Abstract
Background and Objectives
Although dose optimization studies have been performed for piperacillin and tazobactam separately, a combined integral analysis is not yet reported. As piperacillin and tazobactam pharmacokinetics are likely to show correlation, a combined pharmacokinetic model should be preferred to account for this correlation when predicting the exposure. Therefore, the aim of this study was to describe the pharmacokinetics and evaluate different dosing regimens of piperacillin and tazobactam in critically ill patients using an integral population pharmacokinetic model in plasma and urine.
Methods
In this observational study, a total of 39 adult intensive care unit patients receiving piperacillin–tazobactam as part of routine clinical care were included. Piperacillin and tazobactam concentrations in plasma and urine were measured and analyzed using non-linear mixed-effects modeling. Monte Carlo simulations were performed to predict the concentrations for different dosing strategies and different categories of renal function.
Results
A combined two-compartment linear pharmacokinetic model for both piperacillin and tazobactam was developed, with an output compartment for the renally excreted fraction. The addition of 24-h urine creatinine clearance significantly improved the model fit. A dose of 12/1.5 g/24 h as a continuous infusion is sufficient to reach a tazobactam concentration above the target (2.89 mg/L) and a piperacillin concentration above the target of 100% f T>1×MIC (minimum inhibitory concentration [MIC] ≤ 16 mg/L). To reach a target of 100% f T>5×MIC with an MIC of 16 mg/L, piperacillin doses of up to 20 g/24 h are inadequate. Potential toxic piperacillin levels were reached in 19.6% and 47.8% of the population with a dose of 12 g/24 h and 20 g/24 h, respectively.
Conclusions
A regular dose of 12/1.5 g/24 h is sufficient in > 90% of the critically ill population to treat infections caused by Escherichia coli and Klebsiella pneumoniae with MICs ≤ 8 mg/L. In case of infections caused by Pseudomonas aeruginosa with an MIC of 16 mg/L, there is a fine line between therapeutic and toxic exposure. Dosing guided by renal function and therapeutic drug monitoring could enhance target attainment in such cases.
ClinicalTrials.gov identifier
NCT03738683.
Similar content being viewed by others
Regular doses of tazobactam (1–2 g/24 h) are sufficient for target attainment. |
Piperacillin administered at 12 g/24 h as a continuous infusion is sufficient to treat most infections with minimum inhibitory concentrations (MICs) ≤ 8 mg/L. However, for infections caused by pathogens with an of MIC ≥ 16 mg/L, higher doses of piperacillin are needed, which is accompanied by an increased risk of reaching toxic concentrations. |
High concentrations of piperacillin and tazobactam in urine were measured. |
1 Introduction
Piperacillin–tazobactam is a broad-spectrum β-lactam and β-lactamase inhibitor combination, active against most Enterobacterales and Pseudomonas spp., among others [1]. It is one of the most prescribed antibiotics in critically ill patients for the treatment of moderate to severe infections, including severe hospital-associated and ventilator-associated pneumonia, complicated urinary tract infections, complicated intra-abdominal infections, and other causes of sepsis [2, 3]. It is strongly recommended to administer piperacillin–tazobactam as a prolonged (i.e. continuous or extended) infusion to maximize target attainment [4]. A dose of 12/1.5 g/day is generally adequate for infections caused by Enterobacterales, anaerobes, and gram-positive bacteria (clinical breakpoint for susceptibility ≤ 8 mg/L). However, for Pseudomonas aeruginosa, a dose of 16/2 g/24 h is recommended due to higher minimum inhibitory concentrations (MIC) of wild-type P. aeruginosa (clinical breakpoint for susceptibility ≤ 16 mg/L) [5].
Most pharmacokinetic studies of piperacillin–tazobactam have focused on piperacillin. However, the efficacy of piperacillin also depends on a sufficiently high concentration of tazobactam in case of β-lactamase-producing strains. Piperacillin–tazobactam is available in a fixed-dose combination (ratio 8:1), and it is therefore desirable that the pharmacokinetic properties of both the β-lactam and β-lactamase inhibitor are similar and remain similar under changing pathophysiological conditions. The efficacy of piperacillin is driven by the time that the unbound drug concentration remains above the MIC of the targeted pathogen (fT>MIC) [6]. Targets of 100% fT>1–5×MIC are often used in the critically ill population [4, 7]. It is known that pharmacokinetic changes of tazobactam affect the pharmacodynamic outcome [8,9,10]. Time above threshold is the pharmacokinetic/pharmacodynamic index that appears to correlate best with the efficacy of tazobactam [8].
