Evaluation of daptomycin activity against Staphylococcus aureus in an in vitro pharmacodynamic model under normal and simulated impaired renal function.
OBJECTIVE
Daptomycin is a lipopeptide antimicrobial that is primarily excreted by the kidney. We examined daptomycin bactericidal activity in an in vitro pharmacodynamic model (IVPM) under normal and simulated impaired renal function against methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA).


METHODS
Two clinical strains MSSA-1199 and MRSA-494 were used in an IVPM. MICs and MBCs were determined according to CLSI. Daptomycin free concentrations were simulated that corresponded to dose regimens of 4, 6 and 8 mg/kg every 24 h at 8 h t(1/2) (Scheme I) and every 48 h at 30 h t(1/2) (Scheme II). In addition, we simulated daptomycin free concentrations corresponding to fractional dose regimens of 2, 3 and 4 mg/kg every 24 h at 30 h t(1/2) (Scheme III). The targeted C(max free)/MIC for 2, 3, 4, 6 and 8 mg/kg against MSSA-1199 ranged from 5.2 to 21.2. The targeted C(max free)/MIC for 2, 3, 4, 6 and 8 mg/kg against MRSA-494 ranged from 10.4 to 42.2. The targeted AUC(free)/MIC for Schemes I, II and III against MSSA-1199 ranged from 94 to 392. The targeted AUC(free)/MIC for Schemes I, II and III against MRSA-494 ranged from 188 to 581. Bactericidal activity and the potential for resistance were determined over 96 h. All models were completed in triplicate.


RESULTS
Daptomycin MICs (MBCs) for MSSA-1199 and MRSA-494 were 0.5 (1.0) mg/L and 0.25 (0.25) mg/L, respectively. Daptomycin 6 and 8 mg/kg at both 8 and 30 h t(1/2) achieved 99.9% kill as early as 1 h. Daptomycin 4 mg/kg achieved 99.9% kill as early as 1 h when given at 8 and 30 h t(1/2) but was not maintained to an endpoint of 96 h (P > 0.05).


CONCLUSIONS
Overall, there was no difference in kill noted for daptomycin regimens at 4, 6 and 8 mg/kg every 24 h at 8 h t(1/2) versus every 48 h at 30 h t(1/2). Fractional doses of daptomycin at 30 h t(1/2) were inferior to daptomycin regimens of 4, 6 and 8 mg/kg administered every 48 h (P = 0.03).
Huang
Vanthida
V
Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA.
Rybak
Michael J
MJ
D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D017576:Daptomycin / Q000493:pharmacokinetics / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D006207:Half-Life; D007674:Kidney Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D008657:Metabolic Clearance Rate; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development
D000900:Anti-Bacterial Agents; D017576:Daptomycin