Pharmacodynamics of Daptomycin in a Murine Thigh Model of Staphylococcus aureus Infection

Abstract

Daptomycin is a lipopeptide antibiotic with activity against gram-positive bacteria, including Staphylococcus aureus. We defined the pharmacodynamic parameters that determine the activity of daptomycin for S. aureus using in vitro methods and the Craig (W. A. Craig, J. Redington, and S. C. Ebert, J. Antimicrob. Chemother. 27[Suppl. C]:29-40, 1991) neutropenic mouse thigh infection model. In Mueller-Hinton broth, the MICs for three S. aureus isolates were 0.1 to 0.2 g/ml. In mouse serum, the MICs were 1.0 g/ml. The protein binding of daptomycin was 90 to 92.5% in mouse serum. Single-dose intraperitoneal (i.p.) pharmacokinetic studies with infected mice showed a linear relationship between dose versus the maximum concentration of drug in serum and dose versus the area under the concentration-time curve (AUC). The serum half-life of daptomycin in infected mice was approximately 1.8 h. In single-dose, dose-ranging studies using mice, daptomycin showed a dose-response effect described by an inhibitory sigmoid E max (maximum effect) curve (r ‫؍‬ 0.974; P Ͻ Ͻ 0.001). The density of S. aureus in untreated controls was 8.26 log 10 CFU/g, and the E max was 3.97 log 10 CFU/g. The 50% effective dose (ED 50 ) was 3.7 mg/kg of body weight i.p. and the stasis dose was 7.1 mg/kg. Dose fractionation studies at schedules of Q6h, Q12h, and Q24h, for total 24-h ED 30 , ED 60 , and ED 80 doses of 2.5, 5.6, and 15 mg/kg i.p., showed no difference in effect at each total 24-h dose level by schedule, indicating that the AUC/MIC ratio is the dynamically linked variable.The incidence of community-and nosocomially acquired infections due to the bacterium Staphylococcus aureus is rising (24). From 1990 to 1992 this microorganism was the most common cause of nosocomial pneumonias and surgical wound infections (14). Although the antistaphylococcal beta-lactam antibiotics are the most active agents available for the treatment of methicillin-susceptible S. aureus, the National Nosocomial Infections Surveillance System of the Centers for Disease Control and Prevention reports that in 1997, 56.2% of S. aureus isolates were resistant to these agents (24). Vancomycin is considered the drug of choice for the treatment of methicillin-resistant S. aureus infections. However, this drug is slowly bactericidal and is associated with higher failure and relapse rates than beta-lactam therapy for the treatment of S. aureus endocarditis. Also, strains of S. aureus demonstrating decreased susceptibility to vancomycin have been described in Japan (18,19) and the United States (8).Daptomycin is an acidic lipopeptide antibiotic that is active against gram-positive bacteria, including S. aureus and enterococci (13,20,23,31). Importantly, the mechanism of action of daptomycin is distinctly different from that of other antimicrobial agents (2, 3). Thus daptomycin is active against Staphylococcus and Enterococcus species that are resistant to vancomycin (6, 31; N. V. Jacobus, J. R. McDermott, J. M. Lonks, J. M. Boyce, and D. R. Snydman, Abstr. 38th Intersci. Conf....

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Pharmacokinetic/pharmacodynamic (PK/PD) considerations in the management of Gram-positive bacteraemia

“…It is characterized by rapid concentration-dependent killing and a prolonged antibiotic effect against S. aureus and enterococci [62,63]. In murine neutropenic thigh models of S. aureus meticillin-A c c e p t e d M a n u s c r i p t susceptible [64] or meticillin-resistant strains [65] infection, the AUC/MIC ratio has been correlated with outcome. In another neutropenic murine thigh infection model, Safdar et al demonstrated that both the AUC/MIC 0-24 ratio and the C max /MIC ratio were strong predictors of in vivo efficacy [66].…”

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