Emergence of linezolid-resistant coagulase-negative Staphylococcus in a cancer centre linked to increased linezolid utilization

Mulanovich, Victor E.; Huband, Michael D.; McCurdy, Sandra P.; Lemmon, M. Megan; Lescoe, Mary Kay; Jiang, Ying; Rolston, Kenneth V. I.; LaSala, P. Rocco

doi:10.1093/jac/dkq238

Cited by 43 publications

(21 citation statements)

References 10 publications

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“…Mutations in 23S rRNA implicated in linezolid resistance include not only bases near the binding site, like G2061, C2452, A2503, U2504, and G2505, but also bases that are located more distantly from the binding site, such as A2062, G2447, A2453, C2499, U2500, and G2576 (reviewed in reference 8). Additional mechanisms include acquisition of the cfr gene, which encodes a methyltransferase which modifies A2503 in 23S rRNA, and a mutation in the RlmN gene, which naturally modifies A2503 (8)(9)(10)(11)(12)(13)(14). Recently, four nosocomial Staphylococcus epidermidis isolates belonging to the same pulsed-field gel electrophoresis type were described to exhibit partial linezolid dependence, an adaptation reported for only a few antibiotics and bacterial species in the past (15).…”

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confidence: 99%

Linezolid-Dependent Function and Structure Adaptation of Ribosomes in a Staphylococcus epidermidis Strain Exhibiting Linezolid Dependence

Kokkori¹,

Apostolidi²,

Tsakris³

et al. 2014

Antimicrob Agents Chemother

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b Linezolid-dependent growth was recently reported in Staphylococcus epidermidis clinical strains carrying mutations associated with linezolid resistance. To investigate this unexpected behavior at the molecular level, we isolated active ribosomes from one of the linezolid-dependent strains and we compared them with ribosomes isolated from a wild-type strain. Both strains were grown in the absence and presence of linezolid. Detailed biochemical and structural analyses revealed essential differences in the function and structure of isolated ribosomes which were assembled in the presence of linezolid. The catalytic activity of peptidyltransferase was found to be significantly higher in the ribosomes derived from the linezolid-dependent strain. Interestingly, the same ribosomes exhibited an abnormal ribosomal subunit dissociation profile on a sucrose gradient in the absence of linezolid, but the profile was restored after treatment of the ribosomes with an excess of the antibiotic. Our study suggests that linezolid most likely modified the ribosomal assembly procedure, leading to a new functional ribosomal population active only in the presence of linezolid. Therefore, the higher growth rate of the partially linezolid-dependent strains could be attributed to the functional and structural adaptations of ribosomes to linezolid. O xazolidinone antibiotics inhibit protein synthesis by binding to the peptidyltransferase center (PTC) of the ribosome and inhibiting the growth of bacteria (1). Although it has been suggested that they are involved in the initiation of translation, many reports have been contradictory, mainly because the ratio of drug to ribosome that was used was extremely high (2). Moreover, the inhibitory effect of oxazolidinones on peptide bond formation has not been demonstrated so far, despite structural data suggesting the binding of linezolid in the peptidyltransferase center (3-5). In contrast, linezolid perturbs translational accuracy in vivo, even at concentrations lower than the MIC (6).Linezolid (LZD) was the first FDA-approved oxazolidinone used to treat serious infections due to Gram-positive bacteria. Although LZD was completely synthetic (7), resistance readily emerged and was attributed mainly to mutations in 23S rRNA and ribosomal proteins L3 and L4. Mutations in 23S rRNA implicated in linezolid resistance include not only bases near the binding site, like G2061, C2452, A2503, U2504, and G2505, but also bases that are located more distantly from the binding site, such as A2062, G2447, A2453, C2499, U2500, and G2576 (reviewed in reference 8). Additional mechanisms include acquisition of the cfr gene, which encodes a methyltransferase which modifies A2503 in 23S rRNA, and a mutation in the RlmN gene, which naturally modifies A2503 (8-14). Recently, four nosocomial Staphylococcus epidermidis isolates belonging to the same pulsed-field gel electrophoresis type were described to exhibit partial linezolid dependence, an adaptation reported for only a few antibiotics and bacterial species in the ...

