Pharmacokinetics of imipenem-cilastatin in critically ill patients undergoing continuous venovenous hemofiltration

Abstract

The pharmacokinetics of imipenem-cilastatin were investigated in 12 critically ill patients with acute renal failure (ARF) managed by continuous veno-venous hemofiltration (CVVH) while receiving a fixed combination of 500 mg of imipenem-cilastatin intravenously three or four times daily. No adverse drug reactions were observed. Plasma and hemofiltrate samples were taken at specified times during one dosing interval, and the concentrations of imipenem and cilastatin were determined by high-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, respectively, with hemofiltration clearances of 22.9 ؎ 2.5 and 16.1 ؎ 3.1 ml/min, respectively, and nonrenal, nonhemofiltration clearances of 90.8 ؎ 26.3 and 13.2 ؎ 13.9 ml/min, respectively. Mean imipenem dosage requirements were approximately 2,000 mg/24 h (2,111.8 ؎ 493.4 mg/24 h). They were calculated in order to achieve an average steady-state concentration of 12 mg/liter to ensure that concentrations in plasma exceeded the MICs at which 90% of intermediately resistent bacteria are inhibited (8 mg/liter) during the majority of the dosing interval. By contrast, the recommended dosage for patients with end-stage renal failure (ESRF) and infections caused by intermediately resistant bacteria is 1,000 mg/24 h. This remarkable difference may be due (i) to differences in the nonrenal clearance of imipenem between patients with ARF and ESRF and (ii) to the additional clearance by the hemofilter. Since the total clearance of cilastatin was low, marked accumulation occurred, and this was particularly pronounced in patients with additional liver dysfunction. Thus, in patients with ARF managed by CVVH, rather high imipenem doses are required, and these inevitably result in a marked accumulation of cilastatin. The doses of imipenem recommended for patients with ESRF, however, will lead to underdosing and inadequate antibiotic therapy.

How can we ensure effective antibiotic dosing in critically ill patients receiving different types of renal replacement therapy?

“…Substantial clearance of meropenem was also observed during PIRRT (Deshpande et al, 2010;Kielstein et al, 2006). Imipenem data is similar to that reported for meropenem for effluent flow rates between 20 and 37 mL/min where CRRT contributed to 20-30% of the CL total (Fish et al, 2005;Hashimoto et al, 1997;Tegeder et al, 1997). Limited data is available for other carbapenems, with continuous hemodiafiltration (effluent flow rate 13.3-33.3 mL/min) accounting for~20-30% of doripenem clearance (Hidaka et al, 2010;Roberts et al, 2014).…”

“…As for other beta-lactams, CI could be an alternative strategy to better achieve meropenem PK/PD target (N40% T NMIC ) in patients receiving CRRT (Jamal et al, 2015;Langgartner et al, 2008). The usual imipenem doses (1-2 g/day) did not consistently achieve the desired PK/PD targets for effluent flow rates~20 mL/min (Fish et al, 2005;Hashimoto et al, 1997;Tegeder et al, 1997). Alterations in non-renal clearance that have been described for imipenem in critically ill patients with different levels of native renal function receiving CRRT (Mueller et al, 1993), supports the need for higher doses in these scenarios.…”

Using Imipenem and Cilastatin During Continuous Renal Replacement Therapy

“…Two described patients receiving CVVH 8,9 , one described CVVHD 10 , one continuous arteriovenous haemodialysis (CAVHD) 11 , two described continuous arteriovenous haemofiltration (CAVH) 12,13 and one described 'continuous volumeconstant haemofiltration,' presumed to be CVVH 14 .…”

“…Three of the papers 8,9,13 state that no adverse drug reactions (ADRs) occurred during the study; however, since seizures were the only ADR assessed during two of these studies 8,9 , patients may have suffered other effects such as GI disturbances or rash without these being documented. The remaining papers do not comment on the incidence of ADRs.…”

Drug Dosing During Intermittent Hemodialysis and Continuous Renal Replacement Therapy

“…The same process rates, and an almost linear increase in ceftazidime clearance with estimates that, with the more aggressive CRRT dialysate flow and increasing dialysate inflow rates. ultrafiltration rate of >1500 mL/m 2 /h, the CRRT cefepime dosage [83][84][85][86][87] 358. …”