Removal of linezolid by conventional intermittent hemodialysis, sustained low-efficiency dialysis, or continuous venovenous hemofiltration in patients with acute renal failure

OBJECTIVE: To study the removal of linezolid, a new oxazolidinone antibiotic, by renal replacement therapy in patients with acute renal failure. DESIGN: Prospective, single-dose pharmacokinetic study. SETTING: Renal intensive care unit of a tertiary university hospital. PATIENTS: Fifteen critically ill patients with oliguric acute renal failure on renal replacement therapy (seven males, mean age 72.3 yrs, range 60-94; Acute Physiology and Chronic Health Evaluation II score 24.9, range 18-36; mechanical ventilation ten of 15). INTERVENTIONS: All patients received 600 mg of intravenous linezolid before starting renal replacement therapy, which consisted of intermittent hemodialysis lasting 3-4 hrs in eight patients, sustained low-efficiency dialysis lasting 8 hrs in five patients, and continuous venovenous hemofiltration lasting 10.5-12 hrs in two patients. MEASUREMENTS AND MAIN RESULTS: Linezolid concentrations were measured by liquid chromatography/mass spectrometry methods on serum and dialysate/ultrafiltrate samples. At the start of renal replacement therapy, serum levels averaged 11.91 mg/L (range 5.49-21.52) and dropped at the end to levels <4 mg/dL (90% minimum inhibitory concentration values for Staphylococcus aureus) in three of eight patients on hemodialysis, three of five patients on sustained low-efficiency dialysis, and two of two patients on continuous venovenous hemofiltration. Mean removal of the drug was 193.7 mg with hemodialysis (32.3% of the dose administered), 205 mg with sustained low-efficiency dialysis (33.9%), and 74.8 mg (12.4%) and 105 (17.5%) mg following a continuous venovenous hemofiltration session lasting 10.5 and 12 hrs, respectively. CONCLUSIONS: In patients with acute renal failure, serum levels of linezolid can be reduced to the subtherapeutic range following renal replacement therapy.     

Pharmacokinetics and dosing regimen of meropenem in critically ill patients receiving continuous venovenous hemofiltration

OBJECTIVE: To study the pharmacokinetics of meropenem in critically ill patients with acute renal failure receiving continuous venovenous hemofiltration (CWHF). DESIGN: Prospective, open-labeled study. SETTING: Medical intensive care unit of the University Medical Center Utrecht. PATIENTS: Five critically ill patients receiving CWHF for acute renal failure treated with meropenem for documented or suspected bacterial infection. INTERVENTION: All patients received meropenem (500 mg) administered intravenously every 12 hrs. Plasma samples and ultrafiltrate aliquots were collected during one dosing interval. MEASUREMENTS AND RESULTS: Mean age and body weight of the patients studied were 46.6 yrs (range, 28-61 yrs) and 85.8 kg (range, 70-100 kg), respectively. The following pharmacokinetic variables for meropenem were obtained: mean peak plasma concentration was 24.5 +/- 7.2 mg/L, mean trough plasma concentration was 3.0 +/- 0.9 mg/L, mean terminal elimination half-life was 6.37 +/- 1.96 hrs, mean total plasma clearance was 4.57 +/- 0.89 L/hr, mean CWHF clearance was 1.03 +/- 0.42 L/hr, mean nonrenal clearance was 3.54 +/- 1.06 L/hr, and mean volume of distribution was 0.37 +/- 0.15 L/kg. CONCLUSION: In critically ill patients with acute renal failure, nonrenal clearance became the main elimination route. CWHF substantially contributed to the clearance of meropenem (23% of mean total plasma clearance). We recommend meropenem to be dosed at 500 mg intravenously every 12 hrs in patients receiving CWHF, according to our operational characteristics. This dosing regimen resulted in adequate trough plasma levels for susceptible microorganisms.     

