Known mechanisms cannot account for a third of reduced susceptibility in non-aureus staphylococci.

Non-aureus staphylococci (NAS) are implicated in many healthcare-acquired infections and an understanding of the genetics of antimicrobial resistance is important in relation to both clinical intervention and the role of NAS as a reservoir of resistance genes. Gap statement: The burden of antimicrobial resistance in NAS, particularly to clinically relevant antimicrobials, is under-recognised. We sourced 394 NAS isolates from clinical samples, healthy human volunteers, animals and type cultures and subjected them to minimum inhibitory concentration (MIC) testing by agar dilution using eight antimicrobials. Cefoxitin was used to screen for methicillin resistance, as it stimulates the expression of mecA in S. aureus. We performed whole genome sequencing on 366 isolates and analysed these genotypically for the presence of genetic mechanisms responsible for the phenotypic levels of reduced antimicrobial susceptibility. We observed 175 sequenced isolates with a MIC ≥ 4 µg/ml to cefoxitin, of which 50% did not harbour a known mec homologue. Eight clinical NAS isolates displayed high daptomycin MICs (>4 µg/ml), with no known mechanism identified. Differences in MICs against erythromycin were attributable to the presence of different resistance genes (msrA and ermC). In total, 49% of isolates displayed reduced susceptibility to three or more of the antimicrobials tested. The widespread presence of reduced antimicrobial susceptibility in NAS is concerning. An increased likelihood of harder-to-treat infections caused directly by NAS with acquired resistance genes has clinical implications for AMR detection, the horizontal resistance gene pool and the management of patients.