Journal of Antimicrobial Chemotherapy (2001) 48, 881-885
© 2001 The British Society for Antimicrobial Chemotherapy
Elimination of the piperacillin/tazobactam combination during continuous venovenous haemofiltration and haemodiafiltration in patients with acute renal failure
a Department of Medicine, Divisions of Infectious Diseases and b Nephrology, c Department of Anaesthesia and Intensive Care Medicine, Helsinki University Central Hospital, Helsinki; d Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland
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Abstract |
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The elimination of the piperacillin/tazobactam combination was studied in six patients with acute renal failure undergoing either continuous venovenous haemofiltration (CVVH) or continuous venovenous haemodiafiltration (CVVHDF) at 1 L/h and 2 L/h for 12 h. Piperacillin 4 g/tazobactam 0.5 g was given iv on three successive treatment periods and their concentrations in plasma, ultrafiltrate/dialysate and urine were determined for 12 h after each dose. The elimination half-life of piperacillin during CVVH (7.7 ± 2.3 h; mean ± s.d.) was significantly longer than during CVVHDF 1 L/h (6.7 ± 1.9 h) or 2 L/h (6.1 ± 2.0 h) (P< 0.05). Corresponding values for tazobactam were 13.9 ± 3.9, 11.6 ± 3.3 and 9.4 ± 2.4 h, respectively (P< 0.05). Total piperacillin clearance during CVVH (3.89 ± 1.23 L/h) was significantly lower than during CVVHDF 1 L/h (5.06 ± 1.68 L/h) or 2 L/h (5.48 ± 2.11 L/h) (P< 0.05). The corresponding tazobactam clearance values were 2.42 ± 0.75, 3.13 ± 0.66 and 3.75 ± 1.43 L/h, respectively. The mean 12 h elimination of piperacillin and tazobactam in ultrafiltrate/dialysate was 29% and 37% during CVVH, 42% and 57% during CVVHDF (1 L/h), and 46% and 69% during CVVHDF (2 L/h). We recommend 8 hourly dosing of patients with renal failure on CVVH or CVVHDF with dialysis flow rates of 1 or 2 L/h treated with piperacillin 4 g/tazobactam 0.5 g.
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Introduction |
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The combination of the ß-lactam antibiotic piperacillin and ß-lactamase inhibitor tazobactam has a broad spectrum of activity.1 Peak plasma concentrations following an iv infusion of piperacillin 4 g plus tazobactam 0.5 g are 300 and 30 mg/L, respectively.2 Both drugs are renally excreted with an elimination half-life (t1/2) of c. 1 h. Both piperacillin and tazobactam are effectively removed by haemodialysis, with clearance rates of 95 and 70 mL/min, respectively.3
Treatment of acute renal failure now commonly uses continuous replacement therapies based on haemofiltration alone or on a combination of filtration and dialysis (haemodiafiltration) rather than intermittent haemodialysis. Both drugs have a small molecular weight and low protein binding (20–30%),2 and are removed by continuous venovenous haemofiltration (CVVH).4 There are no studies on the effect of continuous venovenous haemodiafiltration (CVVHDF) on piperacillin/tazobactam elimination.
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Materials and methods |
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Patients
The study was performed at the Helsinki University Central Hospital, Finland. Six patients with acute renal failure and having sepsis requiring piperacillin/tazobactam treatment were included (Table). Their underlying conditions were as follows: Patient 1: Crohn's disease, jejunum perforation, peritonitis, pneumonia; Patient 2: acute myocardial infarction, sternotomy, hypotension, pneumonia; Patient 3: diabetes mellitus, severe atherosclerosis, infected vascular prothesis; Patient 4: acute severe pancreatitis; Patient 5: necrotizing fasciitis; Patient 6: pneumonia. All patients were receiving piperacillin 4 g/tazobactam 0.5 g bid as part of their therapy. Approval of the ethics committee and written informed consent from the patients or their legal representatives were obtained.
CVVH and CVVHDF materials and procedure
Patients were dialysed using an ADM 08 dialysis monitor and AV 400S capillary dialyser with a 0.7 m2 polysulphone membrane (Fresenius, Bad Homburg, Germany). Peritoneal dialysis solution, containing 13.6 mg/mL glucose (Baxter SA, Castlebar, Republic of Ireland), warmed to 37°C, was used as dialysis fluid. The substitution fluid for ultrafiltrate was given into central venous catheter (post-dilution). The blood flow rate in the dialyser was 100 mL/min during the study and the average ultrafiltration rate was 0.8 L/h.
