Two step acquisition of resistance to the teicoplanin-gentamicin combination by VanB-type Enterococcus faecalis in vitro and in experimental endocarditis

The activity of vancomycin and teicoplanin combined with gentamicin was inv estigated in vitro against strains of Enterococcus faecalis resistant to va ncomycin and susceptible to teicoplanin (VanB type) and against mutants tha t had acquired resistance to teicoplanin by three different mechanisms. In vitro, gentamicin selected mutants with two- to sixfold increases in the le vel of resistance to this antibiotic at frequencies of 10(-6) to 10(-7). Te icoplanin selected teicoplanin-resistant mutants at similar frequencies. Bo th mutations were required to abolish the activity of the gentamicin-teicop lanin combination. As expected, simultaneous acquisition of the two types o f mutations,vas not observed. In therapy with gentamicin or teicoplanin alo ne, each selected mutants in three of seven rabbits with aortic endocarditi s due to VanB-type E. faecalis BM4275. The vancomycin-gentamicin combinatio n selected mutants that were resistant to gentamicin and to the combination . In contrast, the teicoplanin-gentamicin regimen prevented the emergence o f mutants resistant to one or both components of the combination. These res ults suggest that two mutations are also required to suppress the in vivo a ctivity of the teicoplanin-gentamicin combination.