Assessing potential drug-drug interactions between clofazimine and other frequently used agents to treat drug-resistant tuberculosis.

Clofazimine is included in drug regimens to treat rifampicin/drug-resistant tuberculosis (DR-TB), but there is little information about its interaction with other drugs in DR-TB regimens. We evaluated the pharmacokinetic interaction between clofazimine and isoniazid, linezolid, levofloxacin, and cycloserine, dosed as terizidone. Newly diagnosed adults with DR-TB at Klerksdorp/Tshepong Hospital, South Africa, were started on the then-standard treatment with clofazimine temporarily excluded for the initial 2 weeks. Pharmacokinetic sampling was done immediately before and 3 weeks after starting clofazimine, and drug concentrations were determined using validated liquid chromatography-tandem mass spectrometry assays. The data were interpreted with population pharmacokinetics in NONMEM v7.5.1 to explore the impact of clofazimine co-administration and other relevant covariates on the pharmacokinetics of isoniazid, linezolid, levofloxacin, and cycloserine. Clofazimine, isoniazid, linezolid, levofloxacin, and cycloserine data were available for 16, 27, 21, 21, and 6 participants, respectively. The median age and weight for the full cohort were 39 years and 52 kg, respectively. Clofazimine exposures were in the expected range, and its addition to the regimen did not significantly affect the pharmacokinetics of the other drugs except levofloxacin, for which it caused a 15% reduction in clearance. A posteriori power size calculations predicted that our sample sizes had 97%, 90%, and 87% power at P < 0.05 to detect a 30% change in clearance of isoniazid, linezolid, and cycloserine, respectively. Although clofazimine increased the area under the curve of levofloxacin by 19%, this is unlikely to be of great clinical significance, and the lack of interaction with other drugs tested is reassuring.

Use of multiple pharmacodynamic measures to deconstruct the Nix-TB regimen in a short-course murine model of tuberculosis.

A major challenge for tuberculosis (TB) drug development is to prioritize promising combination regimens from a large and growing number of possibilities. This includes demonstrating individual drug contributions to the activity of higher-order combinations. A BALB/c mouse TB infection model was used to evaluate the contributions of each drug and pairwise combination in the clinically relevant Nix-TB regimen [bedaquiline-pretomanid-linezolid (BPaL)] during the first 3 weeks of treatment at human equivalent doses. The rRNA synthesis (RS) ratio, an exploratory pharmacodynamic (PD) marker of ongoing Mycobacterium tuberculosis rRNA synthesis, together with solid culture CFU counts and liquid culture time to positivity (TTP) were used as PD markers of treatment response in lung tissue; and their time-course profiles were mathematically modeled using rate equations with pharmacologically interpretable parameters. Antimicrobial interactions were quantified using Bliss independence and Isserlis formulas. Subadditive (or antagonistic) and additive effects on bacillary load, assessed by CFU and TTP, were found for bedaquiline-pretomanid and linezolid-containing pairs, respectively. In contrast, subadditive and additive effects on rRNA synthesis were found for pretomanid-linezolid and bedaquiline-containing pairs, respectively. Additionally, accurate predictions of the response to BPaL for all three PD markers were made using only the single-drug and pairwise effects together with an assumption of negligible three-way drug interactions. The results represent an experimental and PD modeling approach aimed at reducing combinatorial complexity and improving the cost-effectiveness of in vivo systems for preclinical TB regimen development.

Population Pharmacokinetics and Dosing Regimen Optimization of Linezolid in Cerebrospinal Fluid and Plasma of Post-operative Neurosurgical Patients.