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confidence: 99%

Linezolid-Dependent Function and Structure Adaptation of Ribosomes in a Staphylococcus epidermidis Strain Exhibiting Linezolid Dependence

Kokkori¹,

Apostolidi²,

Tsakris³

et al. 2014

Antimicrob Agents Chemother

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“…Appropriate dosing schedules, reasonably limited treatment duration, and repeated in vitro testing of relevant microbiological samples are necessary in order to avoid the selection and to foster the timely detection of linezolid-resistant isolates [47,48]. The nosocomial spread of linezolid-resistant multiresistant Gram-positive pathogens is a matter of concern and highlights the critical role of stringent hospital infection control policies [49,50].…”

Section: Discussionmentioning

confidence: 99%

Use of linezolid in neonatal and pediatric inpatient facilities—results of a retrospective multicenter survey

Simon

Müllenborn

Prelog

et al. 2011

Eur J Clin Microbiol Infect Dis

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The purpose of this investigation was to describe the use of linezolid in pediatric inpatient facilities. A retrospective multicenter survey including data from nine participating tertiary care pediatric inpatient facilities in Germany and Austria was undertaken. Data on 126 off-label linezolid treatment courses administered to 108 patients were documented. The survey comprises linezolid treatment in a broad spectrum of clinical indications to children of all age groups; the median age was 6.8 years (interquartile range 0.6-15.5 years; range 0.1-21.2 years; ten patients were older than 18 years of age but were treated in pediatric inpatient units). Of the 126 treatment courses, 27 (21%) were administered to preterm infants, 64 (51%) to pediatric oncology patients, and 5% to patients soon after liver transplantation. In 25%, the infection was related to a medical device. Linezolid iv treatment was started after intensive pre-treatment (up to 11 other antibiotics for a median duration of 14 days) and changed to enteral administration in only 4% of all iv courses. In 39 (53%) of 74 courses administered to children older than 1 week and younger than 12 years of age, the dose was not adjusted to age-related pharmacokinetic parameters. In only 17 courses (13%) was a pediatric infectious disease consultant involved in the clinical decision algorithm. Linezolid seemed to have contributed to a favorable outcome in 70% of all treatment courses in this survey. Although retrospective, this survey generates interesting data on the off-label use of linezolid and highlights several important clinical aspects in which the use of this rescue antibiotic in children might be improved.

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“…Nevertheless, oxazolidinone-resistant strains have appeared worldwide particularly among enterococci and coagulase-negative staphylococci (Jones et al 2009a ;Farrell et al 2011a ;Gu et al 2013 ). In a concerning trend, increasing linezolid utilization rates and clonal spread have led to outbreaks of both linezolid-resistant enterococci and linezolid-resistant MRSA (Mulanovich et al 2010 ;Sanchez Garcia et al 2013 ).…”

Section: Resistancementioning

confidence: 99%

PK/PD of Oxazolidinones

Theuretzbacher

2013

Fundamentals of Antimicrobial Pharmacokinetics and Pharmacodynamics

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Linezolid, the fi rst available compound in the group of oxazolidinones, provides an effective alternative for the treatment of multidrug-resistant (MDR) Gram-positive bacteria. Linezolid's iv and oral availability expands its usage to the outpatient setting. In vitro, animal, and clinical studies have defi ned an appropriate PK/PD index for linezolid, its correlation with the dosage regimen, and clinical outcome. Due to linezolid's wide interpatient variability, some patients may have increased risk of inadequate drug exposure. As these patients are not readily identifi ed, therapeutic drug monitoring may be necessary for critically ill patient populations as well as in long-term treatment. As alternative antibiotics are scarce, resistance development requires special attention. The selection of linezolid resistant mutants, especially with enterococci, and the emergence of mobile resistance determinants that affect a wide range of other ribosome-targeting antibiotics, will most likely spur the emergence and spread of linezolid resistance. Increasing drug exposure in an attempt to reduce selection pressure may not be feasible due to concentration dependent toxicity. On the other hand, combination therapy may positively impact exposure/resistance relationship, but our knowledge in this area remains incomplete. Employing PK/PD models to defi ne dosing strategies and using antibiotic combinations to reduce selection pressure on linezolid-resistant mutants are major tasks yet to be undertaken.

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Emergence of linezolid-resistant coagulase-negative Staphylococcus in a cancer centre linked to increased linezolid utilization

Cited by 43 publications

References 10 publications

Linezolid-Dependent Function and Structure Adaptation of Ribosomes in a Staphylococcus epidermidis Strain Exhibiting Linezolid Dependence

Linezolid-Dependent Function and Structure Adaptation of Ribosomes in a Staphylococcus epidermidis Strain Exhibiting Linezolid Dependence

Use of linezolid in neonatal and pediatric inpatient facilities—results of a retrospective multicenter survey

PK/PD of Oxazolidinones

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