Cost of acute renal failure requiring dialysis in the intensive care unit: clinical and resource implications of renal recovery

OBJECTIVE: Acute renal failure can be treated with continuous renal replacement therapy (CRRT) or intermittent hemodialysis. There is no difference in mortality, although patients treated with CRRT may have a higher rate of renal recovery. Given these considerations, an estimate of the costs by modality may help in choosing the method of dialysis. As such, the objective of this study was to estimate the cost of CRRT and intermittent hemodialysis in the intensive care unit and to explore the impact of renal recovery on subsequent clinical outcomes and costs among survivors. DESIGN: Retrospective cohort study of all patients who developed acute renal failure and required dialysis between April 1, 1996, and March 31, 1999. SETTING: Two tertiary care intensive care units in Calgary, Canada. PATIENTS: A total of 261 critically ill patients. INTERVENTIONS: None. MEASUREMENTS: All patients were followed to determine in-hospital and subsequent clinical outcomes (survival and frequency of renal recovery). The immediate and potential long-term costs of CRRT and intermittent hemodialysis were measured. MAIN RESULTS: The cost of performing CRRT ranged from Can 3,486 dollars to Can 5,117 dollars per week, depending on the modality and the anticoagulant used, and it was significantly more expensive than intermittent hemodialysis (Can 1,342 dollars per week). Survivors with renal recovery spent significantly fewer days in hospital (11.3 vs. 22.5 days, p<.001) and incurred less healthcare costs (11,192 dollars vs. 73,273 dollars, p<.001) over the year after hospital discharge compared with survivors who remained on dialysis. CONCLUSIONS: Immediate cost savings could be achieved by increasing the use of intermittent hemodialysis rather than CRRT for patients with acute renal failure in the intensive care unit. Because of the high cost of ongoing dialysis, CRRT may still be an economically efficient treatment if it improves renal recovery among survivors; further study in this area is required.     

Pharmacokinetics of meropenem in intensive care unit patients receiving continuous veno-venous hemofiltration or hemodiafiltration

OBJECTIVE: To evaluate an intravenous meropenem dosage regimen in adult intensive care patients with acute renal failure treated by continuous renal replacement therapy. DESIGN: A prospective, clinical study. SETTING: General intensive care unit of a university hospital. PATIENTS: Ten critically ill adult patients being treated with meropenem and receiving continuous veno-venous hemofiltration (hemofiltration rates, 1-2 L/hr) (n = 5) or continuous venovenous hemodiafiltration (hemofiltration rates, 1-1.5 L/hr; dialysis rates, 1-1.5 L/hr) (n = 5) via a polyacrylonitrile hollow fiber 0.9-m2 filter. INTERVENTIONS: Patients received a meropenem dose of 1 g iv every 12 hrs as a 5-min bolus. MEASUREMENTS AND MAIN RESULTS: Meropenem concentrations were measured by high-performance liquid chromatography in serum taken at timed intervals and in ultrafiltrate/dialysate to determine serum concentration-time profiles, derive pharmacokinetic variable estimates, and determine sieving coefficients and filter clearances. The serum concentrations were examined to see whether they were above the minimum inhibitory concentrations (MICs) for pathogens that may be encountered in intensive care patients. Serum concentrations exceeded 4 mg/L (MIC90 for Pseudomonas aeruginosa) during 67% of the dosage period in all patients. Sub-MIC90 concentrations were obtained in three patients immediately before treatment and in one patient 12 hrs after treatment. Mean (SD) (n = 10) pharmacokinetic variable estimates were as follows: elimination half-life, 5.16 hrs (1.83 hrs); volume of distribution, 0.35 L/kg (0.10 L/kg); and total clearance, 4.30 L/hr (1.38 L/hr). A sieving coefficient of 0.93 (0.06) (n = 9) indicated free flow across the filter. The fraction cleared by the extracorporeal route was 48% (13%) (n = 9), which is clinically important. CONCLUSIONS: A meropenem dose of 1g iv every 12 hrs provides adequate serum concentrations in the majority of patients receiving continuous veno-venous hemofiltration or continuous venovenous hemofiltration with a 0.9-m2 polyacrylonitrile filter at combined ultrafiltrate/dialysate flow rates of up to 3 L/hr. A lower dose would not be sufficient for the empirical treatment of potentially life-threatening infections in all patients.     

