Single-dose pharmacokinetics and antibacterial activity of daptomycin, a new lipopeptide antibiotic, in healthy volunteers

Woodworth, James R.; Nyhart, Eldon H.; Brier, G. L.; Wolny, J. D.; Black, Henry R.

doi:10.1128/aac.36.2.318

Cited by 152 publications

(135 citation statements)

References 17 publications

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“…Across this dose range, plasma daptomycin concentrations were generally consistent and predictable, and PK parameters following multiple-dose treatment were in agreement with earlier single-dose data (14). Taken together, these results suggest that patients receiving these regimens will have reliable concentrations in plasma.…”

Section: Discussionsupporting

confidence: 79%

“…Following successive doses at least 72 h apart, the pharmacokinetics (PK) of daptomycin was linear over the range of 0.5 to 6 mg/kg (14). Following the administration of 14 C-labeled daptomycin, 83% of the administered radiolabel was recovered in excreta, with the greatest fraction (78%) appearing in the urine.…”

mentioning

confidence: 94%

“…Following the administration of 14 C-labeled daptomycin, 83% of the administered radiolabel was recovered in excreta, with the greatest fraction (78%) appearing in the urine. Specific analysis of daptomycin (microbiologic assay) in both plasma and urine indicated that inactive metabolic products were present in urine but that only daptomycin was present in plasma.…”

mentioning

confidence: 99%

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Daptomycin Pharmacokinetics and Safety following Administration of Escalating Doses Once Daily to Healthy Subjects

Dvorchik

Brazier

DeBruin

et al. 2003

Antimicrob Agents Chemother

334

284

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The purpose of this paper is to establish the pharmacokinetics and safety of escalating, once-daily doses of daptomycin, a novel lipopeptide antibiotic active against gram-positive pathogens, including those resistant to methicillin and vancomycin. This phase 1, multiple-dose, double-blind study involved 24 healthy subjects in three dose cohorts (4, 6, and 8 mg/kg of body weight) who were randomized to receive daptomycin or the control at a 3:1 ratio and administered the study medication by a 30-min intravenous infusion every 24 h for 7 to 14 days. Daptomycin pharmacokinetics was assessed by blood and urine sampling. Safety and tolerability were evaluated by monitoring adverse events (AEs) and laboratory parameters. Daptomycin pharmacokinetics was linear through 6 mg/kg, with a slight (ϳ20%) nonlinearity in the area under the curve and trough concentration at the highest dose studied (8 mg/kg). The pharmacokinetic parameters measured on the median day of the study period, (day 7) were half-life (ϳ9 h), volume of distribution (ϳ0.1 liters/kg), systemic clearance (ϳ8.2 ml/h/kg), and percentage of the drug excreted intact in urine from 0 to 24 h (ϳ54%). Daptomycin protein binding (mean amount bound, 91.7%) was independent of the drug concentration. No gender effect was observed. All subjects who received daptomycin completed the study. The frequencies and distributions of treatment-emergent AEs were similar for the subjects who received daptomycin and the control subjects. There were no serious AEs and no pattern of dose-related events. The pharmacokinetics of once-daily administration of daptomycin was linear through 6 mg/kg. For all three doses, plasma daptomycin concentrations were consistent and predictable throughout the dosing interval. Daptomycin was well tolerated when it was administered once daily at a dose as high as 8 mg/kg for 14 days.Daptomycin is a novel lipopeptide antibiotic that possesses several pharmacologic advantages over other gram-positive antimicrobial agents (3,12). It is a fermentation product of Streptomyces roseosporus that was discovered in the early 1980s (12). Daptomycin exhibits potent in vitro bactericidal activity against most clinically relevant strains of gram-positive bacteria, including antimicrobial-resistant pathogens (5). The MICs at which 90% of the microbes tested are inhibited are Յ1 g/ml, with the exception of those for enterococci, which are approximately 2 to 4 g/ml (5, 7, 8, 10-13). The spontaneous acquisition of resistance to daptomycin is rare in gram-positive bacteria in vitro, and the emergence of resistance to daptomycin is rare during clinical trials.Daptomycin appears to bind to the gram-positive bacterial cell membrane by its fatty acid tail, followed by calcium-dependent insertion (6). The resulting decrease in membrane potential causes cell death by rapidly stopping DNA, RNA, and protein synthesis (1). Because daptomycin does not appear to penetrate into cells, the interactions with the plasma membrane are most likely the basis for its pharmacologic actions...