Both piperacillin and tazobactam are primarily excreted by the kidneys via glomerular filtration and tubular secretion [11]. As a consequence, there is a strong inverse relationship between renal function and systemic exposure of both compounds. It is recommended to adjust the dose of piperacillin–tazobactam based on renal function [1]. Substantial changes in renal function are common in critically ill patients. On the one hand, the glomerular filtration rate (GFR) is lower in patients with acute kidney injury (AKI), and on the other hand, augmented renal clearance (defined as a creatinine clearance of at least 130 mL/min) is increasingly recognized in ICU patients [12]. Although piperacillin and tazobactam are renally excreted to a major extent, little is known about the urinary pharmacokinetics. Evaluating the urinary pharmacokinetics is even more relevant in the light of piperacillin–tazobactam as a non-carbapenem treatment option in urinary tract infections caused by bacteria producing extended-spectrum β-lactamases (ESBLs).
Although dose optimization studies in critically ill patients have been performed for piperacillin and tazobactam separately [13,14,15,16], a combined integral analysis and dose optimization is not yet reported. As piperacillin and tazobactam pharmacokinetics are likely to show correlation, a combined pharmacokinetic model offers the opportunity to predict the exposure of both drugs under different physiological conditions while accounting for this inherent correlation. The aim of this study was to describe the pharmacokinetics of both piperacillin and tazobactam in critically ill patients. An integral population pharmacokinetic model for both piperacillin and tazobactam in plasma and urine was developed and was used to evaluate different dosing regimens based on renal function.
2 Methods
2.1 Study Design and Population
This was a prospective, observational, pharmacokinetic, single-center study performed on the intensive care unit (ICU) of the Radboudumc, Nijmegen, The Netherlands. This study was carried out in accordance with the applicable rules concerning the review of research ethics committees and informed consent in The Netherlands. All patients or legal representatives were informed about the details of this study and could decline to participate (CMO identifier: 2018-4837). The study was registered at ClinicalTrials.gov (identifier: NCT03738683).
All patients admitted to the ICU who were treated with intravenous piperacillin–tazobactam as part of routine clinical care were eligible for inclusion if they were ≥ 18 years of age, started piperacillin–tazobactam therapy ≤ 72 h before inclusion, and were managed with a central venous and/or arterial catheter. Patients were excluded if they received renal replacement therapy or extracorporeal membrane oxygenation. Dose and duration of piperacillin–tazobactam were determined by the attending physician as part of routine clinical care. To estimate pharmacokinetic parameters with sufficient accuracy, we enrolled 40 patients for inclusion, similar to previously published pharmacokinetic studies with piperacillin in critically ill patients [13, 15,16,17].
2.2 Data Collection
Demographic data and biochemical data were extracted from electronic patient records and processed anonymously. These data included age, sex, height, and total body weight. Biochemical data included creatinine (collected as part of clinical care), cystatin C, urine creatinine collected from urine over a 24-h interval, and serum albumin (collected as part of the study). Furthermore, the indication for piperacillin–tazobactam treatment, identified pathogen and drug dose history were collected. In addition, the Acute Physiology and Chronic Health Evaluation II (APACHE II) score on the day of ICU admission and the Sequential Organ Failure Assessment (SOFA) score on the day of inclusion were recorded.
2.3 Pharmacokinetic Sampling
Ethylenediaminetetraacetic acid (EDTA) plasma samples were collected on seven timepoints during a dosing interval: at t = 0 (predose) and at t = 15, 30, 60, 120, 180 and 360 min post-infusion. To determine the interoccasion variability, we sampled on two occasions, with an interval of 24 h and a total of 14 sampling timepoints, in a subgroup of patients. Furthermore, urinary pharmacokinetics, in 24-h urine, were also determined in a subgroup of patients. All samples were centrifuged at 1900 g for 5 min and were stored in a − 40 °C freezer until further analysis.
2.4 Bioanalysis of Piperacillin and Tazobactam
Total plasma and urine concentrations for both piperacillin and tazobactam were determined using a validated ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) [XEVO TQ-S, Waters, Etten-Leur, The Netherlands]. The dynamic range for piperacillin concentrations was 0.2–60 mg/L in plasma and 20–6000 mg/L in urine. The dynamic range for tazobactam concentrations was 0.2–30 mg/L in plasma and 15–3000 mg/L in urine. The accuracy range (n = 15) in plasma samples, which was dependent on the concentration, was 96–101% for piperacillin and 99–101% for tazobactam. The accuracy range (n = 5) in urine samples was 105–110% for piperacillin and 94–101% for tazobactam. Within-day precision of piperacillin varied between 1.8 and 7.6% in plasma samples and 1.0 and 5.0% in urine samples, while within-day precision of tazobactam varied between 2.7 and 10.8% in plasma samples and 2.1 and 3.9% in urine samples. Between-day precision varied between 1.1 and 2.8% in piperacillin plasma samples and 0.3 and 5.3% in tazobactam plasma samples.