Impact of chloride balance in acidosis control: the Stewart approach in hemodialysis critically ill patients

BACKGROUND: Metabolic acidosis is highly prevalent in critically ill patients with acute renal failure. Little is known about the mechanisms by which renal replacement therapy intervenes in such cases. The objective of this study is to analyze the role of hemodialysis in acidosis correction in intensive care unit patients, with an emphasis on chloride levels in plasma and dialysate. METHODS: We studied 19 intermittent hemodialysis procedures in 17 acidotic patients. The patients were grouped by procedure type (conventional or sustained low-efficiency dialysis) and by predialysis plasma chloride level (higher or lower than the dialysate chloride concentration). Immediately before and after each procedure, blood samples were collected for biochemical analysis. The Stewart method was used to calculate the strong ion difference and strong ion gap. RESULTS: The patients presented acidosis related to hyperchloremia, hyperphosphatemia, and high unmeasured anions. Hypoalbuminemia had an alkalinizing effect. Hemodialysis corrected acidosis mainly by reducing phosphate and unmeasured anions. In the group as a whole, chloride levels did not change after dialysis. However, when analyzed according to predialysis plasma chloride, the high-chloride group presented a reduction in plasma chloride, resulting in better base excess improvement (Delta standard base excess) than in the low-chloride group. Among the determinants of acid-base status, the only factors correlating with Delta SBE were Delta strong ion gap and Delta chloride. CONCLUSION: The serum chloride/dialysate chloride relationship during hemodialysis has an important impact on acidosis control.     

Ionic dialysance: a new valid parameter for quantification of dialysis efficiency in acute renal failure?

Objective Several studies have reported a close relationship between an increased dose of dialysis and survival in patients treated for acute renal failure. Unfortunately, the quantification of dialysis in critically ill patients based on the urea nitrogen formula Kt/V is not applicable. Ionic dialysance is a new parameter calculated in real time from the dialysate conductivity and correlated with the effective urea clearance in chronic hemodialysis patients. The aim of our study was to evaluate ionic dialysance in the quantification of dialysis in critically ill patients with acute renal failure. Design Prospective open-label study. Setting An 18-bed medical intensive care unit. Patients Thirty-one patients with multiple organ dysfunction syndrome and acute renal failure requiring intermittenthemodialysis were included. Measurements Using the first dialysis session of each patient, we compared the delivered dose of dialysis based on ionic dialysance measurement (Kt_ID) with the well-accepted gold standard method based on fractional dialysate sampling (Kt_dialysate). The data were analyzed using linear regression and Bland–Altman analysis. Results Thirty-one intermittent hemodialysis sessions were performed in 31 critically ill patients (mean age 58 ± 12 years, SAPS II score 56 ± 10). We found a close correlation between Kt_dialysate and Kt_ID (Kt_dialysate = 36.3 ± 11.4 l; Kt_ID = 38.4 ± 11.8; r = 0.96) with excellent limits of agreement (–2.2 l; 6.4 l). Conclusion The feasibility of dialysis quantification based on ionic dialysance in the critically ill patient is good. This method is a simple and accurate tool for the determination of dialysis dose in critically ill patients.     

A single-pass batch dialysis system: an ideal dialysis method for the patient in intensive care with acute renal failure

PURPOSE OF REVIEW: Conventional intermittent hemodialysis and continuous veno-venous hemofiltration are the opposite poles of current treatment modalities for patients with acute renal failure in the intensive care unit. Because both intermittent and continuous renal replacement techniques have several disadvantages, alternative treatment strategies have been developed. This review summarizes relevant information on these new hybrid techniques, and special attention is paid to the use of a single-pass batch dialysis system in the intensive care unit. RECENT FINDINGS: Prospective controlled studies have been published from several centers that use standard dialysis equipment for hybrid techniques, called sustained low-efficiency dialysis or slow extended dialysis. Their common therapeutic aim is to provide an easy-to-perform treatment with reduced solute clearances maintained for prolonged periods of time. These studies have documented that sustained low-efficiency dialysis offers (1) solute removal that is comparable with that obtained with intermittent hemodialysis and continuous veno-venous hemofiltration, even if high substitution fluid rates are used, (2) cardiovascular tolerability like that observed with continuous veno-venous hemofiltration, (3) significantly reduced heparin use in comparison with continuous veno-venous hemofiltration, (4) simple handling and high acceptance by the intensive care unit staff, (5) reduced treatment costs, and (6) the possibility of nocturnal treatments, allowing unrestricted patient access for daytime procedures. SUMMARY: Sustained low-efficiency dialysis is increasingly being used as renal replacement therapy in critically ill patients in the intensive care unit. It combines several advantages of both intermittent and continuous techniques. The procedural simplicity, particularly if single-pass batch dialysis is used, makes it an ideal treatment for patients with renal failure in the intensive care unit.     

