Possible antibiotic inactivation was studied in 12 subjects with end-stage renal disease who were undergoing thrice-weekly hemodialysis. The study was a randomized three-way crossover. Subjects received (i) gentamicin as a single intravenous dose of 2 mg/kg, (ii) 4 g of piperacillin intravenously every 12 h for four doses or 2 g of carbenicillin intravenously every 8 h for six doses, and (iii) gentamicin as described in (i) plus piperacillin or carbenicillin as described in (ii). Subjects were studied on their off-dialysis days, and each treatment phase was separated by a 3-week wash-out period. Gentamicin was inactivated to a greater extent by carbenicillin than by piperacillin (P < 0.05). In the six subjects in the carbenicillin group, the terminal elimination-phase half-life (t1/2p) of gentamicin was 61.6 h when gentamicin was administered alone, and it was 19.4 h when gentamicin was administered with carbenicillin. In six subjects in the piperacillin group, the mean t1/2p of gentamicin when gentamicin was given alone was 53.9 h, and it was 37.7 h when gentamicin was given with piperacillin. The inactivation rate constant (k,) of gentamicin was 0.0251/h for the carbenicillin group and 0.0064/h for the piperacillin group, demonstrating that carbenicillin inactivated gentamicin four times faster than did piperacillin. No inactivation of either ,3-lactam could be measured. Control samples verified that no in vitro inactivation occurred.

The pharmnacokinetic parameters of piperacillin sodium were studied in eight volunteer subjects with chronic renal failure. Subjects were given a single 30-min intravenous infusion of 70 mg/kg (lean body weight) on their off-dialysis day. Blood was drawn from the contralateral arm at 15 and 30 min and 1, 3, 6, 9, and 12 h from the start of the infusion. Kinetic parameters were determined during the elimination phase with a one-compartment open model for linear kinetics. The following pharmacokinetic parameters (mean ± standard deviation) were determined for the eight subjects: elimination half-life = 3.33 + 0.99 h, elimination rate constant = 0.22 ± 0.06 h-', apparent volume of distribution = 0.18 ± 0.05 liters per kg, and total body clearance = 0.041 ± 0.019 liters per kg/h. The mean peak serum concentration was 372 ± 125 ,ug/ml, and mean trough at 12 h was 39 + 27 ,ug/ml. A dose of 70 mg/kg (lean body weight) or a dose of 4 g appears to provide adequate serum concentrations against susceptible organisms for a 12-h interval. No adverse reactions were noted in any subject throughout the study. Piperacillin has been shown to be effective in the treatment of many serious infections (14; J.

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The concentrations of piperacillin in serum, bile, gallbladder wall, abdominal skeletal muscle, and adipose tissue were measured simultaneously at various times after the intravenous administration of a single 5-g dose to each of 14 patients undergoing biliary tract surgery. Piperacillin concentrated in the bile with peak levels exceeding 4,000 micrograms/ml. In a single patient with cystic duct obstruction, trace gallbladder bile piperacillin levels were measured. Gallbladder wall concentrations of piperacillin tended to be higher than corresponding serum concentrations, with a correlation observed between tissue values and the degree of acute gallbladder inflammation and gallbladder bile piperacillin concentrations. Mean peak muscle and adipose tissue piperacillin concentrations of 31 and 27 micrograms/g, respectively, were reached at between 2 and 3 h after the start of infusion. These concentrations exceeded the minimum inhibitory concentration for a majority of susceptible organisms. A single 5-g dose of piperacillin achieved therapeutic levels in gallbladder wall, intraabdominal skeletal muscle, and adipose tissue and concentrated in the bile of patients with patent biliary tracts.