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Flucytosine is effective in the treatment of serious fungal infections. Some of the patients might have acute renal failure requiring continuous hemofiltration as renal replacement therapy. We evaluated the removal of flucytosine in a patient who received the drug for systemic Candida infection while undergoing continuous hemofiltration for acute renal failure. Arterial, venous, and ultrafiltrate sample pairs were collected to evaluate flucytosine removal. Ultrafiltrate/arterial drug concentration ratios and sieving coefficients obtained with the polysulfone membrane were higher than those obtained with the polyacrylonitrile membrane. Between 2.54 and 22.56 mg of flucytosine was removed from the patient per hour when the serum drug concentrations were 21.1-126.5 mg/l. The amount of hemofiltration flucytosine removal was related to ultrafiltration flow rate, serum drug concentration, and hemofilter type. The mean continuous arteriovenous hemofiltration flucytosine clearance for the polysulfone membrane was 77.0 +/- (SD) 15.6% of the ultrafiltrate flow rate, while the clearance for the polyacrylonitrile membrane was 51.0 +/- (SD) 5.7%. In patients with renal failure, continuous hemofiltration can remove an appreciable quantity of flucytosine when the ultrafiltrate flow rate is high. Serum drug concentration determination is necessary to devise an optimal dosage regimen for the patient.

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Continuous hemofiltration was conducted in vitro to identify parameters that affect drug transport across hemofilter membranes. The removal of seven drugs with different molecular weights and protein binding characteristics was assessed. Sieving coefficients were determined with both blood and saline using polysulfone, polyacrylonitrile and polyamide membranes. Drug sieving coefficients obtained with saline were generally higher than those obtained with blood. Molecular weights of the drugs did not correlate with the magnitude of drug sieving. Sieving coefficients in blood were also predicted from saline data assuming plasma protein binding is responsible for the reduced drug sieving with blood. For drugs that are highly protein bound, protein binding was the primary factor limiting drug sieving. Presence of plasma proteins also had a modest effect on sieving of other drugs. The sieving coefficients obtained with the polyacrylonitrile membrane tend to be different from those obtained with the other hemofilters. Drug-membrane interaction may contribute to the differences in drug transport among the membranes.

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Phenytoin is frequently used to treat seizure episodes in critically ill patients. Some of these patients have acute renal failure, requiring continuous hemofiltration to help maintain fluid and solute balance. We evaluated the removal of phenytoin in patients who received the drug while undergoing continuous hemofiltration treatment. Arterial and ultrafiltrate sample pairs were collected for phenytoin concentration determination. The ultrafiltrate drug concentrations were almost identical to the free serum phenytoin concentrations. Thus the ultrafiltrate/arterial drug concentration ratios resembled the percentages of serum free drug. Between 0.32 and 0.78 mg of phenytoin/h was removed by hemofiltration. The magnitude of hemofiltration phenytoin removal was related to the free drug concentration, total serum drug concentration, and ultrafiltration flow rate. When the ultrafiltration flow rate was low, the amount of phenytoin removed by hemofiltration was small relative to the usual daily dose. However, in patients with renal failure in whom serum phenytoin protein binding is substantially reduced, continuous hemofiltration at a high ultrafiltration rate may remove a clinically significant amount of the drug. Higher daily doses of phenytoin may be needed to maintain the therapeutic effect. Serum drug concentration monitoring will be necessary to determine the optimal dosage regimen.

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The concentration of 18 alpha-amino acids (AAs) in plasma and renal cortical cell water were measured 3 or 24 hr after 1 hr of unilateral renal artery clamping or 24 or 48 hr after 15 mg/kg body weight HgCl2 injection sc as a test of epithelial integrity. Cellular glycine (Gly), hydroxyproline (Hpr), ornithine (Orn), phenylalanine (Phe), serine (Ser), and tryptophan (Trp) concentrations were depressed 24 hr after HgCl2 (p less than 0.05), but the remaining 12 AAs were not distinguishable from control despite the presence of severe renal failure. ARginine (Arg), glutamic acid (Glu), and valine (Val) also were decreased (P less than 0.05) 24 hr later, but concentrations of half of all measured AAs were still normal. Cellular alanine (Ala), Arg, Glu, Gly, Phe, and Ser concentrations were decreased 3 hr after ischemia, p less than 0.05, but 12 AAs were unchanged and only Arg, Phe, Ser, and threonine (Thr) were reduced 24 hr after ischemia was reversed. Concentrations of even the most affected AAs remained notably higher than in plasma in both forms of acute renal failure (ARF). Total loss of AAs from a small proportion of tubular cells would be hidden by essentially normal concentrations in the rest, and such losses may well have occurred. Unless cellular AAs in ARF are almost completely bound, however, the well-maintained cell:plasma AA concentration ratios indicate that cellular energetics were adequate for AA uptake and that epithelial permeability to AAs in the vast majority of cells was not greatly disturbed. Such findings suggest that most of the epithelium, although seriously damaged, had remained viable.

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Cephalosporins are used with increasing frequency for sepsis treatment in patients receiving CAVU and CAVH. The different cephalosporins share the same basic molecular structure, yet they exhibit varied extent of plasma protein binding. Different amounts of the antibiotics may be removed by the ultrafiltration procedure because of these variations of physicochemical properties. We evaluated the sieving of eight new cephalosporins across the hemofilter membrane using an in vitro model. Bovine blood was perfused through polysulfone membranes at blood and ultrafiltrate flow rates of 100 and 20 ml/min respectively. Arterial plasma, venous plasma and ultrafiltrate drug concentrations were used to determine sieving coefficients. The sieving coefficients correlated well with the ultrafiltrate-arterial plasma drug concentration ratio (r = 0.679-0.972) but poorly with the extent of protein binding. Factors other than protein binding may therefore affect the drug sieving. Based on the findings, it was predicted that 0.2-21.9% of the daily cephalosporin dose may be removed by the CAVU and CAVH treatment. The need to alter drug dosages depends on the techniques of the ultrafiltration and hemofiltration procedure, the kinetics of the cephalosporins in patients, the sensitivity of the pathogen and the nature of the infection.

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We evaluated the rate and extent of the systemic absorption of moxalactam given intraperitoneally to patients with peritonitis and end-stage renal disease who were being maintained on continuous ambulatory peritoneal dialysis. Moxalactam was administered at a concentration of 200 mg per 2-liter dialysate for the first dose, followed by 60 mg per 2-liter exchange for 23 1-h exchanges. Moxalactam concentrations in serum (mean +/- standard deviation) were 2.5 +/- 0.9 mg/liter after the first hourly dialysis, increasing to 10.3 +/- 4.8 mg/liter after 24 h of drug administration. Moxalactam levels in serum at 1 h were above the minimal inhibitory concentrations for most gram-negative organisms except Pseudomonas aeruginosa. No adverse effects of the drug were observed.

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