Renal replacement therapy III: IHD, CRRT, SLED

Acute renal failure in critically ill patients is a growing clinical problem. Options for renal replacement therapy in these patients use convective and diffusive clearance and may be intermittent, as in classic hemodialysis, or continuous. New ways of delivering dialysis in the intensive care unit, such as sustained low-efficiency dialysis, are also under development. It may be that renal replacement therapy needs to be tailored to the needs of each individual patient. Current and future research studies should provide the answers to many of these questions.     

Continuous arterial-venous hemodiafiltration in critically ill patients

Intermittent hemodialysis in critically ill patients is often accompanied by circulatory instability and hypotension. This may hamper the removal of fluid. Therefore, slow, continuous arterial-venous hemodiafiltration (CAVHD), using the patient's arterial-venous pressure difference, was developed. In 17 critically ill patients with acute renal failure, CAVHD was initiated. Most patients (n = 13) suffered from septic shock. Five (29%) patients survived and in six (35%), renal function was recovered. Average length of treatment was 15 days. The filter life was 52 h. When a dialysate rate of 1600 ml/h was employed, urea clearance was sufficient and hemodialysis was no longer needed as compared with a dialysate rate of 800 ml/h. Hyponatremia developed in all but one patient, but was more severe in the group treated with a dialysate fluid containing 132 mmol/L Na. After using a dialysate with a higher Na content of 140 mmol/L, the average serum Na concentration was 131 mmol/L. Convective Na transport by ultrafiltration was probably responsible for most of the Na loss. In 13 (76%) patients, thrombocytopenia was present. In one patient a hematoma developed in the groin, but could be controlled by local pressure. It is concluded that CAVHD is a safe technique that might replace intermittent hemodialysis in critically ill patients.     

Nephrotoxicity due to combination antibiotic therapy with vancomycin and aminoglycosides in septic critically ill patients

The aim of this prospective observational study was to evaluate the incidence of nephrotoxicity due to combination therapy with vancomycin and aminoglycosides in septic critically ill patients admitted to the intensive care unit. METHODS: Thirty consecutive critically ill patients were treated with vancomycin concurrent with aminoglycosides for sepsis. Inclusion criteria were: the need for mechanical ventilation and the presence of severe infection due to bacteria susceptible to vancomycin and aminoglycosides. Exclusion criteria were: age <18 years, impaired renal function (24-hour creatinine clearance <90 ml/min) or previous adverse reaction to either drug. Serum creatinine and urea concentrations, creatinine clearance, 24-hour urinary excretion of proteins, beta2-microglobulin and enzymes were measured immediately before starting therapy and at different times thereafter. RESULTS: Eleven of the 30 patients had a transient and modest increase in serum urea, 15 patients presented with urinary excretion of beta2-microglobulin and tubular enzymes, and 14 patients had urinary proteins.In the only patient with severe acute renal failure (serum creatinine 8.2 mg/dl), the clinical course was complicated by prolonged hypotension. CONCLUSION: Concurrent administration of vancomycin and aminoglycosides to critically ill septic patients with normal renal function at baseline induced mainly slight and transient toxic tubular effects. The only clinically significant nephrotoxic event occurred in a patient with septic shock.     

Acute hemodialysis: issues in the critically ill.

Hemodialysis is a commonly used therapy for renal failure in critically ill patients. This article reviews components of the hemodialysis system, including vascular access, and provides an explanation of principles underlying the hemodialysis process. Expected patient responses and potential complications of hemodialysis therapy are emphasized. Critical care nursing interventions for the care of patients before, during, and after dialysis also are outlined.     

Continuous renal replacement therapy: dialytic therapy for acute renal failure in intensive care.

Acute renal failure (ARF) is a common complication of critically ill patients in today's intensive care units. Intermittent renal replacement therapy for these types of patients may be limited or ineffective due to the critical nature of their illness. Volume overload and hemodynamic instability are complications that may not be treated adequately with conventional forms of dialysis, such as hemodialysis or peritoneal dialysis. Continuous renal replacement therapy (CRRT) is rapidly gaining ground as the treatment of choice for ARF in the intensive care unit (ICU) due to its slow, gentle nature of water and solute removal Critical care nurses are responsible for monitoring this therapy, but a collaborative effort with nephrology nurses' expertise and background in dialysis therapies is a key ingredient in implementation of a successful CRRT program. This article will review the causes of ARF, the history of CRRT, current treatment options, trends, and implementation of a successful CRRT program.     