2.5 Pharmacokinetic Analysis
Population pharmacokinetic analysis of piperacillin–tazobactam was performed by means of non-linear mixed-effects modeling using the NONMEM® software package (version 7.4.1). Pirana (version 2.9.7) was used as an interface for NONMEM, Perl-Speaks-NONMEM, Xpose and R. Concentration data were log-transformed. The first-order conditional estimation (FOCE) method was used throughout model building. All flow and volume parameters were allometrically scaled to a standardized fat-free mass of 58.2 kg [18], corresponding to a 1.80 m adult male of 70 kg, a priori, with allometric exponents of 0.75 and 1, respectively [19]. Inter- and intraindividual variability were assumed to be log-normally distributed. Residual variability was evaluated using additive error models on a log-scale (which corresponds to proportional error models on a linear scale) separately for each observation compartment: central and urine compartments for both piperacillin and tazobactam. Parameter precision was calculated using the sampling importance resampling procedure as described previously [20].
Structural model selection and covariate analysis were guided by physiological plausibility and objective function value (OFV). A decrease of > 3.84 points in OFV, corresponding to a significance level of p < 0.05 for nested models, was considered statistically significant in univariate testing. Non-nested models were compared using the Akaike Information Criterion. Various equations for estimated GFR (eGFR) were evaluated as covariates for renal clearance: Modification of Diet in Renal Disease (MDRD) [21], Chronic Kidney Disease Epidemiology Collaboration based on serum creatinine (CKD-EPIcreat) [22], based on serum cystatin C (CKD-EPIcysC) [23] and on both serum creatinine and serum cystatin C (CKD-EPIcreat-cysC) [23], and 24-h urine creatinine clearance. No other covariates were evaluated.
2.6 Simulations
The final model was used to perform Monte Carlo simulations to predict the piperacillin and tazobactam concentrations in both plasma and urine. We simulated different dosing regimens in 5000 virtual patients. Total body weight, height, and sex were extracted from 5000 previous ICU patients at our clinic. A uniform distribution of 24-h urine creatinine clearance between 10 and 200 mL/min was simulated, with 10 mL/min increments, resulting in 20 groups of 250 individuals each. For the distribution of 24-h urine output, we used the geometric mean (1585 mL) and coefficient of variation (59.8%) of our study population.
Four different dosing regimens of piperacillin–tazobactam were simulated: 8/1, 12/1.5, 16/2, and 20/2.5 g daily as a continuous infusion, all preceded by a loading dose of 4/0.5 g administered in 30 min. Total piperacillin and tazobactam concentrations were predicted at steady-state.
Pharmacodynamic targets for piperacillin were defined as 100% fT>1×MIC and 100% fT>5×MIC. We converted the unbound targets to equivalent total concentrations, based on a protein binding of 30% [1]. Probability of target attainment (PTA) was assessed considering the epidemiological cut-off value (ECOFF) from the MIC distribution for P. aeruginosa, i.e. 16 mg/L [24]. This can be considered as a worst-case scenario for empirical dosing. In addition, the cumulative fraction of response (CFR) was calculated against the wild-type MIC distribution for Escherichia coli and Klebsiella pneumoniae (range 0.008–8 mg/L) [25].
The target for tazobactam was based on an in vitro infection model [8] in which an unbound concentration level of 2 mg/L during 85% of the dosing interval was required to reach a 2-log10 CFU/mL reduction for a worst-case scenario, namely high-level β-lactamase-producing E. coli strains. Based on these variables, an unbound tazobactam concentration of 2 mg/L corresponds to a total concentration of 2.86 mg/L, assuming a protein binding of 30% [1].
A previously established total piperacillin concentration of 157 mg/L was used as the upper limit for toxicity [26]. The defined threshold has been associated with neurotoxicity in patients receiving a continuous infusion of piperacillin–tazobactam. A much higher neurotoxicity threshold concentration of 361 mg/L and a trough concentration of 453 mg/L for the development of nephrotoxicity in patients administered intermittent infusions of piperacillin has also been reported [27]. In our study, we used the threshold of 157 mg/L, since this is based on patients receiving piperacillin as a continuous infusion. To our knowledge, a relationship between tazobactam concentration and toxicity is not known.
3 Results
3.1 Patient Characteristics
Forty patients were enrolled in the pharmacokinetic study. One patient was excluded for analysis, since the collection times of the pharmacokinetic sampling were not correctly registered. Patients had a median (range) age of 60 (23–83) years, a median (range) total body weight of 80 (48–133) kg, and a median (range) creatinine clearance of 116 (15–377) mL/min. Nineteen of 39 patients had augmented renal clearance (creatinine clearance > 130 mL/min). Details of the patient characteristics are summarized in Table 1. The majority of patients were treated with piperacillin–tazobactam for sepsis due to pneumonia (43.6%) and sepsis of unknown origin (43.6%). All patients received a dose of 4/0.5 g every 8 h administered in approximately 30 min.
