| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
PHARMACOKINETICS |
From the Laboratory of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of the Basque Country, Vitoria-Gasteiz, Spain (Ms Isla, Dr Gascón, Ms Arzuaga, and Dr Pedraz), the Intensive Care Unit, Santiago Apóstol Hospital, Vitoria-Gasteiz, Spain (Drs Maynar and Corral), and the Intensive Care Unit, Doce de Octubre Hospital, Madrid, Spain (Dr Sánchez-Izquierdo).
Address for reprints: Dr José Luis Pedraz Muñoz, Laboratorio de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia. Paseo de la Universidad no 7. 01006 Vitoria-Gasteiz, Spain.
 |
ABSTRACT |
|---|
 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
Key Words: Continuous renal replacement therapies • meropenem • pharmacokinetics • critically ill
The pharmacokinetic properties of meropenem have been assessed in healthy volunteers, in patients with serious infections, and in patients with renal or hepatic failure. It has been shown that meropenem has a linear pharmacokinetic profile, with an elimination half-life (t
) of approximately 1 hour in healthy volunteers.2-6 Meropenem is eliminated by both metabolism and excretion. In healthy volunteers, 19% to 27% of a 1 g dose is excreted as a microbiologically inactive open ß-lactam metabolite,2 and up to 83% of the dose is recovered in urine.7 Consequently, both the total body and renal clearance of meropenem decrease in patients with impaired renal function, and t increases significantly in correlation with the severity of the renal failure, thus dose reductions are recommended in the event of renal impairment.1,2,6,8-11
Patients in ICU who develop acute renal failure frequently require artificial support, commonly continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis (CVVHD), or continuous venovenous hemodiafiltration (CVVHDF). These processes involve pumping blood from the patient's circulation through an extracorporeal circuit incorporating a synthetic membrane. Plasma water and small molecular weight solutes, including drugs, are removed from the blood via convective forces in hemofiltration and diffusive forces in hemodialysis12 and are lost as dialysate-ultrafiltrate. The elimination of antimicrobials depends on the size of the pores in the membrane used, the molecular size, and the absorption to the filter.13 The structural and pharmacokinetic characteristics of meropenem, that is, water solubility, relatively small molecular weight (383.5 d), and low protein binding, allow for the efficient removal of this drug by both CVVH and CVVHD. This fact may complicate dosing regimens. On one hand, accumulation of the drugs may be associated with adverse effects. On the other hand, subtherapeutic concentrations may be associated with the emergence of bacterial resistance. Therefore, appropriate management of critically ill infected patients is mandatory to avoid treatment failures and to improve survival.
Several studies have been published about meropenem pharmacokinetics in patients with acute renal failure undergoing continuous renal replacement therapies (CRRTs).9,14-22 Although some authors have reported the usefulness of CRRTs in critically ill patients without renal function impairment, such as trauma patients,23 cardiovascular surgery patients,24 and septic patients25,26, all the previous studies have been performed in patients with acute renal failure. Moreover, no comparisons between different membranes have been carried out in those in vivo studies.
The primary goal of the current study was to describe in detail the pharmacokinetics of meropenem in critically ill patients with different degrees of renal impairment undergoing CVVH or CVVHDF. Previously, the permeability of 2 different membranes to meropenem in CVVH and CVVHD was characterized in vitro to detect possible differences dependent on the employed technique and the membranes used.
|
METHODS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
Procedure of CRRT in Vitro
The renal replacement machine (PRISMA, Hospal, Lyon, France) was prepared according to instructions for use. In vitro CRRT procedures were performed with 2 of the membranes frequently used in clinical practice: AN69 HF 0.9 m2 acrylonitrile and sodium methallyl sulfonate copolymer filter (Prisma M100, Hospal) and 1.15 m2 polysulfone (PS) (Prisma HF1000, Hospal). The meropenem vehicle flow rate was kept at 150 mL/min. In the CVVH mode, the ultrafiltrate was removed at the rate of 1500 mL/h. In the CVVHD mode, the counter-current dialysis fluid flow was 1500 mL/h. Replacement fluid (Dialisan, Hospal, Barcelona, Spain) was delivered prefilter.
