Exposure levels and target attainment of piperacillin/tazobactam in adult patients admitted to the intensive care unit: a prospective observational study.

PURPOSE: The objective of this study was to evaluate the exposure and the pharmacodynamic target attainment of piperacillin/tazobactam (PTZ) in adult critically ill patients. METHODS: We conducted a prospective observational study in the intensive care unit (ICU) of the Hôpital du Sacré-Cœur de Montréal (a Level I trauma centre in Montreal, QC, Canada) between January 2021 and June 2022. We included patients aged 18 yr or older admitted to the ICU who received PTZ by intravenous administration. Demographic and clinical characteristics were collected, and clinical scores were calculated. On study day 1 of antimicrobial therapy, three blood samples were collected at the following timepoints: one hour after PTZ dose administration and at the middle and at the end of the dosing interval. The sampling schedule was repeated on days 4 and 7 of therapy if possible. Samples were analyzed by ultra-high performance liquid chromatography with diode array detector to determine the total piperacillin concentration. Middle- and end-of-interval concentrations were used for target attainment analyses, and were defined as a concentration above the minimal inhibitory concentration of 16 mg·L-1, corresponding to the breakpoint of Enterobacteriaceae and Pseudomonas aeruginosa. RESULTS: Forty-three patients were recruited and 202 blood samples were analyzed. The most prevalent dose was 3/0.375 g every six hours (n = 50/73 doses administered, 68%) with a 30-min infusion. We observed marked variability over the three sampling timepoints, and the median [interquartile range] piperacillin concentrations at peak, middle of interval, and end of interval were 109.4 [74.0-152.3], 59.3 [21.1-74.4], and 25.3 [6.8-44.6] mg·L-1, respectively. When assessing target attainment, 37% of patients did not reach the efficacy target of a trough concentration of 16 mg·L-1. The majority of patients who were underexposed were patients with normal to augmented renal clearance. CONCLUSION: In this prospective observational study of adult ICU patients receiving intravenous PTZ, a large proportion had subtherapeutic concentrations of piperacillin. This was most notable in patients with normal to augmented renal clearance. More aggressive dosage regimens may be required for this subpopulation to ensure attainment of efficacy targets.

RéSUMé: OBJECTIF: L'objectif de cette étude était d'évaluer l'exposition et l'atteinte des cibles pharmacodynamiques de la pipéracilline/tazobactam (PTZ) chez la patientèle adulte aux soins intensifs. MéTHODES: Nous avons réalisé une étude observationnelle prospective dans l'unité de soins intensifs (USI) de l'Hôpital du Sacré-Cœur de Montréal (un centre de traumatologie de niveau 1 à Montréal, QC, Canada) entre janvier 2021 et juin 2022. Nous avons inclus les patient·es adultes âgé·es de 18 ans ou plus admis·es à l'USI ayant reçu de la PTZ par administration intraveineuse. Les caractéristiques démographiques et cliniques ont été recueillies, et les scores cliniques ont été calculés. Au jour 1 de la thérapie antimicrobienne, trois échantillons sanguins ont été prélevés aux moments suivants : 1 h après l'administration de la dose de PTZ, au milieu et à la fin de l'intervalle d'administration. Le calendrier d'échantillonnage a été répété aux jours 4 et 7 de la thérapie si possible. Les échantillons ont été analysés par chromatographie liquide à ultra-haute performance avec détecteur à diodes pour déterminer la concentration totale de pipéracilline. Les concentrations du milieu et de fin d'intervalle ont été utilisées pour les analyses d'atteinte de cible, définie comme une concentration supérieure à la concentration minimale inhibitrice de 16 mg·L-1, associée aux Enterobacteriaceae et au Pseudomonas aeruginosa. RéSULTATS: Quarante-trois patient·es ont été recruté·es et 202 échantillons sanguins ont été analysés. La dose la plus prévalente était une dose de 3/0,375 g aux 6 h (n = 50/73 doses administrées, 68 %) avec une perfusion sur 30 min. Nous avons observé une variabilité marquée aux trois temps de prélèvement, et les concentrations médianes [intervalle interquartile] de pipéracilline au pic, au milieu et à la fin de l'intervalle étaient respectivement de 109,4 [74,0-152,3], 59,3 [21,1-74,4] et 25,3 [6,8-44,6] mg·L−1. Lors de l'évaluation de l'atteinte de la cible, 37 % des patient·es n'ont pas atteint la cible d'efficacité d'une concentration de 16 mg·L−1 à la fin de l'intervalle posologique. La majorité des patient·es sous-exposé·es étaient des personnes dont la clairance rénale était normale ou augmentée. CONCLUSION: Dans cette étude observationnelle prospective de patient·es adultes aux soins intensifs recevant de la PTZ par voie intraveineuse, une grande proportion de patient·es présentait des concentrations sous-thérapeutiques de pipéracilline. Ceci était plus marqué chez les patient·es ayant une clairance rénale normale ou augmentée. Des schémas posologiques plus agressifs pourraient être nécessaires pour cette sous-population afin de favoriser l'atteinte des cibles d'efficacité.