For 30 patients, sampling occurred on one occasion, and for nine patients, sampling occurred on two occasions, with an interval of 24 h. A total of 325 plasma samples for both piperacillin and tazobactam were collected. For 12 patients, 24-h urine was collected for pharmacokinetic sampling during the study period. Plasma concentrations ranging from 0.3 to 428 mg/L (piperacillin) and 0.04 to 51.1 mg/L (tazobactam) were measured. Urinary piperacillin concentrations between 1057 and 8967 mg/L and urinary tazobactam concentrations between 238 and 1503 mg/L were measured.
3.2 Pharmacokinetic Analysis
A very high correlation (Spearman’s correlation r = 0.99, p < 0.001) between piperacillin and tazobactam concentrations in plasma was observed (Fig. 1). Two separate pharmacokinetic models were developed for piperacillin and tazobactam. In addition, piperacillin and tazobactam were modeled simultaneously in a joint pharmacokinetic model, since individual pharmacokinetic parameters of piperacillin and tazobactam showed covariance. For both piperacillin, as for tazobactam, a two-compartment linear pharmacokinetic model with an output compartment for the renally excreted fraction described the data best. Interindividual variability could be identified for non-renal clearance and central and peripheral volume of distribution of tazobactam. Interoccasion variability could be identified for renal clearance for both substances. Equations for eGFR were tested as continuous covariates for renal clearance, assuming a linear relationship (Eq. 1):
The addition of eGFR as a covariate for clearance improved the model fit for both piperacillin and tazobactam. All eGFR algorithms improved the model significantly (p < 0.05). As the introduction of 24-h urine creatinine clearance as a covariate resulted in the greatest reduction in OFV, this estimate was chosen for the final model.
Thereafter, the two separate models were combined into one integral model. A schematic depiction of the integral pharmacokinetic model is shown in Fig. 2, and parameter estimates of the model are shown in Table 2. Renal clearance of piperacillin and tazobactam were highly related. Therefore, in the combined model, renal clearance of tazobactam was described as a function of piperacillin renal clearance (Eq. 2):
Interindividual variability could be estimated for non-renal clearance and central and peripheral volume of distribution, while interoccasion variability could be estimated for renal clearance. Interindividual and interoccasion variability for both substances were estimated with the same parameters, which resulted in an improved model fit compared with using separate estimates. The introduction of 24-h urine creatine clearance significantly improved the model fit, with a decrease in objective function of 70 points. Interoccasion variability decreased from 89.6 to 31.5%.
The goodness-of-fit plots are depicted in Figs. 1, 2, 3 and 4 of the electronic supplementary material.
We performed a post hoc design evaluation by means of a stochastic simulation and estimation (SSE) of 250 virtual pharmacokinetic studies. A sample size of 39 patients and a total of 325 plasma samples for both piperacillin and tazobactam resulted in an accurate and precise estimation of the pharmacokinetic parameters (relative bias < 10% and imprecision < 20%).
3.3 Simulations
The simulated piperacillin and tazobactam plasma concentrations for the four dosing regimens (8/1, 12/1.5, 16/2, and 20/2.5 g/24 h) are shown in Figs. 3 and 4. The target concentration for tazobactam (2.86 mg/L) was reached in 100% of the population when a dose of ≥ 2 g/24 h was administered, and in 99.0% and 99.4% of the population with doses of 1 and 1.5 g/24 h, respectively. As the tazobactam target concentration is always achieved, the efficacy of the piperacillin–tazobactam combination is thus mainly dependent on the piperacillin concentration. The PTA for piperacillin, considering an MIC of 16 mg/L, is presented in Table 3. Piperacillin administered at 12 g/24 h is sufficient to attain the target in > 99% of the population when aiming for a target of 100% fT>1×MIC, even for patients with a creatinine clearance of up to 200 mL/min. In case a target of 100% fT>5×MIC is desired, a dose of 20 g/24 h is necessary in patients with a creatinine clearance of 10–60 mL/min, for target attainment in > 90% of the population. Higher doses are required for patients with a creatinine clearance > 60 mL/min.
The CFR for piperacillin against E. coli and K. pneumoniae is presented in Table 4. The CFR at 100% f T>1×MIC was > 90% against E. coli and K. pneumoniae for all simulated dosing regimens and different classes of creatinine clearance. When aiming for a target of 100% f T>5×MIC, a dose of 12 g/24 h or more was sufficient for a CFR > 90% against both E. coli and K. pneumoniae. The CFR was <90% in patients with a creatinine clearance of ≥ 130 mL/min treated with a dose of 8 g/24 h against K. pneumoniae.