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Section: Discussionsupporting

confidence: 79%

mentioning

confidence: 94%

mentioning

confidence: 99%

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Daptomycin Pharmacokinetics and Safety following Administration of Escalating Doses Once Daily to Healthy Subjects

Dvorchik

Brazier

DeBruin

et al. 2003

Antimicrob Agents Chemother

334

284

View full text Add to dashboard Cite

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“…Similar to our findings, they reported achieving lower Cmax values in patients with ESRD than in healthy volunteers. In addition, the percentage of protein binding that we measured (mean unbound fraction 10.8%) was similar to that reported in healthy volunteers (approximately 10%) (10,11) and in patients who were receiving HD (10.70 Ϯ 1.84%; unpublished Cubist data, David P. Benziger, Ph.D., Cubist Pharmaceutical, Inc., Lexington, MA, personal communication, November 19, 2008). The clinical significance of a larger volume of distribution in patients with ESRD and the resultant lower Cmax compared with those achieved in healthy volunteers has yet to be determined.…”

Section: Discussionsupporting

confidence: 64%

Intradialytic Administration of Daptomycin in End Stage Renal Disease Patients on Hemodialysis

Salama

Segal

Churchwell

et al. 2009

Clinical Journal of the American Society of Nephrology

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“…Concentrations of daptomycin were determined by using a high-performance liquid chromatography (HPLC) method (22). Concentrations of vancomycin were determined by using an agar diffusion bioassay with Bacillus subtilis ATCC 6633 as a control strain (12 A daptomycin dose of 50 mg/kg was chosen to obtain an AUC from 0 to 24 h (AUC 0 -24 ) similar to that in humans after a dose of 6 mg/kg (25). In the case of vancomycin, a dose of 110 mg/kg was chosen to target an AUC 0 -24 similar to that in humans after doses of 1 g every 12 hours (q12h) (454 mg · h/liter) (10).…”

Section: Methodsmentioning

confidence: 99%

Efficacy of Daptomycin versus Vancomycin in an Experimental Model of Foreign-Body and Systemic Infection Caused by Biofilm Producers and Methicillin-Resistant Staphylococcus epidermidis

Domínguez-Herrera

Docobo-Pérez

López-Rojas

et al. 2012

Antimicrob Agents Chemother

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Staphylococcus epidermidis is a frequent cause of device-associated infections. In this study, we compared the efficacy of daptomycin versus vancomycin against biofilm-producing methicillin-resistant S. epidermidis (MRSE) strains in a murine model of foreign-body and systemic infection. Two bacteremic biofilm-producing MRSE strains were used (SE284 and SE385). The MIC of daptomycin was 1 mg/liter for both strains, and the MICs of vancomycin were 4 and 2 mg/liter for SE284 and for SE385, respectively. The in vitro bactericidal activities of daptomycin and vancomycin were evaluated by using time-kill curves. The model of foreign-body and systemic infection of neutropenic female C57BL/6 mice was used to ascertain in vivo efficacy. Animals were randomly allocated into three groups (n ‫؍‬ 15): without treatment (controls) or treated with daptomycin at 50 mg/kg/day or vancomycin at 440 mg/kg/day. In vitro, daptomycin showed concentration-dependent bactericidal activity, while vancomycin presented time-dependent activity. In the experimental in vivo model, daptomycin and vancomycin decreased liver and catheter bacterial concentrations (P < 0.05) and increased the survival and the number of sterile blood cultures (P < 0.05) using both strains. Daptomycin produced a reduction in the bacterial liver concentration higher than 2.5 log 10 CFU/g compared to vancomycin using both strains, with this difference being significant (P < 0.05) for infection with SE385. For the catheter bacterial concentrations, daptomycin reduced the concentration of SE284 3.0 log 10 CFU/ml more than did vancomycin (P < 0.05). Daptomycin is more effective than vancomycin for the treatment of experimental foreign-body and systemic infections by biofilmproducing methicillin-resistant S. epidermidis. Staphylococcus epidermidis is a common nosocomial and health care-associated pathogen in several infections, causing important morbidity, mortality, and/or health care costs. Thus, it is the most important cause of infections of orthopedic prostheses, accounting for approximately 40% of all cases, and between 30% and 50% of catheter-related bacteremias are caused by coagulasenegative Staphylococcus (CNS) strains (19,26). Other severe and/or frequent nosocomial and health care-associated infections are also caused by CNS, being the etiology in the 22.7% of endocarditis infections (9, 13) and in 37 to 78% of cerebrospinal fluid shunt-associated infections (4, 11).Moreover, the high frequency of methicillin-resistant S. epidermidis (MRSE) is an important therapeutic problem.

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Single-dose pharmacokinetics and antibacterial activity of daptomycin, a new lipopeptide antibiotic, in healthy volunteers

Cited by 152 publications

References 17 publications

Daptomycin Pharmacokinetics and Safety following Administration of Escalating Doses Once Daily to Healthy Subjects

Daptomycin Pharmacokinetics and Safety following Administration of Escalating Doses Once Daily to Healthy Subjects

Intradialytic Administration of Daptomycin in End Stage Renal Disease Patients on Hemodialysis

Efficacy of Daptomycin versus Vancomycin in an Experimental Model of Foreign-Body and Systemic Infection Caused by Biofilm Producers and Methicillin-Resistant Staphylococcus epidermidis

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