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CRITICAL CARE |
From the Laboratory of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of the Basque Country, Vitoria-Gasteiz, Spain (A. Arzuaga, Dr Gascón, A. Isla, Dr Pedraz); Intensive Care Unit, Santiago Apóstol Hospital, Vitoria-Gasteiz, Spain (Dr Maynar, Dr Corral, Dr Fonesca); Intensive Care Unit, Doce de Octubre Hospital, Madrid, Spain (Dr Sánchez-Izquierdo); Intensive Care Unit, Joan XXIII University Hospital, University Rovira & Virgili, Tarragona, Spain (Dr Rello); and Microbiology Unit, Santiago Apóstol Hospital, Vitoria-Gasteiz, Spain (Dr Canut).
Address for reprints: Dr J. L. Pedraz, Laboratorio de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Paseo de la Universidad no. 7, 01006 Vitoria-Gasteiz, Spain.
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ABSTRACT |
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 TOP ABSTRACT MATERIAL AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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10 mL/min, 10 < CLCR 50 mL/min, and CLCR > 50 mL/min). A noncompartmental analysis was performed. The sieving coefficient (0.78 ± 0.28) was similar to the unbound fraction (0.65 ± 0.24) for tazobactam, but it was significantly different (0.34 ± 0.25) from the unbound fraction (0.78 ± 0.14) for piperacillin. Extracorporeal clearance was 37.0% ± 28.8%, 12.7% ± 12.6%, and 2.8% ± 3.2% for piperacillin in each group and 62.5% ± 44.9%, 35.4% ± 17.0%, and 13.1% ± 8.0% for tazobactam. No patients presented tazobactam accumulation. In patients with CLCR < 50 mL/min, t(%)ss >MIC90 values were 100% for a panel of 19 pathogens, but in those with CLCR > 50 mL/min, t(%)ss >MIC90 indexes were 55.5% and 16.6% for pathogens with MIC90 values of 32 and 64. The extracorporeal clearance of piperacillin/tazobactam is clinically significant in patients with CLCR > 50 mL/min, in which the risk of underdosing and clinical failure is important and extra doses are required.
Key Words: continuous venovenous hemofiltration (CVVH) • appropriate antimicrobial therapy • piperacillin • tazobactam • pharmacokinetics • peritonitis • sepsis
The elimination of antimicrobials depends primarily on the size of the pores in the filter used, the molecular size, the level of protein binding, and adsorption to the filter.8,9 Accumulation of the drug may be associated with serious adverse effects. On the other hand, subtherapeutic levels may be associated with the emergence of bacterial resistance. Therefore, appropriate management of critically ill infected patients is mandatory to avoid treatment failures and to improve survival. Appropriate management is based on in vitro sensitivities, penetration to the infection site, correct dosing of antibiotics, and avoidance of delay therapy onset.10,11
Piperacillin/tazobactam is a ß-lactam/ß-lactamase inhibitor combination with a broad spectrum of antibacterial activity that is frequently prescribed in the intensive care unit (ICU), particularly for sepsis, pneumonia, and intra-abdominal infections.12,13 Both components are particularly suitable for coadministration because it has been reported that they have broadly similar pharmacokinetic profiles in adults and children.14 The physicochemical properties (water solubility, protein binding, and molecular size) of both drugs are highly comparable, 15 and it is anticipated that the elimination kinetics during CVVH will be similar. Van der Werf et al15 reported that the fixed combination of piperacillin/tazobactam during CVVH in anuric patients results in some accumulation of tazobactam.
Our objective was to study the pharmacokinetics of piperacillin and tazobactam during CVVH in ICU patients with various degrees of renal impairment. Although previous studies15-18 have explored this issue, all of them have been performed in patients with acute renal failure and anuria.
