Linezolid Resistance in Staphylococci

Abstract

Linezolid, the first oxazolidinone to be used clinically, is effective in the treatment of infections caused by various Gram-positive pathogens, including multidrug resistant enterococci and methicillin-resistant Staphylococus aureus. It has been used successfully for the treatment of patients with endocarditis and bacteraemia, osteomyelitis, joint infections and tuberculosis and it is often used for treatment of complicated infections when other therapies have failed.Linezolid resistance in Gram-positive cocci has been encountered clinically as well as in vitro, but it is still a rare phenomenon. The resistance to this antibiotic has been, until now, entirely associated with distinct nucleotide substitutions in domain V of the 23S rRNA genes. The number of mutated rRNA genes depends on the dose and duration of linezolid exposure and has been shown to influence the level of linezolid resistance. Mutations in associated ribosomal proteins also affect linezolid activity. A new phenicol and clindamycin resistance phenotype has recently been found to be caused by an RNA methyltransferase designated Cfr. This gene confers resistance to lincosamides, oxazolidinones, streptogramin A, phenicols and pleuromutilins, decrease the susceptibility of S. aureus to tylosin, to josamycin and spiramycin and thus differs from erm rRNA methylase genes. Research into new oxazolidinones with improved characteristics is ongoing. Data reported in patent applications demonstrated that some oxazolidinone derivatives, also with improved characteristics with respect to linezolid, are presently under study: at least three of them are in an advanced phase of development.

Assessment of the Risk to Public Health due to Use of Antimicrobials in Pigs—An Example of Pleuromutilins in Denmark

“…They confer resistance to phenicols and the newest generation of oxazolidinones including linezolid (35–38). optrA genes do not confer resistance to pleuromutilines but might be carried together with cfr genes on the same plasmid (37).…”

Susceptibility Testing and Reporting of New Antibiotics with a Focus on Tedizolid: An International Working Group Report

“…This methylase enzyme confers resistance against five structurally different antibiotic classes (e.g., clindamycin in the lincosamide class, chloramphenicol in the phenicol class, and linezolid, but not tedizolid, in the oxazolidinone class) [58]. The encoded enzyme methylates the A2053 nucleotide in the peptidyl-transferase center of the 23S ribosomal RNA, which is a very highly conserved site, and this methylation prevents binding of antibiotics to peptidyl-transferase center [60]. Importantly, chromosomal mutations in Domain V of rRNA or ribosomal L3 protein identified to date were demonstrated to confer resistance to both linezolid and tedizolid, stressing the need to test tedizolid susceptibility [59,61].…”

Synthesis and <i>in Vitro</i> Evaluation of the Antitubercular and Antibacterial Activity of Novel Oxazolidinones Bearing Octahydrocyclopenta[<i>c</i>]pyrrol-2-yl Moieties

“…[10][11][12] Resistance to linezolid occurs mainly through point mutations in the 23S ribosomal RNA subunit and related proteins or through cfrmediated methylation of 23S rRNA. [13][14][15] Moreover, extended use of linezolid has some safety concerns such as myelosuppression, monoamine oxidase inhibition and mitochondrial toxicity. 16,17) Thus, there is considerable unmet medical demand for newer oxazolidinone antibacterials with improved potency, spectrum, activity against resistant strains, and good safety profiles.…”