A limited fraction of 8.0% of the population reached the putative toxicity threshold of 157 mg/L at a dose of 8 g/24 h. In contrast, this threshold was reached in 19.6% with a dose of 12 g/24 h, in 33.3% with a dose of 16 g/24 h, and in 47.8% with a dose of 20 g/24 h.
The simulated piperacillin and tazobactam concentrations in urine are shown in Fig. 5. The median (interquartile range [IQR]) urine piperacillin concentration was 5371 [3110–8,830] mg/L with a dose of 8 g/24 h, 8057 [4665–13,243] mg/L with a dose of 12 g/24 h, 10,742 [6219–17,652] mg/L with a dose of 16 g/24 h, and 13,424 [7774–22,052] mg/L with a dose of 20 g/24 h.
4 Discussion
This study contributes to the knowledge of piperacillin and tazobactam pharmacokinetics and urinary concentrations in critically ill patients. To the best of our knowledge, we are the first to report on a joint pharmacokinetic model with piperacillin–tazobactam in plasma and urine, enabling us to predict the pharmacokinetics of both compounds simultaneously. A high correlation between the pharmacokinetics of both compounds was observed, indicating the necessity of our approach. Neglecting the inherent correlation between the pharmacokinetics of piperacillin and tazobactam would carry this forward in the Monte Carlo simulations, resulting in incorrect target attainment predictions. Moreover, since the pharmacokinetic observations of piperacillin offer subject-specific information that is helpful in fitting the tazobactam data, and vice versa, using a joint model enlarges the total information density and thus enriches the model. The wide distribution of renal function with a high proportion of subjects in our study with augmented renal clearance (49%) underlines the usefulness of our model in which we have fully characterized the renal clearance by measuring the urine piperacillin and tazobactam concentrations. The proposed dosing recommendations apply to critically ill patients with a creatinine clearance of 10–200 mL/min.
The pharmacokinetic parameters we identified for piperacillin confirm those described in previous papers in critically ill patients [13, 15, 16]. However, total clearance was lower in the current study (11.2 L/h, 95% confidence interval [CI] 9.3–13.5 L/h) than previously reported (17.1 L/h, 95% CI 14.4–20.6 L/h) [16]. This may be explained by the exclusion of patients with plasma creatinine of < 120 µmol/L in the latter study. Considerably less is known about the pharmacokinetics of tazobactam in critically ill patients. The typical total clearance for tazobactam was estimated to be higher (10.3 L/h, 95% CI 9.1–11.7 L/h) than reported in a small study in critically ill patients (5.3 L/h, 95% CI 2.2–9.1 L/h), but similar to reported in patients undergoing colorectal surgery (11.3 L/h, 95% CI 5.1–17.4 L/h) [14, 28].
Piperacillin and tazobactam are predominantly eliminated renally, therefore GFR significantly affects the plasma concentrations. As correct estimation of renal function in critically ill patients is troublesome, we evaluated different equations for GFR to predict renal clearance and found that all tested algorithms for estimating GFR significantly explained the variability in clearance and are useful in predicting piperacillin and tazobactam exposure.
For adequate treatment, it is essential to attain the target for both piperacillin and tazobactam simultaneously. We found that the PTA for tazobactam in regular doses is high, i.e. 100% with a dose of 2 g/24 h. Consequently, the efficacy of piperacillin–tazobactam mainly depends on the piperacillin concentration. Piperacillin administered at 12 g/24 h as a continuous infusion is sufficient to treat infections caused by E. coli, K. pneumoniae, and P. aeruginosa when aiming for a target of 100% fT>1×MIC with creatinine clearances of up to 200 mL/min. The target of 100% fT>1×MIC is recommended by a panel of experts in the field [4]. Often, higher targets of up to 100% fT>5×MIC are used in the critically ill population, suggesting to not only maximize efficacy but also to minimize emergence of resistance [7]. In a worst-case scenario, i.e. an infection caused by P. aeruginosa with an MIC of 16 mg/L, a dose of 20 g/24 h is necessary to reach a target of 100% fT>5×MIC in patients with a creatinine clearance of 10–60 mL/min. Even higher doses are required for patients with a creatinine clearance > 60 mL/min.
However, when aiming for these higher targets, this is accompanied by an increased risk of reaching potential toxic concentrations. Almost half of the population reaches the upper limit of 157 mg/L with a dose of 20 g/24 h. Although β-lactam antibiotics are usually considered to have a wide therapeutic range, this could be argued when a total piperacillin concentration between 114 and 157 mg/L is aimed for. In patients with a creatinine clearance < 50 mL/min, dose reduction is preferred to prevent toxic concentrations, but this may compromise the effectiveness of antibiotic treatment. Dosing guided by therapeutic drug monitoring could enhance target attainment [29]. Further research on the relationship between piperacillin concentration and toxicity is desirable, since concentrations > 157 mg/L might be tolerated [27].