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MATERIAL AND METHODS |
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TOPABSTRACTMATERIAL AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Procedures
Vascular access was obtained with 13.5-FG dual-lumen catheters (Niagara, Bard, Ontario, Canada). A Prisma (HOSPAL, Lyon, France) machine was used for CVVH with a 0.9-m2 AN69 acrylonitrile and sodium methyl sulfonate copolymer filter (PRISMA M100 HOSPAL, Lyon, France). The blood flow was kept between 150 and 220 mL/min, and the ultrafiltrate flow varied depending on the renal function (Table II). Replacement fluid was delivered prefilter. Prefilter blood and ultrafiltrate samples were collected at 0, 0.3, 0.5, 0.75, 1, 3, 6, and 8 hours (in case of administration every 8 hours) after the administration of Tazocel. Time 0 was considered just before the beginning of the 20-minute infusion. Blood samples were obtained using EDTA as anticoagulant. The blood specimens were centrifuged for 10 minutes at 1000g, and the plasma and ultrafiltrate samples were stored at –80°C until drug analysis. Trough (just before the beginning of the next administration) and peak (at the end of the infusion) samples were also obtained for several days. Protein binding of both compounds was measured by ultrafiltration using Sartorius Centrisart I filters (cutoff 10.000) (Sartorius AG, Goettingen, Germany).
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Drug Assay
Determination of piperacillin and tazobactam concentrations in plasma and ultrafiltrate fluid was performed by high-performance liquid chromatography (HPLC) with a Waters (Milford, Mass) apparatus coupled to a spectophotometric detector. All the analytical methods were conveniently validated.19,20 The assay was linear over the concentration range from 5 to 500 µg/mL for plasma samples and from 1 to 100 µg/mL for ultrafiltrate. The intraday and interday coefficients of variation ranged from 2.71% to 10.83% for plasma samples and from 1.30% to 4.60% for ultrafiltrate samples at the 3 concentrations tested (8, 80, and 400 µg/mL for plasma and 5, 40, and 75 µg/mL for ultrafiltrate). The bias at these concentrations ranged from 0.69% to 14.7% in plasma samples and from 0.20% to 9.33% in ultrafiltrate fluid. The limit of quantification was considered the lowest level included in the calibration curve (5 µg/mL in plasma and 1 µg/mL in ultrafiltrate), in which measures of the intraday coefficient of variation and bias were 8.96% and 0.77% for plasma samples and 3.15% and 4.85% for ultrafiltrate samples, respectively. No interfering peaks were detected with the assay. For tazobactam, the assay was linear over the concentration range from 3 to 50 µg/mL. The intraday and interday coefficients of variation ranged from 1.31% to 1.89% in plasma samples and from 0.39% to 2.85% in ultrafiltrate samples at the 3 concentrations tested (8, 20, and 40 µg/mL for all samples). The bias at these concentrations ranged from 0.10% to 7.79% in plasma and from 0.05% to 14.28% in ultrafiltrate fluid. The limit of quantification was considered the lowest level included in the calibration curve (3 µg/mL), in which measures of the intraday coefficient of variation and bias were 3.32% and 1.70% for plasma samples and 3.66% and 2.26% for ultrafiltrate samples, respectively. No interfering peaks were detected with the assay.
Pharmacokinetic and Statistical Analysis
Plasma and ultrafiltrate concentrations of piperacillin and tazobactam were plotted against time, and individual pharmacokinetic parameters were determined from plasma levels according to a noncompartmental analysis by using WinNonlin version 1.1 (Pharsight Corporation, Mountain View, Calif). The plasma and ultrafiltrate areas under the curve (AUCs) were determined from the first to the last data point by the linear trapezoidal method. The terminal elimination rate constant was determined via log-linear regression analysis using the terminal portion of the plasma drug concentration versus time curves. Half-life was derived from this rate constant as follows: t
=ln(2)/ke.Thetotal body clearance (CL) was obtained by the equation CL = dose/AUC. The total mean residence time (MRT) was calculated as MRT = AUMC/AUC, where AUMC is the area under the moment curve, and the volume of distribution at steady-state (Vss) was obtained by Vss = MRT x CL.
The sieving coefficient (Sc) was calculated as Sc = AUCHF/AUCP, where AUCHF is the area under the ultrafiltrate versus time curve, and AUCP is the area under the plasma (collected in the prefilter port) versus time curve.
The hemofiltration clearance (CLHF) of tazobactam and piperacillin was calculated with the following equation: CLHF =AUCHF x QHF/AUCP, where QHF is the ultrafiltrate flow rate. The total amount of the drug eliminated by hemofiltration (XHF) was calculated as XHF =AUCHF x QHF.
