In vitro activity of eravacycline and mechanisms of resistance in enterococci

Abstract

Eravacycline (ERC), the first fluorocycline, is a new tetracycline with superior activity to tigecycline (TGC) against many bacterial species. This work aimed to determine the in vitro activity of ERC compared with other tetracyclines against enterococcal clinical isolates and to analyse corresponding resistance mechanisms. A collection of 60 enterococcal strains was studied: 54 epidemiologically unrelated clinical isolates (46 Enterococcus faecium and 8 Enterococcus faecalis) including 42 vancomycin-resistant enterococci (VRE) (33 vanA and 9 vanB), 3 in vitro TGC-resistant mutants (E. faecium AusTig, HMtig1 and HMtig2) and 3 reference wild-type strains (E. faecium Aus0004 and HM1070, E. faecalis ATCC 29212). In vitro susceptibility was determined using Etest strips (for ERC) or by broth microdilution (for TGC, doxycycline, minocycline and tetracycline). Resistance genes [tet(M), tet(L), tet(O) and tet(S)] were screened by PCR for TGC- and/or ERC-resistant strains as well as sequencing of the rpsJ gene (encoding ribosomal protein S10). MIC50/90 values were 0.016/0.08, ≤0.03/0.5, 4/32, 8/16 and 32/>32 mg/L for ERC, TGC, doxycycline, minocycline and tetracycline, respectively. According to EUCAST guidelines, nine strains were categorised as resistant to TGC (MIC, 0.5-8 mg/L), including four E. faecium vanA(+) strains also resistant to ERC (MIC, 0.19-1.5 mg/L). These four strains all possessed at least one mutation in rpsJ and two tet determinants: tet(M)+tet(L) (n=2); and tet(M)+tet(S) (n=2). Although ERC has excellent in vitro activity against enterococci (including VRE), emergence of resistance is possible due to combined mechanisms (rpsJ mutations+tet genes).