This is the first study to investigate the pharmacokinetics of meropenem during high-volume CVVHF. The results of this study show significant meropenem clearance in patients with acute kidney injury receiving CVVHF with high-volume exchanges.
Meropenem is a frequently used empirical antibiotic treatment in the critical care setting because of its broad spectrum of action. Pharmacodynamically, meropenem shows time-dependent bacterial killing, and optimal bactericidal activity suggests that maintaining a concentration above the MIC for at least 40% of the dosing time is required. However, emerging retrospective clinical studies involving meropenem support a longer f T>MIC
in critically ill patients of up to 100% of the dosing interval (18
). However, for critically ill patients with renal dysfunction or those requiring renal replacement therapy such as CVVHF, there remains significant concern from clinicians that dosing recommendations facilitate optimal pharmacodynamic exposures of meropenem.
The pharmacokinetics of meropenem in CVVHF have been studied previously. However, the operational characteristics of the CVVHF used in these studies have varied greatly; the membrane surface areas have varied between 0.43 and 0.9 m2, the ultrafiltrate flow rate (UFR) between 1 and 2 liters/h, and the blood flow rates between 0.6 and 12 liters/h, and different types of membranes have been used. The local protocol used at our institution uses significantly higher blood flow rates (250 ml/min), higher UFRs (4.4 liters/h), and a membrane with a surface area of 2.15 m2. Hence, our study is able to provide a valuable contrast between each of the studies on the relative effect of UFR on meropenem clearance.
In this study, we observed a median clearance due to this form of hemofiltration of 3.49 liters/h. Compared to the previous studies using low ultrafiltrate flow rates, we have observed that meropenem clearance is largely explained by the differing UFRs. In evaluating the total clearance (CLtot) from each of the studies, the reasons for the differences are not apparent. The effects of residual renal function and the levels of sickness severity were reported inconsistently between these studies, making a systematic interpretation not possible.
Knowledge of drug clearance during a form of renal replacement therapy is important. However, dosing can rarely be based solely on clearance data. Once steady state has been achieved, dosing should be based on drug clearance. In renally impaired patients receiving renal replacement therapy, consideration of possible residual renal clearance or other nonrenal clearance is essential. Although data for upregulated nonrenal clearance exist for ciprofloxacin in renal dysfunction (20
), we are not aware of any similar data for meropenem.
This paper has shown that meropenem clearance during CVVHF is heavily influenced by UFR. It follows that the clinical use of high-volume CVVHF requires a higher meropenem dose than previously considered necessary for CVVHF. Our data suggest that CVVHF settings similar to that used in our study require a steady-state meropenem dose of 1,000 mg every 8 h to maintain concentrations above the MIC of less susceptible pathogens such as B. pseudomallei (MIC90, 4.0 mg/liter, compared with the median [90th percentile] trough concentration observed in this study of 7.6 mg/liter [5.5 mg/liter]). For more susceptible organisms, a lower dose may be used, although a lower dose would be inappropriate for empirical therapy in most centers.
A possible limitation to the comparisons made between this study and others using CVVHF with lower-volume exchanges is the use of prefilter replacement fluid in this study. Of the other studies undertaken, each of them used postfilter dilution with replacement fluid. This is unlikely to affect the conclusions on the importance of UFR for meropenem clearance but may be important.
In conclusion, CVVHF with high-volume exchanges results in significant clearance of meropenem. Comparing the results of our study with previous studies that use lower-volume exchanges, we have been able to show that UFR is the main determinant of meropenem clearance during CVVHF. It follows that, when using CVVHF with high-volume exchanges, higher doses than those usually used in CVVHF are appropriate. Our data suggest that steady-state dosing of 1,000 mg every 8 h provides appropriate meropenem concentrations for less susceptible organisms such as B. pseudomallei.