Daptomycin, a novel lipopeptide, is bactericidal against a broad range of gram-positive strains, including methicillin-(MRSA) and vancomycin-resistant Staphylococcus aureus. Daptomycin is approved at 4 mg/kg of body weight given intravenously once daily for the treatment of complicated skin and skin structure infections and at 6 mg/kg for the treatment of S. aureus bloodstream infections (bacteremia), including right-sided endocarditis caused by methicillin-susceptible S. aureus and MRSA. The present study was designed to evaluate the multiple-dose pharmacokinetics and safety of daptomycin at doses of 6 to 12 mg/kg in healthy volunteers. Three cohorts of 12 subjects each were given daptomycin (10 mg/kg) or placebo once daily for 14 days, daptomycin (12 mg/kg) or placebo once daily for 14 days, or daptomycin (6 or 8 mg/kg) once daily for 4 days. Daptomycin produced dose-proportional increases in the area under the plasma concentration-time curve and in trough daptomycin levels and nearly dose-proportional increases in peak daptomycin concentrations. Other pharmacokinetic parameters measured on day 1 and at steady state were independent of the dose, including the half-life (approximately 8 h), weight-normalized plasma clearance (9 to 10 ml/h/kg), and volume of distribution (approximately 100 ml/kg). Plasma protein binding was 90% to 93% and was independent of the daptomycin concentration. Daptomycin did not produce electrocardiographic abnormalities or electrophysiological evidence of muscle or nerve toxicity. Daptomycin was well tolerated in subjects dosed with up to 12 mg/kg intravenously for 14 days. Doses of daptomycin higher than 6 mg/kg once daily may be considered in further studies to evaluate the safety and efficacy of daptomycin in difficult-to-treat infections.Daptomycin is the first member of the novel cyclicallipopeptide class, which provides rapid, concentration-dependent bactericidal activity against a broad range of gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) (2, 6, 9, 10). Daptomycin causes bacterial cell death by a mechanism unique among available antimicrobial agents (8,11). It binds to the cell membranes of gram-positive bacteria, thereby disrupting their membrane potential, initiating potassium efflux with rapid cell death.The safety and efficacy of daptomycin in treating complicated skin and skin structure infections were demonstrated in two randomized, controlled clinical trials (1). When administered at a dose of 4 mg/kg of body weight intravenously once daily for 7 to 14 days, daptomycin provided clinical success rates comparable to those of vancomycin and penicillinaseresistant penicillins and showed safety and tolerability similar to those of the comparators. On the basis of these studies, daptomycin was approved by the FDA and the European Medicines Agency for the treatment of complicated skin and skin structure infections caused by susceptible gram-positive strains, including MRSA (3). Because of its antibacterial profile, daptomycin may also b...

No abstract

The prevalence of Staphylococcus aureus causing prosthetic joint infection (PJI) supports investigation of higher doses of daptomycin in the management of PJI. This was a prospective, randomized controlled trial studying safety and efficacy of daptomycin (6 and 8 mg/kg of body weight) compared with standard-of-care therapy for PJI. This open-label study randomized 75 patients undergoing 2-stage revision arthroplasty to daptomycin at 6 or 8 mg/kg or a comparator (vancomycin, teicoplanin, or semisynthetic penicillin). After prosthesis removal, patients received 6 weeks of antibiotic treatment and a 2-to 6-week antibiotic-free period before implantation of a new prosthesis. Test of cure (TOC) was within 1 to 2 weeks after reimplantation. The primary objective was evaluation of creatine phosphokinase (CPK) levels. Secondary objectives were clinical efficacy and microbiological assessments. Of 73 CPK safety population patients, CPK elevation of >500 U/liter occurred in 4 of 25 (16.0%) (daptomycin, 6 mg/kg) and 5 of 23 (21.7%) (daptomycin, 8 mg/kg) daptomycin-treated patients and 2 of 25 (8.0%) comparator patients. Adverse-event rates were similar among daptomycin and comparator groups. Among modified intent-to-treat patients at TOC, clinical success rates were 14 of 24 (58.3%) for 6 mg/kg daptomycin, 14 of 23 (60.9%) for 8 mg/kg daptomycin, and 8 of 21 (38.1%) for the comparator. Overall microbiological success at TOC was 12 of 24 (50.0%) for 6 mg/kg daptomycin, 12 of 23 (52.2%) for 8 mg/kg daptomycin, and 8 of 21 (38.1%) for comparator patients. In conclusion, daptomycin at 6 and 8 mg/kg given for up to 6 weeks was safe and appeared to be effective in managing staphylococcal PJI using a 2-stage revision arthroplasty technique in a total of 49 patients. Prosthetic joint infection (PJI) occurs in 0.5% to 1.0% and 0.5% to 2% of hip and knee replacements, respectively (5,20,24,25). PJI is predominantly caused by Staphylococcus aureus (28%) and coagulase-negative staphylococci (CoNS) (25%) (23). PJI is associated with mortality (up to 2.5%) and significant morbidity, and outcomes are poor (8). There are no prospective, randomized controlled trials to guide treatment in this area (16,21). Conducting trials is challenging due to the difficulty of identifying patients and confounding outcomes by prior use of antibiotics.The ideal antimicrobial agent should be bactericidal, with activity against biofilm-producing microorganisms (26). Daptomycin exhibits rapid, concentration-dependent bactericidal activity in vitro against Gram-positive organisms, including S. aureus (regardless of methicillin susceptibility), Staphylococcus haemolyticus, and Staphylococcus epidermidis (4). Clinical outcomes in osteomyelitis from a retrospective, noncomparative registry showed that daptomycin doses of Ͼ4 mg/kg of body weight were more effective than doses of Յ4 mg/kg (88% versus 65%; P ϭ 0.013) (15).This study assessed the safety and efficacy of 6 and 8 mg/kg daptomycin compared with standard-of-care therapy in patients with hip or knee PJI c...

No abstract

The results of this exploratory study of SSI are consistent with those of previous studies of daptomycin in the treatment of diverse complicated skin and skin-structure infections, and suggest that wound classification should be treated as an important covariate in future studies of daptomycin and other antibiotics.