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Objectives: The therapeutic arsenal for MRSA infections is limited. The aim of this study was to assess the non-inferiority of a combination of trimethoprim/sulfamethoxazole plus rifampicin versus linezolid alone for the treatment of MRSA infection., Methods: We conducted a randomized, open-label, single-centre, non-inferiority trial comparing trimethoprim/sulfamethoxazole (160 mg/800 mg three times daily) plus rifampicin (600 mg once a day) versus linezolid (600 mg twice a day) alone in adult patients with various types of MRSA infection. Patients were allocated 1:1 to either regimen. The primary outcome was clinical cure at 6 weeks after the end of treatment (non-inferiority margin 20%) assessed by both ITT and PP analyses. Secondary outcomes included the microbiologically documented persistence of MRSA in clinical cultures, mortality and adverse events. The study protocol has been registered with ClinicalTrials.gov (NCT00711854)., Results: Overall, 150 patients were randomized to one of the two treatment arms between January 2009 and December 2013 and were included in the ITT analysis. Of these 56/75 (74.7%) in the linezolid group and 59/75 (78.7%) in the trimethoprim/sulfamethoxazole and rifampicin group experienced clinical success (risk difference 4%, 95% CI -9.7% to 17.6%). The results were confirmed by the PP analysis, with 54/66 (81.8%) cured patients in the linezolid group versus 52/59 (88.1%) in the trimethoprim/sulfamethoxazole and rifampicin group (risk difference 6.3%, 95% CI -6.8% to 19.2%). There were no statistically significant differences between the two groups in any of the secondary outcomes, including microbiologically documented failure. Four adverse drug reactions attributed to the study medication occurred in the linezolid group versus nine in the trimethoprim/sulfamethoxazole and rifampicin group., Conclusions: Compared with linezolid, trimethoprim/sulfamethoxazole and rifampicin seems to be non-inferior in the treatment of MRSA infection., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Purpose: The optimal therapy involving linezolid or vancomycin for suspected methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia (NP) remains controversial. This study compared the efficacy and safety of linezolid and vancomycin therapies in patients with NP., Methods: A systematic review of randomized controlled trials with meta-analyses performed by searching PubMed, EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials. We screened for relevant randomized controlled studies in which patients with NP were enrolled and linezolid and vancomycin therapies were compared., Results: Nine trials involving 2618 pneumonia patients were reviewed. Linezolid was not found to be superior to vancomycin for clinical cure when categories of pathogen were not considered and in a subgroup of NP patients with MRSA infection [relative risk (RR)=1.16, 95 % confidence interval (CI)=0.95-1.43, P=0.15]. Compared with vancomycin, linezolid has no difference in the overall microbiological eradication rate (RR=1.12, 95 % CI=0.96-1.30, P=0.15) and specific MRSA eradication rate (RR=1.16, 95 % CI=0.93-1.45, P=0.19) in NP patients. In addition, nephrotoxicity was more frequent with vancomycin (RR=0.50, 95 % CI=0.31-0.81, P=0.005), but no differences between the treatments were found for all-cause mortality, thrombocytopenia, gastrointestinal effects, and drug discontinuation due to adverse events., Conclusion: These results suggest that linezolid is not superior to vancomycin with respect to both clinical and microbiological cure rates in patients with MRSA NP.

GSK1322322 represents a new class of antibiotics that targets an essential bacterial enzyme required for protein maturation, peptide deformylase. This multicenter, randomized, phase IIa study compared the safety, tolerability, and efficacy of GSK1322322 at 1,500 mg twice daily (b.i.d.) with that of linezolid at 600 mg b.i.d. in patients suspected of having Gram-positive acute bacterial skin and skin structure infections (ABSSSIs). The primary endpoint was assessment of the safety of GSK1322322, and a key secondary endpoint was the number of subjects with a ≥20% decrease in lesion area from the baseline at 48 and 72 h after treatment initiation. GSK1322322 administration was associated with mild-to-moderate drug-related adverse events, most commonly, nausea, vomiting, diarrhea, and headache. Adverse events (86% versus 74%) and withdrawals (28% versus 11%) were more frequent in the GSK1322322-treated group. Treatment with GSK1322322 and linezolid was associated with ≥20% decreases from the baseline in the lesion area in 73% (36/49) and 92% (24/26) of the patients, respectively, at the 48-h assessment and in 96% (44/46) and 100% (25/25) of the patients, respectively, at the 72-h assessment. Reductions in exudate/pus, pain, and skin infection scores were comparable between the GSK1322322 and linezolid treatments. The clinical success rates within the intent-to-treat population and the per-protocol population that completed this study were 67 and 91%, respectively, in the GSK1322322-treated group and 89 and 100%, respectively, in the linezolid-treated group. These results will be used to guide dose selection in future studies with GSK1322322 to optimize its tolerability and efficacy in patients with ABSSSIs. (This study has been registered at ClinicalTrials.gov under registration no. NCT01209078 and at http://www.gsk-clinicalstudyregister.com [PDF113414].)., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Hypoglycemia was not previously known to be a linezolid-associated adverse reaction. A case report describing symptomatic hypoglycemia in a linezolid recipient prompted a review of the US Food and Drug Administration Adverse Event Reporting System, which demonstrated a relationship between linezolid and hypoglycemia. A warning with this information was added to the linezolid package insert., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Over the last 50 years methicillin-resistant S. aureus (MRSA) spread globally. Vancomycin is still the most recommended antibiotic for MRSA-infections. Teicoplanin is an alternative glycopeptide with longer elimination half-life. Telavancin is a more recently developed derivative of vancomycin with similar clinical efficacy as vancomycin. It is not recommended for treatment of patients with renal insufficiency. Nephrotoxicity limits the therapeutic use of glycopeptide antibiotics. The oxazolidinone linezolid exhibits similar to superior therapeutic efficacy. Hematologic controls are necessary during treatment with this antibacterial agent. Neurotoxic effects have been observed mainly in patients who received prolonged linezolid treatment. Attention must be paid to possible interactions with concomitantly given drugs acting on the serotonergic system. New therapeutic options arise with ceftaroline, the first β-lactam antibiotic with activity against MRSA. However, controlled clinical trials with pulmonary MRSA infections have not been conducted with ceftaroline. Daptomycin, a lipopeptide, and tigecycline, a glycylcyclin are active in vitro against MRSA as well, but are also not indicated in pulmonary MRSA infections. These antibiotics show in an exemplary manner that antibacterial activity in vitro is an important prerequisite, but relevant data for a therapeutic decision should be derived from randomized controlled clinical double-blind trials., (© Georg Thieme Verlag KG Stuttgart · New York.)