Ringer lactate solution, bovine albumin–containing Ringer lactate solution (concentration, 2 g/dL), or human fresh plasma were circulated as meropenem vehicles in the blood space of the system for 60 minutes. Initial concentrations of meropenem in all vehicles were close to the maximum concentrations we expected to find in vivo. Prefilter and dialysate-ultrafiltrate samples (4 mL) were collected at 0, 5, 10, 15, 30, 45, and 60 minutes. Samples were immediately stored at –80°C until analysis. New filters were used for the procedures performed with every vehicle.
Procedure of CRRT in Vivo
The study group consisted of 20 patients in the ICU undergoing CVVHDF or CVVH. Table I shows the characteristics of the patients included. The study protocol was approved by the Medical Ethical Committee of the Santiago Apóstol Hospital (Vitoria-Gasteiz, Spain) and Doce de Octubre Hospital (Madrid, Spain). All patients or guardians provided written informed consent. Complete medical histories were obtained for all patients, and complete physical examinations and laboratory review of serum chemistry and hematology profiles were performed and reviewed before collection of samples for pharmacokinetic analysis.
|
Vascular access was obtained with 13.5 fg dual lumen catheters (Niagara, Bard Canada Inc, Mississauga, Ontario, Canada). Hemodialfiltration machines (PRISMA, Hospal; MULTIFILTRATE, Fresenius Medical Care, Bad Homburg, Germany) were used with polyacrylonitrile AN69 HF 0.9 m2 (PRISMA M100, Hospal) membranes in 15 patients, or PS membranes (Ultraflux AV600S, 1.4 m2 Fresenius polysulfone, Fresenius Medical Care) in 5 patients. The blood flow was kept between 100 and 220 mL/min. In the CVVHDF procedures, the dialysate flow rate (Qd) was 500 or 1000 mL/h into the dialysate compartment of the filter in a blood flow countercurrent direction. The ultrafiltrate obtained was replaced as clinically indicated at rates between 800 and 2500 mL/h. Replacement fluids were delivered prefilter. Table I shows the flows used in each patient, as well as their demographic characteristics.
Creatinine clearance (Clcr) of meropenem was determined as Clcr = (Ucr•Vu)/(Pcr•t), where Ucr and Pcr are creatinine concentration in urine and plasma, respectively; Vu is the urine volume collected in 24 hours; t is urinary collection time (1440 min).17,27
Patients received 500, 1000, or 2000 mg of meropenem intravenously every 6 or 8 hours. Meropenem was dissolved in 100 mL saline solution just before it was infused into a central venous catheter during a period of 20 minutes. Patients had received several doses before analysis, so steady-state conditions were guaranteed. Blood samples (lithium heparin as anticoagulant, 4 mL) were obtained from a prefilter device immediately before dosing, at the end of the infusion, and at 20, 30, 45 minutes and at 1, 3, and 6 hours after the beginning of the infusion. Another sample was collected 8 hours after the beginning of the infusion in patients to whom meropenem was administered every 8 hours. Simultaneously, dialysate-ultrafiltrate samples (3 mL) were taken directly from the dialysate-ultrafiltrate device. Blood specimens were centrifuged within 1 hour for 10 minutes at 1500 g at 4°C. Plasma and dialysate-ultrafiltrate samples were immediately frozen at –20°C. Within the following week, samples were stored at –80°C and were analyzed within 1 month. Blood samples were obtained in all patients, but dialysate-ultrafiltrate samples were collected in only 14 subjects.