A relationship between tazobactam concentration and toxicity is not known. We found high tazobactam plasma concentrations. Our data suggest that reduced doses of tazobactam might be possible, while still achieving the unbound target of 2 mg/L.
We demonstrated high urinary concentrations of both piperacillin and tazobactam. These concentrations might be sufficient for the treatment of uncomplicated urinary tract infections caused by Enterobacterales with MICs that would conventionally classify them as being resistant to this drug combination. Normally, a clinical breakpoint of 8 mg/L is used for Enterobacterales [5], but highly resistant urinary organisms, including carbapenemase-producers, with MICs up to 4096 mg/L could be treated in vitro with piperacillin–tazobactam at approximately 50% fT>1×MIC [30]. Our data show that these high concentrations are indeed reached in vivo. It should be noted that this applies only to urinary tract infections without microbial invasion in tissue. In case of a bloodstream infection with E. coli and K. pneumoniae resistant to ceftriaxone, piperacillin–tazobactam appeared inferior compared to meropenem [31].
Several limitations may apply to our study. First, only the total drug concentrations were measured, where it is the unbound concentration that is responsible for the effect. The unbound fraction of both piperacillin and tazobactam is about 30% [1], which is relatively low. Variation in protein binding is therefore of limited significance for interpretation of unbound pharmacokinetics compared to situations in highly protein bound drugs. Second, pharmacokinetic sampling on a second occasion was only performed in a small subset of nine patients. Still, this limited number of patients was sufficient to identify interoccasion variability on clearance. Finally, patients on renal replacement therapy were excluded in our study, thus limiting the extrapolation of our findings to this population. We argued that the role of renal replacement therapy in the pharmacokinetics of piperacillin–tazobactam has already been extensively evaluated [32,33,34].
There is conflicting evidence on whether or not piperacillin elimination is saturable at therapeutic plasma concentrations. Some previous pharmacokinetic studies found evidence for non-linear, saturable elimination of piperacillin [17, 35, 36], while other studies are in agreement with our findings of linear piperacillin clearance [16, 37]. Piperacillin is cleared through glomerular filtration and tubular secretion. Tubular secretion is a saturable, non-linear, process, while glomerular filtration is a linear process. The extent of saturation of nonrenal clearance was reported to be small [36]. In critically ill patients, the large increases in glomerular filtration and volume of distribution might outweigh the effect of saturable elimination. Also, in the current study all patients received piperacillin 12 g/day. Doses of 12 g/24 h or lower are less likely to saturate the process of tubular secretion than higher doses. Finding a reliable marker for tubular secretion could be helpful in predicting renal clearance of antimicrobial drugs that are secreted by glomerular filtration and tubular secretion, such as piperacillin.
5 Conclusion
We showed that piperacillin–tazobactam in a dose of 12/1.5 g/24 h as continuous infusion is sufficient to reach a target of 100% fT>1×MIC.. Doses up to 20/2.5 g/24 h are still inadequate to reach the frequently used target of 100% fT>5×MIC for infections caused by P. aeruginosa with an MIC of 16 mg/L. Yet, these high doses may on the other hand lead to toxicity. Since creatinine clearance explains 65% of the variability in piperacillin–tazobactam clearance, target attainment is strongly related to renal function. Thus, dosing should be based on renal function and might be guided by therapeutic drug monitoring. In addition, our data suggest that highly resistant urinary organisms could be treated with piperacillin–tazobactam, as very high urinary concentrations are found, independent of renal function.
Change history
10 August 2022
A Correction to this paper has been published: https://doi.org/10.1007/s40262-022-01165-8
References
Summary of Product Characteristics: Piperacillin/Tazobactam 4g/0.5g Powder for Solution for Infusion 2017. https://www.medicines.org.uk/emc/product/6526/smpc#gref. Accessed 7 Oct 2021.
Beovic B, Dousak M, Ferreira-Coimbra J, Nadrah K, Rubulotta F, Belliato M, et al. Antibiotic use in patients with COVID-19: a ‘snapshot’ Infectious Diseases International Research Initiative (ID-IRI) survey. J Antimicrob Chemother. 2020;75(11):3386–90.
Remschmidt C, Schneider S, Meyer E, Schroeren-Boersch B, Gastmeier P, Schwab F. Surveillance of antibiotic use and resistance in intensive care units (SARI). Dtsch Arztebl Int. 2017;114(50):858–65.
Abdul-Aziz MH, Alffenaar JC, Bassetti M, Bracht H, Dimopoulos G, Marriott D, et al. Antimicrobial therapeutic drug monitoring in critically ill adult patients: a position paper. Intensive Care Med. 2020;46(6):1127–53.