Linezolid, an oxazolidinone class antibiotic, is used to treat Gram-positive infections, including those due to meticillin-resistant staphylococci and vancomycin-resistant enterococci. In paediatric clinical trials, the frequency of possible linezolid-related adverse events ranged from 18.8% to 25.6%. The most commonly reported side effects are gastrointestinal disturbances, headache, rash and liver function alterations. Lactic acidosis has been reported as a side effect of linezolid treatment, and limited data suggest it may be more common in children. We report on our experience of treating 50 children aged 1 month to years with linezolid. Eight patients (16%) developed lactic acidosis and another eight (16%) had lactic acidaemia without acidosis. Onset of lactic acidaemia (median 1.5 days; range 1-72 days) and lactic acidosis (median 2 days; range 1-13 days) tended to be early. Being an ICU patient and requiring mechanical ventilation significantly increased the risk of lactic acidaemia or acidosis (OR=22.75, 95% CI 4.24-122.09; OR=32.67, 95% CI 5.83-183.19, respectively; P<0.001). All 16 patients were able to continue linezolid treatment. Linezolid therapy was effective (microbiologic and/or clinical cure) in 39 patients (78%). Nine patients died whilst receiving linezolid treatment; the deaths were not considered to be a result of linezolid treatment failure. Two patients who did not respond clinically to linezolid recovered after their treatment was changed to vancomycin. Linezolid use in children appears to be as safe and effective as in adults. However, lactic acidosis appears to be more common, and occur earlier, in children., (Copyright © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

The pharmacokinetic/pharmacodynamic (PK/PD) index for the efficacy of linezolid is a 24-h area under the plasma drug concentration-time curve (AUC₂₄)/minimum inhibitory concentration (MIC) ratio of ≥100. The main adverse event associated with administration of linezolid is thrombocytopenia. Therefore, the aims of the present study were to define PD thresholds that would minimise linezolid-induced thrombocytopenia and to perform a population PK analysis to identify factors influencing the pharmacokinetics of linezolid. Population PK analysis revealed that creatinine clearance (CLCr) significantly affected linezolid pharmacokinetics: the mean parameter estimate of drug clearance (CL; in L/h)=0.0258 × CLCr + 2.03. A strong correlation (r=0.970) was found between AUC₂₄ and trough plasma concentrations (Cmin) [AUC₂₄=18.2 × Cmin + 134.4]. The Cmin value for AUC₂₄=200 (in the case of MIC=2 μg/mL) was estimated to be 3.6 μg/mL. Regarding safety, Cmin was a significant predictor of thrombocytopenia during treatment, and its threshold to minimise linezolid-induced thrombocytopenia was 8.2 μg/mL. A Kaplan-Meier plot revealed that the median time from initiation of therapy to the development of thrombocytopenia was 15 days. Therefore, the target Cmin range was 3.6-8.2 μg/mL. The following formula to achieve a target Cmin in patients with different degrees of renal function was proposed based on these results: initial daily dose (mg/day)=CL × AUC₂₄=(0.0258 × CLCr + 2.03)×(18.2 × Cmin + 134.4). This recommended initial dosage and subsequent dosage adjustment for the target concentration range should avoid adverse events, thereby enabling effective linezolid-based therapies to be continued., (Copyright © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

Gram-positive cocci are commonly isolated in orthopaedic implant infections and their resistance to β-lactams and fluoroquinolones is increasing. The high oral bioavailability of linezolid makes it an attractive oral alternative to glycopeptides and its use has increased in the last decade. To evaluate experience with linezolid in orthopaedic implant infections a systematic review of the literature available in English was undertaken. Only those articles describing series of ≥10 patients with acute or chronic orthopaedic implant infections treated with linezolid and with a clear definition of diagnosis and outcome were selected. A total of 293 patients (79.9% had prosthetic joint infections) were analysed in the 10 articles included. The overall remission rate with at least 3 months of follow-up was 79.9%, depending on whether the implant was removed or not (94% versus 69.9%). The addition of rifampicin was described in only two articles and no significant difference was observed. Adverse events were frequent during prolonged administration of linezolid (34.3%), requiring treatment discontinuation in 12.8%. The most common event was anaemia (13.4%) followed by gastrointestinal symptoms (11.1%). In conclusion, linezolid seems a good oral treatment alternative for orthopaedic implant infections due to Gram-positive cocci resistant to β-lactams and fluoroquinolones. However, close monitoring of adverse events is required., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Oxazolidinones comprise an important class of antibacterial protein synthesis inhibitors. Myelosuppression and monoamine oxidase inhibition (MAOI) are key independent causes for limiting adverse effects in therapy with the sole approved drug of this class, linezolid. This annotation describes a novel oxazolidinone agent, (S)-5-((isoxazol-3-ylamino)methyl)-3-(2,3,5-trifluoro-4-(4-oxo-3,4-dihydropyridin-1(2H)-yl)phenyl)oxazolidin-2-one (MRX-I), distinguished by its high activity against Gram-positive pathogens coupled with markedly reduced potential for myelosuppression and MAOI. The medical need, medicinal chemistry rationale, preclinical data, and phase I clinical trial summary for this new agent are reviewed herein.

Introduction: Controversy exists regarding optimal treatment for ventilator-associated pneumonia (VAP) due to methicillin-resistant Staphylococcus aureus (MRSA). The primary objective of this study was to compare clinical success of linezolid versus vancomycin for the treatment of patients with MRSA VAP., Methods: This was a multicenter, retrospective, observational study of patients with VAP (defined according to Centers for Disease Control and Prevention criteria) due to MRSA who were treated with linezolid or vancomycin. MRSA VAP was considered when MRSA was isolated from a tracheal aspirate or bronchoalveolar lavage. Clinical success was evaluated by assessing improvement or resolution of signs and symptoms of VAP by day 14. After matching on confounding factors, logistic regression models were used to determine if an association existed between treatment arm and clinical success., Results: A total of 188 patients were evaluated (101 treated with linezolid and 87 with vancomycin). The mean ± standard deviation Acute Physiology and Chronic Health Evaluation (APACHE) II score was 21 ± 11 for linezolid- and 19 ± 9 for vancomycin-treated patients (P = 0.041). Clinical success occurred in 85% of linezolid-treated patients compared with 69% of vancomycin-treated patients (P = 0.009). After adjusting for confounding factors, linezolid-treated patients were 24% more likely to experience clinical success than vancomycin-treated patients (P = 0.018)., Conclusions: This study adds to the evidence indicating that patients with MRSA VAP who are treated with linezolid are more likely to respond favorably compared with patients treated with vancomycin.

Background: Dalbavancin, a lipoglycopeptide antibiotic agent that is active against gram-positive pathogens, has a long plasma half-life, allowing for once-weekly dosing. DISCOVER 1 and DISCOVER 2 were identically designed noninferiority trials of dalbavancin for the treatment of acute bacterial skin and skin-structure infection., Methods: We randomly assigned patients to receive dalbavancin intravenously on days 1 and 8 or vancomycin intravenously for at least 3 days with the option to switch to oral linezolid to complete 10 to 14 days of therapy. The primary end point, early clinical response, required the cessation of spread of infection-related erythema and the absence of fever at 48 to 72 hours. Secondary end points at the end of therapy included clinical status and investigator's assessment of outcome., Results: Analysis of the primary end point showed noninferiority of dalbavancin in both DISCOVER 1 and DISCOVER 2. In the pooled analysis, 525 of 659 patients (79.7%) in the dalbavancin group and 521 of 653 (79.8%) in the vancomycin-linezolid group had an early clinical response indicating treatment success (weighted difference, -0.1 percentage point; 95% confidence interval, -4.5 to 4.2). The outcomes were similar in the analyses by study and the pooled analyses of clinical status at the end of therapy and the investigator's assessment of outcome. For patients infected with Staphylococcus aureus, including methicillin-resistant S. aureus, clinical success was seen in 90.6% of the patients treated with dalbavancin and 93.8% of those treated with vancomycin-linezolid. Adverse events and study days with an adverse event were less frequent in the dalbavancin group than in the vancomycin-linezolid group. The most common treatment-related adverse events in either group were nausea, diarrhea, and pruritus., Conclusions: Once-weekly intravenous dalbavancin was not inferior to twice-daily intravenous vancomycin followed by oral linezolid for the treatment of acute bacterial skin and skin-structure infection. (Funded by Durata Therapeutics; DISCOVER 1 and DISCOVER 2 ClinicalTrials.gov numbers, NCT01339091 and NCT01431339.).

