S Piva1,2, Antonello Di Paolo3, Laura Galeotti4, Francesco Ceccherini4, Francesco Cordoni4, Liana Signorini5, Tommaso Togni6, Amedeo De Nicolò7, Frank A Rasulo6,8, Nazzareno Fagoni6, N Latronico6,8, Antonio D'Avolio7. 1. Department of Anesthesia, Critical Care and Emergency, Spedali Civili University Hospital, Piazzale Spedali Civili di Brescia 1, Brescia, Italy. simone.piva@unibs.it. 2. Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Piazza del Mercato, 15, Brescia, Italy. simone.piva@unibs.it. 3. Department of Clinical and Experimental Medicine, Section of Pharmacology, University of Pisa, Via Roma, 67, Pisa, Italy. 4. Phymtech Srl (Physical and Mathematical Technologies), Via Giuntini 63, Navacchio di Cascina, Pisa, Italy. 5. Second Division of Clinical Infectious Diseases, Department of Infectious Diseases, Spedali Civili University Hospital, Piazzale Spedali Civili di Brescia, Brescia, Italy. 6. Department of Anesthesia, Critical Care and Emergency, Spedali Civili University Hospital, Piazzale Spedali Civili di Brescia 1, Brescia, Italy. 7. Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy. 8. Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Piazza del Mercato, 15, Brescia, Italy.
Abstract
BACKGROUND: There are currently few data concerning the cerebrospinal fluid (CSF) penetration of daptomycin in patients with healthcare-associated meningitis. This study aims (1) to better characterize the pharmacokinetics of daptomycin in humans during a 7-day intravenous (IV) therapy course, and (2) to study the penetration of daptomycin in the CSF after IV infusion at the dose of 10 mg/kg. RESULTS: In this prospective observational study, we enrolled nine patients with an implanted external ventricular drainage and a diagnosis of a healthcare-associated meningitis. Daptomycin was administered at 10 mg/kg for a maximum of 7 days. The pharmacokinetic of daptomycin was studied using a two-compartment population/pharmacokinetic (POP/PK) model and by means of a nonlinear mixed effects modeling approach. A large inter-individual variability in plasma area under the curve (Range: 574.7-1366.3 h mg/L), paralleled by high-peak plasma concentration (Cmax) (all values > 60 mg/L), was noted. The inter-individual variability of CSF-AUC although significant (range: 1.17-6.81 h mg/L) was narrower than previously reported and with a late occurrence of CSF-Cmax (range: 6.04-9.54 h). The terminal half-life between plasma and CSF was similar. tmax values in CSF did not show a high inter-individual variability, and the fluctuations of predicted CSF concentrations were minimal. The mean value for daptomycin penetration obtained from our model was 0.45%. CONCLUSIONS: Our POP/PK model was able to describe the pharmacokinetics of daptomycin in both plasma and CSF, showing that daptomycin (up to 7 days at 10 mg/kg) has minimal penetration into central nervous system. Furthermore, the observed variability of AUC, tmax and predicted concentration in CSF was lower than what previously reported in the literature. Based on the present findings, it is unlikely that daptomycin could reach CSF concentrations high enough to have clinical efficacy; this should be tested in future studies.
BACKGROUND: There are currently few data concerning the cerebrospinal fluid (CSF) penetration of daptomycin in patients with healthcare-associated meningitis. This study aims (1) to better characterize the pharmacokinetics of daptomycin in humans during a 7-day intravenous (IV) therapy course, and (2) to study the penetration of daptomycin in the CSF after IV infusion at the dose of 10 mg/kg. RESULTS: In this prospective observational study, we enrolled nine patients with an implanted external ventricular drainage and a diagnosis of a healthcare-associated meningitis. Daptomycin was administered at 10 mg/kg for a maximum of 7 days. The pharmacokinetic of daptomycin was studied using a two-compartment population/pharmacokinetic (POP/PK) model and by means of a nonlinear mixed effects modeling approach. A large inter-individual variability in plasma area under the curve (Range: 574.7-1366.3 h mg/L), paralleled by high-peak plasma concentration (Cmax) (all values > 60 mg/L), was noted. The inter-individual variability of CSF-AUC although significant (range: 1.17-6.81 h mg/L) was narrower than previously reported and with a late occurrence of CSF-Cmax (range: 6.04-9.54 h). The terminal half-life between plasma and CSF was similar. tmax values in CSF did not show a high inter-individual variability, and the fluctuations of predicted CSF concentrations were minimal. The mean value for daptomycin penetration obtained from our model was 0.45%. CONCLUSIONS: Our POP/PK model was able to describe the pharmacokinetics of daptomycin in both plasma and CSF, showing that daptomycin (up to 7 days at 10 mg/kg) has minimal penetration into central nervous system. Furthermore, the observed variability of AUC, tmax and predicted concentration in CSF was lower than what previously reported in the literature. Based on the present findings, it is unlikely that daptomycin could reach CSF concentrations high enough to have clinical efficacy; this should be tested in future studies.
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