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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Introduction |
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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 (2030%),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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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 concentrationtime 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 concentrationtime 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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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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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.4,810 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. 912 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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Acknowledgements |
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Notes |
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References |
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2 . Sörgel, F. & Kinzig, M. (1993). The chemistry, pharmacokinetics and tissue distribution of piperacillin/tazobactam. Journal of Antimicrobial Chemotherapy 31, Suppl. A, 3960.[ISI][Medline]
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, 3241.
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, 8737.[ISI][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, 16779.[Medline]
6 . Valtonen, M., Tiula, E. & Neuvonen, P. J. (1997). Effect of continuous venovenous haemofiltration and haemodiafiltration on the elimination of fluconazole in patients with acute renal failure. Journal of Antimicrobial Chemotherapy 40, 695700.[Abstract]
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Valtonen, M., Tiula, E., Backman, J. T. & Neuvonen, P. J. (2000). Elimination of meropenem during continuous venovenous haemofiltration and haemodiafiltration in patients with acute renal failure. Journal of Antimicrobial Chemotherapy 45, 7014.
8 . Joos, B., Schmidli, M. & Keusch, G. (1996). Pharmacokinetics of antimicrobial agents in anuric patients during continuous venovenous haemofiltration. Nephrology, Dialysis and Transplantation 11, 15825.
9 . Capellier, G., Cornette, C., Boillot, A., Guinhard, C., Jacques, T., Blasco, G. et al. (1998). Removal of piperacillin in critically ill patients undergoing continuous venovenous hemofiltration. Critical Care Medicine 26, 8891.[ISI][Medline]
10 . Keller, E., Böhler, J., Busse-Grawitz, A., Reetze-Bonorden, P., Krumme, B. & Schollmeyer, P. (1995). Single dose kinetics of piperacillin during continuous arteriovenous hemodialysis in intensive care patients. Clinical Nephrology 43, Suppl. 1, 202.[ISI][Medline]
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MacGowan, A. P. & Wise, R. (2001). Establishing MIC breakpoints and the interpretation of in vitro susceptibility tests. Journal of Antimicrobial Chemotherapy 48, Suppl. 1, 1728.
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Received 1 February 2001; returned 26 June 2001; revised 12 July 2001; accepted 31 August 2001