In vivo activities of evernimicin (SCH 27899) against vancomycin-susceptible and vancomycin-resistant enterococci in experimental endocarditis

To assess the potential efficacy of evernimicin (SCH 27899) against serious enterococcal infections, we used a rat model of aortic valve endocarditis established with either a vancomycin-susceptible Enterococcus faecalis or a vancomycin-resistant Enterococcus faecium strain. Animals infected with ei ther one of the test strains were assigned to receive no treatment (control s) or 5-day therapy with one of the following regimens: evernimicin 60-mg/k g of body weight intravenous (i.v.) bolus once daily, 60-mg/kg i.v. bolus t wice daily (b.i.d.), 60 mg/kg/day i.v. by continuous infusion, or 120 mg/kg /day i.v. by continuous infusion. These regimens were compared with vancomy cin at 150 mg/kg/day. In animals infected with E. faecalis, evernimicin at 120 mg/kg/day by continuous infusion significantly reduced bacterial counts in vegetations (final density, 5.75 +/- 3.38 log(10) CFU/g) compared with controls (8.51 +/- 1.11 log(10) CFU/g). In animals infected with 0.5 ml of an 8 x 10(7)-CFU/ml inoculum of the vancomycin-resistant E. faecium, both 6 0 mg/kg bolus once a day and b.i.d. dose regimens of evernimicin were very effective (viable counts, 3.45 +/- 1.44 and 3.81 +/- 1.98 log(10) CFU/g, re spectively). Vancomycin was unexpectedly active against infections induced with that inoculum. In animals infected with a 10(9)-CFU/ml inoculum of the vancomycin-resistant E. faecium, the evernimicin 60-mg/kg i.v. bolus b.i.d . reduced viable counts in vegetations compared with controls (6.27 +/- 1.6 3 versus 8.34 +/- 0.91 log(10) CFU/g; P < 0.05), whereas vancomycin was ine ffective. Although resistant colonies could be selected in vitro, we were n ot able to identify evernimicin-resistant clones from cardiac vegetations. An unexplained observation from these experiments was the great variability in final bacterial densities within cardiac vegetations from animals in ea ch of the evernimicin treatment groups.