Genomic and Phenotypic Analysis of Linezolid-Resistant Staphylococcus epidermidis in a Tertiary Hospital in Innsbruck, Austria

Abstract

Whole genome sequencing is a useful tool to monitor the spread of resistance mechanisms in bacteria. In this retrospective study, we investigated genetic resistance mechanisms, sequence types (ST) and respective phenotypes of linezolid-resistant Staphylococcus epidermidis (LRSE, n = 129) recovered from a cohort of patients receiving or not receiving linezolid within a tertiary hospital in Innsbruck, Austria. Hereby, the point mutation G2603U in the 23S rRNA (n = 91) was the major resistance mechanism followed by the presence of plasmid-derived cfr (n = 30). The majority of LRSE isolates were ST2 strains, followed by ST5. LRSE isolates expressed a high resistance level to linezolid with a minimal inhibitory concentration of ≥256 mg/L (n = 83) in most isolates, particularly in strains carrying the cfr gene (p < 0.001). Linezolid usage was the most prominent (but not the only) trigger for the development of linezolid resistance. However, administration of linezolid was not associated with a specific resistance mechanism. Restriction of linezolid usage and the monitoring of plasmid-derived cfr in LRSE are potential key steps to reduce linezolid resistance and its transmission to more pathogenic Gram-positive bacteria.

Multiple mechanisms of linezolid resistance in Staphylococcus haemolyticus detected by whole-genome sequencing

“…The presence of the cfr gene, which encodes 23S rRNA methylases A2503, plays a crucial role in the development of PhLOPS A phenotype. Many published reports stated that cfr gene-carrying isolates showed higher phenotypic resistance levels compared to cfr -negative isolates [6, 22, 31, 32]. In the present study, all of the cfr -carrying isolates exhibited the PhLOPS A phenotype, including phenotypically susceptible isolates that carried cfr gene, which confers resistance to phenicols, lincosamides, oxazolidinones, pleuromutilins and streptogramin A antibiotics.…”

“…Linezolid is not suitable for treating infections caused by Gram-negative organisms that are intrinsically resistant due to efflux pumps that export linezolid out of the cell quicker than it can accumulate. Both Zyvox Annual Appraisal of Potency and Spectrum (ZAAPS) and Linezolid Experience and Accurate Determination of Resistance (LEADER) surveillance programmes have found that Gram-positive organisms have a susceptibility rate of >99 % to linezolid [22]. However, case reports of acquired LR in clinical staphylococcal isolates with various resistance mechanisms were published immediately after the introduction of linezolid in clinical practice.…”

Molecular mechanisms of antibiotic resistance revisited

“…Altered target sites can be generated by random point mutations that accumulate during growth and can expand to dominance under drug pressure. Alternatively, mutant alleles of target genes can be generated at high frequency by recombination between alleles if multiple copies exist within the cell (for example, mutation and recombination between homologues of the 23S ribosomal RNA (rRNA) gene can rapidly confer linezolid resistance in Gram-positive species 78 ) or by transformation, whereby alternative alleles can be gained from related species and mosaic genes are generated by recombination, an approach common in competent species such as members of the Neisseria genus 79 .…”

Clinical, Bacteriological, and Genetic Characterization of Bone and Joint Infections Involving Linezolid-Resistant Staphylococcus epidermidis: a Retrospective Multicenter Study in French Reference Centers

“…Linezolid-resistant phenotype is most often associated with multidrug resistance, directly related to the mechanism involved, or to the combination with other resistance mechanisms ( 13 ). It may be subject to clonal epidemic dissemination as already described in several hospital departments, including French ones ( 14 – 19 ).…”