Journal of Antimicrobial Chemotherapy (2000) 45, 701-704
© 2000 The British Society for Antimicrobial Chemotherapy
Brief reports |
Elimination of meropenem during continuous veno-venous haemofiltration and haemodiafiltration in patients with acute renal failure
a Department of Medicine, Divisions of Infectious Diseases and b Nephrology, Helsinki University Central Hospital, Helsinki; c Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland
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Abstract |
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Meropenem elimination was studied in six patients with acute renal failure on continuous venovenous haemofiltration (CVVH) or continuous veno-venous haemodiafiltration (CVVHDF) 1 L/h and 2 L/h for 12 h. Meropenem 1 g was given iv over three dialysis periods, and plasma, ultrafiltrate/dialysate and urine concentrations of meropenem were determined. The half-life of meropenem was significantly longer (P < 0.05) during CVVH (7.5 ± 2.0 h; mean ± S.D.) than during CVVHDF 1 L/h (5.6 ± 1.4 h) or 2 L/h (4.8 ± 1.2 h). Meropenem clearance was 3.27 ± 2.30 L/h, 4.72 ± 2.69 L/h and 5.71 ± 3.58 L/h in CVVH, CVVHDF 1 L/h and CVVHDF 2 L/h, respectively (P < 0.05 between CVVH and CVVHDF). Patients with renal failure on CVVHDF 1 or 2 L/h should be treated with meropenem 1 g bid; 500 mg tid may be enough for patients on CVVH.
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Meropenem is a carbapenem antibiotic with a broad spectrum of activity. Its peak plasma concentrations following an intravenous infusion of 0.5 or 1 g are 25 and 50 mg/L, respectively.1 It is eliminated mainly by renal excretion and its elimination half-life is 1 h.1 Meropenem is effectively cleared by haemodialysis, with a dialysis clearance of 80 mL/min.1,2
In the treatment of acute renal failure, there is a trend to use continuous renal replacement therapies based solely on filtration (haemofiltration) or on a combination of filtration and dialysis (haemodiafiltration) rather than intermittent haemodialysis. As meropenem is of low molecular weight and low protein binding (2–12%),1 it is removed by continuous veno-venous haemofiltration (CVVH) or continuous veno-venous haemodiafiltration (CVVHDF).3–6 There have been no comparative studies on the effect of CVVH and CVVHDF on meropenem elimination.
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Materials and methods |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Patients
The study was performed at the Helsinki University Central Hospital, Finland. Six patients with acute renal failure requiring continuous renal replacement therapy and meropenem treatment were included in the study (Table
). All but patient 2 had received meropenem before the study. Approval of the Ethics Committee and written informed consent from the patients or their legal representatives were obtained.
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CVVH and CVVHDF materials and study procedure
Patients were dialysed using an ADM 08 dialysis monitor and AV 400S capillary dialyser with a 0.7 m2 polysulphone membrane (Fresenius Ag, Bad Homburg, Germany). Peritoneal dialysis solution, containing 13.6 mg/mL glucose (Baxter SA, Castlebar, Republic of Ireland) and warmed to 37°C, was used as dialysis fluid. The blood flow rate in the dialyser was 100 mL/min during the study and the average ultrafiltration rate was 0.4 L/h.
The elimination of meropenem was determined in three consecutive 12 h periods: (i) on CVVH; (ii) on CVVHDF with a dialysis fluid flow rate of 1 L/h; (iii) on CVVHDF with a dialysis fluid flow rate of 2 L/h. Before each period, 1 g of meropenem (Meronem, Zeneca, Macclesfield, UK) was given as an iv infusion over 30 min. Before the first period, patients 1 and 2 were given 0.5 g (instead of 1 g) meropenem. Immediately before drug infusion, the blood pump was switched off and the dialysis fluid compartment closed for 1 h, to achieve an even distribution of meropenem in the body. Ten timed blood samples, taken into heparinized tubes in an ice bath, and aliquots of ultrafiltrate/dialysate collected from timed fractionated collection bags, were taken 0, 0.5, 1, 2, 3, 4, 5, 7, 9 and 12 h after each infusion. The blood was centrifuged and the plasma separated immediately. Urine was collected in fractions of 12 h. All samples were kept at –70°C until assayed.
Determination of meropenem
Concentrations of meropenem in plasma, urine and ultrafiltrate/dialysate were determined by high-performance liquid chromatography using cefotaxime as an internal standard.7 The limit of quantification was 0.2 mg/L and the coefficient for day-to-day variation was 2.4% at 2.62 mg/L (n = 6).
Pharmacokinetics and statistical analysis
The elimination half-life (t
) of meropenem was determined after identification of the terminal log-linear phase of the plasma concentration–time curve. The plasma clearance (Cl) of meropenem was calculated from the equation 
, where V (the volume of distribution) = dose/C0. If no meropenem had been given before the first haemofiltration, C0 was taken as the intercept of the line representing the elimination phase and the y-axis. After the further doses, the difference between the pre-dose concentration and the calculated intercept concentration was regarded as the C0.
The pharmacokinetic data were analysed by the Friedman two-way analysis of variance and the Wilcoxon signed ranks test. The level of statistical significance was P < 0.05.
