Efficacy and Safety of High Vs Standard Daptomycin Doses Examined in Chinese Patients With Severe Burn Injuries by Pharmacokinetic Evaluation

Abstract

Previous studies and the concentration-dependent antibacterial actions of daptomycin suggested that a high dose would be needed for difficult-to-treat infections in burn patients. Here, we evaluated the effects of administration of low and high doses of daptomycin in patients with severe burn injuries. The study retrospectively analyzed 10 patients with severe burn injuries, using pharmacokinetic (PK) and pharmacodynamic (PD) evaluations of daptomycin doses given to combat serious infections. Daptomycin was administered as a single dose or by multiple doses intravenously at a standard dose of 6 mg/kg/d or a high dose of 12 mg/kg/d for 7 to 14 days. The serum concentrations of daptomycin from patients were analyzed by liquid chromatography–mass spectrometry/mass spectrometry (LC-MS/MS). Burn injury patients treated with high-dose daptomycin had a linear PK profile and a negative correlation between the AUC0–24 and Baux score (R2 = .953 and R2 = .801). The Cmax, AUC0–24, and t(h)½ increased significantly compared with patients given a standard dose. The efficacy of daptomycin against Staphylococcus aureus showed significantly higher rates of (AUC0–24)/MIC and Cmax/MIC after high-dose daptomycin compared with the standard dose, reflected in a significant correlation between a high dose and the Baux score (r = .976, P < .001). Positive S. aureus cultures from two of three high-dose and none of two daptomycin low-dose patients converted from positive to negative after therapy. No serious adverse events or discontinuation of the drug occurred during the treatment period. Daptomycin doses up to 12 mg/kg/d were well tolerated in Chinese patients with severe burn injuries, which were complicated by infections with S. aureus.

Daptomycin Pharmacokinetics in Blood and Wound Fluid in Critical Ill Patients with Left Ventricle Assist Devices

“…To the best knowledge, we are the first to determine the daptomycin concentration in LVAD recipients. We observed a serum peak, reached after one hour, and gradually decreasing concentrations over the following 24 h. Our daptomycin serum concentration aligned with pharmacokinetic observations from previous clinical studies, including burn injuries and sepsis [29,47]. The typical serum pharmacokinetics of daptomycin have been observed already in previous studies and were confirmed by our serum findings [48,49].…”

High-Dose Daptomycin and Clinical Applications

“…The present evidence does not reflect true high-dose daptomycin because these high doses are used to achieve concentrations comparable to standard doses. Indeed, the steady-state AUCs achieved from 12 mg/kg/24-hours in this study reached exposure similar to 6 mg/kg/d in healthy volunteers (642 former 109 vs 632 latter 92 ). Whether doses >12 mg/kg would be beneficial in an MRSA bacteremia secondary to thermal burns to achieve the comparable 8- to 10-mg/kg dose remains undescribed.…”

“…106,108 A 10-to 12-mg/kg/d dose may be prudent to achieve efficacy in burn patients; however, as burn wounds heal, daptomycin dosing may require reductions as clearance normalizes. Recently, Huang et al 109 retrospectively compared 10 patients receiving high-dose daptomycin 12 mg/ kg/d with 6 mg/kg/d. High-dose daptomycin had significantly higher peak concentrations than 6 mg/kg/d and a doubled AUC, with no difference in adverse events.…”

Role of Daptomycin in Cutaneous Wound Healing: A Narrative Review

“…Interestingly, a higher dose of 4 mg/kg may be more effective in patients with cSSSI as daptomycin has a dose-dependent bactericidal action and 7 mg/kg may help both to maximize the bactericidal action and avoid the development of bacterial resistance [ 38 ]. A recent study of Chinese patients with severe burns and MRSA infection also found that high doses of daptomycin (from 6 mg/kg/day up to 12 mg/kg/day) were more effective than the standard dose [ 53 ]. Even if this dosage is higher than what is recommended, no significant differences of endogenous creatinine clearance rate (Ccr), blood urea nitrogen (BUN), and total protein (TP) were found in patients before and 7 days after high-dose daptomycin treatment.…”

“…The mean concentration of albumin on day 7 after high-dose daptomycin treatment was significantly higher than the baseline value (40.5 ± 4.6 vs. 35.0 ± 6.5, respectively, p = 0.006). [ 53 ] We recommend that the physician should always assess the risk-benefit ratio in the individual patient before considering high doses of daptomycin.…”