PK/PD Analysis of High-Dose Daptomycin Use in the Treatment of Bone and Joint Infections: Data from a Real-World Setting

Abstract

Background: Daptomycin is widely used in bone and joint infections (BJIs) caused by Gram-positive cocci. The pharmacokinetics of daptomycin are characterized by relevant variability in terms of drug exposure. Due to these pharmacological properties, the dosing suggested by the Summary of medical Product Characteristics could result in sub-therapeutic or toxic concentrations, especially considering the high doses recommended for BJIs. Therapeutic Drug Monitoring (TDM) of daptomycin helps clinicians in verifying the patient's exposure, due to the lack of pharmacokinetic/pharmacodynamic (PK/PD) data in this clinical setting.

Methods: We retrospectively analyzed 170 daptomycin plasma concentrations of 77 patients with BJIs from July 2022 to December 2023. We focused on the pharmacokinetics of daptomycin to investigate when drug plasma concentrations achieved adequate PK/PD targets.

Results: In the first TDM, 7.8% of patients were underexposed according to the estimated area under the curve (eAUC_0-24h < 666 mg·h/L), whereas 35.1% were on target according to both the eAUC and trough plasma concentration (eAUC_0-24h 666 - 939 mg·h/L; C_min < 24.3 mg/L). The patients who were overexposed had trough plasma concentrations > 24.3 mg/L (27.3%) or eAUC_0-24h > 1174 mg·h/L (33.8%). Differences in drug exposure were observed according to weight and sex.

Conclusions: Due to the difficult management of this drug's dosing, analyzing daptomycin plasma concentrations through TDM represents a powerful tool in BJIs.

Keywords: bone and joint infections; daptomycin; infectious diseases; pharmacodynamic; pharmacokinetics; therapeutic drug monitoring.

Figure 1

Flowchart of patient inclusion and exclusion criteria for daptomycin PK/PD analysis.

Figure 2

Pharmacokinetic safety targets, indicated by trough (C_min) plasma concentration of daptomycin (A) or by estimated area under the daily concentration–time curve (eAUC₀–_24h) (B), according to the most up-to-date literature (see references in the main text).

Figure 3

Pharmacokinetic and pharmacodynamic index, considering the plasma concentrations of daptomycin and the pertinent Minimum Inhibitory Concentration, according to the most up-to-date literature (see references in the main text).

Figure 4

Estimated area under the daily concentration–time curve in different day interval dosing of daptomycin (eAUC_0–24h and eAUC_24–48h) (A) and pertinent PK/PD index (B).

Figure 5

(A) Comparison of estimated area under the daily concentration–time curve of daptomycin (eAUC_0–24h) between males and females. (B) Comparison of dose-adjusted estimated area under the daily concentration–time curve of daptomycin (eAUC_0–24h/D) between males and females. (C) Comparison of plasma trough concentrations (C_min) between males and females. (D) Comparison of dose-adjusted plasma trough concentrations (C_min/D) between males and females. (E) Comparison of plasma peak concentrations (C_max) between males and females. (F) Comparison of dose-adjusted plasma peak concentrations (C_max/D) between males and females. (G) Comparison of drug clearance (CL) between males and females. * = p value < 0.01; ** = p value < 0.001; *** = p value < 0.0001.

Figure 6

Comparison of dose-adjusted estimated area under the daily concentration–time curve of daptomycin (eAUC_0–24h/D) between patients with normal weight (BMI ≤ 25 kg/m²) and overweight patients (BMI > 25 kg/m²). **** = p value < 0.00001.

Figure 7

Vectors with loading values close to ±1 on the X-axis are strongly correlated with PC1, which represents the maximum amount of variance of data. The loading plot also illustrates the relationship between variables as described below.

Figure 8

The score plot points out the tendency of clustering based on sex (males in blue, females in red) according to the vectors described in Figure 7. Males tend to cluster on the left side of the score plot (higher values of CrCL and drug clearance, lower values of plasma concentrations/dose and AUC_0–24h/dose); females tend to cluster on the right side of the score plot (lower values of CrCL and drug clearance, higher values of plasma concentrations/dose and AUC_0–24h/dose).