Observational retrospective single-centre study in Japan to assess the clinical significance of serum daptomycin levels in creatinine phosphokinase elevation.

What Is Known and Objective: Daptomycin-induced creatinine phosphokinase (CPK) elevation is reported to be associated with its trough level (C _trough ; breakpoint of 24.3 μg/mL). However, even with high-dose treatment (ie, > 8 mg/kg), the safety of daptomycin treatment is widely demonstrated with low or no significant incidence of CPK elevation or other adverse effects, despite the possibility of C _trough above 24.3 μg/mL. Therefore, we questioned the clinical significance of C _trough levels of 24.3 μg/mL. In this study, we retrospectively evaluated the significance of C _trough in the clinical setting, in addition to completing a retrospective safety assessment of daptomycin utilizing electronic health records.
Methods: Patients who had received daptomycin treatment for > 4 days from July 2011 to June 2015 were enrolled. Serum daptomycin levels, including C _trough and peak (C _peak ), were measured by high-performance liquid chromatography equipped with a photodiode array. To evaluate the safety, patients' characteristics and relevant laboratory test values were reviewed retrospectively using an electronic medical record system.
Results and Discussion: A total of 52 therapeutic cases for 46 patients were identified; of these, C _trough and C _peak levels were measured in 27 and 28 cases, respectively, and 6 patients received multiple courses of daptomycin treatment. The median age of the 52 patients was 68 years (range: 19-88 years), and 14 patients initially had an estimated creatinine clearance of less than 30 mL/min. Seven cases indicated a C _trough of above 24.3 μg/mL; however, none of these presented CPK elevation, which meets with the study definition for abnormality. Furthermore, of the two patients with abnormal CPK elevations, only one patient had a measured C _trough (of 10.9 μg/mL). Their CPK abnormalities were temporal and did not result in treatment discontinuation. The other four patients discontinued daptomycin treatment due to suspicions of adverse effects. Of the discontinued patients, two had measured C _trough levels; these were 8.6 and 8.1 μg/mL. All patients with abnormal CPK elevation or treatment discontinuation exhibited C _trough levels lower than 24.3 μg/mL. In this study, two patients receiving high-dose daptomycin (ie, 9.4 and 10.0 mg/kg) had observed C _trough levels similar to patients who received doses of daptomycin < 9 mg/kg.
What Is New and Conclusions: The safety of daptomycin treatment was suggested in this study. C _trough level of 24.3 μg/mL was not suggested as a significant clinical index for the incidence of CPK elevation, adverse effects or treatment discontinuation. Thus, acceptable tolerability towards higher C _trough levels than 24.3 μg/mL was also suggested, though further studies are required. On the other hand, low levels of daptomycin in blood were unexpectedly observed in two cases, despite the high-dose treatments. Accordingly, the monitoring of serum daptomycin levels may also be useful to assess cases in which subtherapeutic levels were achieved.
(© 2019 John Wiley & Sons Ltd.)