Sample Analyses
Determination of meropenem concentrations in plasma and dialysate-ultrafiltrate fluid was performed by high-performance liquid chromatography with a Waters (Waters Corp, Milford, Mass) apparatus coupled to a spectrophotometric detector, and the analytical methods were validated.28,29 The method for bovine albumin–containing Ringer lactate and plasma samples consisted of protein precipitation with acetonitrile, followed by washing with dichloromethane. Dialysate-ultrafiltrate samples did not require any preparation. Separation was performed on a µBondapak C18 (30 cm x 3.9 mm x 10 µm; Waters Corp) with ultraviolet detection (296 nm). The mobile phase contained acetate buffer: acetonitrile (95:5, volume:volume) and was delivered at 2 mL/min. The assay was linear over the concentration range of 0.25 to 100 µg/mL for plasma samples and of 0.1 to 100 µg/mL for dialysate-ultrafiltrate. The intraday and interday coefficients of variation ranged from 0.67% to 9.64% for plasma samples and from 0.31% to 10.64% for dialysate-ultrafiltrate samples at the 3 concentrations tested (0.75, 10, and 75 µg/mL for plasma and 0.3, 5, and 75 µg/mL for dialysate-ultrafiltrate). The bias at these concentrations ranged from 2.02% to 14.44% in plasma samples and from 0.11% to 9.85% in dialysate-ultrafiltrate fluid. The limit of quantification was considered the lowest level included in the calibration curve (0.25 µg/mL in plasma and 0.10 µg/mL in dialysate-ultrafiltrate), where measures of intraday coefficient of variation and bias were 3.55% and 8.98% for plasma samples and 7.73% and 3.19% for dialysate-ultrafiltrate samples. No interfering peaks were detected with the assay.
Protein binding was measured by ultrafiltration using Sartorius Centrisart I filters (cut-off, 10 000; Sartorius AG, Goettingen, Germany).
Mathematical Calculations, Pharmacokinetic Analysis
In the in vitro CVVH procedures, the sieving coefficient (Sc), defined as the fraction of drug eliminated across the membrane, was calculated by using the abbreviated formula described by Golper et al30:Sc=Cuf/Cp,where Cuf is the drug concentration in the ultrafiltrate and Cp is the drug concentration in the prefilter port of simultaneously collected specimens. Similarly, in the CVVHD procedures, the saturation coefficient (Sa), defined as the fraction of drug diffused through the membrane to the dialysate fluid, was calculated as Sa = Cd/Cp, where Cd is the meropenem concentration in dialysate. Fraction unbound to proteins (fu) was also determined as fu = Cunbound/Cp, where Cunbound is the unbound drug concentration, and Cp is the total concentration of meropenem in the same sample.
Plasma and dialysate-ultrafiltrate concentrations of meropenem in patients were plotted against time, and individual pharmacokinetic parameters were determined according to a noncompartmental analysis by using the WinNonlin version 1.1 (Pharsight Corp, Mountain View, Calif).
Plasma and dialysate-ultrafiltrate areas under the curve (AUCs) were determined from the first to the last data point by the linear trapezoidal method. The elimination rate constant (ke) was determined via log-linear regression analysis using the terminal portion of the plasma prefilter concentration versus time curves. Values for t were derived from ke as follows: t =ln(2)/ke. The total body clearance (ClT) was obtained by the equation ClT = dose/AUC. The volume of distribution at steady state (Vss) was obtained by Vss = MRT•Cl, where MRT is the total mean residence time. Because area under the moment curve (AUMC) during a dosing interval at steady state (AUMCss) is less than the total AUMC after a single dose,31 MRT and Vss could not be calculated directly from steady-state data. Thus, the reverse superposition method proposed by Bauer and Gibaldi31 was applied. According to this method, each data point on the single-dose curve was calculated by means of the following equation: C(t) = Ci(t) – Ci(0)exp(–knt), where C(t) is the calculated concentration after a single dose at time t, Ci(t) is the observed concentration during the ith dosing interval at time t, Ci(0) is the postabsorbtive, postdistributive drug concentration at the start of the ith dosing interval, and kn is the terminal rate constant.
In patients undergoing CVVH, Sc was calculated as Sc = AUCuf/AUCp, where AUCuf is the area under the ultrafiltrate concentration versus time curve and AUCp is the area under the plasma concentration (collected in the prefilter port) versus time curve.15,32,33 In patients undergoing CVVHDF, the drug clearance occurred by diffusion as well as convection. Sa was calculated as Sa = AUCuf/d/AUCp, where AUCuf/d is the area under the combined ultrafiltrate and dialysate concentration versus time curve.
