Efficacy of daptomycin in the treatment of experimental endocarditis due to susceptible and multidrug-resistant enterococci.
OBJECTIVE
Daptomycin was tested in vitro and in rats with experimental endocarditis against the ampicillin-susceptible and vancomycin-susceptible Enterococcus faecalis JH2-2, the vancomycin-resistant (VanA type) mutant of strain JH2-2 (strain JH2-2/pIP819), and the ampicillin-resistant and vancomycin-resistant (VanB type) Enterococcus faecium D366.


METHODS
Rats with catheter-induced aortic vegetations were treated with doses simulating intravenously kinetics in humans of daptomycin (6 mg/kg every 24 h), amoxicillin (2 g every 6 h), vancomycin (1 g every 12 h) or teicoplanin (12 mg/kg every 12 h). Treatment was started 16 h post-inoculation and continued for 2 days.


RESULTS
MICs of daptomycin were 1, 1 and 2 mg/L, respectively, for strains JH2-2, JH2-2/pIP819 and D366. In time-kill studies, daptomycin showed rapid (within 2 h) bactericidal activity against all strains. Daptomycin was highly bound to rat serum proteins (89%). In the presence of 50% rat serum, simulating free concentrations, daptomycin killing was maintained but delayed (6-24 h). In vivo, daptomycin treatment resulted in 10 of 12 (83%), 9 of 11 (82%) and 11 of 12 (91%) culture-negative vegetations in rats infected with strains JH2-2, JH2-2/pIP819 and D366, respectively (P < 0.001 compared to controls). Daptomycin efficacy was comparable to that of amoxicillin and vancomycin for susceptible isolates. Daptomycin, however, was significantly (P < 0.05) more effective than teicoplanin against the glycopeptide-susceptible strain JH2-2 and superior to all comparators against resistant isolates.


CONCLUSIONS
These results support the use of the newly proposed daptomycin dose of 6 mg/kg every 24 h for treatment of enterococcal infections in humans.
Vouillamoz
Jacques
J
Department of Fundamental Microbiology, University of Lausanne, CH-1015 Lausanne, Switzerland.
Moreillon
Philippe
P
Giddey
Marlyse
M
Entenza
José M
JM
D000658:Amoxicillin / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D001798:Blood Proteins / Q000378:metabolism; D017576:Daptomycin / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D024901:Drug Resistance, Multiple, Bacterial; D004697:Endocarditis, Bacterial / Q000188:drug therapy* / Q000382:microbiology; D013293:Enterococcus faecalis / Q000187:drug effects*; D016984:Enterococcus faecium / Q000187:drug effects*; D005260:Female; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D017334:Teicoplanin / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D014640:Vancomycin / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use
D000900:Anti-Bacterial Agents; D001798:Blood Proteins; D017334:Teicoplanin; D014640:Vancomycin; D000658:Amoxicillin; D017576:Daptomycin