Correlation of Meropenem Plasma Levels with Pharmacodynamic Requirements in Critically Ill Patients Receiving Continuous Veno-Venous Hemofiltration

Abstract

Background: In patients with acute renal failure, the pharmacokinetics of meropenem depend on the operational characteristics of the renal replacement therapy. Dosage recommendations are based on the correlation of plasma levels with pharmacodynamic requirements. Methods: Eight critically ill patients with acute renal failure were treated by continuous veno-venous hemofiltration with a filtrate flow of 1,600 ml/h and received 500 mg of meropenem every 12 h. Plasma and hemofiltrate concentrations of meropenem at steady state were determined by HPLC. Results: Peak levels in plasma amounted to 39.5 ± 10.5 mg/l (mean ± SD) and trough levels were 2.4 ± 1.5 mg/l. The minimal inhibitory concentration (MIC) for susceptible bacteria (4 mg/l) was covered for 40% of the dosing interval or longer in all patients. The MIC for intermediately susceptible organisms (8 mg/l) was covered for 33% in 6 of the 8 patients. The elimination half-life was prolonged to 3.63 ± 0.77 h. The sieving coefficient of meropenem was 0.91 ± 0.10 and the recovery in hemofiltrate amounted to 30.9 ± 11.5% of the dose. Conclusions: A dosage of 500 mg twice daily provides appropriate serum levels for the treatment of infections caused by susceptible bacteria. A higher dosage is adequate for infections by intermediately susceptible bacteria or for renal replacement therapies with markedly higher filtrate flow rates.

Evaluation by Monte Carlo Simulation of the Pharmacokinetics of Two Doses of Meropenem Administered Intermittently or as a Continuous Infusion in Healthy Volunteers

“…This represents a serious challenge for the drug. In the vast majority of instances, populations of ill patients have lower drug clearances, larger volumes of distribution, and, consequently, longer terminal halflives than those seen in healthy volunteer populations (20,28,29,44). Consequently, the conclusions that emerge from an analysis of volunteer data are quite conservative with regard to the probability of target attainment.…”

“…We found a relatively low variability for meropenem, with coefficients of variation of 19% for total clearance and 28% for the volume of distribution of the central compartment in this study with healthy volunteers (Table 1). In severely ill patients, a considerably higher variability of meropenem pharmacokinetics may be observed (28,29). It should be noted that the low variability in pharmacokinetic parameters observed in this study may lead to conclusions that are not conservative enough, especially for the treatment of severely ill patients.…”

Meropenem Population Pharmacokinetics in Critically Ill Patients with Septic Shock and Continuous Renal Replacement Therapy: Influence of Residual Diuresis on Dose Requirements

“…However, this population is subject to conditions that may significantly influence meropenem pharmacokinetics (PKs) and, consequently, modify the dosing requirements, such as hypoproteinemia, variable urine output, or diverse CRRT settings (6). It follows that while several studies have described meropenem PKs in critically ill patients with continuous venovenous hemofiltration (CVVHF) and continuous venovenous hemodiafiltration (CVVHDF) (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19), empirical dosing at the bedside is still challenging in this scenario.…”

Treatment with Tigecycline of Recurrent Urosepsis Caused by Extended-Spectrum-β-Lactamase-Producing Escherichia coli

“…Meropenem was given at 1 g twice daily, as recommended for patients receiving continuous hemofiltration (3,4). Linezolid was stopped on day 4, since the microbiological samples obtained upon admission showed uniform growth of E. coli in blood cultures, the tracheal aspirate, and the sample obtained from the right renal pelvis.…”

“…On the other hand, the half-life of meropenem is prolonged at least fourfold in anuric patients treated with continuous hemofiltration (4). This means that there is a prolonged time above the MIC for the infecting pathogens, and the pharmacokinetic profile of meropenem in such situations meets the pharmacodynamic requirements, even without the use of continuous infusions (3).…”