The clearance by hemofiltration or hemodiafiltration (ClCRRT) was obtained by using the following equations: ClCRRT = Sc•QCRRT in CVVH procedures and ClCRRT = Sa•QCRRT in CVVHDF procedures, where QCRRT is the ultrafiltrate plus the dialysate flow rates (Qd+Quf). The percentage of ClT contributed by ClCRRT (ClCRRT%) was calculated as ClCRRT/ClT•100.
Statistics
Statistical analyses were performed with SPSS 11.5 software for Windows (SPSS Inc, Chicago, Ill). The Shapiro-Wilks test was used to verify normality and the Levene test was used to verify homogeneity of variances. To determine statistical comparisons for the in vitro procedures, t tests were used. The Mann-Whitney U test was used to analyze the data of the pharmacokinetic parameters and the Sc/Sa among the renally impaired groups. Statistical significance was assessed at P < .05.
|
RESULTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
|
During CVVH and CVVHD, the Sc and Sa were close to 1 when the Ringer lactate was used as a meropenem vehicle with both membranes. In albumin-containing samples, such as Ringer lactate plus albumin samples and plasma samples, Sc and Sa decreased and obtained values close to the free fraction.
Statistically significant differences (P < .05) were found in the Sc and Sa between AN69 and PS membranes with bovine serum albumin–containing Ringer lactate samples.
In Vivo Results
Twenty patients aged from 21 to 83 years with different degrees of renal disease who were admitted to the ICU, were treated with CRRT, and had received meropenem, were enrolled in this study (Table I). Meropenem was well tolerated in all patients; no adverse reactions attributable to the treatment with meropenem were reported. Subjects were grouped into 3 categories according to the renal function: 7 patients with severe failure, Clcr less than 10 mL/min (group I); 7 patients with moderate failure, Clcr 10 to 50 mL/min (group II); and 6 patients with Clcr greater than 50 mL/min (group III).
In 14 of 20 patients, Sc/Sa was determined. Mean ± SD Sc/Sa (0.80 ± 0.12) was similar to the fu (0.79 ± 0.08), with no significant differences. Table III details determinations in different subsets of patients. No significant differences depending on renal impairment were found in the Sc.
|
Figure 1 shows the mean meropenem plasma levels in the patients with different degrees of renal impairment and the minimum inhibitory concentration (MIC) values of 0.25, 0.5, 1, 2, and 4 µg/mL. Table III summarizes pharmacokinetic parameters for each individual patient and the mean ± SD values for each group. Plasma levels were similar in patients of groups I and II but lower in patients of group III. Statistics revealed significant differences (P < .05) in ClT and ClCRRT% of group III with respect to groups I and II (Figures 2 A, B, C, and D). Significant differences (P < .05) were also found in the t among the 3 groups (Figures 2 E and F), and in Vss of group III with respect to group II.
