Dataset Information

Population Pharmacokinetics and Safety of Piperacillin-Tazobactam Extended Infusions in Infants and Children.

ABSTRACT: Piperacillin-tazobactam (TZP) is frequently used to treat severe hospital-acquired infections in children. We performed a single-center, pharmacokinetic (PK) trial of TZP in children ranging in age from 2 months to 6 years from various clinical subpopulations. Children who were on TZP per the standard of care were prospectively included and assigned to receive a dose of 80 mg/kg of body weight every 6 h infused over 2 h (ages 2 to 5?months) or a dose of 90?mg/kg every 8 h infused over 4 h (ages 6?months to 6?years). Separate population PK models were developed for piperacillin and tazobactam using nonlinear mixed-effects modeling. Optimal dosing was judged based on the ability to maintain free piperacillin concentrations above the piperacillin MIC for enterobacteria and Pseudomonas aeruginosa for ?50% of the dosing interval. Any untoward event occurring during treatment was collected as an adverse event. A total of 79 children contributed 174 PK samples. The median (range) age and weight were 1.7 years (2 months to 6 years) and 11.4?kg (3.8 to 27.6 kg), respectively. A 2-compartment model with first-order elimination best described the piperacillin and tazobactam data. Both final population PK models included weight and concomitant furosemide administration on clearance and weight on the volume of distribution of the central compartment. The optimal dosing regimens in children with normal renal function, based on the piperacillin component, were 75?mg/kg/dose every 4 h infused over 0.5 h in infants ages 2 to ?6 months and 130?mg/kg/dose every 8 h infused over 4 h in children ages >6 months to 6 years against bacteria with MICs up to 16?mg/liter. A total of 44 children (49%) had ?1 adverse event, with 3 of these (site infiltrations) considered definitely associated with the extended infusions.

SUBMITTER: Thibault C

PROVIDER: S-EPMC6811421 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Population Pharmacokinetics and Safety of Piperacillin-Tazobactam Extended Infusions in Infants and Children.

Thibault Céline C Lavigne Jean J Litalien Catherine C Kassir Nastya N Théorêt Yves Y Autmizguine Julie J

Antimicrobial agents and chemotherapy 20191022 11

Piperacillin-tazobactam (TZP) is frequently used to treat severe hospital-acquired infections in children. We performed a single-center, pharmacokinetic (PK) trial of TZP in children ranging in age from 2 months to 6 years from various clinical subpopulations. Children who were on TZP per the standard of care were prospectively included and assigned to receive a dose of 80 mg/kg of body weight every 6 h infused over 2 h (ages 2 to 5 months) or a dose of 90 mg/kg every 8 h infused over 4 h (ages ...[more]

PMID: 31427292

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Project description:Background and objectivesInfection is the most common cause of death in severe AKI, but many patients receiving continuous RRT do not reach target antibiotic concentrations in plasma. Extended infusion of β-lactams is associated with improved target attainment in critically ill patients; thus, we hypothesized that extended infusion piperacillin-tazobactam would improve piperacillin target attainment compared with short infusion in patients receiving continuous RRT.Design, setting, participants, & measurementsWe conducted an institutional review board-approved observational cohort study of piperacillin-tazobactam pharmacokinetics and pharmacodynamics in critically ill patients receiving continuous venovenous hemodialysis and hemodiafiltration at three tertiary care hospitals between 2007 and 2015. Antibiotic concentrations in blood and/or dialysate samples were measured by liquid chromatography, and one- and two-compartment pharmacokinetic models were fitted to the data using nonlinear mixed effects regression. Target attainment for piperacillin was defined as achieving four times the minimum inhibitory concentration of 16 μg/ml for >50% of the dosing cycle. The probabilities of target attainment for a range of doses, frequencies, and infusion durations were estimated using a Monte Carlo simulation method. Target attainment was also examined as a function of patient weight and continuous RRT effluent rate.ResultsSixty-eight participants had data for analysis. Regardless of infusion duration, 6 g/d piperacillin was associated with ≤45% target attainment, whereas 12 g/d was associated with ≥95% target attainment. For 8 and 9 g/d, target attainment ranged between 68% and 85%. The probability of target attainment was lower at higher effluent rates and patient weights. For all doses, frequencies, patient weights, and continuous RRT effluent rates, extended infusion was associated with higher probability of target attainment compared with short infusion.ConclusionsExtended infusions of piperacillin-tazobactam are associated with greater probability of target attainment in patients receiving continuous RRT.

Project description:Background and objectivesCurrent recommendations for piperacillin-tazobactam dosing in patients receiving continuous renal replacement therapy originate from studies with relatively few patients and lower continuous renal replacement therapy doses than commonly used today. This study measured the pharmacokinetic and pharmacodynamic characteristics of piperacillin-tazobactam in patients treated with continuous renal replacement therapy using contemporary equipment and prescriptions.Design, setting, participants, & measurementsA multicenter prospective observational study in the intensive care units of two academic medical centers was performed, enrolling patients with AKI or ESRD receiving piperacillin-tazobactam while being treated with continuous renal replacement therapy. Pregnant women, children, and patients with end stage liver disease were excluded from enrollment. Plasma and continuous renal replacement therapy effluent samples were analyzed for piperacillin and tazobactam levels using HPLC. Pharmacokinetic and pharmacodynamic parameters were calculated using standard equations. Multivariate analyses were used to examine the association of patient and continuous renal replacement therapy characteristics with piperacillin pharmacokinetic parameters.ResultsForty-two of fifty-five subjects enrolled had complete sampling. Volume of distribution (median=0.38 L/kg, intraquartile range=0.20 L/kg) and elimination rate constants (median=0.104 h(-1), intraquartile range=0.052 h(-1)) were highly variable, and clinical parameters could explain only a small fraction of the large variability in pharmacokinetic parameters. Probability of target attainment for piperacillin was 83% for total drug but only 77% when the unbound fraction was considered.ConclusionsThere is significant patient to patient variability in pharmacokinetic/pharmacodynamic parameters in patients receiving continuous renal replacement therapy. Many patients did not achieve pharmacodynamic targets, suggesting that therapeutic drug monitoring might optimize therapy.