To investigate the risk factors associated with the development of thrombocytopenia, and define the thresholds of efficacy and safety in critically ill patients who received linezolid therapy. A retrospective study was performed in critically ill patients treated with linezolid. Risk factors associated with thrombocytopenia were identified via medical records and trough levels (C(min)) measured during linezolid treatment. By establishing a logistic model, the risks were predicted by the receiver operating characteristic (ROC) curve and the thresholds of efficacy and safety were identified in the patients. Logistic analysis showed that, weight (OR = 0.906; 95% CI, 0.839-0.978; P = 0.011), baseline platelet count (OR = 0.989; 95% CI, 0.977-1.000; P = 0.049), C(min) (OR = 1.545; 95% CI, 1.203-1.983; P = 0.001), and APACHE II score (OR = 1.130; 95% CI, 1.003-1.273; P = 0.044) were significant factors for linezolid-associated thrombocytopenia. The area under the ROC curve of the combined predictor was larger based on the above factors. When the Youden index was the maximum, the best optimal cut-off point was 205.6 on the ROC curve; when C(min) ≥ 2 mg/L, the probability of bacterial eradication was more than 80%; when C(min) ≥ 6.3 mg/L, the probability of thrombocytopenia was more than 50 %. In clinical practice, when the calculating results of the combined predictor ≤205.6, the risk of the development of thrombocytopenia may be higher. Furthermore, maintenance of C(min) between 2 and 6.3 mg/L over time may be helpful in retaining appropriate efficacy and reducing the associated thrombocytopenia.

Purpose: The mechanism of action, pharmacokinetics, pharmacodynamics, and clinical efficacy and safety of an investigational second-generation oxazolidinone are reviewed., Summary: Tedizolid is a protein synthesis inhibitor in clinical development for the treatment of gram-positive infections. Similar to linezolid, tedizolid works by binding to the 23S ribosomal RNA of the 50S subunit, thereby preventing the formation of the 70S initiation complex and inhibiting protein synthesis. Tedizolid has demonstrated potent in vitro activity against multidrug-resistant gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), Streptococcus pneumoniae, and vancomycin-resistant enterococci (VRE), including some linezolid-resistant strains. Tedizolid has a favorable pharmacokinetic profile that allows for once-daily dosing and easy i.v.-to-oral conversion. Unlike linezolid, tedizolid has not been shown to interact with serotonergic agents in clinical studies. Two Phase III studies in patients with acute bacterial skin and skin structure infections have demonstrated the noninferiority of 6 days of tedizolid therapy (200 mg i.v. or orally once daily) relative to 10 days of linezolid therapy. In clinical trials to date, overall rates of treatment-related adverse effects with linezolid and tedizolid were comparable (40.8% versus 43.3%), with nausea being the most commonly reported adverse effect associated with tedizolid use (16% of patients). Planned studies will investigate tedizolid's potential role in the treatment of community-acquired bacterial pneumonia, hospital-acquired/ventilator-associated bacterial pneumonia, and bacteremia., Conclusion: Tedizolid is an investigational oxazolidinone antibiotic for the treatment of multidrug-resistant gram-positive pathogens such as MRSA, Streptococcus pneumoniae, and VRE, including some linezolid-resistant strains.

Purpose: Thrombocytopenia is a common complication in the intensive care unit (ICU), but the incidence of drug-induced thrombocytopenia (DIT) is not well defined. We investigate linezolid-induced thrombocytopenia in patients with impaired renal function. Since recent studies suggest that linezolid clearance is reduced in these patients and there are no precise data confirming that dose-adjustment should be required, we performed a systematic analysis in order to establish whether it is necessary to consider a dose adjustment and promote studies to confirm this concept., Methods: We report a case of thrombocytopenia (nadir 32 × 10(3)/μl) in a patient with acute kidney injury who was treated with linezolid for a MRSA pulmonary infection. We performed a systematic review of the literature through PubMed with the aim to include every case report, case series, prospective and retrospective clinical study reporting linezolid-induced thrombocytopenia with concomitant impaired renal function., Results: An increasing number of clinical studies suggest a correlation between the onset of linezolid-induced thrombocytopenia and renal dysfunction. Close monitoring of platelet count and hemoglobin is recommended in patients treated with linezolid, especially in those with impaired renal function because the reduction of its clearance causes drug accumulation, as some studies have reported., Conclusions: Clinicians should consider the potential risk of this complication, especially in elderly patients with end-stage renal disease. Further studies should be encouraged to determine if the incidence of linezolid-related thrombocytopenia could be reduced by a dose adjustment according to renal function, for which currently there is still no specific recommendation.

Thrombocytopenia is a common side effect of linezolid, an oxazolidinone antibiotic often used to treat multidrug-resistant Gram-positive bacterial infections. Various risk factors have been suggested, including linezolid dose and duration of therapy, baseline platelet counts, and renal dysfunction; still, the mechanisms behind this potentially treatment-limiting toxicity are largely unknown. A clinical study was conducted to investigate the relationship between linezolid pharmacokinetics and toxicodynamics and inform strategies to prevent and manage linezolid-associated toxicity. Forty-one patients received 42 separate treatment courses of linezolid (600 mg every 12 h). A new mechanism-based, population pharmacokinetic/toxicodynamic model was developed to describe the time course of plasma linezolid concentrations and platelets. A linezolid concentration of 8.06 mg/liter (101% between-patient variability) inhibited the synthesis of platelet precursor cells by 50%. Simulations predicted treatment durations of 5 and 7 days to carry a substantially lower risk than 10- to 28-day therapy for platelet nadirs of <100 ×10(9)/liter. The risk for toxicity did not differ noticeably between 14 and 28 days of therapy and was significantly higher for patients with lower baseline platelet counts. Due to the increased risk of toxicity after longer durations of linezolid therapy and large between-patient variability, close monitoring of patients for development of toxicity is important. Dose individualization based on plasma linezolid concentration profiles and platelet counts should be considered to minimize linezolid-associated thrombocytopenia. Overall, oxazolidinone therapy over 5 to 7 days even at relatively high doses was predicted to be as safe as 10-day therapy of 600 mg linezolid every 12 h.

Background: Methicillin-resistant Staphylococcus aureus (MRSA) accounts for 10-40% of hospital-acquired pneumonia, and even more in intensive care units. The current guidelines for the treatment of MRSA nosocomial pneumonia include vancomycin and linezolid. The authors of 2 prospective randomized trials comparing vancomycin and linezolid in nosocomial pneumonia had concluded to the non-inferiority of linezolid. A slight superiority of linezolid was observed in the MRSA pneumonia subgroup, in terms of clinical success and survival, but no definite conclusion could be drawn., Methods: A prospective randomized study was made to compare a fixed linezolid dose to dose-optimized vancomycin for the treatment of bacteriologically proven MRSA nosocomial pneumonia (ZEPHyR Study)., Results: Among the 165 patients treated by linezolid (57.6%) in the PP population, 95 were clinically cured at the end of the study, compared to 81 of the 174 patients treated by vancomycin (46.6%) (IC 95% of the difference 0.5%-21.6%, P=0.042). Nephrotoxicity in the mITT population reached 8.4% in the linezolid group compared to 18.2% in the vancomycin group., Conclusion: LNZ was superior to vancomycin for the treatment of MRSA nosocomial pneumonia., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Background: There are few data on dose optimization and clinical outcomes of antimicrobial agents based on patients' weight, despite the rising prevalence of obesity. Because there are physiologic, pharmacologic, and dosing differences related to weight, it is important to evaluate the impact of weight on antimicrobial agents to optimize clinical outcomes., Objectives: This study compared effects of weight on efficacy and safety in patients treated with linezolid or vancomycin for complicated skin and skin structure infections (cSSSIs) and nosocomial pneumonia (NP) caused by methicillin-resistant Staphylococcus aureus (MRSA)., Methods: We analyzed data from 2 clinical trials of patients randomized to receive a fixed dose of linezolid or weight-based dosing of vancomycin for the treatment of cSSSIs or NP caused by MRSA. For each study, patients were stratified into quartiles (Q1-4 [lowest to highest weight, respectively]). Clinical success, microbiologic success, and adverse events (AEs) were evaluated., Results: The analysis included 632 patients with cSSSIs (linezolid, n = 316; vancomycin, n = 316) and 447 patients with NP (linezolid, n = 224; vancomycin, n = 223). Among patients with cSSSIs, clinical success rates at the study end with fixed-dose linezolid were similar across all weight quartiles and similar to weight-based dosing of vancomycin for Q1-3. Among Q4 (the highest weight quartile [97-295 kg]), clinical success with vancomycin was significantly lower compared with linezolid (69.5% vs 86.2%; P = 0.03). Among patients with NP, no significant differences in success rates between fixed-dose linezolid and weight-based dosing of vancomycin were observed across all quartiles. Frequencies of AEs were consistent across the quartiles for both indications and by treatment., Conclusions: Except for Q4 within the vancomycin-treated patients for MRSA cSSSI, the efficacy of fixed-dosed linezolid and weight-based dosing of vancomycin was maintained across all weight quartiles and MRSA infection types. The AEs were consistent with the known safety profiles of each drug regardless of weight quartile. ClinicalTrials.gov identifiers: NCT00087490 and NCT00084266., (© 2013 Elsevier HS Journals, Inc. All rights reserved.)

