Salvatore D’Agate (1,3), Shani Maboko (1), Giuseppe Pontrelli (2), Nicole Olivini (2), Lorenza Romani (2), Francesca Calò Carducci (2), Raffaele Simeoli (2), Massimiliano Angelini (2), Marco Ciabattini (2), Bianca M Goffredo (2), Oscar Della Pasqua (1,3)
(1) Clinical Pharmacology & Therapeutics Group, University College London, UK, (2) Metabolic Pathology Laboratory, Ospedale Pediatrico Bambino Gesù, Rome, Italy, (3) Istituto per le Applicazioni del Calcolo, National Research Council, Rome, Italy
Introduction: Despite high mortality rate, first-line treatment of paediatric sepsis remains empirical, with interventions based on high-dose antibiotic therapy. Since neonates, infants and toddlers are often excluded from clinical trials, most drugs lack adequate information on pharmacokinetics. Consequently, there is limited evidence to support the dose rationale for this population. There is an urgent need to ensure that interindividual differences in pharmacokinetics and bacterial susceptibility are taken into account when assessing treatment performance in neonatal and paediatric sepsis, enhancing the probability of clinical cure.
Objectives: The primary objective of the current investigation was to evaluate treatment performance, as assessed by PKPD indices (i.e., time above the minimum inhibitory concentration (T>MIC) and probability of target attainment (PTA)) for currently used doses and dosing regimens of amoxicillin, ampicillin, ceftazidime, ceftriaxone in neonatal and paediatric patients with suspected sepsis.
Methods: Pharmacokinetic, clinical and demographic data from a total of 27 patients were retrieved from an observational, prospective, single-centre study in patients with at Bambino Gesù Paediatric Hospital IRCCS, Rome. Using nonlinear mixed effects modelling in conjunction with priors for pharmacokinetic parameter distributions obtained from previously published population pharmacokinetic models, an analysis was performed to describe the individual concentration vs. time profiles and derive secondary PK parameters, including the area under the concentration vs. time curve (AUC), maximum concentration (Cmax) and T>MIC. The probability of target attainment was then calculated to evaluate the suitability of the antibiotic doses and dosing regimens taking MIC findings into account. The PTA was then assessed in relation to the probability distribution of MIC observed in the analysis population. Data set preparation, exploratory data analysis, tabular and graphical results creation were performed using R version 3.6.1 with RStudio 1.3. Post-hoc analysis was conducted using NONMEM 7.3 and PsN 4.6.0.
Results: Our results show that the currently recommended doses of ampicillin, ceftazidime and ceftriaxone resulted in exposure levels that ensure efficacy targets of 50% fT>MIC for MICs up to 32 mg/L in most patients. By contrast, the standard dosing regimen of amoxicillin failed to achieve the desired PTA.
Conclusions: Lack of sufficient information on pharmacokinetics of drugs used in neonates and children results in mismanagement of serious childhood illnesses. This investigation shows how a model-based approach can be used in conjunction with therapeutic drug monitoring to support antimicrobial stewardship and treatment protocols for beta-lactams. In addition, simulations provide insight into dose(s) and dosing regimens for amoxicillin that are required to ensure clinical response and prevent antibiotic overuse in paediatric intensive care unit patients.
Reference: PAGE 29 (2021) Abstr 9829 [www.page-meeting.org/?abstract=9829]
Poster: Drug/Disease Modelling - Paediatrics