BACKGROUND: Linezolid is a valuable therapeutic option for infections of the central nervous system caused by multi-drug resistant Gram-positive pathogens. Data regarding linezolid pharmacokinetics in cerebrospinal fluid from post-operative neurosurgical patients have revealed wide inter-individual variability. The objectives of this study were to establish a population pharmacokinetic model for linezolid in plasma and cerebrospinal fluid, as well as to optimize dosing strategies in this susceptible population. METHODS: This was a prospective pharmacokinetic study in post-operative neurosurgical patients receiving intravenous linezolid. Parallel blood and cerebrospinal fluid samples were collected and analyzed. The population pharmacokinetic modelling and Monte Carlo simulations were performed using the Phoenix NLME software. RESULTS: A two-compartment model (central plasma and cerebrospinal fluid compartments) fit the linezolid data well, with creatinine clearance and serum procalcitonin as significant variables. Linezolid demonstrated highly variable penetration into cerebrospinal fluid, with a mean cerebrospinal fluid/plasma ratio of 0.53. A strong correlation was found between plasma trough concentration and cerebrospinal fluid exposure of linezolid. Based on simulation results, optimal dosage regimens stratified by various renal functions and inflammatory status were proposed. CONCLUSION: A modeling and simulating strategy was employed in dose individualization to improve the efficacy and safety of linezolid treatment.

A Systematic Review of Linezolid Pharmacokinetics/Pharmacodynamics in Patients Undergoing Continuous Renal Replacement Therapy: Does One Size Fit All?

BACKGROUND: Selection of the optimal antimicrobial posology in critically ill patients remains a challenge, especially in patients with sepsis who undergo continuous renal replacement therapy (CRRT). This systematic review aimed to analyze factors that influence the extracorporeal removal of linezolid. METHODS: A comprehensive search was performed to identify studies published up to March 2022 in PubMed, MEDLINE and EMBASE databases. Studies involving adults receiving CRRT and treatment with linezolid were considered eligible if the CRRT setting and linezolid's pharmacokinetic parameters were clearly mentioned. RESULTS: Six out of 110 potentially relevant studies were included. A total of 101 treatments were identified among 97 enrolled patients. Our analysis showed that continuous veno-venous hemodiafiltration (CVVHDF) was the most frequential used modality (52 cases). Despite distribution volume, the clearance (CL) of linezolid in these studies had large variability. Extracorporeal linezolid removal may be markedly impacted by CRRT dose. There is significant between-subject variability in the probability of pharmacokinetics-pharmacodynamics (PK-PD) target attainment of patients treated with CRRT. CONCLUSION: Dose adjustment, shortening the dosing interval, and continuous infusion were proposed as regimen optimization. Therapeutic drug monitoring is recommended due to the high variability of linezolid exposure among patients with CRRT, specifically for those whose bodyweight is high, renal function is preserved, and the MIC of infection bacteria is above 2 µg/mL.

Dose Optimization of Combined Linezolid and Fosfomycin against Enterococcus by Using an In Vitro Pharmacokinetic/Pharmacodynamic Model.

The rapid spread of antibiotic resistance among Enterococcus has prompted considerable interest in determining the dosage regimen of linezolid combined with fosfomycin. A checkerboard assay was employed to evaluate whether linezolid combined with fosfomycin had a synergistic effect on Enterococcus isolates from the hospital, including three drug-resistant strains (MIC of linezolid [MICLZD], ≥8 mg/L; MIC of fosfomycin [MICFOF], ≥256 mg/L). The in vitro static time-kill assay, dynamic pharmacokinetic (PK)/pharmacodynamic (PD) model, and semimechanistic PK/PD model were used to explore and predict effective combined dosage regimens. The checkerboard assay and in vitro static time-kill assay demonstrated that linezolid combined with fosfomycin has a synergistic effect on drug-resistant and sensitive Enterococcus. In the in vitro PK/PD model, the dosage regimen of linezolid (8 mg/L or 12 mg/L, steady-state concentration) combined with fosfomycin (6 g or 8 g) via a 0.5-h infusion every 8 h effectively suppressed bacterial growth at 24 h with a 3 log10 CFU/mL decrease compared with the initial inocula against two resistant and one sensitive Enterococcus isolates. The semimechanistic PK/PD model predicted that linezolid (more than 16 mg/L) combined with fosfomycin (6 g or 10 g) via a 0.5-h infusion every 8 h was required to achieve a 4 log10 CFU/mL decrease at 24 h against Enterococcus isolates (MICLZD ≥ 8 mg/L and MICFOF ≥ 256 mg/L). According to the prediction of the semimechanical PK/PD model, the effect of the combination was driven by linezolid, with fosfomycin enhancing the effect. Our study is the first to explore the synergistic effects of these two drugs from a qualitative and quantitative perspective and provides a simulation tool for future studies. IMPORTANCE In this study, we found that linezolid combined with fosfomycin could kill Enterococcus in vitro and that the administered dose was significantly lower after the combination treatment, which could reduce adverse effects and the development of drug resistance. The potential mechanism of the two-drug combination against Enterococcus was revealed from a quantitative perspective, which is an important step toward dose optimization in simulated humans. We hope that our research will help build a better relationship between clinicians and patients as we work together to address the challenges of antibiotic resistance in the 21st century.