Potential benefits of therapeutic drug monitoring for beta-lactam antibiotics in augmented renal clearance patients: a case report.

Augmented renal clearance (ARC) is commonly described in critically ill patients, making drug pharmacokinetics even harder to predict in this population. This case report displays the value of therapeutic drug monitoring (TDM) of piperacillin/tazobactam (PTZ) in this population. We identified two patients with ARC and intermittent administration of PTZ who took part in a prospective, descriptive study conducted at Hôpital du Sacré-Cœur de Montréal. Both had plasma samples drawn at peak, middle, and end of their dosing intervals of PTZ. Minimal inhibitory concentrations (MICs) of 4 and 8 mg/L were chosen to evaluate therapeutic target attainment at middle and end of dosing interval. The first patient was a 52-year-old male with a renal clearance rate estimated at 147 mL/min who received 3.375 g PTZ every 6 h. The second patient, a 49-year-old male, had an estimated renal clearance rate of 163 mL/min and received the same regimen. Both patients had piperacillin concentrations above the target MICs at middle of the dosing interval, but they failed to reach a trough concentration above 8 mg/L. The present case report showcases two patients with subtherapeutic PTZ concentrations despite strict following of local administration protocols. This suboptimal administration could not only lead to treatment failure, but also to the selection and growth of resistant pathogens. Implementing TDM would offer the possibility to adjust drug regimens in real-time and prevent situations like these from occurring.

Towards model-informed precision dosing of piperacillin: multicenter systematic external evaluation of pharmacokinetic models in critically ill adults with a focus on Bayesian forecasting.

PURPOSE: Inadequate piperacillin (PIP) exposure in intensive care unit (ICU) patients threatens therapeutic success. Model-informed precision dosing (MIPD) might be promising to individualize dosing; however, the transferability of published models to external populations is uncertain. This study aimed to externally evaluate the available PIP population pharmacokinetic (PopPK) models. METHODS: A multicenter dataset of 561 ICU patients (11 centers/3654 concentrations) was used for the evaluation of 24 identified models. Model performance was investigated for a priori (A) predictions, i.e., considering dosing records and patient characteristics only, and for Bayesian forecasting, i.e., additionally including the first (B1) or first and second (B2) therapeutic drug monitoring (TDM) samples per patient. Median relative prediction error (MPE) [%] and median absolute relative prediction error (MAPE) [%] were calculated to quantify accuracy and precision. RESULTS: The evaluation revealed a large inter-model variability (A: MPE - 135.6-78.3% and MAPE 35.7-135.6%). Integration of TDM data improved all model predictions (B1/B2 relative improvement vs. A: |MPE|median_all_models 45.1/67.5%; MAPEmedian_all_models 29/39%). The model by Kim et al. was identified to be most appropriate for the total dataset (A/B1/B2: MPE - 9.8/- 5.9/- 0.9%; MAPE 37/27.3/23.7%), Udy et al. performed best in patients receiving intermittent infusion, and Klastrup et al. best predicted patients receiving continuous infusion. Additional evaluations stratified by sex and renal replacement therapy revealed further promising models. CONCLUSION: The predictive performance of published PIP models in ICU patients varied considerably, highlighting the relevance of appropriate model selection for MIPD. Our differentiated external evaluation identified specific models suitable for clinical use, especially in combination with TDM.

Impact of piperacillin unbound fraction variability on dosing recommendations in critically ill patients.

A common approach to assess the efficacy of piperacillin is to first measure the total concentration and afterwards apply a theoretical unbound fraction of 70% to obtain the unbound concentration. However, hypoalbuminemia is a common phenomenon in critically ill patients, resulting in variations in unbound fraction, therefore we aimed to simulate the impact of piperacillin unbound fraction fluctuations on the predictive performance of a population pharmacokinetic model and on the dosing recommendations of piperacillin. Unbound factors of 70%, 75%, 80% and 85% were applied to total concentrations of piperacillin administered by continuous infusion from an external dataset. A validated model was used for assessment of predictive performance and to estimate patient clearance. Dosing simulations were performed to evaluate target attainment. Variation in unbound fractions caused minimal impact on piperacillin clearance and target attainment but seemed to influence model validity.

Using a Validated Population Pharmacokinetic Model for Dosing Recommendations of Continuous Infusion Piperacillin for Critically Ill Adult Patients.

