Factors affecting creatine phosphokinase elevation during daptomycin therapy using a combination of machine learning and conventional methods

Abstract

Aims: Musculoskeletal toxicity is a typical side effect of daptomycin (DAP). However, the risk factors have not been well established. Here, we aimed to identify independent factors affecting DAP-induced musculoskeletal toxicity using a combination of machine learning and conventional statistical methods.Methods: A population-based, retrospective, observational cohort study was conducted using the Japanese electronic medical record database. Patients who received DAP between October 2011 and December 2020 were enrolled. Two definitions of musculoskeletal toxicity were employed: (1) elevation of creatine phosphokinase (CPK) value more than twice from baseline and >200 IU/L, and (2) >1000 IU/L. First, multiple logistic regression analyses (a conventional statistical method) were performed to identify independent factors affecting CPK elevation. Then, decision tree analyses, a machine learning method, were performed to detect combinations of factors that change CPK elevation risk.Results: Of the 2970 patients who received DAP, 706 were included. Elevation of CPK values >200 IU/L and >1000 IU/L occurred in 83 (11.8%) and 17 (2.41%) patients, respectively. In multiple logistic regression analysis, baseline CPK value and concomitant use of hydrophobic statins were commonly extracted as independent factors affecting each CPK elevation, but concomitant use of hydrophilic statins was not. In decision tree analysis, patients who received hydrophobic statins and had high baseline CPK values were classified into the high-risk group. Conclusion:Our novel approach revealed new risk factors for CPK elevation. Our findings suggest that high-risk patients require frequent CPK monitoring.

Identification of Risk Factors for Daptomycin-Associated Creatine Phosphokinase Elevation and Development of a Risk Prediction Model for Incidence Probability

“…In studies examining the risk factors for CPK elevation during combined daptomycin and statin treatment, African American ethnicity was cited as a risk factor, similar to other findings that African Americans have a higher risk of CPK elevation during statin treatment [ 7 , 8 ]. Similar results were reported by Imai et al, who investigated Japanese patients [ 28 ]. In our study, 8 of the 17 patients with CPK elevation received statins concomitantly with daptomycin.…”

“…Concomitant statin use was described as a risk factor for daptomycin-associated CPK elevation in the package insert of daptomycin [ 9 ]. Case–control studies by Dare et al and Imai et al confirmed the relationship between daptomycin and CPK elevation based on the CPK levels of >ULN and >1000 IU/L or >2000 IU/L, respectively [ 6 , 28 ]. In several studies, statins were not associated with daptomycin-associated CPK elevation [ 7 , 8 , 25 , 27 , 29 ].…”

Incidence of elevated creatine phosphokinase between daptomycin alone and concomitant daptomycin and statins: A systematic review and meta‐analysis

“…We then excluded 87 articles, including studies that lacked data on concomitant statin use (74 articles), those without details on the number of patients taking statins (6 articles), studies without data on the number of patients with elevated CPK (4 articles), studies without patients with concomitant statins (two articles) and studies without data on the daptomycin group (one article). Finally, 9 studies were included in the metaanalysis to define CPK elevation as CPK levels ≥ULN, 20,26,27,[31][32][33][34][35][36] and 9 that defined CPK elevation as levels ≥5Â ULN. 6,10,20,21,28,[36][37][38][39] Two studies were included in the both analyses.…”

“…Finally, 9 studies were included in the metaanalysis to define CPK elevation as CPK levels ≥ULN, 20,26,27,[31][32][33][34][35][36] and 9 that defined CPK elevation as levels ≥5Â ULN. 6,10,20,21,28,[36][37][38][39] Two studies were included in the both analyses. 20,36…”

“…concomitant daptomycin and statin use was 1.6 and 6.1%, respectively (OR 4.09, 95% CI 1.55-10.81), and the concomitant use of daptomycin and statins was a significant risk factor for the incidence of CPK levels >5Â ULN (>1000 IU/L). 36 Berg et al have evaluated CPK elevation defined as CPK levels >336 IU/L and myalgias (including the normal range of CPK levels) with standard doses. 27 The authors reported that 3 patients taking combined daptomycin and statins exhibited myalgias, and 1 of 3 patients discontinued treatment on reported that the incidence of CPK elevation was significantly higher at trough concentrations of ≥24.3 μg/mL when CPK elevation was defined as levels >5Â ULN.…”