Pharmacokinetics and tissue penetration of tazobactam administered alone and with piperacillin

Abstract

The pharmacokinetics of tazobactam (500 mg) administered intravenously alone were compared with the pharmacokinetics of tazobactam coadministered with piperacillin (4 g), and the penetration into an inflammatory exudate in six healthy males was studied. Piperacillin influenced the pharmacokinetics of tazobactam. The mean levels of tazobactam in plasma at 4 h were 0.6 ,ug/ml when it was given alone and 1.2 ,ug/ml when it was given with piperacillin (P = 0.0003). The mean total clearances of tazobactam were 203.5 and 134.2 ml/min (P = 0.035) when it was given alone and with piperacillin, respectively. There were no significant differences in the elimination half lives, areas under the concentration-time curve from 0 h to infinity, or volumes of distribution. Inflammatory exudate penetration was rapid, and the mean maximum levels of tazobactam attained were 6.4 and 11.3 ,Lg/ml when it was given alone or with piperacillin, respectively (P < 0.06). The mean percent penetration of tazobactam and the area under the concentration-time curve from 0 h to infinity in inflammatory exudate were greater when tazobactam was given with piperacillin. The mean 24-h urinary recoveries of tazobactam were 63.7% ± 7.9% when it was given alone and 56.8% ± 2.7% when it was given with piperacillin. The explanation for the differences in the pharmacokinetics of tazobactam when it was administered alone compared with those when it was given with piperacillin was unclear.Piperacillin, a broad-spectrum penicillin (13), is susceptible to hydrolysis by a range of P-lactamases, including the plasmid-mediated enzymes found in the members of the family Enterobacteriaceae and other genera such as Richmond and Sykes group III (12) and the enzymes commonly found in Staphylococcus aureus and Bacteroides fragilis. A number of P-lactamase inhibitors have been combined with other broad-spectrum penicillins, such as clavulanic acid with amoxicillin (8) and ticarcillin (1, 8) and sulbactam with ampicillin (6), which are protective of the active P-lactam.Tazobactam has been combined with piperacillin in a combination of 1:8 (9, 10), and preliminary studies suggest that the pharmacokinetics of these two agents are well matched. Results of preliminary studies in humans (3) and rats (16) suggest that the elimination of tazobactam is slower in the presence of piperacillin than when tazobactam is administered alone. In the present study, the pharmacokinetics and penetration into an inflammatory fluid of tazobactam alone and tazobactam combined with piperacillin were investigated in healthy volunteers by using a cantharidine-induced blister model (15). MATERIALS AND METHODSSix healthy adult male volunteers participated in the study after Ethical Committee approval and written informed consent were obtained. The volunteers were aged 22 to 38 years (mean age, 29.7 years), weighed between 66.2 and 82.5 kg (mean weight, 72.9 kg), and had a mean height of 1.77 m (range, 1.72 to 1.81 m). The body weights were within 10% for their age and height. Their medical histori...

Pharmacokinetics and tissue penetration of tazobactam and piperacillin in patients undergoing colorectal surgery

“…(20) was almost 40% less than that obtained by Cheung et al (1) and was also less than that obtained in this study (extrapolated to normal kidney function). This makes that report (20) unusable for comparison of the basic pharmacokinetics but also for blister fluid penetration since the penetration into blister fluid is related to the plasma AUC, which reflects total clearance.…”

“…Eighteen patients (nine females, nine males) were enrolled in the study. The mean age was 66.8 + (19,20).…”

“…For both tazobactam and piperacillin, clear peaks in levels in the appendix at the 61-to 90-min period over those in the preceding and following periods were observed. Only the fixed combination of piperacillin-tazobactam could be tested in this study of (20), typographic errors prevented our use of those data for comparison. In addition, the total clearance of piperacillin in the young and healthy subjects in that study (20) was far below what is usually reported in the literature for the 4-g dose in volunteers (9,(16)(17)(18)(19)(20).…”

“…Pharmacokinetic studies in healthy male volunteers indicated that 4 p.g or more of tazobactam per ml is maintained in plasma for 3 h after a 30-min infusion of 0.5 g of tazobactam in combination with 4 g of piperacillin (20).…”

Evaluation of Efficacy and Tolerability of Cefotaxime and Sulbactam Versus Cefepime and Tazobactam in Patients of Urinary Tract Infection-A Prospective Comparative Study

“…Combination of tazobactam and beta lactam antibiotic (ceftazidime and cefepime) it demonstrates synergistic activity (reduction in minimal inhibitory concentrations for the combination versus those of each component in a variety of organisms specially in Gram-negative Aerobes [20].…”