every 12 h) were studied when these antimicrobial agents were administered continuously over 7 days as a 15-min infusion of individual agents and as a 3/1.5-g cefoperazone-sulbactam combination. Fourteen (CL). The area under the curve, apparent volume of distribution by the area method (V), t112, and Cmax were not significantly altered. Although cefoperazone pharmacokinetic parameters were not significantly altered when comparing single-agent to combination drug administration, the area under the curve was slightly lower and CL, nonrenal 6earance, and V were modestly higher from day 1 to day 7. Because Cmax and tl2 were unaffected, these minor day effects would not be of clinical significance. Intravenous administration of cefoperazone and sulbactam given as individual agents compared with the combination did not show pharmacokinetic differences that are likely to produce clinically relevant effects. The combination of cefoperazone and sulbactam was well tolerated, and the safety profile of the combination was similar to that of either drug given alone under the conditions of this study.

The single-dose pharmacokinetics of intravenously administered cefoperazone (2.0 g) and sulbactam (1.0 g) were studied in normal subjects and in patients with various degrees of renal failure. In an open, parallel experimental design, six normal subjects (creatinine clearance, greater than 90 ml/min), two patients with mild renal failure (creatinine clearance, 31 to 60 mI/min), eight patients with moderate renal failure (creatinine clearance, 7 to 30 ml/min), and four functionally anephric patients (creatinine clearance, less than 7 mI/min) were studied. The functionally anephric patients were given two test doses to allow study of drug disposition both on and off hemodialysis. Serial blood and urine samples were collected from time zero to 12 h after dosing in normal subjects and from 0 to 72 h in renal patients. Serum concentrations of both drugs declined biexponentially. For cefoperazone, the terminal elimination half-lives averaged from 1.6 to 3.0 h and were similar in subjects and patients. No cefoperazone pharmacokinetic parameters were appreciably altered by renal failure or hemodialysis, and there was no correlation between the total body clearance of cefoperazone and estimated creatinine clearance. In contrast, the sulbactam total body clearance was highly correlated with estimated creatinine clearance (r = 0.92, P < 0.01) and was significantly higher in normal volunteers than in the renally impaired groups (P < 0.01). The sulbactam terminal elimination half-life in functionally anephric patients (9.7 ± 5.3 h) differed significantly from that of normal volunteers (1.0 ± 0.2 h) and patients with mild renal failure (1.7 ± 0.7 h, P < 0.05). The sulbactam half-life in moderate renal failure was 4.6 ± 2.2 h. The hemodialysis extraction ratio of sulbactam (0.44) was significantly higher than that of cefoperazone (0.05) (P < 0.01). The mean percentage of the dose recovered from dialysate was about 4% for cefoperazone and 30% for sulbactam. Hemodialysis patients showed a significantly higher sulbactam apparent volume of distribution at steady state and total body clearance during dialysis periods when compared with those in periods off dialysis. The sulbactam elimination half-life was appreciably altered during the hemodialysis period (mean, 2.0 h). Hemodialysis approximately doubled the sulbactam total body clearance. When cefoperazone and sulbactam are used in combination, adjustment of the dosing regimen for patients with estimated creatinine clearance of less than 30 ml/min can be made to compensate for reduced sulbactam total body clearance. An adjustment may be particularly appropriate at an estimated creatinine clearance of less than 15 ml/min. Under these conditions, the combination may be given once daily, with an additional dose of cefoperazone (given alone) 12 h later. This alternating regimen would not require further adjustment after hemodialysis treatment, but we recommend that dosing be scheduled to follow hemodialysis if possible.

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This study was conducted to determine the pharmacokinetics of the fixed combination antibiotic cefoperazone-sulbactam in patients receiving continuous ambulatory peritoneal dialysis (CAPD). In addition, the pharmacodynamic profile of this combination was determined by the use of mean bactericidal titers against selected bacterial strains. Six noninfected CAPD patients were given a fixed dose of cefoperazone (2 g) and sulbactam (1 g) either intravenously or intraperitoneally over 10 min in a randomized, two-way crossover fashion. The mean peak cefoperazone concentration in serum after intravenous administration was 280.9 ,ug/ml. The mean peak concentration in serum after intraperitoneal cefoperazone administration was 38.9 ,ug/ml and occurred 2 to 4 h postdose. The mean peak sulbactam concentration in serum after intravenous administration was 82.2 ,ug/ml. The mean peak concentration in serum after intraperitoneal sulbactam administration was 24.4 ,ug/ml and occurred at 6 h. The absolute bioavailability of the intraperitoneal dose was 61% for cefoperazone and 70% for sulbactam. Cefoperazone total body and renal clearances were unaffected by renal failure and dialysis. However, both clearance values for sulbactam were reduced markedly. Only intraperitoneal dosing provided peak inhibitory and bactericidal titers in dialysate for all organisms tested.

No abstract