Objectives: Thrombocytopenia is sometimes observed during linezolid therapy. Here, we aimed to investigate the factors affecting linezolid-induced thrombocytopenia., Methods: A prospective observational study was performed between October 2009 and February 2011; 30 patients were included. Plasma linezolid trough concentrations were measured on days 3, 7 and 14 after initial drug administration. Platelet counts and haemoglobin levels were also monitored., Results: Thrombocytopenia occurred in 17 patients (56.7%). Median linezolid trough concentrations on day 3 were significantly higher in patients with renal impairment (creatinine clearance <60 mL/min) than in patients without renal impairment (14.7 versus 4.8 mg/L; P < 0.0001). Median linezolid trough concentrations on day 3 in patients who developed thrombocytopenia were also significantly higher than those in patients who did not (13.4 versus 4.3 mg/L, P < 0.0001). Development of thrombocytopenia occurred significantly more frequently in patients with linezolid trough concentration >7.5 mg/L (OR, 90.0; P < 0.0001) and renal impairment (OR, 39.0; P = 0.0002). The Kaplan-Meier plot showed that the median time from the initiation of therapy to development of thrombocytopenia was 11 days., Conclusions: Patients with renal impairment are more likely to have a high plasma linezolid concentration. In addition, a high plasma linezolid concentration and renal impairment significantly affected the development of linezolid-induced thrombocytopenia. Further studies are required to evaluate whether therapeutic drug monitoring-guided dosage adjustment of linezolid decreases the adverse effects while maintaining treatment efficacy in patients with renal dysfunction.

Background: Vancomycin is the mainstay of treatment for methicillin-resistant Staphylococcus aureus (MRSA) meningitis. However, successful outcomes with linezolid have not been reported in a large series of patients. We conducted a single-center retrospective cohort study to compare vancomycin with linezolid in the treatment of MRSA meningitis., Methods: We extracted data and outcomes for all adult patients (age >18 years) with culture-proved MRSA meningitis who received vancomycin or linezolid between January 2006 and June 2011. A definite diagnosis of meningitis was based on the isolation of MRSA in at least one cerebrospinal fluid (CSF) culture and findings in CSF that are typical of the infection. Linezolid was given intravenously (IV) at a dosage of 600 mg q12h and vancomycin IV at 500 mg q6h., Results: A total of 8 patients with MRSA meningitis (5 male, 3 female; age [mean±SD] 61.6±13.2 years) received vancomycin and 9 patients (7 male, 2 female; age 59.1±15.6 years) received linezolid. All isolated strains of MRSA were susceptible to both vancomycin and linezolid. The rates of microbiologic success with linezolid or vancomycin, in terms of clearance of MRSA from CSF on day 5, were 7/9 and 2/8 (p=0.044, Fisher exact test). No severe adverse events occurred in either treatment arm of the study. One-month survival of the patients in whom treatment was successful microbiologically was 2/2 in the vancomycin-treated group and 4/7 in the linezolid-treated group. Minimum inhibitory concentration (MIC) data for vancomycin were available for 5/6 treatment failures with vancomycin, and vancomycin MIC values of these five strains were 2 mg/L., Conclusion: Analysis of the findings in the limited cohorts in our study suggests that linezolid is superior to vancomycin for treating MRSA meningitis, especially in cases in which there is a high MIC (2 mg/L) for vancomycin. A clinical study involving larger cohorts may increase the evidence available in relation to this question.

Background: The morbidity and treatment costs associated with skin and soft tissue infections (SSTIs) are high. Linezolid and vancomycin are antibiotics that are commonly used in treating skin and soft-tissue infections, specifically those infections due to methicillin-resistant Staphylococcus aureus (MRSA)., Objectives: To compare the effects and safety of linezolid and vancomycin for treating people with SSTIs., Search Methods: In May 2013 we conducted searches of the following databases: Cochrane Wounds Group Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE; and EBSCO CINAHL. We also contacted manufacturers for details of unpublished and ongoing trials. We scrutinised citations within all obtained trials and major review articles to identify any additional trials., Selection Criteria: We included all randomised controlled trials (RCTs) comparing linezolid with vancomycin in the treatment of SSTIs., Data Collection and Analysis: Two review authors independently selected trials, assessed risk of bias and extracted data. The primary outcomes were clinical cure, microbiological cure, and SSTI-related and treatment-related mortality. We performed subgroup analyses according to age, and whether the infection was due to MRSA., Main Results: We included nine RCTs (3144 participants). Linezolid was associated with a significantly better clinical (RR 1.09, 95% CI 1.03 to 1.16) and microbiological cure rate in adults (RR 1.08, 95% CI 1.01 to 1.16). For those infections due to MRSA, linezolid was significantly more effective than vancomycin in clinical (RR 1.09, 95% CI 1.03 to 1.17) and microbiological cure rates (RR 1.17, 95% CI 1.04 to 1.32). No RCT reported SSTI-related and treatment-related mortality. There was no significant difference in all-cause mortality between linezolid and vancomycin (RR 1.44, 95% CI 0.75 to 2.80). There were fewer incidents of red man syndrome (RR 0.04, 95% CI 0.01 to 0.29), pruritus (RR 0.36, 95% CI 0.17 to 0.75) and rash (RR 0.27, 95% CI 0.12 to 0.58) in the linezolid group compared with vancomycin, however, more people reported thrombocytopenia (RR 13.06, 95% CI 1.72 to 99.22), and nausea (RR 2.45, 95% CI 1.52 to 3.94) when treated with linezolid. It seems, from the available data, that length of stay in hospital was shorter for those in the linezolid group than the vancomycin group. The daily cost of outpatient therapy was less with oral linezolid than with intravenous vancomycin. Although inpatient treatment with linezolid cost more than inpatient treatment with vancomycin per day, the median length of hospital stay was three days shorter with linezolid. Thus, total hospital charges per patient were less with linezolid treatment than with vancomycin treatment., Authors' Conclusions: Linezolid seems to be more effective than vancomycin for treating people with SSTIs, including SSTIs caused by MRSA. The available evidence is at high risk of bias and is based on studies that were supported by the pharmaceutical company that makes linezolid. Further well-designed, independently-funded, RCTs are needed to confirm the available evidence.