The Mann-Whitney U-test was used to analyze the data of the pharmacokinetic parameters and the sieving coefficient among the renally impaired groups using SPSS 11.5 for Windows (SPSS, Chicago). Statistical significance was assessed at P < .05.
Antimicrobial Susceptibility Assay
Broth microdilution tests were performed in custom-dried 96-well microdilution trays (Sensititre Division, Accumed International, Westlake, Ohio). Minimum inhibitory concentrations (MICs) were determined in accordance with the methods of the National Committee for Clinical Laboratory Standards (NCCLS).21 Piperacillin/tazobactam was tested with a constant inhibitor concentration of 4 µg/mL in serial 2-fold dilutions (8-64 µg/mL).
Tests were performed with a panel of 19 clinical strains, including Pseudomonas aeruginosa (n = 4), Escherichia coli (n = 3), Enterococcus faecalis (n = 2), Klebsiella pneumoniae (n = 1), Serratia marcenses (n = 1), Burkholderia cepacia (n = 1), Stenotrophomonas maltophilia (n = 1), Staphylococcus aureus (n = 1), and Acinetobacter baumannii (n = 1). The quality control strains used were E. coli ATCC 25922, E. coli ATCC 35218, S. aureus ATCC 29213, E. faecalis ATCC 29212, and B. fragilis ATCC 25285.
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RESULTS |
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TOPABSTRACTMATERIAL AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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These 14 patients were grouped into 3 categories according to the renal function: 4 patients with severe failure, CLCR 10 mL/min; 5 patients with moderate failure, 10 < CLCR 50 mL/min; and 5 patients with mild failure CLCR > 50 mL/min. Patients received Tazocel (4 g of piperacillin plus 0.5 g of tazobactam) every 6 (n = 7) or 8 hours (n = 7) as a 20-minute infusion (Table I).
After antibiotic onset, a mean of 11 previous doses was administered before starting sample collection to achieve steady-state concentrations of the drugs. Figure 1 shows the mean piperacillin plasma levels in the patients with different degrees of renal impairment and the minimum inhibitory concentration (MIC90) values for the microorganisms tested in these patients. Plasma levels were above the MIC90 values for all the pathogens throughout the dose interval in the subset of patients with a clearance of creatinine under 10 mL/min. Table II shows the mean pharmacokinetic parameters of piperacillin in the study population. An increase in the elimination half-life and a decrease in the total clearance with the degree of renal insufficiency were documented. The contribution of the hemofiltration clearance to the total clearance increased with the degree of renal insufficiency.
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Figure 2 shows the mean plasma concentrations of tazobactam in the 3 groups of patients considered. Differences in the plasma profiles, depending on renal impairment, were similar to those found for piperacillin. The mean pharmacokinetic parameters obtained for tazobactam are also presented in Table II. For both drugs, significant differences were documented in the majority of the pharmacokinetic parameters when patients with CLCR > 50 mL/min were compared to patients with CLCR 10 mL/min.
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In addition, plasma and ultrafiltrate levels of piperacillin and tazobactam (trough and peak) were determined at steady state during several dose intervals. Figure 3 shows tazobactam trough levels measured before the administration of a new dose at steady state. There was no evidence of accumulation of either piperacillin or tazobactam after the administration of multiple doses, even in anuric patients.
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Sieving coefficients were 0.34 ± 0.25 and 0.78 ± 0.28 for piperacillin and tazobactam, respectively. Determinations in different subsets of patients are detailed in Table II. The sieving coefficient of tazobactam (0.78 ± 0.28) is similar to the unbound fraction (0.65 ± 0.24), but the sieving coefficient of piperacillin (0.34 ± 0.25) is different from the unbound fraction (0.78 ± 0.14). No significant differences in the sieving coefficient, depending on renal impairment (neither for piperacillin nor for tazobactam), were documented.
