Telavancin possesses low potential for resistant mutant selection in serial passage studies of Staphylococcus aureus and Enterococci
Abstract number: 1134_03_346
Krause K.M., Benton B.M., Higgins D.L., Kaniga K., Renelli M., Humphrey P.K.
Serial passage selection studies are useful for predicting the development of endogenous antibiotic resistance in the clinical setting. Telavancin (TLV) is a rapidly bactericidal lipoglycopeptide with multiple mechanisms of action against Gram-positive bacteria. Previous serial passage mutant selection experiments performed using solid media failed to generate stable TLV-resistant isolates from Staphylococcus aureus or Enterococci. In the present study we report results of multi-step selection studies performed in liquid media.
Selection for spontaneous resistance was performed by serial passage inoculation of liquid media containing a range of TLV concentrations with 106 CFU/mL of each of 7 strains of MRSA (ATCC 33591, MCJ-25, MCJ-10, KPB-08, S-1, SFVA-09, MED-121); MSSA ATCC 29213, VSE E. faecalis ATCC 29212, VanA-type VRE E. faecalis MGH-01 and E. faecium CDC-01, and E. faecium KPB-01 for 20 consecutive passages. Isolates with increased TLV MIC were characterized for stability of resistance, susceptibility to other agents, and growth rate.
Mutants with TLV MICs elevated 24X that of parental levels were selected from each strain. However, TLV failed to select mutants with MICs >4X that of parental strains following 20 passages. No major changes were observed in the growth properties of isolates with reduced susceptibility to telavancin. Two mutants with TLV MIC 4X that of their parental strains (32 mg/mL) were selected from the VRE strains. These mutants exhibited reduced susceptibility to daptomycin at or near the same fold MIC increase observed for telavancin, however, no significant cross-resistance to other antimicrobial agents was observed. Mutant phenotypes were stable upon extended subculture (approximately 300 generations) in drug-free medium.
High-level resistance to TLV was not selected from glycopeptide-sensitive organisms, including MRSA, MSSA, or VSE, following continuous exposure for 20 consecutive passages. Mutants with 4X-reduced susceptibility to TLV were selected from 2 out of the 3 VRE strains. These data suggest that TLV possesses a low potential for resistant mutant selection.
|Session name:||XXIst ISTH Congress|
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