Simultaneous Therapeutic Drug Monitoring Of Amikacin And Beta-Lactams In Intensive Care Unit Patients With Severe Sepsis Or Septic Shock Without Beta-Lactam Serum Concentration Monitoring
F.T. Musuamba(1), I. Delattre(1), P.F. Laterre(3), J. Cumps(4), F. Jacobs(5), R.K. Verbeeck(2 )and P. Wallemacq(1)
(1)Department of Clinical Biochemistry, (2)Department of Pharmacokinetics, (3)Department of Biostatistics, Université Catholique de Louvain, Brussels, Belgium; (3)Department of Intensive Care, St-Luc Hospital, Brussels, Belgium; (5)Department of Infectious Diseases, Erasme Hospital, Brussels; Belgium
Background: Associations of aminoglycosides and β-lactams are the most used treatment in intensive care unit (ICU) patients with severe sepsis or septic shock. These antibiotics dosage regimens take rarely into account pharmacokinetic (PK) variability and disease-induced alterations that may result in inadequate concentrations. Moreover, these antibiotics, except aminoglycosides, are not routinely adjusted by therapeutic drug monitoring (TDM).
The aim of the study was to develop a population pharmacokinetic-pharmacodynamic (PPK/PD) model able to predict the exposure and outcome of 4 Amikacin (AMK)- β-lactam co-medications in order to optimize their dosage regimens.
Methods: 74 ICU critically septic patients were included. All received a first dose of AMK combined with piperacillin/tazobactam, ceftazidime, cefepime or meropenem. The five antibiotic PK parameters were estimated using WinNonlin® software. A PPK/PD analysis was performed using NONMEM software. AMK PK parameters, demographic and routine biochemistry data were used as covariables to predict the β-lactam PK. In a second time, the treatment failure was predicted from the co-medication exposure and patients' characteristics.
Results: Four two-compartments models were built in order to predict Amikacin β-lactam PK parameters (volume of distribution, clearance, elimination half-live and area under the curve). For each β-lactam PK parameter, the corresponding AMK parameter was retained as covariable in the final PK model. Co-medication exposure was well correlated with treatment failure.
Conclusions: The four ß-lactam and AMK exposure have been predicted from AMK TDM in ICU patients with severe sepsis or septic shock. An efficacy-based-TDM can be routinely done for the four ß-lactams without their serum concentration monitoring.