PHARMACOKINETICS OF TAZOBACTAM M1 METABOLITE AFTER ADMINISTRATION OF PIPERACILLIN TAZOBACTAM IN SUBJECTS WITH RENAL IMPAIRMENT/

Tazobactam is a new derivative of penicillinic acid sulfone, which fun ctions as an irreversible inhibitor of many p-lactamases. The disposit ion of tazobactam M1 metabolite after intravenous (IV) infusion of 3 g of piperacillin/0.375 g of tazobactam was evaluated in 26 subjects wi th various degrees of renal impairment. Participants in the study were 18 subjects with creatinine clearances (Cl-CR) ranging from 7.4-41.8 mL/min, 4 subjects maintained on continuous ambulatory peritoneal dial ysis (CAPD), and 4 subjects undergoing chronic hemodialysis (HD). The pharmacokinetic parameters of piperacillin and tazobactam were evaluat ed and were similar to previous reports. Tazobactam MI metabolite maxi mum plasma concentration increased as renal function declined. The ter minal elimination half-life and area under the plasma concentration-ti me curve of the tazobactam M1 metabolite increased as renal function d eclined. The mean rate of recovery of the tazobactam MI metabolite in hemodialysate during a 3- to 4.2-hour HD session I hour after the IV i nfusion of piperacillin/tazobactam was 25.3%. However, when HD was per formed at 36-48 hours after the IV infusion, 57.6% of the tazobactam d ose was recovered as M1 metabolite, suggesting further conversion of t azobactam to M1 metabolite. Peritoneal dialysis removed 15.8% (n=2) of the tazobactam dose as the M1 metabolite. Using a dose of 3 g of pipe racillin/0.375 g of tazobactam, the predicted maximum steady-slate pla sma concentrations of the tazobactam M1 metabolite are 14.6 mu g/mL, 3 4.8 mu g/mL, and 48.8 mu g/mL for subjects with Cl-CR 20-40 mL/min (ev ery 6 hour dosing), Cl-CR < 20 mL/min (every 8 hour dosing), and on CA PD (every 12 hour dosing), respectively.