A prospective study to evaluate high dose daptomycin pharmacokinetics and pharmacodynamics in Staphylococcus spp. infective endocarditis.

Background: Daptomycin pharmacokinetics and pharmacodynamics data relative to higher doses in patients are necessary for clinical practice.

Objectives: A monocentric, prospective study that enrolled patients with a diagnosis of Staphylococcus spp. infective endocarditis treated with daptomycin according to clinical practice, to evaluate the pharmacokinetics/pharmacodynamics of different daptomycin daily doses (group A: 8-10 and group B: 11-12 mg/kg).

Design and methods: A monocentric, prospective, cohort study that enrolled patients with a diagnosis of Staphylococcus spp. infective endocarditis treated with daptomycin. Daptomycin was administered by intravenous infusion over a 30-min period for at least five consecutive days before PK study.

Results: Twenty-two patients were included. Native valve infectious endocarditis (IE) was diagnosed in 9 patients, prosthetic valve IE was diagnosed in 10 patients and 3 patients had concomitant intracardiac device infections. All patients showed a microbiologic response with negative blood cultures by day 5 (1-3 interquartile rate (IQR) 3-8). The median calculated AUC_0-24 was 1298 (1-3 IQR 1069-1484) and 1459 (1-3 IQR 1218-1711) µg*h/mL, with the corresponding clearance of 0.49 (1-3 IQR 0.37-0.57) and 0.57 (1-3 IQR 0.40-0.71) L/h, respectively. A value of area under the curve/minimum inhibitory concentration (AUC/MIC) > 666 was reached by all patients; however, 4 out of 15 patients in group A and 1 out of 14 patients in group B did not reach the pharmacokinetic/pharmacodynamic (PK/PD) target of 1061; therefore, AUC/MIC equal to or above 1061 was reached by 73.3% in group A and 92.9% in group B.

Conclusion: From a PK/PD point of view, all patients reached the value of AUC/MIC > 666, while roughly 70% of patients in group A and 90% in group B reached the target value of AUC/MIC>1061. Even if this cut-off value is arbitrary, 11-12 mg/kg daily dose could be taken into consideration in case of serious infections characterised by a high inoculum or in cases of prosthetic valve infections.