Single-dose pharmacokinetics of daptomycin in pediatric patients 3-24 months of age.

BACKGROUND: Daptomycin is approved for treatment of complicated skin/skin structure infections and Staphylococcus aureus bloodstream infections (bacteremia) in adults. This study was undertaken to determine the pharmacokinetics of daptomycin in pediatric patients 3-24 months of age with proven/suspected bacterial infection. METHODS: In this phase 1, multicenter, open-label, noncomparative pharmacokinetic and safety study, patients were enrolled in 3 age groups: 3-6, 7-12 and 13-24 months. Intravenous daptomycin (single dose) was infused over 30 minutes at 6 mg/kg in subjects 13-24 months of age and at 4 mg/kg in the younger groups. Blood was collected for analysis of daptomycin concentrations. RESULTS: Twenty-four subjects received daptomycin. Daptomycin exposures (area under the curve0-∞) in children 3-6 and 7-12 months of age receiving 4 mg/kg were similar (215 and 219 µg·h/mL, respectively). Children 13-24 months of age receiving a higher dose, 6 mg/kg, had higher exposures (282 µg·h/mL). Mean maximum plasma concentrations in the age groups were 38.7, 37.1 and 67.0 µg/mL, respectively. Daptomycin exposures based on mg/kg dosing were lower than previously reported for older children and adults, likely because of increased clearance and volume of distribution and decreased apparent elimination half-life. Single-dose daptomycin 4 and 6 mg/kg was well tolerated and was not associated with clinical or laboratory adverse events. CONCLUSIONS: To match known clinically and microbiologically effective exposures in adults, infants require higher mg/kg daptomycin doses. Daptomycin safety and efficacy have not been established in pediatric patients. Pediatric clinical trials are ongoing.

Dosing strategy to allow continued therapy with daptomycin after asymptomatic increases in creatine kinase levels.

PURPOSE: A case series in which a novel dosing strategy for managing mild, asymptomatic creatine kinase (CK) increases associated with daptomycin therapy is presented. SUMMARY: Eight patients received a mean daptomycin dosage of 7.75 mg/kg/day for a median duration of 42 days. Seven of the eight patients were being treated for a bone and joint infection, and all but one had methicillin-resistant Staphylococcus aureus. All patients had asymptomatic increases in CK concentrations during daptomycin therapy (peak range, 400-1200 IU/L). A single daptomycin dose was withheld from each patient, and therapy was resumed 24 hours later, most often at the same dosage. The elevated CK values in these patients resolved, and all patients were able to complete daptomycin therapy without further increases in CK elevations. These findings indicate that withholding one dose of daptomycin during treatment may allow patients with asymptomatic, elevated CK concentrations to continue therapy with CK level normalization. Although the mechanism of daptomycin-mediated muscle injury is not fully understood, a reduction in daptomycin exposure via a one-dose cessation of therapy may allow for physiological restoration of sarcolemma membrane integrity that may be disrupted by daptomycin in individuals exhibiting CK elevation. CONCLUSION: A single daptomycin dose was withheld from eight patients with asymptomatic increases in serum CK concentrations, then daptomycin therapy was resumed 24 hours later, most often at the previous dosage. The CK concentrations returned to normal, and all patients were able to complete daptomycin therapy without further increases in CK concentrations.

Clinical and pharmacokinetic considerations for the use of daptomycin in patients with Staphylococcus aureus bacteraemia and severe renal impairment.

OBJECTIVES: To support daptomycin dosing recommendations in patients with Staphylococcus aureus bacteraemia (SAB) and severe renal impairment using simulations from a population pharmacokinetic model for daptomycin. METHODS: A population pharmacokinetic model was developed using 4875 daptomycin plasma concentrations from 442 subjects. Daptomycin 24 h AUC and Cmax were then simulated for subjects with a CL(CR) < 30 mL/min [with or without haemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD)] for different dosing frequencies (every 24 h, every 48 h and three times weekly) with doses of 4 mg/kg and 6 mg/kg. These results were compared with efficacy and safety exposure references based on daily dosing to understand the implications of less frequent dosing (for example, higher exposures on day 1 versus day 2) and to evaluate the 4 mg/kg versus 6 mg/kg regimens. RESULTS: Substantially more patients with SAB and severe renal impairment were underexposed (24 h AUCs compared with an efficacy reference of 6 mg/kg/day, CLCR ≥ 30 mL/min, pivotal trial population) at 4 mg/kg every 48 h compared with 6 mg/kg. Cmax results also favoured 6 mg/kg every 48 h over 4 mg/kg every 48 h. Both exposure metrics at 6 mg/kg every 48 h also stayed below the defined safety limits (based on 12 mg/kg/day, CL(CR) >80 mL/min, the highest dose in controlled clinical trials). CONCLUSIONS: For patients with SAB and CLCR <30 mL/min, or receiving HD or CAPD, the dose recommendation of 6 mg/kg every 48 h provides appropriate daptomycin exposure for this indication; this will not be the case for patients receiving 4 mg/kg every 48 h.

