PHARMACOKINETICS OF IMIPENEM-CILASTATIN IN CRITICALLY ILL PATIENTS UNDERGOING CONTINUOUS VENOVENOUS HEMOFILTRATION

The pharmacokinetics of imipenem-cilastatin were investigated in 12 cr itically ill patients with acute renal failure (ARF) managed by contin uous veno-venous hemofiltration (CVVH) while receiving a fixed combina tion of 500 mg of imipenem-cilastatin intravenously three or four time s daily. No adverse drug reactions were observed, Plasma and hemofiltr ate samples were taken at specified times during one dosing interval, and the concentrations of imipenem and cilastatin were determined by h igh-performance liquid chromatography, Pharmacokinetic variables were calculated by a first-order, two-compartment pharmacokinetic model for both substances, Total clearances of imipenem and cilastatin (mean +/ - standard deviations) were 122.2 +/- 28.6 and 29.2 +/- 13.7 ml/min, r espectively, with hemofiltration clearances of 22.9 +/- 2.5 and 16.1 /- 3.1 ml/min, respectively, and nonrenal, nonhemofiltration clearance s of 90.8 +/- 26.3 and 13.2 +/- 13.9 ml/min, respectively, Mean imipen em dosage requirements were approximately 2,000 mg/24 h (2,111.8 +/- 4 93.4 mg/24 h), They were calculated in order to achieve an average ste ady-state concentration of 12 mg/liter to ensure that concentrations i n plasma exceeded the MICs at which 90% of intermediately resistent ba cteria are inhibited (8 mg/liter) during the majority of the dosing in terval. By contrast, the recommended dosage for patients with end-stag e renal failure (ESRF) and infections caused by intermediately resista nt bacteria is 1,000 mg/24 h, This remarkable difference may be due (i ) to differences in the nonrenal clearance of imipenem between patient s with ARF and ESRF and (ii) to the additional clearance by the hemofi lter. Since the total clearance of cilastatin was low, marked accumula tion occurred, and this was particularly pronounced in patients with a dditional liver dysfunction, Thus, in patients with ARF managed by CVV H, rather high imipenem doses are required, and these inevitably resul t in a marked accumulation of cilastatin, The doses of imipenem recomm ended for patients with ESRF, however, will lead to underdosing and in adequate antibiotic therapy.