Optimization of dosing regimens of vancomycin, teicoplanin, linezolid and daptomycin against methicillin-resistant Staphylococcus aureus in neutropenic patients with cancer by Monte Carlo simulations.

The objective of this study was to evaluate the efficacy of various dosing regimens of vancomycin, teicoplanin, linezolid and daptomycin against methicillin-resistant Staphylococcus aureus (MRSA) in neutropenic patients with cancer. Monte Carlo simulations were conducted using pharmacokinetic parameters and pharmacodynamic data to determine cumulative fraction of response (CFRs) in terms of area under the concentration-time curve/minimum inhibition concentration target. Currently clinical standard dosing regimens of vancomycin, teicoplanin, linezolid and daptomycin were insufficient to provide expected CFRs against MRSA for neutropenic patients with cancer. The high dosing regimens of vancomycin (3500 mg/d), teicoplanin (800 mg/d) and daptomycin (8 mg/kg/d) could provide CFRs of ≥ 80%, showing a higher treatment success. However, the majority of CFRs with linezolid simulated dosing regimens reached < 80% against MRSA. Therefore, a strategy of high dosages of vancomycin, teicoplanin and daptomycin may be needed to attain optimal therapeutic efficacy against MRSA in neutropenic patients with cancer.

Pharmacokinetics of Linezolid Dose Adjustment for Creatinine Clearance in Critically Ill Patients: A Multicenter, Prospective, Open-Label, Observational Study.

PURPOSE: The aim of this study is to use a population pharmacokinetic (PK) approach to evaluate the optimal dosing strategy for linezolid (LNZ) in critically ill patients. METHODS: This multicenter, prospective, open-label, observational study was conducted in 152 patients, and 117 of them were included in the PK model, whereas the rest were in the validation group. The percentage of therapeutic target attainment (PTTA) comprising two pharmacodynamic indices and one toxicity index was used to evaluate dosing regimens based on Monte Carlo simulations stratified by low, normal, and high renal clearance for MICs of 0.25-4 mg/L. RESULTS: A single-compartment model with a covariate creatinine clearance (CrCL) was chosen as the final model. The PK parameter estimates were clearance of 5.60 L/h, with CrCL adjustment factor of 0.386, and a distribution volume of 43.4 L. For MIC ≤2 mg/L, the standard dosing regimen (600 mg q12h) for patients with severe renal impairment (CrCL, 40 mL/min) and standard dosing or 900 mg q12h for patients with normal renal functions (CrCL, 80 mL/min) could achieve PTTA ≥74%. The dose of 2400 mg per 24-h continuous infusion was ideal for augmented renal clearance (ARC) with MIC ≤1 mg/L. For MICs >2 mg/L, rare optimal dose regimens were found regardless of renal function. CONCLUSION: In critically ill patients, the standard dose of 600 mg q12h was sufficient for MIC ≤2 mg/L in patients without ARC. Moreover, a 2400 mg/day 24-h continuous infusion was recommended for ARC patients.

In linezolid underexposure, pharmacogenetics matters: The role of CYP3A5.

