Developmental Pharmacokinetics of Piperacillin and Tazobactam Using Plasma and Dried Blood Spots from Infants

Abstract

f Piperacillin-tazobactam is often given to infants with severe infection in spite of limited pharmacokinetics (PK) data. We evaluated piperacillin-tazobactam PK in premature and term infants of ages <61 days with suspected systemic infection. Infants received intravenous piperacillin-tazobactam (80 to 100 mg/kg of body weight every 8 h [q 8 h]) based on gestational and postnatal age. Sparse plasma samples were obtained after first and multiple doses. Drug concentrations were measured by tandem mass spectrometry. PK data were analyzed using population nonlinear mixed-effect modeling. Target attainment rates for the time unbound piperacillin concentrations remained above the MIC for 50% and 75% of the dosing interval at steady state were evaluated. Bias in population PK parameter estimates was assessed for dried blood spot (DBS) samples, and a comparability analysis was performed for DBS and plasma drug concentrations using linear regression. We obtained 128 plasma samples from 32 infants, median gestational age of 30 weeks (range, 23 to 40 weeks) and postnatal age of 8 days (range, 1 to 60). Piperacillin and tazobactam PK models included body weight (WT) and postmenstrual age (PMA) as covariates for clearance and WT for volume of distribution and were used to optimize dosing in infants. DBS drug concentrations were 50 to 60% lower than those in plasma, but when combined with plasma concentrations and a matrix effect, the data generated PK model parameters similar to those for plasma alone. With PMA-based dosing (100 mg/kg q 8 h, 80 mg/kg q 6 h, and 80 mg/kg q 4 h for PMA of <30, 30 to 35, and 35 to 49 weeks, respectively), 90% of simulated infants achieved the surrogate therapeutic target of time above the MIC (<32 mg/liter) for 75% of the dosing interval. P iperacillin-tazobactam is approved by the U.S. Food and Drug Administration for the treatment of adults and children of Ͼ2 months of age with infections due to susceptible bacteria; however, the drug is not approved for use in younger infants, including those born prematurely. In spite of this, piperacillin-tazobactam is extensively used "off-label" in young infants for treatment of systemic infections, including bacteremia and complicated intra-abdominal infections, such as necrotizing enterocolitis (1). Because these infections in premature infants are associated with devastating outcomes, such as death and neurodevelopmental impairment (2, 3), appropriate dosing recommendations for agents such as piperacillin-tazobactam are needed. Recommended piperacillin-tazobactam dosing for young infants in sources like Neofax (4) and The Harriet Lane Handbook (5) rely on combinations of birth weight, gestational age, postmenstrual age (PMA), and postnatal age (PNA), which are cumbersome to implement clinically and more importantly are supported by very small and limited clinical trials in this population.The pharmacokinetics (PK) of piperacillin-tazobactam has not been well characterized for premature infants. The drug is primarily renally eliminated by glomerular fi...

Dose optimization of piperacillin/tazobactam in critically ill children

“…[8][9][10] To date, the pharmacokinetics of piperacillin/tazobactam have been described in (pre)term neonates and non-ICU children, but only in a small number of children admitted to the paediatric ICU (n=13 and n=12 patients), between 1 and 9 years of age. 7,[11][12][13][14][15] Any effort to define the dose rationale in infants and young children needs to account for the effect of developmental processes, which are known to affect drug exposure and potentially treatment response. 16 Moreover, the impact of pathophysiological changes on pharmacokinetics has been widely demonstrated in critically ill adults.…”

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

“…Pharmacodynamic predictors of efficacy (e.g., T MIC ) for antibiotics do not change from the adult to the child. While evaluations of TZP pharmacokinetics in children are available, there are currently no published pharmacokinetic and pharmacodynamic data from children receiving extended-infusion TZP to guide optimal dosing on the basis of attainment of the target T MIC (14,15,(20)(21)(22)(23)(24)(25)(26)(27)(28). In addition, data regarding the population pharmacokinetics of tazobactam in children are limited (27,28).…”

Assays for therapeutic drug monitoring of β-lactam antibiotics: A structured review

“…We found one method that measured ertapenem from dried blood spots for TDM in neonates, in whom sampling of larger volumes is not practical, and two that measured piperacillin/tazobactam [39,50,65]. However, it must be noted that using this sampling strategy it is not possible to determine free concentrations, which may be a problem for highly protein-bound drugs such as ertapenem (ca.…”

“…A bridging study has been performed for piperacillin and tazobactam and found concentrations in dried blood spots to be on average 62% and 52% lower compared with plasma, suggesting that piperacillin and tazobactam do not partition into red blood cells. A large range in the dried blood spot-to-plasma ratios was observed [65]. Moreover, one of the biggest potential advantages of dried blood spots, namely stability, has been shown to be insufficient to allow for transportation at room temperature [50].…”