Surotomycin Demonstrates Low In Vitro Frequency of Resistance and Rapid Bactericidal Activity in Clostridium difficile, Enterococcus faecalis, and Enterococcus faecium

Surotomycin (CB-183,315) is an orally administered, minimally absorbed, selective bactericidal cyclic lipopeptide in phase 3 development for the treatment of C. difficile -associated diarrhea. The aim of this study was to evaluate the emergence of resistance in C. difficile (ATCC 700057 and three recent clinical isolates from the restriction endonuclease analysis groups BI, BK and K), vancomycin-susceptible (VS) E. faecalis (ATCC 49452), vancomycin-resistant (VR) E. faecalis (ATCC 700802), VS E. faecium (ATCC 6569), and VR E. faecium (ATCC 51559), under anaerobic conditions. The rate of spontaneous resistance was below the limit of detection ( -8 to -9 ) for surotomycin at 16 and 32X the MIC for all isolates tested. Under selective pressure by serial passage, C. difficile grew in a maximum of 4 μg/mL surotomycin (final MICs 2 to 8 μg/mL; 4- to 16-fold higher than naive) at day 15, with the exception of the C. difficile BK strain, which grew in 16 to 32 μg/mL (final MICs 8 to 32 μg/mL; 16- to 64-fold higher than naive). Enterococci remained relatively unchanged over 15 days, growing in a maximum of 8 μg/mL surotomycin (final MICs 2 to 16 μg/mL; 8- to 64-fold higher than naive). Of the isolates tested, no cross resistance to vancomycin, rifampicin, ampicillin, metronidazole or moxifloxacin was observed. Surotomycin at 20X MIC demonstrated equally rapid bactericidal activity (≥3-log reduction in CFU/mL in ≤8 h) against naive and reduced susceptibility isolates of C. difficile , VSE and VRE, except for C. difficile BK (2.6-log reductions for both). These results suggest that emergence of resistance to surotomycin against C. difficile , E. faecalis and E. faecium is likely to be rare.