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Antimicrobial Agents and Chemotherapy, September 1998, p. 2421-2424, Vol. 42, No. 9
Department of
Anesthesiology1 and
Department of
Internal Medicine,3 Tübingen
University Hospital, Tübingen, Germany, and
ZENECA
Pharmaceuticals,2 Mereside, Alderly Park,
Macclesfield, Cheshire, United Kingdom
Received 29 December 1997/Returned for modification 6 April
1998/Accepted 22 June 1998
The pharmacokinetics of meropenem were studied in nine anuric
critically ill patients treated by continuous venovenous
hemodiafiltration. Peak levels after infusion of 1,000 mg over 30 min
amounted to 103.2 ± 45.9 µg/ml, and trough levels at
12 h were 9.6 ± 3.8 µg/ml. A dosage of 1,000 mg of
meropenem twice a day provides plasma drug levels covering
intermediately susceptible microorganisms. Further reductions of the
dosage might be appropriate for highly susceptible bacteria or when
renal replacement therapies with lower clearances are applied.
Meropenem is a carbapenem
antibacterial agent. It is highly active against a broad spectrum of
gram-positive and gram-negative bacteria (8) and may be
applied as an empirical treatment of severe infections (16,
17). The purpose of this investigation was to study the
pharmacokinetics of meropenem in critically ill patients with acute
renal failure treated by continuous venovenous hemodiafiltration.
Nine critically ill patients were included in the study after informed
consent was obtained by close relatives and after the protocol had been
approved by the Ethics Committee of the
Eberhard-Karls-Universität, Tübingen, Germany. All patients
suffered from acute renal failure with anuria in the course of septic
multiple organ failure or due to cardiac failure (Table
1) and were treated by continuous venovenous hemodiafiltration (BSM 22-SC; Hospal, Myezieu, France). A
blood flow of 100 ml/min and a countercurrent dialysate flow of 1,600 ml/h were maintained throughout the study period. The dialysate fluid
(SH 44-HEP; Schiwa, Glandorf, Germany) was buffered with 8.4%
bicarbonate. The hemofilter consisted of AN69 hollow fibers with an
effective surface area of 0.90 m2 (Multiflow 100; Hospal),
and the amount of hemodiafiltrate was adjusted as necessary and
measured hourly (Table 1). A dose of 1,000 mg of meropenem was
administered every 12 h intravenously (i.v.) in 100 ml of 0.9%
NaCl through a central venous catheter. Trough levels in plasma were
monitored over several days. Blood samples were drawn through an
arterial line at 0, 15, 30, 45, 60, 120, 240, 360, and 720 min after
the start of a 1,000-mg dose, which was infused over exactly 30 min.
Samples of hemodiafiltrate were collected simultaneously with the
plasma samples. All blood samples were immediately centrifuged at
693 × g for 10 min at 4°C. Aliquots of plasma and
diafiltrate were instantly frozen and stored at
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Copyright © 1998, American Society for Microbiology. All rights reserved.
Pharmacokinetics of Meropenem in Critically Ill Patients with
Acute Renal Failure Treated by Continuous Hemodiafiltration
ABSTRACT
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80°C. Two to seven
days later, levels of meropenem were determined by
high-performance liquid chromatography and UV detection by
slight modifications of methods described by others (3, 4,
12).
TABLE 1.
Demographic and diagnostic information and
pharmacokinetic parameters following administration of 1,000 mg of
meropenem i.v. for nine anuric critically ill patients treated by
continuous hemodiafiltrationa
The limit of quantification of meropenem was 0.8 µg/ml in plasma and 2.0 µg/ml in diafiltrate. The response from calibration standards was linear from 1.0 to 100.0 µg/ml for plasma and from 2.0 to 100 µg/ml for diafiltrate. Precision control standards for six different concentrations between 3.0 and 100 µg/ml yielded a relative recovery of 94 to 107%, and the coefficients of variance were 0.6 to 10.3% for plasma and 2.4 to 10.7% for diafiltrate.
Plasma meropenem concentration-time data were analyzed by the trapezoidal method and by linear regression of the terminal phase to determine the area under the concentration-time curve from 0 to 12 h (AUC0-12), the clearance, and the elimination half-life. The data were fitted by the pharmacokinetic modelling program MODFIT (1) with a repeated-dose, two-compartment infusion model by weighted least-square regression with weighting as 1/y2, and the fit was evaluated from the standard errors of the parameter estimates. The estimated values from the fitted model were used to derive the volume of distribution at steady state and the distribution half-life. The saturation coefficients (Sc) were calculated as AUC0-12 values of meropenem in diafiltrate divided by AUC0-12 values in plasma. The hemodiafiltration clearance was calculated as (Qf + Qd) × Sc, where Qf is the filtrate flow and Qd is the dialysate flow (20).
Trough levels of meropenem in plasma were obtained 1 to 7 days after all inclusion criteria had been met and amounted to 9.1 ± 3.2 µg/ml (n = 24; range, 4.7 to 16.3 µg/ml). According to these results, the dosage of 1,000 mg of meropenem twice a day (b.i.d.) was considered appropriate, and the pharmacokinetic investigation was started. Peak levels of meropenem in plasma were reached at the end of the infusion (Fig. 1) and ranged from 67.0 to 205.1 µg/ml (mean, 103.2 ± 45.9). Trough levels at 0 min and after 12 h were 9.4 ± 3.6 µg/ml and 9.6 ± 3.8 µg/ml, respectively (Fig. 1). The saturation coefficient of meropenem was 1.06. Additional pharmacokinetic parameters are listed in Table 1.
