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      Safety of high-dose daptomycin in patients with severe renal impairment

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          Treatment options are limited for infections due to multidrug-resistant Gram-positive pathogens. Daptomycin is a lipopeptide antibiotic with concentration-dependent killing characteristic and dose-dependent post-antibiotic effect. To achieve optimized pharma-codynamic effect, some experts advocated using a high dose of daptomycin (≥9 mg/kg) for severe infections. However, the safety of high-dose therapy in patients with renal impairment remains unknown. This study was aimed to evaluate the safety of daptomycin in patients with severe renal impairment.


          This was a retrospective study performed by reviewing electronic medical records. Patients with severe renal impairment who were treated with daptomycin in a tertiary teaching hospital between January 1, 2013, and June 30, 2016, were included for evaluation. The incidence rates of creatine kinase (CK) elevation between high-dose (≥9 mg/kg) and standard-dose (<9 mg/kg) groups were compared.


          Overall, 164 patients met the inclusion criteria, and 114 (69.5%) of them were on renal replacement therapy. Vancomycin-resistant enterococci were the most common pathogens (61.3%) of the patients with documented pathogens. The treatment success rate was 51.6% in the 91 patients with bacteremia. The average dose of daptomycin was 8.0±2.3 mg/kg, and 37 (22.6%) patients received ≥9 mg/kg. CK levels were followed in 108 (65.9%) patients. Significantly higher incidence of CK elevation was found in the high-dose group compared with that in the standard-dose group (10.8% vs 1.6%, P<0.05). Moreover, patients with elevated CK received a higher dose of daptomycin than those without (9.3±1.2 vs 7.9±2.3 mg/kg, P<0.05). There was no significant difference in the rate of CK elevation between patients treated with different dosing frequency or with the concurrent use of statins, fibrate, or colchicine.


          In patients with severe renal impairment, high-dose (≥9 mg/kg) daptomycin therapy may result in a significantly higher incidence of CK elevation. More frequent CK monitoring is warranted to avoid potential harm in this population.

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          Most cited references 14

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          Prediction of creatinine clearance from serum creatinine.

          A formula has been developed to predict creatinine clearance (Ccr) from serum creatinine (Scr) in adult males: (see article)(15% less in females). Derivation included the relationship found between age and 24-hour creatinine excretion/kg in 249 patients aged 18-92. Values for Ccr were predicted by this formula and four other methods and the results compared with the means of two 24-hour Ccr's measured in 236 patients. The above formula gave a correlation coefficient between predicted and mean measured Ccr's of 0.83; on average, the difference predicted and mean measured values was no greater than that between paired clearances. Factors for age and body weight must be included for reasonable prediction.
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            Daptomycin exposure and the probability of elevations in the creatine phosphokinase level: data from a randomized trial of patients with bacteremia and endocarditis.

            The objective of this analysis was to evaluate the relationship between daptomycin exposure and the probability of an elevation in the creatine phosphokinase (CPK) level (hereafter, "CPK elevation") in patients with Staphylococcus aureus bacteremia with or without infective endocarditis. Phase 3 data for patients with S. aureus bacteremia, with or without infective endocarditis, who received intravenous daptomycin (6 mg/kg daily) and in whom pharmacokinetic data were collected were evaluated. On the basis of univariate logistic regression, the relationship between Bayesian post hoc exposure estimates and the probability of a CPK elevation was evaluated. Time to CPK elevation was examined with Kaplan-Meier analysis and Cox proportional hazards regression. Significant relationships between the minimum concentration of drug (C(min)) and area under the plasma concentration time curve and probability of CPK elevation were observed in 108 evaluable patients. Of the 108 patients evaluated, 6 (5.56%) demonstrated a defined CPK elevation, regardless of treatment relationship. C(min) (breakpoint of 24.3 mg/L) was most significantly associated with CPK elevation (P = .002). The probabilities of a CPK elevation with a C(min) 24.3 mg/L and <24.3 mg/L were 0.5 and 0.029, respectively. Increases in C(min), evaluated as a continuous variable, were also significantly associated with CPK elevation (P = .01). Stratified Kaplan-Meier analysis and Cox proportional hazards regression demonstrated C(min) to be a significant predictor of time to a CPK elevation (P .003). The probability of a CPK elevation was 0 and 0.01 after 7 days of treatment in patients with a C(min) 24.3 mg/L or <24.3 mg/L, respectively. After 14 days, the probabilities were 0.5 and 0.025, respectively. This analysis demonstrated that a daptomycin C(min) 24.3 mg/L was associated with an increased probability of a CPK elevation. Clinical trials registration. Clinical trials.gov NCT00093067 .
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              Daptomycin: the role of high-dose and combination therapy for Gram-positive infections.

              Daptomycin, a cyclic lipopeptide with rapid bactericidal activity, is approved at doses of 4 mg/kg and 6 mg/kg for the treatment of its respective indications [i.e. complicated skin and soft-tissue infections (cSSTIs) caused by Gram-positive bacteria; and Staphylococcus aureus bacteraemia associated with right-sided infective endocarditis (RIE) or cSSTIs, or RIE due to S. aureus]. Higher doses and combination therapy strategies have been investigated in some difficult-to-treat infections in order to: enhance clinical success rates; treat pathogens that may be non-susceptible to standard doses; and minimise the risk of resistance development in patients, particularly those who may need an extended treatment duration, who may have had suboptimal surgical management and/or who may have not responded to prior antibiotic therapy. Although clinical trial data of daptomycin doses >6 mg/kg and of daptomycin in combination with other antibiotics are limited, clinical experience reported to date suggests that daptomycin is effective and well tolerated at higher doses and in combination. In this review, the rationale both for high-dose and combination therapy strategies with daptomycin is explored and the available evidence is presented by indication and evaluated from a clinical perspective. Safety and efficacy are discussed from prospective and retrospective clinical studies, together with case reports for a variety of infections, including bacteraemia, endocarditis, cSSTIs and osteomyelitis, and expert recommendations are provided in summary of the evidence. The use of high-dose daptomycin, alone or in combination, may be useful for difficult-to-treat Gram-positive infections and further evaluation of these strategies is warranted.

                Author and article information

                Ther Clin Risk Manag
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                13 March 2018
                : 14
                : 493-499
                [1 ]Department of Pharmacy, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
                [2 ]School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan
                [3 ]Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan
                Author notes
                Correspondence: Chien-Chih Wu, Department of Pharmacy, National Taiwan University Hospital, College of Medicine, National Taiwan University, 7 Chung Shan S. Rd., Taipei 110, Taiwan, Tel +886 22 312 3456 ext 63702, Fax +886 22 331 0930, Email 101440@ 123456ntuh.gov.tw
                © 2018 Tai et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Original Research


                daptomycin, safety, renal impairment, rhabdomyolysis


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