Multiple-dose pharmacokinetics of intravenously administered cefoperazone and sulbactam when given in combination to infected, seriously ill, elderly patients

Abstract

The pharmacokinetics of cefoperazone and sulbactam in combination were evaluated in six, elderly, seriously ill patients treated with the drug combination for intra-abdominal infections. After giving informed consent, three males and three females aged 63.5 to 77.5 (mean, 67.9) years and weighing 54.5 to 86.8 (mean, 67.6) kg were treated with cefoperazone (2.0 g) and sulbactam (1.0 g) infused intravenously every 12 h for at least 5 days. Cefoperazone and sulbactam pharmacokinetics were characterized on both days 1 and 5 of treatment. Eleven serial blood samples were obtained just prior to and following dose 1 on days 1 and 5 of treatment. Mean estimates of cefoperazone maximal concentration in plasma (C..), area under the curve of drug concentration in plasma versus time (AUC), half-life (t112), apparent volume of distribution by the area method (Yarne), apparent volume of distribution at steady state (V.), and total body clearance (CL) for day 1 (day 5) were 297.5 (237.5) ,ug/ml, 1,247 (1,063) ug. h/ml, 7.0 (4.9) h, 16.1 (13.4) liter, 13.1 (14.4) liter, and 28.9 (34.2) ml/min, respectively. Day 1 (day 5) mean values for sulbactam Cm.., AUC, t1/2, Varea, V., and CL were 110.3 (78.0),ug/ml, 228 (217) ug. h/ml, 3.4 (2.5) h, 26.1 (18.5) liter, 18.9 (15.4) liter, and 97 (94) ml/min, respectively. Both drugs evidenced slower elimination and greater pharmacokinetic variability in these patients compared with values previously reported for normal volunteers. As patients improved during the course of therapy, the only pharmacokinetic parameter significantly changed between days 1 and 5 was a shortened sulbactam t112. Our inability to find substantial evidence of pharmacokinetic normalization may have been related to sample size and study duration. Both drugs were present in potentially therapeutic concentrations for the entire 12-h dosing interval, but without undue accumulation from days 1 to 5.

Crossover assessment of serum bactericidal activity and pharmacokinetics of five broad-spectrum cephalosporins in the elderly

“…In two prior noncrossover studies of cefotaxime in the elderly, in which different drug administration methods and older individuals were studied, different values were reported for the volume of distribution, CL, and AUC, although t1/2, was similar to that observed for cefotaxime in this study (31,32). The results obtained for the pharmacokinetic parameters of cefoperazone examined in our study differed from those in a noncrossover study (30) of the elderly but were similar to results from a cefoperazonesulbactam study (42) of the elderly. Differences in the results of this and the earlier study of cefoperazone (30) were noted for volumes of distribution, CL, AUC, and t1/2, (10.3 h in this study versus 2.2 h in the previous report [30]).…”

“…In studies in which serum bactericidal testing has been used in young volunteers, differences in the broad-spectrum cephalosporins have been shown, including pharmacokinetics, in vitro activity, and serum bactericidal activity (SBA) (3,4,15,17,18,23,38,49,50). Although elderly individuals may exhibit altered metabolism and pharmacokinetics of these antimicrobial agents (1,19,21,24,26,27,(31)(32)(33)42), no studies of SBA have been done in this population. Therefore, we administered single 2-g doses of cefoperazone, cefotaxime, ceftriaxone, ceftazidime, and ceftizoxime to six healthy elderly volunteers and studied both the pharmacokinetics and SBAs of these agents.…”

Improving antimicrobial use in critically ill patients

“…The PK studies including IAI patients consistently show higher V d values than in healthy volunteers except for cefoperazone [105]. The increment of V d , was twice as high for both meropenem [86,87] and piperacillin [95] and 20% higher for ceftazidime [97].…”

“…A study with cefoperazone (co-formulated with sulbactam) [105] described a half life 3.9 times that observed in healthy volunteers [106] because of a 50% larger V d and a 43% lower CL. However, analysis of unbound concentrations was not undertaken in this study, which would have been significantly more relevant, as cefoperazone is highly protein bound (95%).…”

“…Five cephalosporin antibiotics have been studied, although only two studies were conducted in patients with IAI [97,105]. The first study [97] was a non-randomized study and compared the PK of CI with II administration of ceftazidime.…”