The exposure to linezolid is characterized by a large inter-individual variability; age, renal dysfunction and body weight explain this variability only to a limited extent and a considerable portion of it remains unexplained; therefore, we decided to investigate the role of individual genetic background focusing in particular on the risk of linezolid underexposure. 191 patients in therapy with linezolid at the standard dose of 600 mg twice daily were considered. Linezolid plasma concentration was determined at the steady state and classified as "below", "within" or "above" reference range. Genetic polymorphisms for ATP Binding Cassette Subfamily B Member 1 (ABCB1), Cytochrome P450 (CYP) enzymes CYP3A4 and CYP3A5, and Cytochrome P450 Oxidoreductase (POR) were investigated. Age significantly correlated with drug exposure, and patients CYP3A5 expressers (GA and AA) were found at high risk to be underexposed to the drug when treated at standard dose. This association was confirmed even after correction with age. No association was found with ABCB1 polymorphism. Our data suggest that CYP3A5 polymorphisms might significantly affect linezolid disposition, putting patients at higher risk to be underexposed, while P-glycoprotein polymorphism seem not to play any role.

Proposal of initial and maintenance dosing regimens with linezolid for renal impairment patients.

BACKGROUND: Linezolid is administered as a fixed dose to all patients despite evidence of overexposure and thrombocytopenia in renal impairment. The aims of this study were to evaluate the risk of thrombocytopenia and the utility of therapeutic drug monitoring (TDM), and to propose alternate dosing regimens in patients with renal impairment. METHODS: We retrospectively reviewed patients ≥13 years old for whom serum linezolid trough concentration (Cmin) was measured during linezolid treatment. Patients with episodes of infection were divided into groups by presence of renal impairment (RI group) or absence of renal impairment (non-RI group), and by use of Cmin-based TDM (TDM group) or not (non-TDM group) during linezolid treatment. RESULTS: In the 108 patients examined by multivariable analyses, renal impairment was independently associated with increased risk of thrombocytopenia (OR 3.17, 95%CI 1.10-9.12) and higher Cmin. Analysis of the utility of TDM in the RI group showed that clinical failure rate was significantly lower in the TDM subgroup than in the non-TDM subgroup. Furthermore, in the RI group, dosage adjustments were needed in 90.5% of the TDM subgroup. All episodes administered a reduced dose of 300 mg every 12 h in the RI group showed Cmin ≥ 2.0 mg/L. Additional analysis of 53 episodes in which Cmin was measured within 48 h after starting administration showed that the initial standard dose for 2 days was sufficient to rapidly reach an effective therapeutic concentration in the RI group. CONCLUSIONS: Empirical dose reduction to 300 mg every 12 h after administration of the initial fixed dose for 2 days and Cmin-based TDM may improve safety outcomes while maintaining appropriate efficacy among patients with renal impairment.

Preparation and Evaluation of a Xanthan Gum-Containing Linezolid Ophthalmic Solution for Topical Treatment of Experimental Bacterial Keratitis.

PURPOSE: To formulate a xanthan gum-containing linezolid ophthalmic solution (LZD-XG) as a new antibiotic treatment against ocular bacterial infection. METHODS: LZD-XG was prepared and evaluated for its in vitro/in vivo ocular tolerance, in vitro/in vivo antibacterial activity, and in vivo ocular penetration. RESULTS: The optimized LZD-XG exhibited good in vitro/in vivo eye tolerance. A prolonged ocular surface residence time of LZD-XG was observed after topical instillation, and the ocular permeation was significantly better for LZD-XG than fora linezolid (LZD) ophthalmic solution. The in vitro antimicrobial activity was significantly better with LZD-XG than with LZD. In vivo evaluation also confirmed a strong therapeutic treatment effect of LZD-XG, as it significantly improved the clinical symptoms, ameliorated the damage of Staphylococcus aureus to ocular tissues, lowered the colony forming unit counts in the cornea, and decreased the myeloperoxidase activity in the cornea. CONCLUSION: LZD-XG was deemed a viable ophthalmic solution against ocular bacterial infection due to its excellent in vitro and in vivo characterizations.