The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. Version 11.0, 2021. http://www.eucast.org. Accessed 7 Oct 2021.
Drusano GL. Antimicrobial pharmacodynamics: critical interactions of ‘bug and drug.’ Nat Rev Microbiol. 2004;2(4):289–300.
Delattre IK, Taccone FS, Jacobs F, Hites M, Dugernier T, Spapen H, et al. Optimizing beta-lactams treatment in critically-ill patients using pharmacokinetics/pharmacodynamics targets: are first conventional doses effective? Expert Rev Anti Infect Ther. 2017;15(7):677–88.
Nicasio AM, VanScoy BD, Mendes RE, Castanheira M, Bulik CC, Okusanya OO, et al. Pharmacokinetics–pharmacodynamics of tazobactam in combination with piperacillin in an in vitro infection model. Antimicrob Agents Chemother. 2016;60(4):2075–80.
Zander J, Dobbeler G, Nagel D, Scharf C, Huseyn-Zada M, Jung J, et al. Variability of piperacillin concentrations in relation to tazobactam concentrations in critically ill patients. Int J Antimicrob Agents. 2016;48(4):435–9.
Liu Q, Rand K, Derendorf H. Impact of tazobactam pharmacokinetics on the antimicrobial effect of piperacillin–tazobactam combinations. Int J Antimicrob Agents. 2004;23(5):494–7.
Komuro M, Maeda T, Kakuo H, Matsushita H, Shimada J. Inhibition of the renal excretion of tazobactam by piperacillin. J Antimicrob Chemother. 1994;34(4):555–64.
Bilbao-Meseguer I, Rodriguez-Gascon A, Barrasa H, Isla A, Solinis MA. Augmented renal clearance in critically ill patients: a systematic review. Clin Pharmacokinet. 2018;57(9):1107–21.
Alobaid AS, Wallis SC, Jarrett P, Starr T, Stuart J, Lassig-Smith M, et al. Population pharmacokinetics of piperacillin in nonobese, obese, and morbidly obese critically ill patients. Antimicrob Agents Chemother. 2017;61(3):e01276-e1316.
Kalaria SN, Gopalakrishnan M, Heil EL. A population pharmacokinetics and pharmacodynamic approach to optimize tazobactam activity in critically ill patients. Antimicrob Agents Chemother. 2020;64(3):e02093-e2119.
Klastrup V, Thorsted A, Storgaard M, Christensen S, Friberg LE, Obrink-Hansen K. Population pharmacokinetics of piperacillin following continuous infusion in critically ill patients and impact of renal function on target attainment. Antimicrob Agents Chemother. 2020;64(7):e02556-e2619.
Roberts JA, Kirkpatrick CM, Roberts MS, Dalley AJ, Lipman J. First-dose and steady-state population pharmacokinetics and pharmacodynamics of piperacillin by continuous or intermittent dosing in critically ill patients with sepsis. Int J Antimicrob Agents. 2010;35(2):156–63.
Dhaese SAM, Colin P, Willems H, Heffernan A, Gadeyne B, Van Vooren S, et al. Saturable elimination of piperacillin in critically ill patients: implications for continuous infusion. Int J Antimicrob Agents. 2019;54(6):741–9.
Janmahasatian S, Duffull SB, Ash S, Ward LC, Byrne NM, Green B. Quantification of lean bodyweight. Clin Pharmacokinet. 2005;44(10):1051–65.
Holford NHG, Anderson BJ. Allometric size: the scientific theory and extension to normal fat mass. Eur J Pharm Sci. 2017;109S:S59–64.
Dosne AG, Bergstrand M, Harling K, Karlsson MO. Improving the estimation of parameter uncertainty distributions in nonlinear mixed effects models using sampling importance resampling. J Pharmacokinet Pharmacodyn. 2016;43(6):583–96.
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130(6):461–70.
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604–12.
Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T, et al. Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med. 2012;367(1):20–9.
Roberts JA, Norris R, Paterson DL, Martin JH. Therapeutic drug monitoring of antimicrobials. Br J Clin Pharmacol. 2012;73(1):27–36.
Roberts JA, Boots R, Rickard CM, Thomas P, Quinn J, Roberts DM, et al. Is continuous infusion ceftriaxone better than once-a-day dosing in intensive care? A randomized controlled pilot study. J Antimicrob Chemother. 2007;59(2):285–91.
Quinton MC, Bodeau S, Kontar L, Zerbib Y, Maizel J, Slama M, et al. Neurotoxic concentration of piperacillin during continuous infusion in critically ill patients. Antimicrob Agents Chemother. 2017;61(9):e00654-e717.