Pharmacokinetics of ciprofloxacin in ICU patients on continuous veno-venous haemodiafiltration

OBJECTIVES: To investigate the pharmacokinetics of intravenous ciprofloxacin 200 mg every 8 h in critically ill patients on continuous veno-venous haemodiafiltration (CVVHDF), one form of continuous renal replacement therapy (CRRT). DESIGN AND SETTING: Open, prospective clinical study in a multidisciplinary, intensive care unit in a university-affiliated tertiary referral hospital. PATIENTS: Six critically ill patients with acute renal failure on CVVHDF. INTERVENTIONS: Timed blood and ultrafiltrate samples were collected to allow pharmacokinetics and clearances to be calculated of initial and subsequent doses of 200 mg intravenous ciprofloxacin. CVVHD was performed with 1 l/h of dialysate and 2 l/h of predilution filtration solution, producing 3 l/h of dialysis effluent. The blood was pumped at 200 ml/min using a Gambro BMM-10 blood pump through a Hospal AN69HF haemofilter. MEASUREMENTS AND RESULTS: Ten pharmacokinetic profiles were measured. The CVVHDF displayed a urea clearance of 42 +/- 3 ml/min, and removed ciprofloxacin with a clearance of 37 +/- 7 ml/min. This rate was 2-2.5 greater than previously published for ciprofloxacin in other forms of CRRT. On average the CVVHDF was responsible for clearing a fifth of all ciprofloxacin eliminated (21 +/- 10%). The total body clearance of ciprofloxacin was 12.2 +/- 4.3 l/h. The trough concentration following the initial dose was 0.7 +/- 0.3 mg/l. The area under the plasma concentration time curves over a 24-h period ranged from 21 to 55 mg.h l-1. CONCLUSIONS: Intravenous ciprofloxacin 600 mg/day in critically ill patients using this form of CRRT produced adequate plasma levels for many resistant microbes found in intensive care units.     

Effect of Renal Failure and Dialysis on the Serum Concentration of the Aminoglycoside Amikacin

Serum and dialysate levels of amikacin were determined at appropriate intervals after a 300-mg intravenous dose as a continuous infusion in six patients with end-stage renal failure undergoing hemodialysis and in three patients on peritoneal dialysis. The mean serum half-life of amikacin was 3.75 h during (or after) hemodialysis and 29 h during (or after) peritoneal dialysis. Although not on hemodialysis in the same six patients, the serum half-life was 28 h. The results indicate that the maintenance dose of amikacin should be markedly decreased in patients with severe renal failure even if they are treated with peritoneal dialysis, and that serial serum antibiotic concentrations are essential to prevent cumulative toxicity of the drug.     

Long-term intermittent renal replacement therapy at an intensive care unit

Standard intermittent hemodialysis (IHD) used for the treatment of acute renal failure (ARF) at an intensive care unit has significant biochemical and physiological drawbacks. In the past 20 years, these drawbacks have stimulated the development of continuous renal replacement therapy (CRRT) and its ever-increasing use. However, CRRT is technically complicated and requires 24-hour monitoring. In some clinics, the use of CRRT leads to that each patient is under his/her nurse's surveillance, instead 1 nurse per 2 patients as before; this change has economic consequences and may limit nursing accessibility to other patients. The procedures prolonging intermittent therapy do not require 24-hour monitoring may benefit the treatment of ARF at the intensive care therapy. In this paper the authors call such procedures for continuous intermittent renal replacement therapy. They are characterized by a number of basic principles: (1) the use of modified or standard dialysis apparatuses; (2) the application of diffuse, convection, or both; (3) a certain reduction in the rate of elimination of dissolved substances as compared with IHD; (4) more prolonged treatment: above usual 3 or 4 hours of IHD, but not more than 8-12 hours (hence the term "intermittent"); (5) the use of on-line generation dialysate or substituting fluid. Information on the effectiveness and safety of this procedure is being now compiled.     

Continuous renal replacement therapy for critically ill patients: an update

Despite continuous progress in intensive care during the last decades, the outcome of critically ill patients in whom acute renal failure (ARF) develops is still poor. This outcome may be explained partially by the frequent occurrence of ARF as part of multiple organ systems failure (MOSF). In this complex and unstable patient population, the provision of adequate renal support with either intermittent hemodialysis or peritoneal dialysis may pose major problems. Continuous renal replacement therapy (CRRT) is now increasingly accepted as the preferred treatment modality in the management of ARF in these patients. The technique offers adequate control of biochemistry and fluid balance in hemodynamically unstable patients, thereby enabling aggressive nutritional and inotropic support without the risk of exacerbating azotemia or fluid overload. In addition, experimental and clinical data suggest that CRRT may have a beneficial influence on hemodynamics and gas exchange in patients with septic shock and (nonrenal) MOSF, independent of an impact on fluid balance. We review both technical and clinical aspects of various continuous therapies, including their impact on serum drug levels and nutrient balance. In addition, an attempt is made to clarify the possible beneficial role of CRRT in reducing patient morbidity and mortality in the ICU.     

