PhD Student Universidad Autónoma de San Luis Potosí San Luis Potosí, San Luis Potosi, Mexico
Background: Nosocomial infections are associated with high morbidity and mortality rate in neonates. Piperacillin/tazobactam has been used extensively for late-onset neonatal sepsis treatment, although safety and pharmacokinetic (PK) data in this population are limited. The organic immaturity of the newborns contribute to a high piperacillin PK variability. This affects the clinical efficacy of the antibiotic treatment and increases the probability of developing drug resistance and nephrotoxicity. Objective: In this study we aimed to evaluate the pharmacokinetic/pharmacodynamic (PK/PD) target attainment of piperacillin/tazobactam in preterm and term Mexican neonates with severe infections. Design/Methods: The study was approved by the Institutional Ethics Committee of the Hospital Central “Dr. Ignacio Morones Prieto” and an informed consent was obtained from parents. Patients received intravenous piperacillin/tazobactam based on the Neofax dosing recommendations. The PK/PD target (70% fT>MIC, free drug concentration above minimum inhibitory concentration during 70% of the dosing interval) attainment was evaluated using the individual Bayesian estimates method in NONMEM VII. Piperacillin plasma concentrations were determined by liquid chromatography/tandem mass spectrometry (UPLC/MS/MS). The clinical treatment data were collected. Results: A total of 65 plasma samples were collected from 25 patients of the Neonatal Intensive Care Unit (NICU): 8 term neonates, 8 medium-late preterm neonates and 9 very preterm neonates. The overall median value (range) postnatal age, gestational age, body weight and serum creatinine were 14 (8-28) days, 34.2 (28-41.1) weeks, 1760 (995-3430) grams 0.4 (0.2-0.9) mg/dL, respectively. A significant difference was found in piperacillin plasma concentrations observed at the 70% of the dosing interval between the very preterm (49.8 mg/L) and term neonates (23.7 mg/L) (p=0.041). The 72% and 88% of preterm and term neonates achieved the PK/PD target for a MIC of 16 mg/L, however, of each category, respectively, 56% and 12% attained the PK/PD target for a MIC of 32 mg/L. Potential toxicity piperacillin plasma concentration >150 mg/L were observed in 44% our population.
Conclusion(s): In neonates with life-threatening infections the rapid pathophysiological fluctuations and the organic immaturity can impact the pharmacokinetics of antibiotics and difficult to achieve the PK/PD target. The importance of this study lies in the necessity to monitor the piperacillin plasma concentrations in NICU patients to optimize the antibiotic therapy and minimize the risk of toxicity.
