical relevance of haematological toxicity in augmented renal clearance patients. Thrombocytopenia was the major event in both populations. This might be related to a lower exposure to the drug due to the higher clearance and likely lower therapeutic efficiency. These results suggest a potential benefit of therapeutic drug monitoring on high risk patients.

Prolonged use of linezolid in bone and joint infections: a retrospective analysis of adverse effects.

OBJECTIVES: Antibiotic treatment for bone and joint infections generally lasts for 6 weeks or longer. Linezolid may be a good option for treating bone and joint infections, but there is an increased risk of potential serious adverse drug events (ADEs) when used for more than 28 days. The aim of this study was to obtain detailed information on the type and time to occurrence of the patient-reported ADEs, the dynamics of haematopoiesis over time, and the reasons for early discontinuation of linezolid when used for an intended maximum duration of 12 weeks. METHODS: This single-centre retrospective study was conducted at the Sint Maartenskliniek in The Netherlands. Patients were included if they were planned to use linezolid for more than 28 days. The main reason for discontinuation of linezolid, the ADE according to the Naranjo score, and the time to occurrence of ADEs were analysed. RESULTS: Among 78 patients, drug toxicity led to early discontinuation of linezolid in 11 (14%) patients before and nine (12%) after 28 days of therapy. The median treatment duration was 42 days. Gastrointestinal intolerance (42%) and malaise (32%) were the most common ADEs. In 75% of the cases the ADE occurred within 28 days of therapy. Sixty-seven patients were able to continue linezolid beyond 28 days, 87% of whom completed therapy as scheduled. Severe cytopenia, according to the Common Terminology Criteria for Adverse events (CTCA), was observed in four patients and was reversible after discontinuation of linezolid. One patient suffered optic neuropathy related to linezolid use. CONCLUSIONS: Linezolid could be considered an alternative option to the current standard of IV glycopeptides for the treatment of bone and joint infection for up to 12 weeks. If patients pass the first 28 days of therapy, the likelihood of successful completion of therapy is high with a low risk of serious ADEs.