Pharmacokinetic and Pharmacodynamic Characteristics of Vancomycin and Meropenem in Critically Ill Patients Receiving Sustained Low-efficiency Dialysis

PurposeAntibiotic dosing is challenge in critically ill patients undergoing renal replacement therapy. Our aim was to evaluate the pharmacokinetic and pharmacodynamic (PK/PD) characteristics of meropenem and vancomycin in patients undergoing SLED.MethodsConsecutive ICU patients undergoing SLED and receiving meropenem and/or vancomycin were prospectively evaluated. Serial blood samples were collected before, during, and at the end of SLED sessions. Antimicrobial concentrations were determined using a validated HPLC method. Noncompartmental PK analysis was performed. AUC was determined for vancomycin. For meropenem, time above MIC was calculated.FindingsA total of 24 patients receiving vancomycin and 21 receiving meropenem were included; 170 plasma samples were obtained. Median serum vancomycin and meropenem concentrations before SLED were 24.5 and 28.0 μg/mL, respectively; after SLED, 14 and 6 μg/mL. Mean removal was 42% with vancomycin and 78% with meropenem. With vancomycin, 19 (83%), 16 (70%), and 15 (65%) patients would have achieved the target (AUC_0–24 >400) considering MICs of 1, 2, and 4 mg/L, respectively. With meropenem, 17 (85%), 14 (70%), and 10 (50%) patients would have achieved the target (100% of time above MIC) if infected with isolates with MICs of 1, 4, and 8 mg/L, respectively.ImplicationsSLED clearances of meropenem and vancomycin were 3-fold higher than the clearance described by continuous methods. Despite this finding, overall high PK/PD target attainments were obtained, except for at higher MICs. We suggest a maintenance dose of 1 g TID or BID of meropenem. With vancomycin, a more individualized approach using therapeutic drug monitoring should be used, as commercial assays are available     

Efficiency of High‐Flux Hemodialysis in the Treatment of Valproic Acid Intoxication

Abstract

Recently, highly efficient (i.e., high volume) dialysis systems have been successfully introduced for the treatment of critically ill patients in the intensive care unit. They also can be a safer, more effective, and less costly alternative to traditional extracorporal techniques in the treatment of severe intoxication. This holds true even if the substance to be eliminated is believed to be a poor candidate for dialysis treatment. We report a case of successful treatment of potentially life‐threatening intoxication, with valproic acid (VPA) using a GENIUS^® batch dialysis system for combined standard and extended high‐volume hemodialysis therapy. Concentration of VPA in the total collected dialysate were measured.     

Pharmacokinetics of meropenem (ICI 194,660) and its metabolite (ICI 213,689) in healthy subjects and in patients with renal impairment.

The pharmacokinetics of meropenem (ICI 194,660) and its open-ring metabolite (ICI 213,689) were studied in 6 healthy volunteers and 16 patients with moderate to severe renal impairment after a single intravenous dose of 500 mg given as a 30-min infusion. Concentrations of unchanged meropenem in plasma and urine were measured by both microbiological and high-pressure liquid chromatographic (HPLC) assays. A good correlation was found between the two techniques. Pharmacokinetic parameters of unchanged meropenem were determined by using the HPLC data. The terminal half-life of unchanged meropenem increased in relation to the degree of renal impairment, being 1.2 h in subjects with normal renal function and 10 h in patients with end-stage renal failure. Total body clearance and renal clearance of unchanged meropenem are linearly related to creatinine clearance. The concentrations of the metabolite in plasma, which are very low in healthy subjects, significantly increased in uremic patients. The apparent half-life of ICI 213,689 increased in uremic patients and was about 35 h in patients with severe renal insufficiency. Meropenem and its metabolite are effectively removed by hemodialysis. The dialysis clearance of the unchanged drug was 81 +/- 22 ml/min. Dosage adjustments of meropenem will be necessary in patients with severe renal impairment.