Risk factors of daptomycin overexposure: a case-control study

Abstract

In our institution, therapeutic drug monitoring of daptomycin is performed routinely and cases of high trough concentrations have been observed in patients without known risk factors. The aim of this study was to identify risk factors of daptomycin overexposure. We performed a case-control study of daptomycin overexposure in patients who received daptomycin between 2013 and 2021. Cases and controls were defined as patients with trough concentration (Cmin) ≥60 mg/L and Cmin <60 mg/L, respectively. Univariate and multivariate analyses were performed with logistic regression models. Retained variables were further analyzed by subgroup analysis and comparison of the pharmacokinetic parameters of daptomycin. We analyzed data from 78 and 26 patients in the control and case groups, respectively. The male-to-female ratio was 1.5. The median (interquartile range) of age, body weight, and creatinine clearance was 66.5 (55-77) years, 77 (65-96) kg, and 98.5 (53-124) mL/min, respectively. Increasing body mass index (BMI) and co-administration of irbesartan were identified as risk factors of daptomycin overexposure with odds ratio (OR) (95% confidence interval [CI]) of 2.9 [1.4-6.2], and 6.1 [1.1-40.8], respectively, whereas increasing creatinine clearance was associated with decreasing risk, with OR of 0.16 [0.05-0.35]. The influence of BMI was attributed to the non-linear relationship between body weight and daptomycin PK parameters and the use of weight-based dosing in patients with high BMI. In addition to renal impairment, high BMI and irbesartan co-administration may be associated with an augmented risk of daptomycin overexposure. Dosing based on actual body weight should be avoided in obese patients.

Keywords: bone joint infection; daptomycin; pharmacokinetics; therapeutic drug monitoring.

Fig 1

Correlation between daptomycin trough concentration and creatinine clearance. The black line represents the regression line. The color scale of dots reflects the level of trough concentrations from the lowest (green) to the highest (dark red). The ρs represents Spearman’s correlation coefficient, and P represents the associated P value.

Fig 2

Correlation between daptomycin trough concentration and body mass index. The black line represents the linear regression line. The ρ_s represents Spearman’s correlation coefficient, and P represents the associated P value.

Fig 3

Receiver operating characteristic curve for classification of overexposure by the logistic regression model. The blue line represents the ROC curve, the blue area represents the 95% confidence interval, and the dashed line represents the random classification.

Fig 4

Distribution of daptomycin clearance in groups of body mass index. Panels show total daptomycin clearance (A), daptomycin clearance/total body weight (B), daptomycin clearance/adjusted body weight (C), and daptomycin clearance/ideal body weight (D).