Pharmacokinetics of piperacillin and tazobactam in critically ill patients with renal failure, treated with continuous veno-venous hemofiltration (CVVH).
OBJECTIVE
Kinetics of piperacillin (pip), in combination with the beta-lactamase inhibitor tazobactam (taz) have been studied in volunteers and patients in relatively stable conditions. The fixed drug preparation appeared to have ideal pharmacokinetic properties if renal function was normal or slightly impaired, but no data are available for critically ill patients in anuric renal failure. This study should provide such data. PATIENTS, DESIGN: We studied the pharmacokinetics in nine patients with multiple organ failure, including anuric renal failure, treated with continuous veno-venous hemofiltration (CVVH). Patients received a standard schedule of 4 g pip and 0.5 g taz administered over 0.5 h intravenously, 8 hourly. During 2 consecutive days, the serum levels of both compounds were determined, and total clearance (CIT) was calculated from serum concentrations.


RESULTS
All nine patients completed day 1, and 8 completed day 2 of the protocol. On day 1, single-dose kinetics showed considerable spread, but pip/taz serum levels followed the pattern as expected, with a pip/taz concentration ratio of 20:1. On day 2, however, taz serum concentrations showed a relative increase as compared to pip, resulting in a change in the serum pip/taz concentration ratio to 10:1 on day 2. The CIT of pip was 2.52 +/- 1.38 l/h (t 1/2: 5.9 +/- 2.9 h), and CIT of taz 4.44 +/- 2.28 l/h (t 1/2: 8.1 +/- 3.7 h). The CIT and t 1/2 of pip and taz correlated highly significantly with clearance by CVVH. Despite a higher CIT, taz has a longer half-life, because of a higher volume of distribution.


CONCLUSIONS
In CVVH dependent patients, pip/taz fixed drug preparations can be used initially, but the pip dosage should be increased relative to that of taz (or interval-adjusted) to prevent cumulation of taz, as compared to the active antimicrobial agent pip.
van der Werf
T S
TS
Department of Internal Medicine, University Hospital Groningen, The Netherlands. t.s.van.der.werf@int.azg.nl
Mulder
P O
PO
Zijlstra
J G
JG
Uges
D R
DR
Stegeman
C A
CA
D000328:Adult; D000368:Aged; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006440:Hemofiltration; D006801:Humans; D016018:Least-Squares Analysis; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure / Q000628:therapy; D010397:Penicillanic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D010406:Penicillins / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010878:Piperacillin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051437:Renal Insufficiency / Q000188:drug therapy* / Q000628:therapy; D000078142:Tazobactam; D001618:beta-Lactamases / Q000493:pharmacokinetics* / Q000627:therapeutic use
D004791:Enzyme Inhibitors; D010406:Penicillins; D010397:Penicillanic Acid; D001618:beta-Lactamases; D000078142:Tazobactam; D010878:Piperacillin