Assessment of pharmacokinetic changes of meropenem during therapy in septic critically ill patients

Background: Meropenem is a carbapenem antibiotic commonly used in critically ill patients to treat severe infections. The available pharmacokinetic (PK) data has been mostly obtained from healthy volunteers as well as from clinical studies addressing selected populations, often excluding the elderly and also patients with renal failure. Our aim was to study PK of meropenem in a broader population of septic critically ill patients. Methods: We characterized the PK of meropenem in 15 critically ill patients during the first 36 hrs of therapy. Aditionally, whenever possible, we collected a second set of late plasma samples after 5 days of therapy to evaluate PK intra-patient variability and its correlation with clinical course. Patients received meropenem (1 g every 8 hrs IV). Drug plasma profiles were determined by high-performance liquid chromatography. The PK of meropenem was characterized and compared with clinical parameters. Results: Fifteen septic critically ill patients (8 male, median age 73 yrs) were included. The geometric mean of the volume of distribution at the steady state (V-ss)/weight was 0.20 (0.15-0.27) L/kg. No correlation of Vss/weight with severity or comorbidity scores was found. However the Sequential Organ Failure Assessment score correlated with the Vss/ weight of the peripheral compartment (r(2) = 0.55, p = 0.021). The median meropenem clearance (Cl) was 73.3 (45-120) mL/min correlated with the creatinine (Cr) Cl (r(2)=0.35, p = 0.033). After 5 days (N = 7) although Vss remained stable, a decrease in the proportion of the peripheral compartment (V-ss2) was found, from 61.3 (42.5-88.5)\% to 51.7 (36.6-73.1)\%. No drug accumulation was noted. Conclusions: In this cohort of septic, unselected, critically ill patients, large meropenem PK heterogeneity was noted, although neither underdosing nor accumulation was found. However, Cr Cl correlated to meropenem Cl and the Vss2 decreased with patient's improvement.