|
|
|
DISCUSSION |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
1) and CVVHD (Sa 1). In the procedures carried out in albumin-containing Ringer lactate solutions and in plasma, a correlation of the Sc with the free fraction of the drug was shown, as had been previously reported for many drugs.34,35 No differences were found in the Sc obtained by CVVH and the Sa obtained by CVVHD; both membranes showed a similar permeability to meropenem, with the exception of the procedures carried out in albumin-containing Ringer lactate, where Sc during CVVH and Sa during CVVHD were higher with PS membranes. However, this fact can be attributable to the lower fu values obtained with AN69 membranes. When the permeability of the 2 different membranes was compared, the study was designed to evaluate the pharmacokinetics of meropenem on patients with different renal function. Previously published studies dealing with meropenem in CRRT included patients with acute renal failure; but the pharmacokinetics of meropenem in nonanuric patients has not been studied, although CRRT has become an important modality of treatment in various acute situations without renal failure and the role of CRRT in nonrenal indications is expanding.23-26,36
The mean Sc/Sa values measured in the 14 patients whose dialysate-ultrafiltrate samples were obtained were consistent with the mean fu. Therefore, extracorporeal clearance was calculated as ClCRRT = fu•QCRRT in the 6 patients from whom dialysate-ultrafiltrate samples were not analyzed. No significant differences were found in the Sc/Sa values between groups I and II. No statistical comparison among the 3 groups could be made because dialysate-ultrafiltrate samples were extracted from only 1 patient of group III. However, the Sc value of meropenem in that patient was in the range of the other 2 groups. This finding means that renal function does not affect the fraction of drug that crosses the membranes. The absence of significant differences in the Sc depending on renal impairment had also been previously documented for piperacillin and tazobactam.37 The results showed no differences between both membranes, as in the in vitro procedures. A bibliographical search through the Medline database (1950-present) using SciFinder Scholar (CAS, Columbus, Ohio) and WinSpirs (Silverplatter Information, Norwood, Mass) software (search terms included meropenem, hemofiltration, hemodialysis,and renal failure) failed to identify other publications in which the permeability of 2 different membranes is evaluated in vivo. Most of the previous studies in patients were performed by using only polyacrylonitrile membranes,15-19,21-22 whereas 2 other studies were performed with only PS membranes.14,20
Although the fraction of drug crossing the membranes did not differ across groups, the patient renal function could influence the pharmacokinetics of meropenem in critically ill patients undergoing CVVH or CVVHDF, as it has been shown for other antibiotics.37 As Figure 2 shows, the total clearance was significantly higher in group III than in the other 2 groups. This finding could be attributable to the lower t (1.51 ± 0.52 hours in group III versus 2.73 ± 0.68 hours and 3.72 ± 0.82 hours in groups II and I, respectively) and to the high volume of distribution observed in those patients (1.31 ± 0.90 L/kg in group III, 0.37 ± 0.10 L/kg in group II, and 0.57 ± 0.29 L/kg in group I). Most patients with CLcr greater than 50 mL/min were critically ill trauma patients receiving large quantities of intravenous fluid during an extended treatment period. This outcome can result in an expanded extracellular compartment, which could be the reason for the increased distribution volume, as happens with other drugs.18,38
The contribution of CRRT to total clearance diminished in the extent that Clcr increased (Figure 2). Although there were no statistically significant differences between groups I and II, ClCRRT% was significantly lower in group III. It is necessary to consider that the extracorporeal clearance depends not only on the renal function of the patient, but it also depends on ultrafiltrate and dialysate flow rates, which were lower in group III. In any case, the elimination of meropenem by CRRT was clinically relevant in patients with moderate or severe renal failure, as previously reported by other authors, but the contribution of extracorporeal elimination to the ClT was lower in patients with Clcr higher than 50 mL/min.
The mean elimination t of meropenem in patients with the higher Clcr was similar to that observed in healthy volunteers7 and increased in accordance with the severity of the renal impairment (Figure 2), as is the case in patients not undergoing CRRT.11 However, when comparing meropenem t in patients with the same degree of renal impairment, with or without CRRT treatment, the t was lower in those undergoing CRRT because of the extracorporeal clearance of meropenem.
Because ß-lactam antibiotics show time-dependent antibacterial activity,39 the most important pharmacokinetic-pharmacodynamic predictor of clinical efficacy is the time during which serum drug concentrations are above the MIC (T > MIC) of the infecting pathogen.39,40 In critically ill patients, T > MIC = 100% should be obtained. The National Committee for Clinical Laboratory Standards41 has established the breakpoints for susceptible, intermediate susceptible, and resistant strains of enterobacteriaceae, Pseudomonas and Staphylococcus in 
4 µg/mL, 8 µg/mL and 
16 µg/mL, respectively. The breakpoint for susceptible Haemophilus and group viridians streptococci is 0.5 µg/mL, and the value for susceptible Streptococcus pneumoniae and Meningococcus is 0.25 µg/mL. In group I patients, trough plasma concentrations were above 4 µg/mL, with the exception of the only patient who received 500 mg/8 h. In group II, plasma concentrations were above 2 µg/mL during the entire dose interval, except in the patient to whom 1000 mg/8 h was administered. In spite of the higher doses the patients of group III received, 4 of 6 patients showed concentrations below 0.5 µg/mL. Therefore, it may happen that the patients do not reach adequate efficacy indexes to deal with specific infections.
