Linezolid resistance in clinical isolates of Staphylococcus aureus

Wilson, Peter; Andrews, J.; Charlesworth, R.; Walesby, R; Singer, Mervyn; Farrell, David J.; Robbins, M J

doi:10.1093/jac/dkg104

Cited by 267 publications

(154 citation statements)

References 3 publications

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“…The MICs for all of our isolates were 32 g/ml, which is not as high as that reported by Potoski et al (MIC Ͼ 256 g/ml) (8). We believe that there might be a correlation between the number of genes carrying the G2576T mutation and the MIC of linezolid for S. epidermidis, as has been described for enterococci (5) and S. aureus (11). It would be interesting to determine whether most or all of the 23S rRNA genes in isolates with much higher linezolid MICs (Ͼ256 g/ml) carry the mutation.…”

Section: Discussionmentioning

confidence: 85%

Sequential Linezolid-Resistant Staphylococcus epidermidis Isolates with G2576T Mutation

Hong

Wang

et al. 2007

J Clin Microbiol

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We report on an analysis of sequential isolates of Staphylococcus epidermidis from cultures of blood obtained from a patient with acute myeloid leukemia while the patient was receiving linezolid treatment. All 12 isolates had a linezolid MIC of 32 g/ml. A 420-bp domain V region of the 23S rRNA gene from all isolates was amplified, and their nucleotide sequences were determined. A G2576T mutation was identified in all isolates. It was estimated that 67% of the 23S rRNA genes carried this mutation. This is the first report of the failure of linezolid treatment for Staphylococcus epidermidis bacteremia associated with a G2576T mutation in an immunocompromised patient.

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Section: Discussionmentioning

confidence: 85%

Sequential Linezolid-Resistant Staphylococcus epidermidis Isolates with G2576T Mutation

Hong

Wang

et al. 2007

J Clin Microbiol

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“…In the isolate NRS119, which had the highest MIC against linezolid, the sequence of the SAV1444 gene revealed a 39-bp deletion in the SAM-methylation domain (Table 4). No mutations were observed Tsiodras et al (2001) and Wilson et al (2003).…”

Section: Mutations In a Chromosomally Encoded Rna Methylase And Clinimentioning

confidence: 84%

Genome sequencing of linezolid-resistant Streptococcus pneumoniae mutants reveals novel mechanisms of resistance

Feng¹,

Lupien²,

Gingras³

et al. 2009

Genome Res.

103

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Linezolid is a member of a novel class of antibiotics, with resistance already being reported. We used whole-genome sequencing on three independent Streptococcus pneumoniae strains made resistant to linezolid in vitro in a step-by-step fashion. Analysis of the genome assemblies revealed mutations in the 23S rRNA gene in all mutants including, notably, G2576T, a previously recognized resistance mutation. Mutations in an additional 31 genes were also found in at least one of the three sequenced genomes. We concentrated on three new mutations that were found in at least two independent mutants. All three mutations were experimentally confirmed to be involved in antibiotic resistance. Mutations upstream of the ABC transporter genes spr1021 and spr1887 were correlated with increased expression of these genes and neighboring genes of the same operon. Gene inactivation supported a role for these ABC transporters in resistance to linezolid and other antibiotics. The hypothetical protein spr0333 contains an RNA methyltransferase domain, and mutations within that domain were found in all S. pneumoniae linezolid-resistant strains. Primer extension experiments indicated that spr0333 methylates G2445 of the 23S rRNA and mutations in spr0333 abolished this methylation. Reintroduction of a nonmutated version of spr0333 in resistant bacteria reestablished G2445 methylation and led to cells being more sensitive to linezolid and other antibiotics. Interestingly, the spr0333 ortholog was also mutated in a linezolid-resistant clinical Staphylococcus aureus isolate. Whole-genome sequencing and comparative analyses of S. pneumoniae resistant isolates was useful for discovering novel resistance mutations.

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“…Linezolid has a low molecular weight (337 Da), only 31% protein binding, and a distribution volume ranging from 0.5 to 0.8 L/kg, which approximates that of total body water. It is therefore likely that an important fraction of linezolid is removed during renal replacement therapy, potentially resulting in plasma concentrations below therapeutic concentrations, thereby promoting resistance and limiting linezolid effectiveness in severe infections caused by multiresistant Gram-positive bacteria [8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of linezolid in septic patients with and without extended dialysis

Swoboda

Ober

Lichtenstern

et al. 2009

Eur J Clin Pharmacol

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Purpose Linezolid is an option for the treatment of infections caused by multiresistant Gram-positive bacteria. The survival of critically ill patients with acute renal failure (ARF) can be improved by increasing the dose of renal replacement therapy. Extended (daily) dialysis (ED) is a new and important approach to renal replacement therapy in intensive care units. The aim of the study was to evaluate the pharmacokinetics of linezolid in septic patients without ED and on ED, respectively. Methods We studied the pharmacokinetics of linezolid in adult intensive care patients with sepsis (n=5) and anuric septic patients with ARF being treated with ED (n=10). Linezolid 600 mg was administered intravenously twice daily. The pharmacokinetic parameters, their variability, and possible covariates were analyzed using NONMEM. , and peripheral volume of distribution (V 2 )=0.271 L/kg. The clearance in ED patients while on dialysis was increased by 3.5 L/h, and patients with liver transplantation/resection had their clearance reduced by 60%. Intra-individual variability was much smaller than inter-individual variability. Conclusions Our results suggest that linezolid pharmacokinetics in critically ill patients with ARF undergoing ED is not comparable to that in healthy subjects and patients without ARF. The best method of managing linezolid dosage in such a complex group of patients, whose physiology can vary daily, would be to use therapeutic drug monitoring.

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Linezolid resistance in clinical isolates of Staphylococcus aureus

Cited by 267 publications

References 3 publications

Sequential Linezolid-Resistant Staphylococcus epidermidis Isolates with G2576T Mutation

Sequential Linezolid-Resistant Staphylococcus epidermidis Isolates with G2576T Mutation

Genome sequencing of linezolid-resistant Streptococcus pneumoniae mutants reveals novel mechanisms of resistance

Pharmacokinetics of linezolid in septic patients with and without extended dialysis

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