Project description:We have previously demonstrated the pharmacokinetic-pharmacodynamic (PK-PD) index best associated with the efficacy of tazobactam when used in combination with ceftolozane to be the percentage of the dosing interval during which tazobactam concentrations remained above a threshold value (%time>threshold). Using anin vitroinfection model and the same isogenic CTX-M-15-producingEscherichia colitriplet set genetically engineered to transcribe different levels ofblaCTX-M-15, herein we describe dose fractionation studies designed to evaluate the PK-PD index associated with tazobactam efficacy, when given in combination with piperacillin, and the impact of the presence of a different ?-lactam agent, or differentblaCTX-M-15transcription levels, on the magnitude of the tazobactam PK-PD index necessary for efficacy. The recombinant strains demonstrated piperacillin MIC values of 128, >256, and >256 ?g/ml for the low-, moderate-, and high-level CTX-M-15-producingE. colistrains, respectively. The MIC value for piperacillin in the presence of 4 ?g/ml of tazobactam was 2 ?g/ml for all three strains. The PK-PD index associated with tazobactam efficacy was confirmed to be %time>threshold, regardless of ?-lactamase transcription (r(2)= 0.839). The tazobactam concentration thresholds, however, changed with the CTX-M-15 transcription level and were 0.25, 0.5, and 2 ?g/ml for the low-, moderate-, and high-level CTX-M-15-producing strains, respectively (r(2)= 0.921, 0.773, and 0.875, respectively). The %time>threshold values for tazobactam necessary for net bacterial stasis and a 1- and 2-log10-unit CFU/ml decrease from baseline at 24 h were 44.9, 62.9, and 84.9%, respectively. In addition to verifying our previous study results, these results also demonstrated that the magnitude of bacterial-cell killing associated with a ?-lactam-?-lactamase inhibitor combination is dependent on the amount of ?-lactamase produced. These data provide important information for the development of ?-lactam-?-lactamase inhibitor combination agents.

Project description:What is known and objectiveTimely and appropriate dosing of antibiotics is essential for the treatment of bacterial sepsis. Critically ill patients treated with continuous kidney replacement therapy (CKRT) often have physiologic derangements that affect pharmacokinetics (PK) of antibiotics and dosing may be challenging. We sought to aggregate previously published piperacillin and tazobactam (pip-tazo) pharmacokinetic data in critically ill patients undergoing CKRT to better understand pharmacokinetics of pip-tazo in this population and better inform dosing.MethodsThe National Library of Medicine Database was searched for original research containing piperacillin or tazobactam clearance (CL) or volume of distribution (V) estimates in patients treated with CKRT. The search yielded 77 articles, of which 26 reported suitable estimates of CL or V. Of the 26 articles, 10 for piperacillin and 8 for tazobactam had complete information suitable for population pharmacokinetic modelling. Also included in the analysis was piperacillin and tazobactam PK data from 4 critically ill patients treated with CKRT in the Military Health System, 2 with burn and 2 without burn.Results and discussionMedian and range of literature reported PK parameters for piperacillin (CL 2.76 L/hr, 1.4-7.92 L/hr, V 31.2 L, 16.77-42.27 L) and tazobactam (CL 2.34 L/hr, 0.72-5.2 L/hr, V 36.6 L, 26.2-58.87 L) were highly consistent with population estimates (piperacillin CL 2.7 L/hr, 95%CI 1.99-3.41 L/hr, V 25.83 22.07-29.59 L, tazobactam CL 2.49 L/hr, 95%CI 1.55-3.44, V 30.62 95%CI 23.7-37.54). The proportion of patients meeting pre-defined pharmacodynamic (PD) targets (median 88.7, range 71%-100%) was high despite significant mortality (median 44%, range 35%-60%). High mortality was predicted by baseline severity of illness (median APACHE II score 23, range 21-33.25). Choice of lenient or strict PD targets (ie 100%fT >MIC or 100%fT >4XMIC) had the largest impact on probability of target attainment (PTA), whereas presence or intensity of CKRT had minimal impact on PTA.What is new and conclusionPip-tazo overexposure may be associated with increased mortality, although this is confounded by baseline severity of illness. Achieving adequate pip-tazo exposure is essential; however, risk of harm from overexposure should be considered when choosing a PD target and dose. If lenient PD targets are desired, doses of 2250-3375 mg every 6 h are reasonable for most patients receiving CKRT. However, if a strict PD target is desired, continuous infusion (at least 9000-13500 mg per day) may be required. However, some critically ill CKRT populations may need higher or lower doses and dosing strategies should be tailored to individuals based on all available clinical data including the specific critical care setting.

Dataset Information

Population Pharmacokinetics and Safety of Piperacillin-Tazobactam Extended Infusions in Infants and Children.

Publications

Population Pharmacokinetics and Safety of Piperacillin-Tazobactam Extended Infusions in Infants and Children.

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