Retrospective studies have documented a significant association between linezolid (LNZ) plasma concentrations and drug-related haematological toxicity. However, the safe upper threshold level for LNZ plasma trough concentrations (Cmin values) has not been defined with certainty. A prospective observational study was performed aimed at comparing LNZ Cmin values in patients developing drug-related side effects with those measured in patients not experiencing LNZ toxicity. LNZ Cmin values were measured from the first week after starting therapy and were repeated periodically up to the end of treatment. Fifty patients, for a total of 210 LNZ Cmin evaluations, were considered. All patients (n=9) who developed drug-related haematological toxicity also had significantly higher plasma LNZ Cmin values during the first week of therapy (9.0±6.4 mg/L vs. 4.9±3.7 mg/L; P<0.01) and thereafter (9.3±5.4 mg/L vs. 4.4±3.4 mg/L; P<0.01). The significant association between LNZ plasma concentrations and haematological toxicity was also confirmed by multivariate logistic regression analysis including age, serum creatinine and concomitant medications as independent variables. A causal relationship between LNZ concentrations and the risk of developing drug-related haematological toxicity was observed. Accordingly, application of therapeutic drug monitoring may improve the safety outcome of patients receiving LNZ therapy., (Copyright © 2013 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

Linezolid is the first available oxazolidinone, possessing broad-spectrum activity against Gram-positive bacteria and a favourable pharmacokinetic profile. The aim of this study was to compare the efficacy and safety of linezolid with vancomycin, the gold-standard treatment, for meticillin-resistant Staphylococcus aureus (MRSA)-related infections. A meta-analysis of randomised controlled trials (RCTs) identified in PubMed, the Cochrane Library and Embase was performed. Nine RCTs, involving 5249 patients, were included in the meta-analysis. The results indicated that linezolid was associated with superior efficacy compared with vancomycin for MRSA-related infection in terms of clinical treatment success [8 RCTs, 2174 patients, odds ratio (OR) = 1.77, 95% confidence interval (CI) 1.22-2.56] and microbiological treatment success (9 RCTs, 1555 patients, OR = 1.78, 95% CI 1.22-2.58). Although no difference was found regarding the overall incidence of drug-related adverse events (AEs) and serious AEs (SAEs) between the linezolid and vancomycin therapy groups (drug-related AEs, 8 RCTs, 5034 patients, OR = 1.20, 95% CI 0.98-1.48; SAEs, 5 RCTs, 2072 patients, OR = 1.00, 95% CI 0.74-1.36), the linezolid therapy group was associated with significantly fewer patients experiencing abnormal renal function (reduced by ca. 60% compared with the vancomycin therapy group; 4 RCTs, 2531 patients, OR = 0.39, 95% CI 0.28-0.55), which is a well-recognised limitation of vancomycin. This meta-analysis provides evidence that linezolid possesses significant advantages compared with vancomycin and may be a superior alternative for MRSA-related infection., (Copyright © 2013 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

Linezolid is an antibiotic with time-dependent activity, and both the percentage of time that plasma concentrations exceed the MIC and the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC24/MIC ratio) are associated with clinical response. The aim of this study was to analyze the linezolid trough plasma concentration (C(min)) and to determine factors associated with a C(min) < 2 mg/liter and other clinically relevant thresholds. Characteristics of 78 patients receiving 600 mg/12 h of linezolid with a C(min) determination at the steady state and within the first 10 days of treatment were retrospectively reviewed. Concentrations were measured using high-pressure liquid chromatography. Univariate and multivariate analysis were performed to identify risk factors of low C(min). A total of 29.5% of patients had a C(min) < 2 mg/liter. The percentage was significantly higher in patients with an estimated glomerular filtration (eGF) > 80 ml/min, in intensive care unit (ICU) patients, and in patients with an infection due to Staphylococcus aureus. The independent predictors of C(min) < 2 mg/liter were an eGF > 80 ml/min (odds ratio [OR], 10; 95% confidence interval [CI], 2.732 to 37.037; P = 0.001) and infection due to S. aureus (OR, 5.906; 95% CI, 1.651 to 21.126; P = 0.006). A linezolid C(min) of <2 mg/liter was found in 29.5% of cases, and the risk was significantly higher among those with an eGF > 80 ml/min and in infections due to S. aureus. In patients with severe sepsis, a loading dose or continuous infusion and drug monitoring could improve the pharmacodynamic parameters associated with linezolid efficacy.

To assess the effectiveness and safety of linezolid in comparison with glycopeptides (vancomycin and teicoplanin) for the treatment of Staphylococcus aureus infections, we conducted a meta-analysis of relevant randomized controlled trials. A thorough search of Pubmed and other databases was performed. Thirteen trials on 3863 clinically assessed patients were included. Linezolid was slightly more effective than glycopeptides in the intent-to-treat population (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.01-1.10), was more effective in clinically assessed patients (OR 95% CI: 1.38, 1.17-1.64) and in all microbiologically assessed patients (OR 95% CI: 1.38, 1.15-1.65). Linezolid was associated with better treatment in skin and soft-tissue infections (SSTIs) patients (OR 95% CI: 1.61, 1.22-2.12), but not in bacteraemia (OR 95% CI: 1.24, 0.78-1.97) or pneumonia (OR 95% CI: 1.25, 0.97-1.60) patients. No difference of mortality between linezolid and glycopeptides was seen in the pooled trials (OR 95% CI: 0.98, 0.83-1.15). While linezolid was associated with more haematological (OR 95% CI: 2.23, 1.07-4.65) and gastrointestinal events (OR 95% CI: 2.34, 1.53-3.59), a significantly fewer events of skin adverse effects (OR 95% CI: 0.27, 0.16-0.46) and nephrotoxicity (OR 95% CI: 0.45, 0.28-0.72) were recorded in linezolid. Based on the analysis of the pooled data of randomized control trials, linezolid should be a better choice for treatment of patients with S. aureus infections, especially in SSTIs patients than glycopeptides. However, when physicians choose to use linezolid, risk of haematological and gastrointestinal events should be taken into account according to the characteristics of the specific patient populations.

A randomized, investigator-blind, multicenter phase 2 trial involving patients with complicated skin and skin structure infections (cSSSI) compared the safety and efficacy of omadacycline, a broad-spectrum agent with activity against methicillin-resistant Staphylococcus aureus (MRSA), to those of linezolid (with or without aztreonam). Patients were randomized 1:1 to omadacycline (100 mg intravenously [i.v.] once a day [QD] with an option to transition to 200 mg orally QD) or linezolid (600 mg i.v. twice daily [BID] with an option to transition to 600 mg orally BID) at 11 U.S. sites. Patients suspected or documented to have infections caused by Gram-negative bacteria were given aztreonam (2 g i.v. every 12 h [q12h]) if randomized to linezolid or matching placebo infusions if randomized to omadacycline. Adverse events were reported in 46 (41.4%) omadacycline-treated and 55 (50.9%) linezolid-treated patients. Adverse events related to treatment were assessed by investigators in 24 (21.6%) omadacycline-treated and 33 (30.6%) linezolid-treated patients. The gastrointestinal tract was most commonly involved, with adverse events reported in 21 (18.9%) patients exposed to omadacycline and 20 (18.5%) exposed to linezolid. Rates of successful clinical response in the intent-to-treat (ITT) and clinical evaluable (CE) populations favored omadacycline (ITT, 88.3% versus 75.9%; 95% confidence interval [CI], 1.9 to 22.9; CE, 98.0% versus 93.2%; 95% CI, -1.7 to 11.3). For microbiologically evaluable (ME) patients with S. aureus infections, the clinical success rates were 97.2% (70/72) in omadacycline-treated and 92.7% (51/55) in linezolid-treated patients. This phase 2 experience supports conclusions that omadacycline is well tolerated in cSSSI patients and that this aminomethylcycline has potential to be an effective treatment for serious skin infections.

