Linezolid: The First Oxazolidinone Antimicrobial

Moellering, Robert C.

doi:10.7326/0003-4819-138-2-200301210-00015

Cited by 441 publications

(291 citation statements)

References 22 publications

Supporting

Mentioning

270

Contrasting

Unclassified

Order By: Relevance

“…Gram negatif bakterilerin endojen efluks pompasına sahip olmaları nedeniyle linezolid bu bakterilere etkisizdir (21) . Linezolid, etki mekanizması yönünden diğer protein sentez inhibitörlerin-den farklıdır; ribozomlarda 50S alt birimine bağlanarak, 70S başlangıç kompleksinin oluş-masını önler (16) . Bu nedenle linezolide in-vitro direnç gelişimi güçtür.…”

Section: Discussionunclassified

Identification and Antibiotic Resistance Rates of Coagulase-Negative Staphylococci Isolated from Blood Cultures

Çiftçi¹,

Türk‐Dağı²,

Demircan³

et al. 2016

Ankem Derg

View full text Add to dashboard Cite

show abstract

Section: Discussionunclassified

Identification and Antibiotic Resistance Rates of Coagulase-Negative Staphylococci Isolated from Blood Cultures

Çiftçi¹,

Türk‐Dağı²,

Demircan³

et al. 2016

Ankem Derg

View full text Add to dashboard Cite

show abstract

“…1D). AUC 12 values from the covariate population pharmacokinetic model (at linezolid treatment days 1 and 4) were computed to explore the influence of covariates identified in the population pharmacokinetic analysis (Fig. 1E).…”

Section: Methodsmentioning

confidence: 99%

“…Reactive oxygen species are assumed to play an important role in this pathway (11). About 30% of linezolid is eliminated unchanged by the kidney (12).…”

mentioning

confidence: 99%

Predictors of Inadequate Linezolid Concentrations after Standard Dosing in Critically Ill Patients

Taubert

Zöller

Maier

et al. 2016

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Adequate linezolid blood concentrations have been shown to be associated with an improved clinical outcome. Our goal was to assess new predictors of inadequate linezolid concentrations often observed in critically ill patients. Fifty-two critically ill patients with severe infections receiving standard dosing of linezolid participated in this prospective observational study. Serum samples (median, 32 per patient) were taken on four consecutive days, and total linezolid concentrations were quantified. Covariates influencing linezolid pharmacokinetics were identified by multivariate analysis and a population pharmacokinetic model. Target attainment (area under the concentration-time curve over 12 h [AUC 12 ]/MIC ratio of >50; MIC ‫؍‬ 2 mg/liter) was calculated for both the study patients and a simulated independent patient group (n ‫؍‬ 67,000). Target attainment was observed for only 36% of the population on both days 1 and 4. Independent covariates related to significant decreases of linezolid concentrations included higher weight, creatinine clearance rates, and fibrinogen and antithrombin concentrations, lower concentrations of lactate, and the presence of acute respiratory distress syndrome (ARDS). Linezolid clearance was increased in ARDS patients (by 82%) and in patients with elevated fibrinogen or decreased lactate concentrations. In simulated patients, most covariates, including fibrinogen and lactate concentrations and weight, showed quantitatively minor effects on target attainment (difference of <9% between the first and fourth quartiles of the respective parameters). In contrast, the presence of ARDS had the strongest influence, with only <6% of simulated patients reaching this target. In conclusion, the presence of ARDS was identified as a new and strong predictor of insufficient linezolid concentrations, which might cause treatment failure. Insufficient concentrations might also be a major problem in patients with combined alterations of other covariate parameters. (This study has been registered at ClinicalTrials.gov under registration number NCT01793012.)

show abstract

“…This drug has shown excellent efficacy for the treatment of respiratory tract and skin infections caused by Gram-positive pathogens and is effective against pathogens resistant to other drugs, including methicillin-resistant Staphylococcus aureus, Nocardia spp., and multidrugresistant Mycobacterium tuberculosis (2). Linezolid has 100% oral bioavailability and reaches high concentrations in most tissues, making it a good alternative for the long-term treatment of infections related to foreign bodies.…”

mentioning

confidence: 99%

Influence of Mitochondrial Genetics on the Mitochondrial Toxicity of Linezolid in Blood Cells and Skin Nerve Fibers

Garrabou

Soriano

Pinós

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The antibiotic linezolid is a ribosomal inhibitor with excellent efficacy. Although the administration period has been reduced to 28 days, side effects, usually of hematologic or neuropathic origin, are still reported due to secondary inhibition of mitochondrial protein synthesis. Susceptibility to linezolid toxicity remains unknown. Therefore, the objective of this study was to gain an understanding of clinical heterogeneity in response to identical linezolid exposures through exhaustive examination of the molecular basis of tissue-dependent mitotoxicity, consequent cell dysfunction, and the association of mitochondrial genetics with adverse effects of linezolid administered for the recommended period. Peripheral blood mononuclear cells (PBMC) and skin nerve fibers from 19 and 6 patients, respectively, were evaluated before and after a 28-day linezolid treatment in order to assess toxic effects on mitochondria and cells. Mitochondrial DNA haplotypes and single nucleotide polymorphisms (SNPs) in ribosomal sequences where linezolid binds to mitochondrial ribosomes were also analyzed to investigate their genetic contributions. We found that linezolid reduced mitochondrial protein levels, complex IV activity, and mitochondrial mass in PBMC and was associated with a trend toward an increase in the rate of apoptosis. In skin tissue, mitochondrial mass increased within nerve fibers, accompanied by subclinical axonal swelling. Mitochondrial haplogroup U, mutations in 12S rRNA, and the m.2706A¡G, m.3197T¡C, and m.3010G¡A polymorphisms in 16S rRNA showed a trend toward an association with increased mitochondrial and clinical adverse effects. We conclude that even when linezolid is administered for a shorter time than formerly, adverse effects are reported by 63% of patients. Linezolid exerts tissue-dependent mitotoxicity that is responsible for downstream cellular consequences (blood cell death and nerve fiber swelling), leading to adverse hematologic and peripheral nervous side effects. Multicentric studies should confirm genetic susceptibility in larger cohorts.

show abstract

Linezolid: The First Oxazolidinone Antimicrobial

Cited by 441 publications

References 22 publications

Identification and Antibiotic Resistance Rates of Coagulase-Negative Staphylococci Isolated from Blood Cultures

Identification and Antibiotic Resistance Rates of Coagulase-Negative Staphylococci Isolated from Blood Cultures

Predictors of Inadequate Linezolid Concentrations after Standard Dosing in Critically Ill Patients

Influence of Mitochondrial Genetics on the Mitochondrial Toxicity of Linezolid in Blood Cells and Skin Nerve Fibers

Contact Info

Product

Resources

About