Serotonin syndrome by drug interactions with linezolid: clues from pharmacovigilance-pharmacokinetic/pharmacodynamic analysis.

PURPOSE: To characterize the post-marketing reporting of serotonin syndrome (SS) due to drug-drug interactions (DDIs) with linezolid and investigate the relationship with pharmacokinetic/pharmacodynamic (PK/PD) properties of serotonergic agents. METHODS: We queried the worldwide FDA Adverse Event Reporting System to extract SS records due to DDIs where linezolid was reported as suspect. For each serotonergic agent concomitantly reported, proportion of SS reports and mean number of DDIs were calculated and three different "SS reporting zones" were created. Relevant PK (peak concentration, area under plasma concentration curve, volume of distribution (VD), and lipophilicity) and PD (values of binding affinity (Ki) and IC50 for serotonin reuptake transporter (SERT) and 5-HT2A) parameters were extracted for each serotonergic agent, and relevant PK/PD indexes were calculated to assess correlation with mean number of DDIs (PV index). RESULTS: Six hundred sixty-nine reports of SS mentioning linezolid were found, being linezolid-citalopram (N = 69; 10.3%) the most frequently DDI reported. Citalopram and methadone showed respectively the highest proportion of SS reports (0.28%) and the lowest mean number of DDIs (1.41). Citalopram, escitalopram, and methadone emerged as red (i.e., alert)-zone medications: they exhibited high lipophilicity and large VD (proxies of excellent central nervous system penetration) coupled with high potency. Among PK/PD indexes, a significant correlation with PV index was found for VD/Ki SERT ratio (p = 0.05). DISCUSSION: Our integrated approach suggests that linezolid is more likely to cause SS when co-administered with citalopram, escitalopram, and methadone, as inferred from their pharmacological properties. Proper management of SS should be tailored on a case-by-case basis.

External Evaluation of Population Pharmacokinetics and Pharmacodynamics in Linezolid-Induced Thrombocytopenia: The Transferability of Published Models to Different Hospitalized Patients.

BACKGROUND: The objective of this study was to perform an external evaluation of published linezolid population pharmacokinetic and pharmacodynamic models, to evaluate the predictive performance using an independent data set. Another aim was to offer an elegant environment for display and simulation of both the concentration and platelet count after linezolid administration. METHODS: We performed a systematic literature search in PubMed for all studies evaluating the population pharmacokinetic and pharmacodynamic parameters of linezolid in patients and selected the models to be used for the external validation. The bias of predictions was visually evaluated by plotting prediction errors (PEs) and relative PEs. The precision of prediction was evaluated by calculating the mean absolute error (MAE), root mean squared error (RMSE), and mean relative error (MRE). RESULTS: Three articles (models A, B, and C) provided linezolid-induced platelet dynamic models using population pharmacokinetic and pharmacodynamic modeling approaches. The PE and relative PE of both linezolid concentrations and platelet counts for models A and C showed similar predictive distributions. With respect to the prediction accuracy of total linezolid concentration, the MAE, RMSE, and MRE of population prediction values for model C was the smallest. The comparison of the MAE, RMSE, and MRE of patient-individual prediction values for the 3 pharmacodynamic models revealed no large differences. CONCLUSIONS: We confirmed the transferability of published population pharmacokinetic and pharmacodynamic models and showed that they were suitable for extrapolation to other hospitals and/or patients. This study also introduced application software based on model C for the therapeutic drug monitoring of linezolid.

Prolonged infusion of linezolid is associated with improved pharmacokinetic/pharmacodynamic (PK/PD) profiles in patients with external ventricular drains.

