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

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.

Thibault C ，Lavigne J ，Litalien C ，Kassir N ，Théorêt Y ，Autmizguine J ... -  《-》

Population Pharmacokinetics and Dosing Optimization of Piperacillin-Tazobactam in Critically Ill Patients on Extracorporeal Membrane Oxygenation and the Influence of Concomitant Renal Replacement Therapy.

Hahn J ，Min KL ，Kang S ，Yang S ，Park MS ，Wi J ，Chang MJ ... -  《Microbiology Spectrum》

Population pharmacokinetics of extended-infusion piperacillin-tazobactam in hospitalized patients with nosocomial infections.

Felton TW ，Hope WW ，Lomaestro BM ，Butterfield JM ，Kwa AL ，Drusano GL ，Lodise TP ... -  《-》

Population Pharmacokinetics and Pharmacodynamics of Extended-Infusion Piperacillin and Tazobactam in Critically Ill Children.

The study objective was to evaluate the population pharmacokinetics and pharmacodynamics of extended-infusion piperacillin-tazobactam in children hospitalized in an intensive care unit. Seventy-two serum samples were collected at steady state from 12 patients who received piperacillin-tazobactam at 100/12.5 mg/kg of body weight every 8 h infused over 4 h. Population pharmacokinetic analyses were performed using NONMEM, and Monte Carlo simulations were performed to estimate the piperacillin pharmacokinetic profiles for dosing regimens of 80 to 100 mg/kg of the piperacillin component given every 6 to 8 h and infused over 0.5, 3, or 4 h. The probability of target attainment (PTA) for a cumulative percentage of the dosing interval that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (TMIC) of ≥50% was calculated at MICs ranging from 0.25 to 64 mg/liter. The mean ± standard deviation (SD) age, weight, and estimated glomerular filtration rate were 5 ± 3 years, 17 ± 6.2 kg, and 118 ± 41 ml/min/1.73 m(2), respectively. A one-compartment model with zero-order input and first-order elimination best fit the pharmacokinetic data for both drugs. Weight was significantly associated with piperacillin clearance, and weight and sex were significantly associated with tazobactam clearance. Pharmacokinetic parameters (mean ± SD) for piperacillin and tazobactam were as follows: clearance, 0.22 ± 0.07 and 0.19 ± 0.07 liter/h/kg, respectively; volume of distribution, 0.43 ± 0.16 and 0.37 ± 0.14 liter/kg, respectively. All extended-infusion regimens achieved PTAs of >90% at MICs of ≤16 mg/liter. Only the 3-h infusion regimens given every 6 h achieved PTAs of >90% at an MIC of 32 mg/liter. For susceptible bacterial pathogens, piperacillin-tazobactam doses of ≥80/10 mg/kg given every 8 h and infused over 4 h achieve adequate pharmacodynamic exposures in critically ill children.

Nichols K ，Chung EK ，Knoderer CA ，Buenger LE ，Healy DP ，Dees J ，Crumby AS ，Kays MB ... -  《-》

Population pharmacokinetics of continuous infusion of piperacillin/tazobactam in very elderly hospitalized patients and considerations for target attainment against Enterobacterales and Pseudomonas aeruginosa.

Continuous infusion (CI) piperacillin/tazobactam is frequently used to treat infections in very elderly patients. This study aimed to conduct a population pharmacokinetic analysis of CI piperacillin/tazobactam, and to identify optimal dosages for safe and effective probability of target attainment (PTA) against Enterobacterales and Pseudomonas aeruginosa. Non-linear mixed-effects modelling was performed with Pmetrics. Monte Carlo simulations assessed the steady-state concentration (Css) of increasing piperacillin/tazobactam regimens (from 2.25 to 18 g daily by continuous infusion). Permissible doses were defined as those associated with <10% probability of Css >157.2 mg/L. PTA at the pharmacodynamic targets of free plasma steady-state concentration (fCss)/minimum inhibitory concentration (MIC) ≥1 and ≥4 and cumulative fraction of response (CFR) against EUCAST MIC distribution were also calculated. A total of 141 patients (median age 85 years) provided 217 plasma piperacillin Css. Most patients (55.2%) had hospital-acquired pneumonia and intra-abdominal infections. A one-compartment pharmacokinetic model with parallel linear and Michaelis-Menten elimination best described piperacillin data. Creatinine clearance (CLCR) was the covariate retained by the model. Pharmacokinetic estimates were 6.05 L/h for clearance and 3.39 mg/L for the Michaelis-Menten constant. Permissible doses were up to 4.5, 9, 11.25 and 13.5 g daily by continuous infusion for patients with CLCR of 0-19, 20-39, 40-59 and 60-79 mL/min/1.73 m2, respectively. At the clinical breakpoint of 8 mg/L, the permissible doses only achieved optimal PTA for fCss/MIC ≥1 in patients with CLCR 20-79 mL/min/1.73 m2. Optimal CFRs with the permissible doses were only attained against Escherichia coli and Proteus mirabilis. Permissible dosages and CLCR should be considered for prescribing CI piperacillin/tazobactam in very elderly patients.

Cojutti PG ，Morandin E ，Baraldo M ，Pea F ... -  《-》