Resistance to oxazolidinones (linezolid and tedizolid) is rare (<1% of Gram-positive isolates), but is observed in enterococci and staphylococci referred to the national reference laboratory and is usually attributed to mutations (most often G2576T) within chromosomal genes encoding the 23S ribosomal RNA (rRNA), which is targeted by oxazolidinone antibiotics.
In 2012 a National Resistance Alert was issued in the UK to highlight the first identification of plasmid-mediated linezolid resistance conferred by the cfr gene in enterococci and staphylococci. More recently, transferable oxazolidinone resistance has also been described mediated by the optrA gene, which encodes an ABC transporter that confers resistance to oxazolidinones and phenicols (chloramphenicol and florfenicol) via active efflux. The optrA gene is not yet widely sought, but has been described, mostly in enterococci from both humans and animals, in China, Italy, Malaysia, the Republic of Ireland and Austria. There has been only one report of optrA in a staphylococcal isolate, which was of animal origin and from China, but optrA has been shown to be functionally active in Staphylococcus aureus. Prior to the events below optrA had not been found in the UK.
Public Health England’s Antimicrobial Resistance and Healthcare Associated Infections (AMRHAI) Reference Unit has recently detected the optrA gene, via non-structured retrospective screening, in five Enterococcus faecalis isolates referred by three laboratories. These were isolated in 2014 (n=1), 2015 (n=3) and 2016 (n=1) from five GP patients with no known history of travel abroad. optrA was also identified in a similar number of E. faecalis isolates submitted by four hospitals in the Republic of Ireland, which led to the Health Protection Surveillance Centre (in RoI) issuing its own alert. All optrA-positive isolates were resistant to linezolid (MICs >8 mg/L) and lacked the G2576T 23S rRNA mutation and cfr gene. So far no epidemiological links have been identified between these isolates, all of which were from urine samples submitted via different general practices, and all isolates exhibited susceptibility to other routinely available antimicrobials. Typing is being undertaken to assess clonality. The isolates retained susceptibility to the glycopeptides.
Consultant medical microbiologists and infection control teams should be aware of this novel form of oxazolidinone resistance, and are advised:
- for enterococci and staphylococci from sterile sites or infections where an oxazolidinone may be a viable treatment option, susceptibility to linezolid should be tested by MIC determination, disc diffusion (EUCAST) or automated methods;
- distinguishing isolates with optrA or cfr-mediated resistance from those with mutational linezolid resistance requires molecular techniques;
- all linezolid-resistant enterococci or staphylococci (with co-resistance to phenicols, where tested) should be sent to the AMRHAI Reference Unit for confirmation and reference investigation. Screening for optrA, cfr and the G2576T mutation will be performed on all isolates confirmed as linezolid-resistant by AMRHAI;
- patients yielding linezolid-resistant enterococci or staphylococci in secondary care should be isolated to prevent onwards transmission.
Scotland should be well placed to detect emerging optrA-mediated linezolid resistance due to the widespread use of the Vitek 2 automated system for antimicrobial susceptibility testing. The nationally agreed Scottish susceptibility cards include linezolid susceptibility testing for Gram-positive organisms.
As demonstrated in the HPS and ISD report on Antimicrobial Use and Resistance in Humans in 2014 (available at http://www.isdscotland.org/Health-Topics/Prescribing-and-Medicines/SAPG/AMR-Annual-Report/), linezolid resistance in enterococcal bloodstream infections in Scotland is currently a very rare event. Nonetheless, adherence to current UK-wide guidance should ensure rapid detection of any change in this situation.