OBJECTIVE: We previously investigated the pharmacokinetic and pharmacodynamic (PK/PD) parameters of routine linezolid infusions (1 h) in patients with external ventricular drains (EVD). The aim of the study was to determine whether extended linezolid infusions (200 mg/h for 3 h) were more efficacious than short linezolid infusions (600 mg/h for 1 h). METHODS: We collected cerebrospinal fluid (CSF) and plasma samples from 10 patients who received linezolid infusions after cerebral hemorrhage surgery with EVDs. Linezolid concentrations were measured by high-performance liquid chromatography (HPLC). A Monte Carlo simulation was used to measure the probability of target attainments (PTA) and the PK/PD indexes at four minimum inhibitory concentrations (MIC). RESULTS: When the same dose (600 mg) was given as an extended infusion (3 h), linezolid reached its maximum concentrations in the plasma and CSF at 3.00 h and 4.40 h, respectively. The mean penetration of linezolid in CSF was 41.31%. Using the parameter of AUC0-24 h/MIC ≥ 100, the plasma PTA provided good coverage at > 90% when MIC was ≤ 1 µg/mL, while the values were 0 in CSF. Using the parameter %T (time) > MIC ≥ 85%, the PTA in both the plasma and CSF provided good coverage when MIC ≤ 2 µg/mL. Compared with routine infusions, prolonged infusion times (3 h) showed increased PTA of linezolid. CONCLUSIONS: Prolonged infusion times increased the concentration of linezolid in the plasma, leading to improved therapeutic outcomes. However, this improvement did not exist in CSF. Lastly, the PK/PD indicator AUC/MIC ≥ 100 may be used to achieve improved outcomes in patients with critical infections.

Bone penetration of linezolid in osteoarticular tuberculosis patients of China.

BACKGROUND: Linezolid presents strong antimicrobial activity against multidrug-resistant (MDR) pulmonary tuberculosis (TB), but its application in osteoarticular tuberculosis treatment remains understudied. Our objective was to analyze the bone penetration efficiency of linezolid in osteoarticular TB patients. METHODS: Osteoarticular TB patients, treated with 600 mg q 24 h linezolid-containing regimens and undergoing surgery, were prospectively and consecutively enrolled. One dose linezolid was administered before surgery. Blood and bone samples were collected simultaneously during operation, and their linezolid concentrations were then detected using high-performance liquid chromatography-tandem mass spectrometry. Pus samples were subjected to mycobacterial culture and GeneXpert MTB/RIF assay. The minimum inhibition concentrations (MICs) and drug susceptibility testing were performed with the recovered isolates. RESULTS: A total of 36 eligible osteoarticular TB patients were enrolled, including five MDR/rifampicin-resistant cases. All the 12 recovered isolates had MICs ≤0.5 µg/mL for linezolid. Mean concentrations in plasma, collected 100-510 min after the preoperative dosing, were 10.43 ± 4.83 µg/mL (range 3.29-22.26 µg/mL), and median concentrations in bone were 3.93 µg/mL (range 0.61-16.34 µg/mL). The median bone/plasma penetration ratio was 0.42 (range 0.14-0.95 µg/mL). Linezolid concentration in bone had a linear correlation with the drug concentration in plasma (r = 0.7873, p < 0.0001), while plasma concentration could explain 61.98% of the variation of concentration in bone (R2 = 0.6198). Notably, stratification analysis by sampling time demonstrated that samples collected 200-510 min after dosing had very good linear relationships between their bone and plasma concentrations (r = 0.9323). CONCLUSIONS: Linezolid penetrates from blood to bone efficiently, and the penetration further stabilizes ∼3 h after dosing.

Treatment Considerations for CNS Infections Caused by Vancomycin-Resistant Enterococcus faecium: A Focused Review of Linezolid and Daptomycin.