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DISCUSSION |
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TOPABSTRACTMATERIAL AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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One of the most important factors in the extracorporeal elimination of a drug is the sieving coefficient. This parameter describes the drug fraction eliminated through the membrane and is mainly dependent on drug protein binding.23-25 Golper23 has shown that the sieving coefficient of 66 drugs measured during continuous hemofiltration in humans correlates well (r = 0.72, P < .001) with the known unbound fraction. In our case, the sieving coefficient of tazobactam (0.78 ± 0.28) is similar to the unbound fraction (0.65 ± 0.24), but the sieving coefficient of piperacillin (0.34 ± 0.25) is very different from the unbound fraction (0.78 ± 0.14). In a previous study, Capellier et al16 described the pharmacokinetics of piperacillin in critically ill patients undergoing CVVH. Although they did not calculate the sieving coefficient, they presented a graphic with the ultrafiltrate and serum levels, and it is evident that the sieving coefficient is much lower than the unbound fraction. Moreover, in Golper's list, there are several examples of drugs with very different values of the sieving coefficient and the unbound fraction (phosphomycin, phenytoin, cyclosporin). Because patients in our study had multiple organ failure and could have had the protein binding modified, literature values14,26 may be inappropriate for individual patients. Thus, we have measured the protein binding in our patients to compare it with the sieving coefficient. Mueller et al18 have reported a piperacillin sieving coefficient value of 0.84, similar to the unbound fraction, although they employed continuous venovenous hemodialysis (CVVHD). It has been reported that amikacin's sieving coefficient during slow hemodialysis is smaller than that obtained by continuous hemofiltration.27,28 Thus, the sieving coefficient depends on the technique employed.29 Continuous replacement techniques that involve hemodialysis (CVVHD and CVVHDF) eliminate low–molecular weight molecules as with these antibiotics more efficiently than continuous venovenous hemofiltration.23,30,31 Other factors, such as the protein layer in the filter membrane, 32 can also affect the hemofiltration efficacy. Caution must be taken when using the unbound fraction instead of the sieving coefficient to calculate the supplemental dose of a drug during hemofiltration processes.
The observed sieving coefficient of piperacillin and tazobactam plus the effluent amount gave a relevant extracorporeal clearance only in the severe renal impairment group, with more than 25% of total clearance for both drugs. In the group of patients with moderate renal impairment, only tazobactam features elimination with repercussions on the total clearance. Johnson et al33 had already shown that the pharmacokinetic parameters of piperacillin and tazobactam are dependent mainly on renal function. Piperacillin and tazobactam elimination half-life values progressively increased with decreasing CLCR, and total plasma clearance decreased with decreasing CLCR. For piperacillin and tazobactam, the estimated values of CL and CLHF (%) in patients with severe renal failure and their variability are comparable with values reported for intensive care patients undergoing CRRT.15,17,18
In terms of tazobactam pharmacokinetics, our findings disagree with a prior study by Van der Werf et al, 15 who reported that the administration of a fixed piperacillin/tazobactam combination during CVVH in anuric patients resulted in some accumulation of tazobactam. These authors suggested alternating the doses of piperacillin alone and piperacillin/tazobactam, although the toxicity of tazobactam is low. It is important to consider that the characteristics of the system, such as the ultrafiltration rates and the filter membrane, influence the elimination of piperacillin/tazobactam. In the current study, using a convection dose in a range from 20 to 35 mL/min, the accumulation of tazobactam was not observed, even in those patients with no residual renal function. The clinical implications of these differences in the outcomes of patients with severe infections remain uncertain, but it is a practical issue: nowadays, it is not possible to administer piperacillin alone to our patients. Besides, even if the tazobactam sieving coefficient were found to be higher than the piperacillin sieving coefficient, with tazobactam being eliminated more efficiently through the hemofiltration membrane, the piperacillin-tazobactam plasma level relationship would not be altered, so ß-lactamase inhibitor activity of tazobactam would be good enough, and no changes in the efficacy due to differences in the sieving coefficient between piperacillin and tazobactam would be expected.
The volume of distribution in patients with CLCR > 50 mL/min presented a trend toward being higher than the one for the group of CLCR 10 mL/min. Most patients with CLCR > 50 mL/min were critically ill trauma patients receiving copious quantities of intravenous fluid over an extended term of treatment. This can result in an expanded extracellular compartment, which could be the reason for the increased distribution volume. There are several examples of drugs with distribution volume values that increase in critically ill trauma patients, such as ceftazidime34 and aminoglycosides.35-38 For piperacillin, Kroh39 reported a distribution volume greater than the 200% in critically ill patients. In our study, the distribution volume values in the 3 groups agree with the different impacts of the CVVH in the elimination of both drugs. The groups with a smaller distribution volume have been shown to have a higher impact on the pharmacokinetic data.