Linezolid, an oxazolidinone antibiotic, exhibits a broad spectrum of activity against Gram-positive bacteria. It has been licensed for adult use in Japan since 2006 for MRSA infections, and has also been used off-label for pediatric patients. At our university hospital, a total of 16 infants and children (including one non-Japanese Asian) were administered linezolid owing to infection with multidrug-resistant Gram-positive bacteria, after consent had been provided. All patients had severe underlying diseases or indications for surgery. Eighty-eight percent of the causal microorganisms were methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant coagulase-negative Staphylococcus and all were sensitive to linezolid. Linezolid was administered because the antecedent anti-MRSA medications were ineffective or contraindicated, or intravenous-to-oral switch therapy was requested owing to cardiac or orthopedic surgical-site infections. The median duration of administration was 13 days (range 3-31 days). The overall efficacy was 91 % (10/11) in those for whom efficacy could be evaluated. Only two patients (both teen-aged) encountered linezolid-related adverse effects (13 %, 2/16). One patient showed elevation of liver enzymes (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), requiring that administration be withdrawn, but enzyme levels returned to normal after the patient had been switched to vancomycin. The other patient showed transiently decreased platelet counts. Linezolid is considered generally safe and effective for children in Japan, especially for those who cannot use other anti-MRSA medications or those who require oral antibiotics for infections with multidrug-resistant Gram-positive bacteria.

This minireview explores mitochondria as a site for antibiotic-host interactions that lead to pathophysiologic responses manifested as nonantibacterial side effects. Mitochondrion-based side effects are possibly related to the notion that these organelles are archaic bacterial ancestors or commandeered remnants that have co-evolved in eukaryotic cells; thus, this minireview focuses on mitochondrial damage that may be analogous to the antibacterial effects of the drugs. Special attention is devoted to aminoglycosides, chloramphenicol, and fluoroquinolones and their respective single side effects related to mitochondrial disturbances. Linezolid/oxazolidinone multisystemic toxicity is also discussed. Aminoglycosides and oxazolidinones are inhibitors of bacterial ribosomes, and some of their side effects appear to be based on direct inhibition of mitochondrial ribosomes. Chloramphenicol and fluoroquinolones target bacterial ribosomes and gyrases/topoisomerases, respectively, both of which are present in mitochondria. However, the side effects of chloramphenicol and the fluoroquinolones appear to be based on idiosyncratic damage to host mitochondria. Nonetheless, it appears that mitochondrion-associated side effects are a potential aspect of antibiotics whose targets are shared by prokaryotes and mitochondria-an important consideration for future drug design.

Objectives: Prolonged treatment with linezolid may cause toxicity. The purpose of this study was to define pharmacodynamic thresholds for improving safety outcomes of linezolid., Methods: We performed a retrospective study of patients who had trough (C(min)) and peak (C(max)) plasma levels measured during prolonged linezolid treatment. Dosage adjustments were performed when C(min) ≥10 mg/L and/or AUC₂₄ ≥400 mg/L · h. Patients were divided into two subgroups according to the absence or presence of co-treatment with rifampicin (the linezolid group and the linezolid + rifampicin group, respectively). Data on demographic characteristics, disease, microbiology and haematochemical parameters were collected and outcomes in relation to drug exposure were compared between groups., Results: A total of 45 patients were included. Dosage adjustments were needed in 40% versus 0% of patients in the linezolid group (n = 35) versus the linezolid + rifampicin group (n = 10), respectively. Patients in the linezolid group had either significantly higher C(min) [3.71 mg/L (1.43-6.38) versus 1.37 mg/L (0.67-2.55), P < 0.001] or AUC₂₄ [212.77 mg/L · h (166.67-278.42) versus 123.33 mg/L · h (97.36-187.94), P < 0.001]. Thrombocytopenia appeared in 51.4% versus 0% of cases in the linezolid group versus the linezolid + rifampicin group, respectively. In 33.3% of those patients who were experiencing thrombocytopenia, therapeutic drug monitoring (TDM)-guided dosage reductions allowed recovery from toxicity and prosecution of therapy with good outcome. A logistic regression model for thrombocytopenia estimated a probability of 50% in the presence of C(min) of 6.53 mg/L and/or of AUC₂₄ of 280.74 mg/L · h., Conclusions: Maintenance over time of C(min) between 2 and 7 mg/L and/or of AUC₂₄ between 160 and 300 mg/L · h may be helpful in improving safety outcomes while retaining appropriate efficacy in adult patients receiving prolonged linezolid treatment.

Anemia and/or thrombocytopenia are the most relevant adverse effects of linezolid treatment. We report the case of a patient under hemodialysis who developed osteomyelitis involving the amputation stump of the left limb due to a vancomycin-resistant and teicoplanin-resistant Enterococcus faecium successfully treated with linezolid for 6 months. Close monitorization of the patient probably contributed to maintenance of treatment with linezolid despite hematological alterations observed, which could be attributed to either the underlying patient's clinical condition or antimicrobial treatment.

Background: Linezolid is 100% bioavailable in oral and intravenous formulations. In a recent prospective, randomized, open-label, comparator-controlled, multicenter, phase 4 clinical trial in adults with complicated skin and soft tissue infections (cSSTIs) caused by methicillin-resistant Staphylococcus aureus (MRSA), linezolid achieved clinical and microbiologic success comparable to appropriately dosed intravenous vancomycin. Although patients were randomly assigned to receive linezolid or vancomycin, the protocol allowed patients to start therapy using oral or intravenous linezolid on the basis of investigator discretion and patient ability to tolerate oral medication., Objective: The objective of this study was to assess the efficacy and tolerability of linezolid when administered orally in adults with cSSTI caused by MRSA. In this retrospective analysis, we examined data collected from the aforementioned trial to compare outcomes in patients who received either oral linezolid or intravenous vancomycin therapy., Methods: This study analyzed outcomes in patients who received treatment for 7 to 14 days with either oral linezolid (600 mg q12h; n = 95) or intravenous vancomycin (15 mg/kg q12h, adjusted for creatinine clearance and trough concentration; n = 210). By design, these groups were not randomized. Propensity score matching on baseline variables was used to balance these groups by identifying a comparable group of patients who received vancomycin therapy and comparing them with patients who received oral linezolid therapy. Clinical and microbiologic success rates at the end of treatment and the end of the study (EOS) were then directly compared between the groups using matched-pair logistic regression. The tolerability of the 2 treatments (within this matched group) was also described., Results: Ninety-two patients with well-matched baseline characteristics were included in each treatment group. At EOS, the odds ratio for clinical success of oral linezolid therapy vs intravenous vancomycin therapy was 4.0 (95% CI, 1.3-12.0; P = 0.01), and the odds ratio for microbiologic success at EOS was 2.7 (95% CI, 1.2-5.7; P = 0.01). Overall rates of adverse events in each group were consistent with reported safety profiles for each drug., Conclusion: A favorable clinical cure rate was achieved with oral linezolid therapy when compared with intravenous vancomycin therapy in propensity score-matched patients with cSSTI proved to be caused by MRSA. ClinicalTrials.gov Identifier: NCT00087490., (Published by EM Inc USA.)

Background: We evaluated drug efficacy and safety among patients with and without vascular disease who were treated with linezolid or vancomycin for a lower-extremity complicated skin and skin structure infection (cSSSI) caused by methicillin-resistant Staphylococcus aureus (MRSA)., Methods: We pooled data from two randomized clinical trials evaluating the efficacy and safety of linezolid 600 mg intravenously (IV) or orally every 12 h and vancomycin 15 mg/kg or 1 g IV every 12 h for the treatment of cSSSI caused by culture-proved MRSA., Results: There were 477 patients for analysis. Among patients with vascular disease (linezolid n=139, vancomycin n=135), the clinical success rate was 80.4% and 66.7% (p=0.02) for patients treated with linezolid and vancomycin, respectively. Among patients without vascular disease (linezolid n=91, vancomycin n=112), the clinical success rate was 94.5% and 89.4%, respectively (p=0.24). Linezolid-treated patients had fewer IV catheter-site complications and less kidney impairment but more frequent thrombocytopenia than those who received vancomycin, regardless of the presence or absence of vascular disease., Conclusion: Linezolid is an effective treatment for patients with and without vascular disease who have a lower-extremity cSSSI caused by MRSA. The safety data were consistent with the known safety profiles of linezolid and vancomycin given for this indication.

