Barker, Charlotte IS, Kipper, Karin, Lonsdale, Dagan O, Wright, Kirstie, Thompson, Georgina, Kim, Min, Turner, Mark A 
ORCID: 0000-0002-5299-8656, Johnston, Atholl, Sharland, Mike, Standing, Joseph F et al (show 1 more authors)
(2023)
The Neonatal and Paediatric Pharmacokinetics of Antimicrobials study (NAPPA): investigating amoxicillin, benzylpenicillin, flucloxacillin and piperacillin pharmacokinetics from birth to adolescence.
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 78 (9).
pp. 2148-2161.
Abstract
<h4>Background</h4>Pharmacokinetic (PK) data underlying paediatric penicillin dosing remain limited, especially in critical care.<h4>Objectives</h4>The primary objective of the Neonatal and Paediatric Pharmacokinetics of Antimicrobials study (NAPPA) was to characterize PK profiles of commonly used penicillins using data obtained during routine care, to further understanding of PK variability and inform future evidence-based dosing.<h4>Methods</h4>NAPPA was a multicentre study of amoxicillin, co-amoxiclav, benzylpenicillin, flucloxacillin and piperacillin/tazobactam. Patients were recruited with informed consent. Antibiotic dosing followed standard of care. PK samples were obtained opportunistically or at optimal times, frozen and analysed using UPLC with tandem MS. Pharmacometric analysis was undertaken using NONMEM software (v7.3). Model-based simulations (n = 10 000) tested PTA with British National Formulary for Children (BNFC) and WHO dosing. The study had ethical approval.<h4>Results</h4>For the combined IV PK model, 963 PK samples from 370 participants were analysed simultaneously incorporating amoxicillin, benzylpenicillin, flucloxacillin and piperacillin data. BNFC high-dose regimen simulations gave these PTA results (median fT>MIC at breakpoints of specified pathogens): amoxicillin 100% (Streptococcus pneumoniae); benzylpenicillin 100% (Group B Streptococcus); flucloxacillin 48% (MSSA); and piperacillin 100% (Pseudomonas aeruginosa). Oral population PK models for flucloxacillin and amoxicillin enabled estimation of first-order absorption rate constants (1.16 h-1 and 1.3 h-1) and bioavailability terms (62.7% and 58.7%, respectively).<h4>Conclusions</h4>NAPPA represents, to our knowledge, the largest prospective combined paediatric penicillin PK study undertaken to date, and the first paediatric flucloxacillin oral PK model. The PTA results provide evidence supportive of BNFC high-dose IV regimens for amoxicillin, benzylpenicillin and piperacillin.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Humans, Penicillins, Floxacillin, Amoxicillin, Piperacillin, Anti-Bacterial Agents, Microbial Sensitivity Tests, Prospective Studies, Adolescent, Child, Infant, Newborn |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 06 Oct 2023 13:36 |
| Last Modified: | 06 Oct 2023 13:39 |
| DOI: | 10.1093/jac/dkad196 |
| Open Access URL: | https://doi.org/10.1093/jac/dkad196 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3173499 |
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