Pharmacokinetics and safety of intravenous ceftolozane-tazobactam in healthy adult subjects following single and multiple ascending doses.

The pharmacokinetics and safety of ceftolozane, a novel cephalosporin, and tazobactam, a ß-lactamase inhibitor, alone and in combination as a 2:1 ratio in single doses of up to 2,000 and 1,000 mg of ceftolozane and tazobactam, respectively, and multiple doses of up to 3,000 and 1,500 mg of ceftolozane and tazobactam, respectively, per day were evaluated in healthy adult subjects. In part 1, groups of six subjects each received single ascending doses of ceftolozane, tazobactam, and ceftolozane-tazobactam in a within-cohort crossover design. In part 2, groups of 5 or 10 subjects each received multiple doses of ceftolozane, tazobactam, or ceftolozane-tazobactam for 10 days. After a single dose of ceftolozane alone, the ranges of mean values for half-life (2.48 to 2.64 h), the total clearance (4.35 to 6.01 liters/h), and the volume of distribution at steady state (11.0 to 14.1 liters) were consistent across dose levels and similar to those observed when ceftolozane was coadministered with tazobactam. Mean values after multiple doses for ceftolozane alone and ceftolozane-tazobactam were similar to those seen following a single dose. The pharmacokinetics of the dosing regimens evaluated were dose proportional and linear. Ceftolozane-tazobactam was well tolerated and systemic adverse events were uncommon. Mild infusion-related adverse events were the most commonly observed following multiple-dose administration. Adverse events were not dose related, and no dose-limiting toxicity was identified.

Single-dose pharmacokinetics and tolerability of daptomycin 8 to 10 mg/kg in children aged 2 to 6 years with suspected or proved Gram-positive infections.

A pharmacokinetic analysis was performed for single intravenous doses of daptomycin 8 or 10 mg/kg in subjects aged 2 to 6 years. Proportional increases in maximum plasma concentration (68.4 µg/mL, 79.2 µg/mL) and area under the curve (429.1 µg · h/mL, 549.7 µg · h/mL) were observed for each dose cohort, respectively. Half-life, clearance, and distribution volume were similar between groups. Both doses were well tolerated.

Single-dose pharmacokinetics of daptomycin in children with suspected or proved gram-positive infections.

BACKGROUND: New antimicrobials such as daptomycin fill a void in the growing need for antibiotics effective against resistant Gram-positive pathogens. Although the pharmacokinetics of daptomycin have been well characterized in adults, no studies have evaluated the pharmacokinetics and tolerability in a pediatric population. METHODS: Twenty-five children (12-17 years, n = 8; 7-11 years, n = 8; 2-6 years, n = 9) were enrolled in this multicenter, open-label study. Daptomycin was administered as a single 4-mg/kg intravenous dose followed by repeated blood sampling for 24 hours. Daptomycin was quantitated from plasma using a validated high performance liquid chromatography method and pharmacokinetic variables determined using a model-dependent approach. RESULTS: Daptomycin systemic exposure decreased with decreasing age, reflecting more rapid rates of clearance in younger children. Total body exposure estimates in adolescents were approximately 1.7x those observed in children <6 years of age (374.4 versus 215.3 microg*h/L), they were comparable to those observed in adult historic controls. Estimates of apparent elimination half-life averaged 6.7 hours in adolescents, 5.6 hours in children 7-11 years of age, and 5.3 hours in children <6 years of age. One child had an adverse event (infusion site reaction) considered to be related to study drug. CONCLUSIONS: Systemic drug exposure after a single weight-adjusted daptomycin dose is reduced in younger children compared with adolescents and adults consequent to an apparent age-associated change in total plasma clearance.

Pharmacokinetics and tolerability of daptomycin at doses up to 12 milligrams per kilogram of body weight once daily in healthy volunteers.

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.