The elimination of piperacillin/tazobactam was determined in three consecutive 12 h periods: (i) on CVVH; (ii) on CVVHDF with a dialysis fluid flow rate of 1 L/h; (iii) on CVVHDF with a dialysis fluid flow rate of 2 L/h. Before each period piperacillin 4 g plus tazobactam 0.5 g (Tazocin, Wyeth Lederle Nordiska Ab, Solna, Sweden) was given as an iv infusion over 30 min. Immediately before drug infusion, the blood pump was switched off and the dialysis fluid compartment closed for 1 h in order to achieve an even distribution of piperacillin/tazobactam in the body. Blood samples, taken into heparinized tubes in an ice bath, and aliquots of ultrafiltrate/dialysate collected from timed fractionated collection bags, were taken just before (0 h) and 0.5, 1, 2, 3, 4, 5, 7, 9 and 12 h after the end of each infusion. The blood was centrifuged and the plasma separated immediately. Urine was collected in fractions of 12 h. All samples were stored at -70°C until assayed.
Determination of piperacillin and tazobactam
Concentrations of piperacillin/tazobactam in plasma, urine and ultrafiltrate/dialysate were determined by high-performance liquid chromatography.5 The limit of quantification was 2.5 mg/L for piperacillin and 5 mg/L for tazobactam. The between-run coefficient of variation was 1% at 99 mg/L (n = 14) for piperacillin and 1.1% at 24.6 mg/L (n = 14) for tazobactam.
Pharmacokinetics and statistical analysis
The elimination t1/2 was determined after visual identification of the terminal log-linear phase of each individual plasma log concentration–time curve. The plasma clearance (CL) was calculated from the equation CL = 0.693 x V/t1/2, where V (the volume of distribution) = dose/C0. C0 was taken as the intercept of the line representing the terminal elimination phase extrapolated to the concentration axis of the log concentration–time curve, minus the pre-dose concentration.
The pharmacokinetic data were analysed by the Friedman two-way analysis of variance followed by Student's t-test for paired values. The level of statistical significance was P < 0.05.
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Results |
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Mean plasma piperacillin and tazobactam concentrations are illustrated in the Figure. Pharmacokinetic parameters and cumulative amounts removed in ultrafiltrate/dialysate are presented in the Table.
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The mean t1/2 of piperacillin during CVVH (7.7 ± 2.3 h) was significantly longer than that during CVVHDF 1 L/h (6.7 ± 1.9 h) and CVVHDF 2 L/h (6.1 ± 2.0 h) (P < 0.05) (Table
). In addition, the tH of tazobactam during CVVH (13.9 ± 3.9 h) was significantly longer than during CVVHDF 1 L/h (11.6 ± 3.3 h) and CVVHDF 2 L/h (9.4 ± 2.4 h) (P < 0.05).
The total piperacillin clearance was significantly lower during CVVH (3.89 ± 1.23 L/h) than during CVVHDF 1 L/h (5.06 ± 1.68 L/h) or 2 L/h (5.48 ± 2.11 L/h) (P < 0.05). The corresponding tazobactam clearance values were 2.42 ± 0.75, 3.13 ± 0.66 and 3.75 ± 1.43 L/h, respectively (Table).
The amount of piperacillin removed in ultrafiltrate/ dialysate by CVVH (1175 ± 565 mg) was less than that removed by CVVHDF 1 L/h (1675 ± 569 mg) or by CVVHDF 2 L/h (1854 ± 524 mg) (P < 0.05). In addition, the amount of tazobactam removed in ultrafiltrate/ dialysate by CVVH (183 ± 93 mg) was significantly lower than that removed by CVVHDF 1 L/h (293 ± 95 mg) or by CVVHDF 2 L/h (345 ± 103 mg) (P < 0.05). Renal excretion of piperacillin ranged between 0% and 10.5% and that of tazobactam between 0% and 23% according to the residual renal function (Table).
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Discussion |
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This is the first study that has compared these three methods of renal replacement therapy on the elimination of piperacillin/tazobactam. CVVHDF was significantly more effective than CVVH alone, in accordance with our earlier findings for fluconazole and meropenem.6,7 Furthermore, increased dialysis fluid flow increased the mean elimination of piperacillin and tazobactam in ultrafiltrate/dialysate. The 12 h mean elimination of piperacillin and tazobactam in ultrafiltrate (calculated from the 12 h dose) was 29% and 37% during CVVH, 42% and 57% during CVVHDF 1 L/h, and 46% and 69% during CVVHDF 2 L/h. Thus, treatment with CVVHDF nearly equalled normal renal elimination of piperacillin and tazobactam, whereas their removal was moderate during CVVH.