Imani S, Buscher H, Marriott D, Gentili S, Sandaradura I. Too much of a good thing: a retrospective study of beta-lactam concentration–toxicity relationships. J Antimicrob Chemother. 2017;72(10):2891–7.
Kinzig M, Sorgel F, Brismar B, Nord CE. Pharmacokinetics and tissue penetration of tazobactam and piperacillin in patients undergoing colorectal surgery. Antimicrob Agents Chemother. 1992;36(9):1997–2004.
Richter DC, Frey O, Rohr A, Roberts JA, Koberer A, Fuchs T, et al. Therapeutic drug monitoring-guided continuous infusion of piperacillin/tazobactam significantly improves pharmacokinetic target attainment in critically ill patients: a retrospective analysis of four years of clinical experience. Infection. 2019;47(6):1001–11.
Gould M, Ginn AN, Marriott D, Norris R, Sandaradura I. Urinary piperacillin/tazobactam pharmacokinetics in vitro to determine the pharmacodynamic breakpoint for resistant Enterobacteriaceae. Int J Antimicrob Agents. 2019;54(2):240–4.
Harris PNA, Tambyah PA, Lye DC, Mo Y, Lee TH, Yilmaz M, et al. Effect of piperacillin–tazobactam vs meropenem on 30-day mortality for patients with E. coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance: a randomized clinical trial. JAMA. 2018;320(10):984–94.
van der Werf TS, Mulder PO, Zijlstra JG, Uges DR, Stegeman CA. Pharmacokinetics of piperacillin and tazobactam in critically ill patients with renal failure, treated with continuous veno-venous hemofiltration (CVVH). Intensive Care Med. 1997;23(8):873–7.
Roger C, Cotta MO, Muller L, Wallis SC, Lipman J, Lefrant JY, et al. Impact of renal replacement modalities on the clearance of piperacillin–tazobactam administered via continuous infusion in critically ill patients. Int J Antimicrob Agents. 2017;50(2):227–31.
Asin-Prieto E, Rodriguez-Gascon A, Troconiz IF, Soraluce A, Maynar J, Sanchez-Izquierdo JA, et al. Population pharmacokinetics of piperacillin and tazobactam in critically ill patients undergoing continuous renal replacement therapy: application to pharmacokinetic/pharmacodynamic analysis. J Antimicrob Chemother. 2014;69(1):180–9.
Bulitta JB, Kinzig M, Jakob V, Holzgrabe U, Sorgel F, Holford NH. Nonlinear pharmacokinetics of piperacillin in healthy volunteers – implications for optimal dosage regimens. Br J Clin Pharmacol. 2010;70(5):682–93.
Landersdorfer CB, Bulitta JB, Kirkpatrick CM, Kinzig M, Holzgrabe U, Drusano GL, et al. Population pharmacokinetics of piperacillin at two dose levels: influence of nonlinear pharmacokinetics on the pharmacodynamic profile. Antimicrob Agents Chemother. 2012;56(11):5715–23.
Dhaese SAM, Roberts JA, Carlier M, Verstraete AG, Stove V, De Waele JJ. Population pharmacokinetics of continuous infusion of piperacillin in critically ill patients. Int J Antimicrob Agents. 2018;51(4):594–600.
Acknowledgments
The authors thank the research nurses of the ICU, the analytical staff of the Department of Pharmacy, and Angela Colbers for their contributions to this study.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Funding
This study was supported by the Department of Pharmacy at Radboudumc, Nijmegen. No additional funding was received for this work.
Transparency declarations
None to declare.
Conflicts of interest
All authors declared no competing interests related to this work.
Ethics approval
This study was evaluated by the local Ethics Committee. The research was conducted in accordance with the Declaration of Helsinki, and national and institutional standards.
Consent to participate
All patients or legal representatives were informed about the details of this study and could decline to participate (CMO identifier: 2018-4837). Subsequently, verbal consent was obtained and documented in the patient’s medical record. The need for a written informed consent was waived by the local Ethics Committee due to the observational nature of the study.
Consent for publication
Not applicable.
Availaility of data and materials
Not applicable.
Code availability
The NONMEM control stream is provided in the electronic supplementary files.
Author contributions
All authors contributed to the study conception and design. Preparation of the study was performed by EW. JS, PP and TF recruited patients. Data collection was performed by EW and JR. EW, RtH and RB analyzed the data. The first draft of the manuscript was written by EW and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
About this article
Cite this article
Wallenburg, E., ter Heine, R., Schouten, J.A. et al. An Integral Pharmacokinetic Analysis of Piperacillin and Tazobactam in Plasma and Urine in Critically Ill Patients. Clin Pharmacokinet 61, 907–918 (2022). https://doi.org/10.1007/s40262-022-01113-6
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40262-022-01113-6