The influence of inducible cross-resistance to
macrolides,
lincosamides, and
streptogramin B (MLS(B)) type
antibiotics (inducible MLS(B) phenotype) on the activity of
quinupristin-dalfopristin was investigated against Enterococcus faecium in vitro and in rabbits with experimental
endocarditis. In vitro,
quinupristin-dalfopristin displayed bacteriostatic and bactericidal activities against a MLS(B)-susceptible strain similar to those against two strains with the inducible MLS(B) phenotype. In addition, induction of the two MLS(B)-resistant strains with
quinupristin (0.016 to 1 microg/ml) or
quinupristin-dalfopristin (0.08 to 0.25 microg/ml) increased the MICs of
quinupristin from 8 microg/ml to 32 to > 128 microg/ml, but did not modify the MIC of
dalfopristin (2 microg/ml) or
quinupristin-dalfopristin (0.5 microg/ml). In a rabbit
endocarditis model,
quinupristin-dalfopristin was as active as
amoxicillin against the MLS(B)-susceptible E. faecium strain. In contrast, the activity of
quinupristin-dalfopristin was significantly decreased in animals infected with either of the two inducible MLS(B)-resistant strains (P < 0.05), although no mutants resistant to
quinupristin-dalfopristin were detected. Against the clinical strain with the inducible MLS(B) phenotype,
quinupristin-dalfopristin was not effective and was less active than
amoxicillin (P < 0.001); however, the activity of the combination of
amoxicillin and
dalfopristin-
quinupristin was superior to that of
amoxicillin (P < 0.01). The different impact of the inducible MLS(B) phenotype in E. faecium on the activity of
quinupristin-dalfopristin in vitro and in experimental
endocarditis may be related to the reduced diffusion of
dalfopristin compared with that of
quinupristin into cardiac vegetations that we previously reported. This result emphasizes the importance of the constant presence of
dalfopristin at the site of
infection to ensure synergism with
quinupristin.