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Results |
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Plasma meropenem concentration–time profiles and cumulative amounts of meropenem removed in ultrafiltrate/dialysate are presented in the Figure
. The amount of meropenem removed in ultrafiltrate/dialysate by CVVH (mean 130 mg; range 51–221 mg) was significantly (P < 0.05) less than that removed by CVVHDF 1 L/h (327 mg; 179–601 mg) or by CVVHDF 2 L/h (399 mg; 219–590 mg) (Table
). The t of meropenem during CVVH (7.5 ± 2.0 h; mean ± S.D.) was significantly (P < 0.05) longer than that during CVVHDF 1 L/h (5.6 ± 1.4 h) and CVVHDF 2 L/h (4.8 ± 1.2 h). Renal elimination of meropenem was minimal compared with the elimination by CVVH or CVVHDF except in patient 3, who had some renal function (Table).
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), CVVHDF with a dialysis flow of 1 L/h (
) and CVVHDF with a dialysis flow rate of 2 L/h (
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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This is the first study that has compared the effect of these three methods of renal replacement therapy on the elimination of meropenem. CVVHDF was significantly more effective than CVVH alone. Furthermore, increasing the dialysis fluid flow increased the elimination of meropenem although in some patients both CVVHDF methods seemed to be about equally effective. The 12 h mean elimination of meropenem in the ultrafiltrate/dialysate was 13% during CVVH, 33% during CVVHDF 1 L/h and 40% during CVVHDF 2 L/h.
Our results agree with a case report and recent studies.4–6 However, the nature of the dialyser, and variations in blood and dialysis fluid flow rates and ultrafiltration rates influence the elimination of meropenem.3,6 In the CVVH study of Thalhammer et al.,3 the t was only 2.46 h, but the ultrafiltration flow rate used (about 3 L/h) was much higher than that in our study (0.4 L/h).
The t of meropenem is about 1.4–2.9 h during haemodialysis and 10 h between dialysis periods;1,2 the lost antimicrobial agent can be easily replaced after each haemodialysis session. In contrast, continuous dialysis treatments have an uninterrupted effect on drug elimination, which could lead to ineffective antibiotic therapy. Studies in neutropenic animals have shown that the concentration of ß-lactam antibiotics should exceed MICs of pathogens during the whole dosing interval.8 As the clinical relevance of a post-antibiotic effect of ß-lactams is uncertain,8 keeping plasma meropenem concentration above MICs seems to be justified, especially in critically ill patients. Plasma meropenem concentrations in our study were above MICs for pathogens such as Pseudomonas aeruginosa and Enterococcus faecalis, which are classified as susceptible (MICs 4 and 8 mg/L, respectively) in all but one patient (who had some renal function).1
In conclusion, in patients with acute renal failure undergoing CVVHDF treatment (1 or 2 L/h) meropenem dosing 1 g bid is recommended; during CVVH 500 mg tid may be enough.
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Notes |
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* Correspondence address. Department of Medicine, Helsinki University Central Hospital, Haartmaninkatu 4, PO Box 340, FIN-00029 HYKS, Finland. Tel: +358-9-471-73573; Fax: +358-9-471-74013; E-mail: matti.valtonen{at}huch.fi
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References |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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1 . Dollery, C. (1999). Meropenem. In Therapeutic Drugs, 2nd edn, (Dollery, C., Ed.), pp. 54–61. Churchill Livingstone, Edinburgh.
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Leroy, A., Fillastre, J. P., Borsa-Lebas, F., Etienne, I. & Humbert, G. (1992). Pharmacokinetics of meropenem (ICI 194,660) and its metabolite (ICI 213,689) in healthy subjects and in patients with renal impairment. Antimicrobial Agents and Chemotherapy 36, 2794–8.
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Thalhammer, F., Schenk, P., Burgmann, H., El Menyawi, I., Hollenstein, U. M., Rosenkranz, A. R. et al. (1998). Single-dose pharmacokinetics of meropenem during continuous venovenous hemofiltration. Antimicrobial Agents and Chemotherapy 42, 2417–20.
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Krueger, W. A., Schroeder, T. H., Hutchison, M., Hoffmann, E., Dieterich, H. J., Heininger, A. et al. (1998). Pharmacokinetics of meropenem in critically ill patients with acute renal failure treated by continuous hemodiafiltration. Antimicrobial Agents and Chemotherapy 42, 2421–4.
5 . Tegeder, I., Neumann, F., Bremer, F., Brune, K., Lotsch, J. & Geisslinger, G. (1999). Pharmacokinetics of meropenem in critically ill patients with acute renal failure undergoing continuous venovenous hemofiltration. Clinical Pharmacology and Therapeutics 65, 50–7.[Web of Science][Medline]
6 . Meyer, M. M., Munar, M. Y., Kohlhepp, S. J. & Bryant, R. E. (1999). Meropenem pharmacokinetics in a patient with multiorgan failure from meningococcemia undergoing continuous venovenous hemodiafiltration. American Journal of Kidney Diseases 33, 790–5.[Web of Science][Medline]
7 . Al-Meshal, M. A., Ramadan, M. A., Lotfi, K. M. & Shibl, A. M. (1995). Determination of meropenem in plasma by high-performance liquid chromatography and a microbiological method. Journal of Clinical Pharmacy and Therapeutics 20, 159–63.[Web of Science][Medline]
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Craig, W. A. & Ebert, S. C. (1992). Continuous infusion of ß-lactam antibiotics. Antimicrobial Agents and Chemotherapy 36, 2577–83.
Received 23 June 1999; returned 29 September 1999; revised 10 November 1999; accepted 13 December 1999
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