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.

Pharmacokinetics of piperacillin and tazobactam in critically Ill patients treated with continuous kidney replacement therapy: A mini‐review and population pharmacokinetic analysis

“…The main limitations of our model are possible model misspecification and lack of covariates to explain significant between study variability. Both piperacillin and tazobactam are likely to be best explained by 2‐compartment models, and in some circumstances, a non‐linear clearance model 29–33 . Nevertheless, the distribution phases of piperacillin and tazobactam are very rapid and our diagnostic plots demonstrate that a 1‐compartment model was adequate and regardless of analysis technique with high consistency among CL estimates across the literature (Table 2).…”

“…Both piperacillin and tazobactam are likely to be best explained by 2-compartment models, and in some circumstances, a non-linear clearance model. [29][30][31][32][33] Nevertheless, the distribution phases of piperacillin and tazobactam are very rapid and our diagnostic plots demonstrate that a 1-compartment model was adequate and regardless of analysis technique with high consistency among CL estimates across the literature (Table 2). Furthermore, our PTA analyses were similar to Bue et al 30…”

Population pharmacokinetics of piperacillin in critically ill children including those undergoing continuous kidney replacement therapy

“…In this study, an extended 4 h infusion in children without AKI receiving 100 mg/kg every 8 hours provided an adequate probability of target attainment and represents a good alternative to the 400 mg/kg (100 mg/kg every six hours) dosing schedule, which showed similar results in the simulations and has also been proposed in other PK studies [6,9,25]. In patients with CKRT, for whom the standard renal adjustments for piperacillin fail to achieve an adequate exposure, a dose of 100 mg/Kg every 8 hours given in a 30 min infusion without renal adjustment represents an appropriate regimen (and better than extended dosing intervals, every 12 hours).…”

Optimizing Antibiotic Treatment Strategies for Neonates and Children: Does Implementing Extended or Prolonged Infusion Provide any Advantage?

“…Lastly, according to Thibault et al, infants and children older than six months seem to need extended TZP administrations to achieve a favorable PD target. The proposed dosage against bacteria with MICs of up to 16 mg/L, in patients from six months to six years of age, was 130 mg/kg/dose every 8 h infused over 4 h (total daily dose, 390 mg/kg/day; total infusion time, 12 h) [57].…”