Background: Post hoc analyses of clinical trial data suggested that linezolid may be more effective than vancomycin for treatment of methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia. This study prospectively assessed efficacy and safety of linezolid, compared with a dose-optimized vancomycin regimen, for treatment of MRSA nosocomial pneumonia., Methods: This was a prospective, double-blind, controlled, multicenter trial involving hospitalized adult patients with hospital-acquired or healthcare-associated MRSA pneumonia. Patients were randomized to receive intravenous linezolid (600 mg every 12 hours) or vancomycin (15 mg/kg every 12 hours) for 7-14 days. Vancomycin dose was adjusted on the basis of trough levels. The primary end point was clinical outcome at end of study (EOS) in evaluable per-protocol (PP) patients. Prespecified secondary end points included response in the modified intent-to-treat (mITT) population at end of treatment (EOT) and EOS and microbiologic response in the PP and mITT populations at EOT and EOS. Survival and safety were also evaluated., Results: Of 1184 patients treated, 448 (linezolid, n = 224; vancomycin, n = 224) were included in the mITT and 348 (linezolid, n = 172; vancomycin, n = 176) in the PP population. In the PP population, 95 (57.6%) of 165 linezolid-treated patients and 81 (46.6%) of 174 vancomycin-treated patients achieved clinical success at EOS (95% confidence interval for difference, 0.5%-21.6%; P = .042). All-cause 60-day mortality was similar (linezolid, 15.7%; vancomycin, 17.0%), as was incidence of adverse events. Nephrotoxicity occurred more frequently with vancomycin (18.2%; linezolid, 8.4%)., Conclusions: For the treatment of MRSA nosocomial pneumonia, clinical response at EOS in the PP population was significantly higher with linezolid than with vancomycin, although 60-day mortality was similar.

Objectives: The primary objectives were to compare the incidences of severe thrombocytopenia, critical thrombocytopenia and a relative decline in platelets from baseline (≥50% decline) between patients receiving linezolid and those receiving vancomycin. The secondary objective was to assess the relationship between vancomycin trough concentration and adverse platelet outcomes., Methods: A matched cohort study was performed at the Upstate New York Veterans' Affairs Healthcare Network from January 2005 until February 2008. Eligibility criteria were: (i) receipt of linezolid or vancomycin therapy for ≥48 h; (ii) initiation of therapy as an inpatient; and (iii) baseline platelets available for evaluation. Patients who received linezolid were matched 1:1 to patients who received vancomycin. Cumulative incidences and times to event for (i) platelet count ≤50,000 cells/mm(3), (ii) platelet count ≤20,000 cells/mm(3) and (iii) ≥50% decline in platelets from baseline were evaluated. Multivariate analyses were performed., Results: The study included 502 patients (251 matched pairs). The occurrences of platelet counts ≤50,000 cells/mm(3) and ≤20,000 cells/mm(3) did not differ significantly between linezolid and vancomycin patients. A ≥50% decline in platelets from baseline was observed in 78 (31.1%) patients receiving vancomycin and 43 (17.1%) patients receiving linezolid (risk ratio 0.55; 95% CI 0.40-0.77). A clear exposure-response relationship was observed between vancomycin trough concentration and ≥50% decline in platelets from baseline., Conclusions: The incidence of thrombocytopenia was low and did not differ significantly among vancomycin and linezolid patients.

The ability of viridans group streptococci to bind human plasminogen and its subsequent activation into plasmin may contribute to the pathogenesis of infective endocarditis (IE) by leading to a decreased stability of the streptococcal vegetation and facilitating dehiscence of emboli. At levels greater than or equal to their MICs, penicillin, vancomycin, and linezolid are efficacious in the treatment of streptococcal endocarditis. However, at sub-MICs, antibiotics can modulate the expression of bacterial genes, including virulence-associated genes, which can have counterproductive effects on the treatment of endocarditis. The effects of 1/8× and 1/4× MICs of penicillin, vancomycin, and linezolid on the plasminogen binding ability of IE isolates Streptococcus mitis 881/956, Streptococcus oralis 12601, and Streptococcus sanguinis 12403 were assessed phenotypically and the expression of plasminogen receptors α-enolase and glyceraldehyde 3-phosphate dehydrogenase of S. oralis 12601 when exposed to 1/4× MIC of penicillin, was analyzed through quantitative reverse transcription (qRT)-PCR. The plasminogen binding ability of S. mitis 881/956 and S. sanguinis 12403 remained unaffected by exposure to sub-MICs of all of the antibiotics tested, while that of S. oralis 12601 was significantly enhanced by all of the antibiotics tested at sub-MICs. qRT-PCR analysis of S. oralis 12601 demonstrated an upregulation of the eno and gapdh genes, indicating an overexpression of plasminogen receptors. These findings suggest that for some endocarditis isolates, the effect of antibiotic sub-MICs, in addition to a reduced antibacterial effect, may influence the clinical response to nonsurgical therapy. It remains difficult to accurately predict isolate responses to sub-MIC antimicrobials since there appears to be interspecies variation.

Bacterial infections, particularly those due to gram-positive bacteria, continue to predominate in patients with cancer. Coagulase-negative and coagulase-positive staphylococci and enterococci remain as common pathogenic microorganisms. Clostridium difficile has emerged as a significant pathogen. Major clinical syndromes include vascular catheter-related infection, febrile neutropenia, diarrhea and colitis. Rising antimicrobial resistance among gram-positive bacteria is of serious concern. The clinical utility of penicillin against streptococci and vancomycin against coagulase-negative and coagulase-positive staphylococci and enterococci may be rapidly diminishing. Liberal empiric use of vancomycin during neutropenic fever needs careful reconsideration. Newer promising anti-gram-positive bacterial drugs with activity against methicillin-resistant staphylococci include daptomycin, linezolid, tigecycline and telavancin. However, toxicity concerns, limited data in immunocompromised populations and high cost prevent the widespread use of these drugs among patients with cancer.

Objective: Linezolid represents an important advance in the treatment of methicillinresistant staphylococci. Its effectiveness should be preserved by appropriate uses. The aims of this survey were to describe the use of linezolid in clinical practice and to assess its overall safety., Methods: This retrospective observational study included patients treated with linezolid in 2008 in all departments at the CHU Nantes. A data-collection card was completed using the patients' medical files., Results: A total of 179 patients from 23 different departments were included. Fifty-four per cent of indications were outside the Marketing Authorization criteria, and were mainly osteoarticular infections and septicaemia (22% and 8% of total prescriptions, respectively). Inefficacy of first-line antibiotic treatment (23%) and alterations in renal function (23%) were the main reasons for using linezolid, which was prescribed as a first-line therapy in 28% of patients. Fifty-three per cent of infections were documented microbiologically, of which 58% were due to a methicillin-resistant Staphylococcus., Conclusions: Linezolid seems to be a possible therapeutic strategy in case of multiresistant bacteria and/or complex clinical situations. Because many prescriptions fall outside the Marketing Authorization criteria, this study highlights the need to have clinical data available for such situations.