In spite of the results obtained in this study, the following issues should still be considered. First, the penetration of antibiotics to the target site is variable, and the efficacy may be different in sites with poor drug penetration. Second, Clcr is variable in critically ill patients. Thus, frequent monitoring and further adjustments should be performed to note fluctuations. Third, the sample size is small, and findings based on small sample size should be confirmed by further studies. Most studies are about anuric patients, but this study is the only work that evaluates the pharmacokinetics of meropenem in patients with different degrees of renal dysfunction. Fourth, the pharmacokinetics of the microbiologically inactive metabolite of meropenem (ICI-213689) has not been studied. The nonrenal clearance of meropenem has been demonstrated to increase from 20% of total elimination in healthy volunteers to about 50% in patients with Clcr less than 30 mL/min.11 Fifth, the case mix and the volume of distribution may be different in other series (other modalities of ventilation, different proportion of shock). Indeed, variations in pharmacokinetic parameters are encountered frequently in critically ill patients. Thus, one should be cautious before generalizing the findings to individual patients in other institutions.
In summary, meropenem was significantly removed by CRRT. No significant differences were found in the Sc or the Sa of meropenem between AN69 and PS membranes used in CVVH or CVVHD in the in vitro study. Differences in meropenem pharmacokinetics in critically ill patients undergoing CRRT with different degrees of renal impairment have been observed, and they should be taken into account when dosing critically ill patients. In those with no renal impairment, the total meropenem clearance was higher because of the lower elimination t and the higher distribution volume observed, and it lowered the contribution of extracorporeal clearance. In these patients, the risk of underdosing and clinical failure is important, and we have shown how the administration of meropenem 2000 mg every 8 hours did not reach plasma levels to ensure adequate T > MIC values against many bacteria. In anuric patients and in those with moderate renal failure, extracorporeal clearance might significantly contribute to the ClT, and no statistically significant differences were found in the ClT of meropenem between these 2 groups. Therefore, the dose regimen in these 2 groups probably should not be different. Further pharmacokinetic studies would be necessary to determine the efficacy of different meropenem dose regimens in patients undergoing CRRT without renal failure.
|
ACKNOWLEDGEMENTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
|
REFERENCES |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
1. Wiseman LR, Wagstaff AAJ, Brogden RN, Bryson HM. Meropenem: a review of its antibacterial activity, pharmacokinetic properties and clinical efficacy. Drugs. 1995;50: 73-101.[Web of Science][Medline] [Order article via Infotrieve]
2. Hurst M, Lamb HM. Meropenem: a review of its use in patients in intensive care. Drugs. 2000;59: 653-680.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
3. Burman LA, Nilsson-Ehle I, Hutchison M, Haworth SJ, Norrby SR. Pharmacokinetics of meropenem and its metabolite ICI 213,689 in healthy subjects with known renal metabolism of imipenem. J Antimicrob Chemother. 1991;27: 219-224.
4. Kelly HC, Hutchison M, Haworth SJ. A comparison of the pharmacokinetics of meropenem after administration by intravenous injection over 5 min and intravenous infusion over 30 min. J Antimicrob Chemother. 1995;36(SupplA): 35-41.
5. Bax RP, Bastain W, Featherstone A, Wilkinson DM, Hutchison M, Haworth SJ. The pharmacokinetics of meropenem in volunteers. J Antimicrob Chemother. 1989;24(SupplA): 311-320.
6. Moon YSK, Chung KC, Gill MA. Pharmacokinetics of meropenem in animals, healthy volunteers, and patients. Clin Infect Dis. 1997;24(Suppl2): 249-255.
7. Mouton JW, van der Anker JN. Meropenem clinical pharmacokinetics. Clin Pharmacokinet. 1995;28: 275-286.[Web of Science][Medline] [Order article via Infotrieve]
8. Leroy A, Fillastre JP, Borsa-Lebas F, Etienne I, Humbert G. Pharmacokinetics of meropenem (ICI 194,660) and its metabolite (ICI 213,689) in healthy subjects and in patients with renal impairment. Antimicrob Agents Chemother. 1992;36: 2794-2798.