There were considerable inter-individual differences in the pharmacokinetics of piperacillin and tazobactam in this study as found also in another study.4 For example, the half-life of tazobactam ranged from 9 to 20 h during CVVH in our study. The longest half-life was found in the patient with no residual renal function. As a result of sepsis the volume of distribution (Vd) may be increased in our patients, which may partly explain the extended half-lives observed in some of them. Tazobactam is likely to accumulate in some patients, especially in those with no residual renal function. To avoid potential toxicity of tazobactam, alternating doses of piperacillin alone and piperacillin/ tazobactam could be considered in prolonged therapy in some patients if pure piperacillin preparation is available; however, the toxicity of tazobactam is low.4
The characteristics of a dialyser, different blood and dialysis fluid flows and ultrafiltration rates influence the elimination of piperacillin/tazobactam.4,8–10 Surprisingly, in the study by Capellier et al.,9 piperacillin was not removed significantly by CVVH. In the CVVH study by van der Werf et al.,4 the t1/2 of piperacillin was only c. 5 h, but the ultrafiltration flow was higher (c. 1.5 L/h) than that in our study (0.8 L/h) where the t1/2 of piperacillin ranged from 4.3 to 9.7 h. In the study by Keller et al.,10 continuous arteriovenous haemodialysis (CAVHDF) with a dialysis fluid flow rate of c. 1 L/h reduced piperacillin by 29%. It is probable that the use of a high-flux filter increases the amount of piperacillin/tazobactam removed by CVVH.
The t1/2s of piperacillin and tazobactam are 0.69 h and 0.64 h, respectively, during intermittent haemodialysis, and 2.2 h and 7.9 h between dialyses.3 In contrast, continuous dialysis treatments have a continuous effect on drug elimination, which could compromise effective antibiotic therapy. In the present study, with dosing of piperacillin 4 g and tazobactam 0.5 g bd, plasma piperacillin/tazobactam concentrations in four of the six patients were below breakpoint MIC for pathogens such as Enterobacteriaceae and Pseudomonas spp. 9–12 h post-dose.11 As the clinical relevance of a post-antibiotic effect of ß-lactams is uncertain,12 keeping plasma piperacillin/tazobactam concentration above MICs for the whole dosing interval seems appropriate, especially in critically ill patients. Thus, in patients with acute renal failure undergoing CVVH or CVVHDF therapy (1 or 2 L/h), piperacillin 4 g and tazobactam 0.5 g tds is recommended.
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), CVVHDF with a dialysis flow of 1 L/h (
) and CVVHDF with a dialysis flow of 2 L/h (
) following intravenous administration of piperacillin 4 g and tazobactam 0.5 g bd. Number of observations (n) = 6, S.D. = 
n x s.e. |
Acknowledgements |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionAcknowledgementsReferences |
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This study was supported by a grant from Wyeth Lederle Nordiska.
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Notes |
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* Correspondence address. Department of Medicine, Helsinki University Central Hospital, Haartmaninkatu 4, PO Box 340, FIN-00029 HUS, Finland. Tel: +358-9-471-73573; Fax: +358-9-471-74013; E-mail: matti.valtonen{at}hus.fi
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References |
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1 . Sanders, W. E., Jr & Sanders, C. C. (1996). Piperacillin/tazobactam: a critical review of the evolving clinical literature. Clinical Infectious Diseases 22, 107–23.[Web of Science][Medline]
2 . Sörgel, F. & Kinzig, M. (1993). The chemistry, pharmacokinetics and tissue distribution of piperacillin/tazobactam. Journal of Antimicrobial Chemotherapy 31, Suppl. A, 39–60.
3 . Johnson, C. A., Halstenson, C. E., Kelloway, J. S., Shapiro, B. E., Zimmerman, S. W., Tonelli, A. et al. (1992). Single-dose pharmacokinetics of piperacillin and tazobactam in patients with renal disease. Clinical Pharmacological Therapy 51, 32–41.
4 . Van der Werf, T. S., Mulder, P. O. M., Zijlstra, J. G., Uges, D. R. A. & Stegeman, C. A. (1997). Pharmacokinetics of piperacillin and tazobactam in critically ill patients with renal failure, treated with continuous veno-venous hemofiltration (CVVH). Intensive Care Medicine 23, 873–7.[Web of Science][Medline]
5 . Ocampo, A. P., Hoyt, K. D., Wadgaonkar, N., Carver, A. H. & Puglisi, C. V. (1989). Determination of tazobactam and piperacillin in human plasma, serum, bile and urine by gradient elution reversed-phase high performance liquid chromatography. Journal of Chromatography 496, 167–79.[Web of Science][Medline]
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Received 1 February 2001; returned 26 June 2001; revised 12 July 2001; accepted 31 August 2001
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