Due to their prokaryotic origins, mitochondria are susceptible to a number of antibiotics that target the bacterial ribosome, and this vulnerability is exacerbated by certain mutations of the mitochondrial genome. MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) syndrome is characterised by biochemical and structural abnormalities of the muscle mitochondria, in which episodes of lactic acidosis stem from dysfunction of assembled respiratory complex I. Linezolid is an oxazolidinone antibiotic that has been reported to induce lactic acidosis, especially after prolonged administration, through inhibition of the mitochondrially synthesised components of oxidative phosphorylation. We report a patient with longstanding MELAS who suffered a severe lactic acidosis of rapid onset, with associated features of mitochondrial failure, shortly after the commencement of linezolid therapy and in the context of an otherwise improving clinical picture. This case emphasises the importance of circumspection when utilising drugs known to be toxic to the mitochondrion in patients with mitochondrial disease. In particular, given the biochemically plausible interaction, it would seem prudent to avoid the use of linezolid in patients with MELAS whenever possible., (Copyright © 2011 Elsevier B.V. and Mitochondria Research Society. All rights reserved. All rights reserved.)

Background: Linezolid is frequently used in critically ill patients with ventilator-associated pneumonia. Its potent activity against Gram-positive microorganisms and its high tissue penetration may favour Gram-negative colonization and infection. The aim of our study was to evaluate the risk for Gram-negative infections in critically ill patients treated with linezolid or vancomycin., Methods: The cases of all patients admitted over an 18-month period to a hepatic intensive care unit for ≥ 1 week, and treated with linezolid or vancomycin, were retrospectively reviewed. The main clinical characteristics and infections due to Gram-negative bacteria in the month after starting linezolid or vancomycin were obtained., Results: Seventy-one patients treated with linezolid and 68 treated with vancomycin fulfilled the inclusion criteria. Co-morbidities were similar in both groups. Patients on linezolid treatment had a longer stay in the ICU (mean ± standard deviation 41 ± 38 days vs 18.4 ± 13 days), received this treatment later (14.3 ± 15.1 days vs 6.3 ± 6.5 days), had a higher mean serum creatinine concentration (1.71 ± 1.18 mg/dl vs 1.04 ± 1.04 mg/dl), more often required haemodiafiltration (29.6% vs 13.2%), and 30 day-mortality was higher (42.3% vs 20.6%) than in patients receiving vancomycin. More than 95% in both groups received a broad-spectrum beta-lactam in addition to linezolid or vancomycin. The rate of Gram-negative infection during the following month was 28.2% in the linezolid group and 26.5% in the vancomycin group (p > 0.5)., Conclusions: Linezolid was more frequently used in critically ill patients with longer ICU stay and renal failure. The rate of infection due to Gram-negative microorganisms was similar in patients who received linezolid or vancomycin.

Background: Linezolid is a bacteriostatic antibiotic with good cerebrospinal fluid penetration. The aim of this study was to evaluate the efficacy of linezolid in methicillin-resistant staphylococcal (methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant coagulase-negative Staphylococcus (MRCoNS)) meningitis., Methods: We extracted data and outcomes for all adult patients (age > 18 y) with culture-proven MRSA or MRCoNS meningitis treated with linezolid between January 2006 and September 2010 in our hospital. Demographic, clinical, and laboratory data and predisposing factors, as well as information on response to treatment and outcome were obtained by regular visits., Results: A total of 17 cases (9 MRCoNS, 7 MRSA, and 1 MRCoNS and MRSA mixed) fulfilled the inclusion criteria. All patients had hospital-acquired meningitis and had undergone neurosurgery. Cumulative microbiological success on day 5 was 88%. There was 1 staphylococcal meningitis-related death. There were no severe adverse events., Conclusions: Our experience with linezolid suggests that it can be an alternative for the treatment of MRCoNS- and MRSA-related meningitis.

Linezolid administration has been associated with lactic acidosis in adults; however, the same phenomenon has not been reported in children. Mitochondrial protein synthesis inhibition is a demonstrated mechanism for toxicity, which therefore may manifest as lactic acidosis. Three cases of linezolid-associated lactic acidosis in children are reported to reinforce the need for pediatric caregivers to be vigilant of this potential side effect.

Fusidic acid (CEM-102), an orally bioavailable fusidane antibiotic with a unique mode of action, is under development for treatment of acute gram-positive bacterial skin and skin structure infections, including those caused by methicillin-susceptible and methicillin-resistant Staphylococcus aureus and streptococci. A phase 2, adaptive design, randomized, double-blind, multiple-center study of 198 adult patients with cellulitis or wound infections was conducted to evaluate an oral CEM-102 loading-dose regimen (1500 mg twice per day on day 1 followed by 600 mg twice per day) compared with oral linezolid (600 mg twice per day) administered for 10-14 days. The CEM-102 loading-dose regimen demonstrated efficacy, safety, and tolerability that was comparable to linezolid for the treatment of acute gram-positive bacterial skin and skin structure infections. Clinical Trials registration. NCT00948142.

The worldwide spread of multidrug-resistant organisms has required the development of new antimicrobials. Linezolid, the first oxazolidinone, has a broad spectrum of activity against Gram-positive bacteria, including resistant strains. Although approved by the Food and Drug Administration in 2002, the clinical experience with linezolid in the paediatric population is still limited, also given the fact that in most European countries the paediatric use of linezolid is off-label. In this paper we summarize the actual evidence on both licensed and off-label clinical uses of linezolid in children, including efficacy, safety and tolerability issues. Taking into account the potential bias in comparing heterogeneous clinical trials and reports, the available literature data suggest that linezolid is a safe and effective agent for the treatment of serious Gram-positive bacterial infections in neonates and children. At present, linezolid is reserved for those children who are intolerant to or fail conventional agents. A linezolid-containing regimen can be a valuable option for treating multidrug-resistant and extensively drug-resistant tuberculosis in children as well as disseminated non-tuberculous mycobacterial infections. Given the rare occurrence of serious side effects, careful monitoring of haematological parameters, possible drug interactions and neurological manifestations is recommended in linezolid-treated children, especially in case of prolonged treatments. Appropriate linezolid dosage and hospital infection control measures are essential to avoid the spread of linezolid resistance. Further studies are needed to establish novel paediatric indications for linezolid use and to assess the tolerability of long-term treatments.

The aim of this study was to assess the impact of vancomycin (VAN) versus linezolid (LZD) on renal function in patients with renal failure (RF) admitted to intensive care units. This was a multicenter, retrospective, comparative cohort study. Renal failure patients were treated with VAN or LZD for proven or suspected infections by multiresistant Gram-positive cocci. Changes in plasma creatinine levels and creatinine clearance at the start and end of treatment were used as endpoints. A total of 147 patients were treated with VAN (group A, n = 68) or LZD (group B, n = 79). Group B included more patients with diabetes mellitus [9 (13.2%) vs. 25 (31.6%); p = 0.007], septic shock [39 (57.4%) vs. 60 (75.9%); p = 0.013] and greater RF (mean ClCr 42.24 ml/min vs. 37.57 ml/min; p = 0.04). Renal function improved in patients from both groups who did not require renal replacement therapy. A greater improvement was seen in group B [percent decrease in Cr (27.94 vs. 9.48; p = 0.02) and percent increase in ClCr (95.96 vs. 55.06; p = 0.05)]. In group A, nine patients (13.2%) experienced an antibiotic-related increase in RF, and antibiotic was discontinued in five patients due to adverse effects. It is reasonable to avoid use of VAN in critically ill patients with acute renal failure.

Linezolid has been in general use in the UK since 2000. Although toxicity, particularly haematological and neurological, has been an issue, linezolid has proved to be an effective alternative to glycopeptides in the treatment of Gram-positive infections. Since its original licence for the treatment of skin and soft tissue infections and pneumonia, there have been reports of its successful use in the treatment of bone and joint infections, endocarditis, and other difficult-to-treat infections.