Die Pharmakokinetic von Meropenem bei Patienten mit schweren Infektionen

Abstract

Meropenem is a carbapenem antibiotic with a broad antibacterial spectrum, good tolerability and high penetration into infected tissues. Due to its excellent pharmacokinetic and pharmacodynamic properties it is frequently used for empirical treatment in patients with severe infections. However, there is only very limited information on its pharmocokinetic properties in these critically ill patients. Dosage recommondations are based on pharmacokinetic studies in healthy volunteers and patients with moderate infections. Studies with critically ill patients are scarce. In the present study meropenem pharmacokinetics was analysed in selected febrile hemato-oncological patients (n=10) and ICU-patients with severe infections (n=15).Under recommended standard dosing schedules defervescence could not be achieved in 25% of cases. A frequent source of therapy failure was an early rapid fall of meropenem plasma concentrations. Thus, efficacious plasma levels were obtained only during a short part of the dosing interval. The pharmacokinetic parameter best predicting the in vitro antibactericidal activity in beta lactame antibiotics is the time when the plasma concentration is above the MIC (minimal inhibitory concentration) of the causative pathogen. Using meropenem in life-threatening infections, concentrations above the MIC are recommended for 70-100% of the dosing intervall. Under standard dosage schedules the obtained concentrations lay below the MIC of the most common pathogens (4 mg/L) in 56 % of the studied patients already after less than 70 % of the dosing intervall. In febrile hemato-oncological patients an unexpected high meropenem clearance (217 mL/min) was often found which led to an early decrease of meropenem plasma levels. The high meropenem clearance correlated closely with the creatinine clearance and was probably caused by an increased renal elimination. This finding of a significantly increased meropenem clearance could particularly be shown in hemato-oncological patients with neutropenia (255 mL/min). In these patients the minimum inhibitory concentration for highly suspectible Enterobacteriaceae (MIC90 = 2 mg/L) was undercut after 66 % of the dosing interval, and for less suspectible Pseudomonas aeruginosa (MIC90 = 4 mg/L) already after 49 %. The aim of exceeding the minimal inhibitory concentration during the whole dosage interval was not reached in any of the studied hemato-oncological patients. This was the most likely reason for therapy failure in 20 % of the cases. Hemato-oncological patients are vitally threatened by insufficient antibiotic therapy as demonstrated also in the present study. The results of this investigation should lead to a deeper insight into the potential benefits of drug monitoring and dosage adjustment especially in critically ill neutropenic patients.The interindividual variability of pharmacokinetic parameters in the group of non-hemato-oncological intensive care patients with serious infections was significant higher than in the group of hemato-oncological patients. Higher interindividual fluctuations of meropenem-concentrations have been noticed. In intensive care patients an interindividual variability of renal function (Clkrea = 10,4-114 mL/min) as well as an increased and varying volume of distribution (Vss = 34,5 ± 15,9 L) were found. The meropenem clearance was often much higher than expected from the renal function of the patient. This could be the result of an increased extrarenal clearance. The described pharmacokinetic factors influenced the course of the meropenem plasma concentrations in an often unforeseeable way. Especially in intensive care patients without reduced renal function (Clkrea > 60 mL/min) a significant increase of the meropenem clearance (225 mL/min) was found. In these patients the MIC90 of Enterobacteriaceae (2 mg/L) was undercut after 73 % of the dosage interval and the MIC90 of Pseudomonas aeruginosa (4 mg/L) after 56 % of the dosage interval. This was the mostly supposable cause for the persistency of the infection in 27 % of the ICU patients. Many patients with sepsis and septic shock developed (60 %) renal failure. These patients often showed a drug accumulation with meropenem minimum concentrations above 10 mg/L. The present study showed that also the intensive care patients could potentially benefit from drug monitoring and dose adaption in the sense of therapy efficacy andsafety . Through measurement of meropenem plasma concentrations extreme accumulation and especially insufficient plasma concentrations could be avoided by dosage individualisation.