BACKGROUND AND OBJECTIVE: Piperacillin is a broad-spectrum ß-lactam antibiotic commonly prescribed in intensive care units. Many piperacillin population pharmacokinetic models have been published, but few underwent an external evaluation. External evaluation is an important process to determine a model's capability of being generalized to other hospitals. We aimed to assess the predictive performance of these models with an external validation dataset. METHODS: Six models were evaluated with a dataset consisting of 30 critically ill patients (35 samples) receiving piperacillin by continuous infusion. Models were subject to prediction-based (bias and imprecision) and simulation-based evaluations. When a model had an acceptable evaluation, it was used for dosing simulations to evaluate the probability of target attainment. RESULTS: Bias and imprecision ranged from - 35.7 to 295% and from 22.7 to 295%, respectively. The models of Klastrup et al. and of Udy et al. were acceptable according to our criteria and were used for dosing simulations. Simulations showed that a loading dose of 4 g followed by a maintenance dose of 16 g/24 h of piperacillin infused continuously was necessary to remain above a pharmacokinetic-pharmacodynamic target set as a minimal inhibitory concentration of 16 mg/L in 90% of patients, for a median patient with a creatinine clearance of 76 mL/min. CONCLUSIONS: Despite the considerable variation in the predictive performance of the models with the external validation dataset, this study was able to validate two of these models and led to the elaboration of a dosing nomogram for piperacillin by continuous infusion that can be used by clinicians in intensive care units.

An Update on Population Pharmacokinetic Analyses of Vancomycin, Part II: In Pediatric Patients.

Vancomycin is widely used in pediatric patients, however, large inter- and intraindividual variability are observed in vancomycin pharmacokinetics, affecting proper therapeutic monitoring. This review aimed at providing a comprehensive synthesis of the population pharmacokinetic models of vancomycin in pediatric patients and identifying potential factors responsible for the variability observed in various subpopulations. We conducted a literature search of the PubMed and EMBASE databases to obtain population pharmacokinetic studies for vancomycin published between January 2011 and January 2020, which resulted in a total of 33 studies. Vancomycin pharmacokinetics were generally characterized using a one-compartment model (n = 27), while a two-compartment model was used in six studies. The median (interquartile range) of the typical vancomycin clearance (CL) and the total volume of distribution adjusted to the median or mean body weight of the respective study was 0.103 L/h/kg (0.071-0.125) and 0.64 L/kg (0.59-1.03), respectively. Median weight-adjusted CL between different child age groups, such as infants and adolescents, did not appear to vary significantly, although the sample size for many age groups was very small. Examples of the conditions with relatively abnormal vancomycin pharmacokinetic values include renal insufficiency, sepsis, hematological and solid malignancy, and hypothermia treatment. Factors influencing pediatric vancomycin pharmacokinetics after adjusting for size and maturation include various renal function descriptors and some case-specific variables such as dialysate flow rate, ultrafiltrate output, and hypothermia. This review was able to document possible variables explaining the high variability observed in certain subpopulations and contrast vancomycin pharmacokinetics in different pediatric subpopulations.

Piperacillin-Tazobactam in Intensive Care Units: A Review of Population Pharmacokinetic Analyses.

Piperacillin-tazobactam is a potent ß-lactam/ß-lactamase inhibitor antibiotic commonly prescribed in the intensive care unit setting. Admitted patients often show large variability in treatment response due to multiple pathophysiological changes present in this population that alter the drug's pharmacokinetics. This review summarizes the population pharmacokinetic models developed for piperacillin-tazobactam and provides comprehensive data on current dosing strategies while identifying significant covariates in critically ill patients. A literature search on the PubMed database was conducted, from its inception to July 2020. Relevant articles were retained if they met the defined inclusion/exclusion criteria. A total of ten studies, published between 2009 and 2020, were eligible. One- and two-compartment models were used in two and eight studies, respectively. The lowest estimated piperacillin clearance value was 3.12 L/h, and the highest value was 19.9 L/h. The estimations for volume of distribution varied between 11.2 and 41.2 L. Tazobactam clearance values ranged between 5.1 and 6.78 L/h, and tazobactam volume of distribution values ranged between 17.5 and 76.1 L. The most frequent covariates were creatinine clearance and body weight, each present in four studies. Almost all studies used an exponential approach for the interindividual variability. The highest variability was observed in piperacillin central volume of distribution, at a value of 75.0%. Simulations showed that continuous or extended infusion methods performed better than intermittent administration to achieve appropriate pharmacodynamic targets. This review synthesizes important pharmacokinetic elements for piperacillin-tazobactam in an intensive care unit setting. This will help clinicians better understand changes in the drug's pharmacokinetic parameters in this specific population.