OBJECTIVE: To review the current literature describing pharmacology, pharmacokinetics/pharmacodynamics (PK/PD), efficacy, and safety of linezolid and daptomycin for the treatment of central nervous system (CNS) infections caused by vancomycin-resistant Enterococcus (VRE) faecium. DATA SOURCES: A literature search of PubMed/MEDLINE databases was conducted (from 1950 to April 2020) utilizing the following key terms: vancomycin-resistant Enterococcus, VRE, meningitis, ventriculitis, CNS infection, daptomycin, and linezolid. STUDY SELECTION AND DATA EXTRACTION: All relevant studies and case reports describing the treatment of VRE faecium from the CNS with linezolid or daptomycin were included. DATA SYNTHESIS: A total of 17 reports describing 22 cases were identified. There were 15 of 19 cases involving linezolid that reported clinical cure, of which 53.3% were monotherapy. Only 5 of 9 cases involving intravenous (IV) daptomycin resulted in cure; all 4 cases reporting daptomycin administration via the intrathecal or intraventricular route achieved clearance from the cerebrospinal fluid (CSF). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: The preferred treatment option for VRE faecium infections involving the CNS remains unclear. Supporting evidence through observational case reports have described varying outcomes with linezolid and daptomycin. This review compares reported outcomes between the 2 agents and provides a thorough discussion on drug- and patient-specific variables to consider. CONCLUSIONS: Linezolid monotherapy appears to be safe and effective for the treatment of susceptible-VRE faecium CNS infections, with consideration of therapeutic drug monitoring in special populations and with prolonged treatment duration. Daptomycin is an effective treatment option via intrathecal or intraventricular administration when neurosurgical access is available. The role of IV daptomycin remains inconclusive.

Pharmacokinetics of linezolid for methicillin-resistant Staphylococcus aureus pneumonia in an adult receiving extracorporeal membrane oxygenation.

PURPOSE: We present a case of a 55-year-old man post right lung transplantation receiving ECMO for treatment of respiratory failure secondary to methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. SUMMARY: Extracorporeal membrane oxygenation (ECMO) is a frequently utilized support therapy for patients with cardiac and/or respiratory failure. Dosing of medications during ECMO can be challenging due to several factors, including sequestration of medications within ECMO circuits, alterations in volume of distribution, and changes in drug clearance. The patient was initiated on empiric antibiotics, then switched to linezolid at a dose of 600 mg every 8 hours. Linezolid plasma concentrations were collected 30 minutes prior to the sixth administered dose and 30 minutes following the 1-hour infusion of the sixth dose, which resulted in values of 0.4 and 1.7 µg/mL, respectively. The ratio of 24-hour area under the curve (AUC0-24) to minimum inhibitory concentration (MIC), assuming a MIC of 2 µg/mL, was calculated using the extrapolated maximum concentration (1.9 µg/mL) and minimum concentration (0.35 µg/mL), resulting in an AUC0-24/MIC value of 10.8. Due to subtherapeutic linezolid plasma concentrations, ceftaroline was initiated and continued for a total of 18 days. To our knowledge, this is the second report to describe inadequate plasma concentrations of linezolid during ECMO. CONCLUSION: In the case described here, linezolid at a dose of 600 mg every 8 hours did not achieve target plasma concentrations in a patient receiving concomitant venovenous ECMO support.

Risk of target non-attainment in obese compared to non-obese patients in calculated linezolid therapy.

OBJECTIVES: The aim was to characterize linezolid population pharmacokinetics in plasma and interstitial space fluid of subcutaneous adipose tissue (target site) of obese compared with non-obese patients and to determine dosing regimens enabling adequate therapy using Monte Carlo simulations. METHODS: In this prospective, parallel group, open-label, controlled, single-centre trial, 30 surgery patients (15 obese, 15 non-obese) received 600 mg of intravenous linezolid. A population pharmacokinetic analysis characterizing plasma and microdialysis-derived target site pharmacokinetics was followed by Monte Carlo simulations using twice/thrice daily 600-1200 mg short-term and extended infusions of linezolid. Adequacy of therapy was assessed by the probability of pharmacokinetic/pharmacodynamic target attainment for time and exposure-related indices. RESULTS: In the model, lean body weight and obesity status largely explained between-patient variability in linezolid PK parameters (12.0-44.9%). Both factors caused lower area under the concentration-time curve in typical obese patients in plasma (-20.4%, 95% CI -22.0% to -15.9%) and at target-site (-37.7%, 95% CI -47.1% to -24.2%) compared with non-obese patients. Probability of target attainment showed improvement with increasing linezolid doses. Depending on lean body weight, adequate therapy was partially attained for 900- and 1200-mg linezolid doses and minimum inhibitory concentrations (MICs) ≤2 mg/L (probability of target attainment 62.5-100%) but could not be reached for MIC = 4 mg/L (probability of target attainment ≤82.3%). Additionally, lower linezolid distribution into the target site in obese patients as described above might compromise the plasma-based probability of target attainment analysis. DISCUSSION: This analysis revealed risks of linezolid underdosing in empirical antibiotic therapy of most resistant bacteria for obese and non-obese patients. Doubling the standard dose is associated with adequate probability of target attainment throughout most body masses for MIC ≤2 mg/L. Further clinical studies with adjusted dosing regimens in for example intensive care patients are needed.