9. Talhammer F, Hörl WH. Pharmacokinetics of meropenem in patients with renal failure and patients receiving renal replacement therapies. Clin Pharmacokinet. 2000;39: 271-279.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
10. Lovering AM, Vickery CJ, Leaper D, et al. The pharmacokinetics of meropenem in surgical patients with moderate or severe infections. J Antimicrob Chemother. 1995;36: 165-172.
11. Christensson BA, Nilsson-Ehle I, Hutchison M, Haworth SJ, Óqvist B, Norrby SR. Pharmacokinetics of meropenem in subjects with various degrees of renal impairment. Antimicrob Agents Chemother. 1992;36: 1532-1537.
12. Brunet S, Leblanc M, Geadah D, Parent D, Courteau S, Cardinal J. Diffusive and convective solute clearances during continuous renal replacement therapy at various dialysate and ultrafiltration flow rates. Am J Kidney Dis. 1999;34: 486-492.[Web of Science][Medline] [Order article via Infotrieve]
13. Joos B, Schimidli M, Keusch G. Pharmacokinetics of antimicrobial agents in anuric patients during continuous veno-venous haemofiltration. Nephrol Dial Transplant. 1996;11: 1582-1585.
14. Thalhammer F, Schenk P, Burgmann H, et al. Single-dose pharmacokinetics of meropenem during continuous venovenous hemofiltration. Antimicrob Agents Chemother. 1998;42: 2417-2420.
15. Krueguer WA, Schroeder TH, Hutchison M, et al. Pharmacokinetics of meropenem in critically ill patients with acute renal failure treated by continuous hemodiafiltration. Antimicrob Agents Chemother. 1998;42: 2421-2424.
16. Meyer MM, Munar MY, Kohlhepp SJ, Bryant RE. Meropenem pharmacokinetics in a patient with multiorgan failure from meningococcemia undergoing continuous venovenous hemodiafiltration. Am J Kid Dis. 1999;33: 790-795.[Web of Science][Medline] [Order article via Infotrieve]
17. Tegeder I, Neumann F, Bremer F, Brune K, Lötsch J, Geisslinger G. Pharmacokinetics of meropenem in critically ill patients with acute renal failure undergoing continuous venovenous hemofiltration. Clin Pharmacol Ther. 1999;65: 50-57.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
18. Giles LJ, Jennings AC, Thomson AH, Creed G, Beale RJ, McLuckie A. Pharmacokinetics of meropenem in intensive care unit patients receiving continuous veno-venous hemofiltration or hemodiafiltration. Crit Care Med. 2000;28: 632-637.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
19. Ververs TFT, van Dijk A, Vinks SATMM, et al. Pharmacokinetics and dosing regimen of meropenem in critically ill patients receiving continuous venovenous hemofiltration. Crit Care Med. 2000;28: 3412-3416.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
20. Valtonen M, Tiula E, Backman JT, Neuvonen PJ. Elimination of meropenem during continuous veno-venous haemofiltration and haemodiafiltration in patients with acute renal failure. J Antimicrob Chemother. 2000;45: 701-704.
21. Krueger WA, Neeser G, Schuster H, et al. Correlation of meropenem plasma levels with pharmacodynamic requirements in critically ill patients receiving continuous veno-venous hemofiltration. Pharmacology. 2003;49: 280-286.
22. Robatel C, Decosterd LA, Biollaz J, Exkert P, Schaller MD, Buclin Y. Pharmacokinetics and dosage adaptation of meropenem during continuous venovenous hemodiafiltration in critically ill patients. J Clin Pharmacol. 2003;43: 1329-1340.
