Evaluation of daptomycin treatment of Staphylococcus aureus bacterial endocarditis: an in vitro and in vivo simulation using historical and current dosing strategies.
OBJECTIVE
A failure to daptomycin therapy and subsequent emergence of a daptomycin non-susceptible isolate occurred during the 1990 clinical investigation of daptomycin for the treatment of Staphylococcus aureus bacteraemia and endocarditis. We attempted to determine if this occurrence was reproducible in vitro and if it could be prevented by various daptomycin dosing strategies.


METHODS
The daptomycin susceptible parent strain (SA-675) and the subsequent non-susceptible derivative (SA-684) were evaluated. In the rabbit endocarditis model, daptomycin 3 mg/kg every 8 h for 4 days was administered to simulate the study patient's pharmacokinetic exposure. Daptomycin doses of 1.5 and 3 mg/kg every 12 h and 6 and 10 mg/kg every 24 and 48 h were simulated in the in vitro model with simulated endocardial vegetations (SEVs).


RESULTS
Daptomycin significantly reduced bacterial counts of SA-675 in rabbits, but one in 10(5)-10(6) organisms from vegetations of one animal had an 8-fold increase in MIC. Daptomycin 1.5 mg/kg every 12 h in the in vitro model demonstrated no activity against either strain; reduced susceptibility emerged in SA-675 (4-fold increase in MIC). Bactericidal activity was noted with 6 and 10 mg/kg dosing against SA-675 with no resistance detected. The activity of the 6 mg/kg regimen was reduced against SA-684 but significantly improved activity was noted with 10 mg/kg daily.


CONCLUSIONS
The emergence of resistance was successfully recreated at suboptimal dosing regimens while the current recommended regimen of 6 mg/kg/day prevented the emergence of non-susceptible mutants. Daptomycin 10 mg/kg/day demonstrated even more enhanced killing. Further investigation with daptomycin 10 mg/kg is warranted.
Rose
Warren E
WE
Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, and Detroit Receiving Hospital, MI 48201, USA.
Rybak
Michael J
MJ
Kaatz
Glenn W
GW
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D015169:Colony Count, Microbial; D003470:Culture Media; D017576:Daptomycin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D024881:Drug Resistance, Bacterial; D004697:Endocarditis, Bacterial / Q000188:drug therapy* / Q000382:microbiology; D006207:Half-Life; D006801:Humans; D007202:Indicators and Reagents; D008297:Male; D008826:Microbial Sensitivity Tests; D011817:Rabbits; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology
D000900:Anti-Bacterial Agents; D003470:Culture Media; D007202:Indicators and Reagents; D017576:Daptomycin