Clinical Pharmacokinetics of Daptomycin

Abstract

Due to the low level of resistance observed with daptomycin, this antibiotic has an important place in the treatment of severe Gram-positive infections. It is the first in class of the group of calcium-dependent, membrane binding lipopeptide. It is a cyclic peptide constituted of 13 amino acids and a n-decanoyl fatty acid chain. The antibacterial action of daptomycin requires its complexation with calcium.Daptomycin is not absorbed from the gastrointestinal tract and needs to be administered parenterally. The distribution of daptomycin is limited (volume of distribution of 0.1 L/kg in healthy volunteers) due to its negative charge at physiological pH and its high binding to plasma proteins (about 90%). Its elimination is mainly renal, with about 50% of the dose excreted unchanged in the urine, justifying dosage adjustment for patients with renal insufficiency. Pharmacokinetics of daptomycin is altered under certain pathophysiological conditions, resulting in high inter-individual variability. As a result, therapeutic drug monitoring (TDM) of daptomycin may be of interest for certain patients such as intensive care unit (ICU) patients, patients with renal or hepatic insufficiency, dialysis patients, obese patients or children. A target for the ratio of the area under the curve to the minimum inhibitory concentration (AUC/MIC) greater than 666 is usually recommended for clinical efficacy, whereas in order to limit the risk of undesirable muscular effects the residual concentration (Cmin) should not exceed 24.3 mg/L.

Population Pharmacokinetic/Pharmacodynamic Modelling of Daptomycin for Schedule Optimization in Patients with Renal Impairment

“…This is correlated with CPK elevations and, therefore, muscle toxicity [ 1 , 2 , 3 , 5 ] ( Figure 5 ). These results are in agreement with previous works, suggesting that higher dose levels than the approved ones of daptomycin may be required [ 19 , 21 , 49 , 64 , 65 , 66 ]. Therefore, it is evident for the need to explore more frequent schemes with lower dosage levels in order to guarantee optimal PTA levels and safety.…”

Phosphate Ions Alter the Binding of Daptomycin to Living Bacterial Cell Surfaces

“…This ratio of Dap/Ca 2+ was chosen for two specific reasons. First, the physiological concentration of calcium implicated for the successful pharmacological activity of daptomycin is 1.25 mM . This is orders of magnitude higher than the pharmacological concentration of daptomycin .…”

“…First, the physiological concentration of calcium implicated for the successful pharmacological activity of daptomycin is 1.25 mM. 48 This is orders of magnitude higher than the pharmacological concentration of daptomycin. 49 Second, as shown in Figure S3 and discussed more below, concentrations of calcium higher than the 8 mM maximum for this ratio in the isotherm experiments resulted in significant background scattering due to the formation of calcium phosphate precipitates.…”

Structure–activity relationships of antibacterial peptides

“…Daptomycin was reported to be an antibacterial approximately 100 times more effective than Vancomycin on a hamster model of Clostridium difficile (Dong et al, 1987 ). Its antibacterial activity is strictly concentration‐dependent (Wenzler et al, 2016 ), and requires complexation with calcium (Gregoire et al, 2021 ). Because it is not absorbed from the gastrointestinal tract, it has to be administered parentally.…”