Introduction: Piperacillin-tazobactam (PIP-TAZ) is a β-lactam and β-lactamase inhibitor combination, commonly used in children. As it is indicated for a variety of serious bacterial infections, achieving therapeutic PIP-TAZ concentrations at invasive infection sites, such as cerebrospinal fluid (CSF), peritoneal fluid, and pleural fluid is critical. Also, previous studies have highlighted the high inter-individual variability in pharmacokinetics in children, therefore, determining an effective dosing strategy is imperative.
Aims: (1) to characterize the pharmacokinetics of PIP-TAZ in children aged 0 to 18 years, (2) to investigate the penetration of PIP-TAZ into three target sites: CSF, peritoneal fluid, and pleural fluid, (3) to evaluate the probability of target attainment (PTA) in plasma, CSF, peritoneal fluid, and pleural fluid with standard dosing.
Methods: PIP-TAZ concentrations were measured in plasma and CSF, pleural and peritoneal fluid samples from children aged 0-18 years receiving the drug. The samples were obtained through two methods: (1) prospectively from patients at the Royal Children’s Hospital with informed consent and (2) from leftover samples after clinical assessments were completed. Separate PopPK model of PIP and TAZ were developed using NONMEM. One- and two-compartment models were tested for plasma, with CSF, peritoneal fluid and pleural fluid subsequently integrated. Allometric scaling, a sigmoidal renal maturation function1, and the effect of serum creatinine (SCR) were adopted a priori. Other covariates (e.g. sex, albumin) were tested using stepwise covariate modeling (SCM). Monte Carlo simulations were performed to evaluate exposure of PIP-TAZ in serum, CSF, peritoneal fluid and pleural fluid, comparing three dosing regimens: q6h, q4h, and continuous infusion, all with a dose of 400 mg/kg/day. The PTA of PIP was calculated against Streptococcus pneumoniae (MIC=0.06 mg/L), Staphylococcus aureus (MIC=4 mg/L), Escherichia coli (MIC=8 mg/L) and P. aeruginosa (MIC=16 mg/L). The MIC breakpoints were acquired from the European Committee on Antimicrobial Susceptibility Testing (EUCAST). For plasma, peritoneal and pleural fluid, the PK/PD target was defined as 50%fT>MIC, whereas 100% fT>MIC was applied for CSF. For TAZ, 50%fT>Ct (concentration thresholds) were evaluated for Ct of 0.25, 0.5 and 2 mg/L.
Results: A total of 104 patients (median age 6.96 years, range 0 to 17.3) were enrolled of whom 18 (17.3%) were aged between 3 months and 2 years, 51 (49.0%) were between 2 and 12 years, and 25 (24.0%) between 12 and 18 years. A four-compartment model with first-order elimination from the central compartment most adequately describe the PIP-TAZ concentrations in plasma and CSF, peritoneal fluid and pleural fluid. No other covariates were included after SCM. GOF plots, pcVPC and individual concentration-time profile suggested a good performance of the final model. The pharmacokinetic parameters were precisely estimated (RSE<30%). The bootstrap result further indicated the robustness of the PopPK model. In the final model of PIP, the distribution volumes of the CSF, peritoneal fluid, and pleural fluid compartment were 0.331, 0.101, and 0.112 L, respectively; Clearance is represented by the following equation:
CL (L/h) =11.6 * (29/SCR)0.324 * (WT/70)0.75 * (PMA3.27/(43.43.27 + PMA3.27))
The penetration ratios for CSF: serum penetration ratios were 0.0287 for PIP and 0.100 for TAZ; for peritoneal fluid: plasma 0.985 for PIP and 1.50 for TAZ, and for pleural fluid: plasma 0.837 for PIP and 1.06 for TAZ. Monte Carlo simulations demonstrated that: (1) for children between 3 months and 12 years, 4-hourly dosing or continuous infusion was needed for P. aeruginosa infection in plasma; (2) for peritoneal and pleural infection, ≥90% PTA was achieved against all the tested pathogens under 6-hourly dosing; (3) for CSF infection, ≥90% PTA was only achieved for Streptococcus pneumoniae (0.06 mg/L) even with continuous infusion.
Conclusion: The developed PopPK model of PIP-TAZ in Children aged 0 to 18 years could describe the distribution into CSF, peritoneal fluid and pleural fluid. PIP-TAZ could achieve antibacterial effect in peritoneal and pleural fluid under standard 6-hourly dosing; and its exposure in CSF is insufficient to achieve therapeutic efficacy against common pathogens.
Reference: 1. Germovsek, et al. Scaling clearance in paediatric pharmacokinetics: All models are wrong, which are useful? Br J Clin Pharmacol. 2017;83(4):777-790.