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There was no evidence of adverse drug reactions. Three patients died due to cardiocirculatory failure 2, 6, and 18 days after the end of the study, respectively. One patient (patient 5) recovered from renal failure after the third trough level had been determined. No meropenem pharmacokinetic parameters were obtained for this patient.
The elimination half-life of meropenem for our patients was 4.53 ± 1.35 h, which is approximately four times as long as that reported for healthy volunteers (0.8 to 1.2 h) (2, 4, 6, 11,
15, 18). In healthy subjects, meropenem is eliminated by both
glomerular filtration and tubular secretion (2). About 62 to
79% of the dose is recovered unchanged in urine, and most of the
remainder is also eliminated in urine as the ring-opened metabolite ICI
213,689 (2, 4, 11). In our patients, the hemodiafiltration
clearance of meropenem was tightly controlled by the fixed operational
characteristics of the renal replacement therapy and amounted to
30.4 ± 2.0 ml/min. This accounted for roughly half of the total
body clearance, which had a larger variation and amounted to 54.6 ± 17.0 ml/min. In humans, the 1
-methyl substituent of meropenem
confers a high resistance to renal dehydropeptidase I (9),
but the -lactam ring is hydrolyzed in plasma and the relative
proportion of this ring-opened metabolite excreted in urine increases
with time after administration of the mother compound (11).
The high concentrations of circulating metabolite observed in renally
impaired subjects suggest that hydrolysis is greater in such patients
and that the renal excretion of the metabolite is an important but slow
process (5, 6, 15). Thus, it may be assumed that most of the
remaining clearance of meropenem in our patients had been accomplished
by diafiltration of the metabolite, which is readily dialysable
(6, 15).
For patients with normal renal function, meropenem is usually administered every 8 h (3, 17, 19). In end-stage chronic renal failure, the half-life of meropenem is prolonged to 7 to 10 h, so one dose every 24 h is considered appropriate and an additional dose is recommended after dialysis (5, 6, 15). The application interval of 12 h which we had chosen for our patients corresponds well to the recommendations for patients whose creatinine clearances amount to 30 ml/min (5). In such patients, the nonrenal clearance of meropenem contributes to up to 50% of the total body clearance (6), as was the case in our patients.
However, for any dosage recommendations, the operational characteristics of renal replacement therapies as well as physicochemical properties of the drug have to be considered. Only the unbound drug may pass through the hemofilter membrane, which is demonstrated by the close correlation of the unbound fractions of drugs with the corresponding sieving coefficients (10). While sieving refers to the connective transport of drugs along with plasma water in hemofiltration, an additional mechanism of elimination in hemodiafiltration is the diffusion of drugs into the countercurrently flowing dialysis fluid. In this technique, the drug concentration in diafiltrate divided by the concentration in plasma gives the saturation coefficient, which may become smaller with high flow rates that do not allow complete saturation of the dialysis fluid (20). In our study, the saturation coefficient of 1.06 indicates both free passage of meropenem across the filter membrane and enough contact time for complete saturation. This is consistent with the 2% plasma protein binding of meropenem (13), which also largely excludes factors which may influence the hemofiltration of highly protein-bound drugs such as coadministered drugs, bilirubin concentrations, and pH changes (10). There was also no evidence of binding of meropenem to the AN69 filter membrane used in this study nor with polyamide or polysulphone membranes (21). Thus, in the absence of these complicating factors, the clearance of the renal replacement therapy is determined by the amount of filtrate produced and by the dialysate flow rate.
The plasma meropenem concentrations immediately following the infusions
were considerably higher in our patients (103.2 ± 45.9 µg/ml)
than in healthy volunteers (54.8 ± 6.8 µg/ml) (14, 22). However, these values might not be directly comparable, as
we administered meropenem through central venous catheters and drew the
blood samples through arterial lines, whereas peripheral veins of
opposite arms are used with healthy volunteers. Our approach might have
resulted in less distribution of the drug, especially in patients with
severe cardiac impairment. However, the antimicrobial effectiveness of
-lactam antibiotics is not enhanced by high peak levels; the most
important determinant is the length of time the drug levels remain
above the minimal inhibitory concentration (MIC) (7, 23,
24). The mean levels of meropenem in plasma in our study exceeded
the MICs for pathogens classified as susceptible or of intermediate
susceptibility (MICs of <4 and 8 µg/ml, respectively) (8)
throughout the dosing interval (Fig. 1). Indeed, in the case of highly
susceptible bacteria, a reduction of the dose might even have been
possible.
In conclusion, we consider 1,000 mg of meropenem b.i.d. an appropriate dosage in anuric critically ill patients treated by hemodiafiltration. A lower dosage might be adequate when renal replacement therapies with lower filtrate or dialysate flow are applied or when the MICs for the infecting bacteria are low, so lower trough levels should still be therapeutically effective.
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ACKNOWLEDGMENTS |
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We thank the ICU staff for their support, especially R. Fretschner, B. Kottler, and T. Risler. We also thank M. Deeg for his advice concerning the high-performance liquid chromatography analysis and M. Trick for his skillful assistance.
The study was supported by a grant from ZENECA GmbH, Plankstadt, Germany.
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FOOTNOTES |
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* Corresponding author. Present address: Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, 181 Longwood Ave., Boston, MA 02115. Phone: (617) 525-2680. Fax: (617) 731-1541. E-mail: wkrueger{at}rics.bwh.harvard.edu.
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Copyright © 1998, American Society for Microbiology. All rights reserved.
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