23. Sánchez-Izquierdo Riera JA, Alted E, Lozano MJ, Ambros A, Caballero R. Influence of continuous hemofiltration on the hemodynamics of trauma patients. Surgery. 1997;122: 902-908.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
24. Journois D, Israel-Biet D, Pouard P, et al. High-volume, zero balanced hemofiltration to reduce delayed inflammatory response to cardiopulmonary bypass in children. Anesthesiology. 1996;85: 965-976.[Web of Science][Medline] [Order article via Infotrieve]
25. Oudemans-van Straaten HM, Bosman RJ, van der Spoel JI, Zandstra DF. Outcome of critically ill patients treated with intermittent high-volume haemofiltration: a prospective cohort analysis. IntensiveCareMed. 1999;25: 814-821.
26. Honoré PM, Jamez J, Wauthier M, et al. Prospective evaluation of short-term, high-volume isovolemic hemofiltration on the hemodynamic course and outcome in patients with intractable circulatory failure resulting from septic shock. Crit Care Med. 2000;28: 3581-3587.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
27. Wuyts B, Bernard D, Van Den Noortgate N, et al. Reevaluation of formulas for predicting creatinine clearance in adults and children, usingcompensated creatinine methods. Clin Chem. 2003;49: 1011-1014.
28. Shah VP, Midha KK, Findlay JWA, et al. Bioanalytical method validation: a revisit with a decade of progress. Workshop/Conference Report. Pharm Res. 2000;17: 1551-1557.[CrossRef][Medline] [Order article via Infotrieve]
29. Food and Drug Administration. Guidance for industry: bioanalytical methods validation for human studies. Rockville, Md: Center for Drug Evaluation and Research; 1998.
30. Golper TA, Wedel SK, Kaplan AA, Saad AM, Donta ST, Paganini EP. Drug removal during continuous arteriovenous hemofiltration: theory and clinical observations. IntJArtif Organs. 1985;8: 307-312.
31. Bauer LA, Gibaldi M. Computation of model-independent pharmacokinetic parameters during multiple dosing. J Pharm Sci. 1983;72: 978-979.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
32. Lee CC, Marbury TC. Drug therapy in patients undergoing hemodialysis: clinical pharmacokinetic considerations. Clin Pharm. 1984;9: 42-66.
33. Kroh UF. Drug administration in critically ill patients with acute renal failure. New Horiz. 1995;3: 748-759.[Medline] [Order article via Infotrieve]
34. Golper TA. Drug removal during continuous hemofiltration or hemodialysis. Contrib Nephrol. 1991;93: 110-116.[Medline] [Order article via Infotrieve]
35. Isla A, Gascón AR, Maynar J, Arzuaga A, Toral D, Pedraz JL. Cefepime and continuous renal replacement therapy (CRRT): in vitro permeability of two CRRT membranes and pharmacokinetics in four critically ill patients. Clin Ther. 2005;27: 599-608.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
36. Beck LL, O'Keefe HJ. The challenges of CRRT delivery following a hospital merger. The 10th International Conference on Continuous Renal Replacement Therapies (CRRT). Abstracts. Blood Purif. 2005;23: 149-174.
37. Arzuaga A, Maynar J, Gascón AR, et al. Influence of renal function on the pharmacokinetics of piperacillin/tazobactam in intensive care unit patients during continuous venovenous hemofiltration. J Clin Pharmacol. 2005;45: 168-176.
38. Hanes SD, Wood GC, Herring V, et al. Intermittent and continuous infusion for critically ill trauma patients. Am J Surg. 2000;179: 436-440.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
39. Hyatt JM, McKinnon S, Zimmer GS, Schentag JJ. The importance of pharmacokinetic/pharmacodynamic surrogate markers to outcome: focus on antibacterial agents. Clin Pharmacokinet. 1995;28: 143-160.[Web of Science][Medline] [Order article via Infotrieve]
40. Craig WA. Interrelationship between pharmacokinetics and pharmacodynamics in determining dosage regimens for broad spectrum cephalosporins. Diagn Microbiol Infect Dis. 1995;22: 89-93.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
41. National Committee for Clinical Laboratory Standards (NCCLS). Performance standards for antimicrobial susceptibility testing. 14th informational supplement. NCCLS document M100-S14. Wayne, Pa: National Committee for Clinical Laboratory Standards; 2004.
CiteULike 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