Radiosynthesis and Biodistribution of 18F-Linezolid in Mycobacterium tuberculosis-Infected Mice Using Positron Emission Tomography.

Oxazolidinones are a novel class of antibacterials with excellent activity against resistant Gram-positive bacteria including strains causing multidrug-resistant tuberculosis (TB). Despite their excellent efficacy, optimal dosing strategies to limit their toxicities are still under development. Here, we developed a novel synthetic strategy for fluorine-18-radiolabeled oxazolidinones. As proof-of-concept, we performed whole-body 18F-linezolid positron emission tomography (PET) in a mouse model of pulmonary TB for noninvasive in situ measurements of time-activity curves in multiple compartments with subsequent confirmation by ex vivo tissue gamma counting. After intravenous injection, 18F-linezolid rapidly distributed to all organs with excellent penetration into Mycobacterium tuberculosis-infected lungs. Drug biodistribution studies with PET can provide unbiased, in situ drug measurements, which could boost efforts to optimize antibiotic dosing strategies.

Dosage regimen and toxicity risk assessment of linezolid in sepsis patients.

BACKGROUND: Significant alterations in the pharmacokinetic characteristics of linezolid are often seen in sepsis patients. The study aimed to identify a target pharmacokinetics/pharmacodynamics (PK/PD) index of the efficacy of linezolid treatment, and to estimate the optimum dosage regimen of linezolid in sepsis patients. METHODS: The PK data were modeled using the one-compartment model, which determined the target PK/PD index for successful treatment by logistic regression. The probability of thrombocytopenia was identified by establishing a logistic model. Different dosing regimens were evaluated using Monte Carlo simulation. RESULTS: Reaching 80% bacterial eradication required an AUC24/MIC of 100, which defined the therapeutic target. The proposed regimen to attain a cumulative fraction of response ≥80% was 800 mg/12 h (safety probability 66.8%) for sepsis patients with normal renal function or mild kidney damage. By contrast, the target cumulative fraction of response was attained with a standard dosing regimen in sepsis patients on continuous renal replacement therapy [600 mg/12 h (safety probability 49.7%)]. CONCLUSIONS: This study identified different dosing strategies to achieve target linezolid PK/PD values according to whether sepsis patients were treated with continuous renal replacement therapy. Due to the high incidence of thrombocytopenia in sepsis patients on continuous renal replacement therapy, therapeutic drug monitoring should be encouraged for optimizing linezolid exposure in sepsis patients.

Accumulation of Major Linezolid Metabolites in Patients with Renal Impairment.

In patients with renal impairment (n = 22 of 39), the median serum concentrations of linezolid, PNU-142300, and PNU-142586 were 1.6-, 3.3-, 2.8-fold higher, respectively, than in patients without renal impairment. Metabolite concentrations in paired samples were poorly correlated with linezolid concentrations (r2 = 0.26 for PNU-142300 and 0.06 for PNU-142586). Linezolid and its metabolites share potential toxicophores that deserve characterization to mitigate higher myelosuppression risk in patients with renal impairment.