It has been shown that a surrogate marker to predict the outcome for ß-lactam antibiotics is the duration of time that the plasma concentration exceeds the MIC40 (
>MIC90). For nonsevere infections, it is desirable to maintain the concentration of these time-killing antibiotics in plasma over the MIC throughout half of the dosing interval. However, studies in neutropenic animals have shown that the concentration of ß-lactam antibiotics should exceed MICs of pathogens during the whole dosing interval.41 As the clinical relevance of a postantibiotic effect is uncertain, 41 keeping the plasma of the ß-lactam antibiotic concentration above the MIC seems to be justified, especially in critically ill patients.31 In this way, Turnidge42 stated that ß-lactam levels need to exceed the MIC for 90% to 100% of the dosing interval to be effective against gram-negative bacilli and streptococci. The > MIC90 values obtained in our study were 100% for all the pathogens in the patients with creatinine clearance < 10 mL/min. In the patients who had a creatinine clearance between 10 and 50 mL/min, >MIC90 was 100% for pathogens with MIC90 32, but it decreased to 50% for microorganisms with an MIC90 of 64, such as S. marcenses and B. cepacia. However, in patients with creatinine clearance > 50 mL/min, as piperacillin elimination was faster, > MIC90 was only 55.5% and 16.6% for pathogens with MIC90 values of 32 and 64, respectively. Thus, to increase the >MIC90 index, administration of the piperacillin/tazobactam combination every 4 hours could be a better dosage regimen in patients presenting CLCR > 50 mL/min.
This study has several limitations. First, penetration of antibiotics to the target site is variable, and the efficacy may be different in sites with poor drug penetration. Second, creatinine clearance is variable in critically ill patients. Thus, frequent monitoring and further adjustments should be done to note fluctuations, and the calculated dose should take into account eventual treatment interruptions or the presence of dialysis. Obviously, differences between hemofiltration and hemodialysis may be more pronounced in the presence of higher dialysate flow rates. Similarly, the time dependency of the diffusion process can lead to some inaccurate calculations. Third, in vitro sensitivities present frequent variations between different institutions, and these data should not be extrapolated without taking into account local patterns of sensitivity. Fourth, the sample size is small, and findings based on a small sample size should be confirmed by further studies. Indeed, larger study populations would document significant findings in patients with lower creatinine clearances (e.g., 25 mL/min). Fifth, the case mix and the volume of distribution may be different in other series (other modalities of ventilation, different proportion of shock). Indeed, variations in pharmacokinetic parameters are frequently encountered in critically ill patients. Thus, one should be cautious before generalizing the findings to individual patients in other institutions.
In summary, our study indicates that it may not be correct to assume the equivalence between the unbound fraction and the sieving coefficient of piperacillin. In addition, one should not expect some accumulation of tazobactam in patients with severe renal impairment and who have undergone CVVH. Our findings suggest that clearance of piperacillin/tazobactam is clinically significant in patients undergoing CVVH with a creatinine clearance smaller than 50 mL/min and a convection dose more than 25 mL/min. In this subset of patients, the risk of underdosing and clinical failure is important, and it may require the administration of extra doses of piperacillin/tazobactam. In critically ill patients with no renal impairment, we have seen how the administration of piperacillin 4 g every 6 hours did not achieve serum levels to ensure adequate >MIC90 values.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMATERIAL AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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FOOTNOTES |
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Submitted for publication May 27, 2004; Revised version accepted August 3, 2004.
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TOPABSTRACTMATERIAL AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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  C. Ronco, P. Honore, J. Bouchard, E. Macedo, R. L. Mehta, J. Maynar-Moliner, J. A. Sanchez-Izquierdo-Riera, M. Herrera-Gutierrez, S. M. Bagshaw, N. Gibney, et al. Renal support in critically ill patients with acute kidney injury. N. Engl. J. Med., October 30, 2008; 359(18): 1959 - 1960. [Full Text] [PDF]
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