Population Pharmacokinetic Study of Benzylpenicillin in Critically Unwell Adults

Reya V Shah; Karin Kipper; Emma H Baker; Charlotte I S Barker; Isobel Oldfield; Barbara J Philips; Atholl Johnston; Jeffrey Lipman; Andrew Rhodes; Marina Basarab; Mike Sharland; Sarraa Almahdi; Rachel M Wake; Joseph F Standing; Dagan O Lonsdale

doi:10.3390/antibiotics12040643

Population Pharmacokinetic Study of Benzylpenicillin in Critically Unwell Adults

Antibiotics (Basel). 2023 Mar 24;12(4):643. doi: 10.3390/antibiotics12040643.

Authors

Reya V Shah^{1

2}, Karin Kipper^{1

3

4}, Emma H Baker^{1

2}, Charlotte I S Barker⁵, Isobel Oldfield¹, Barbara J Philips⁶, Atholl Johnston^{4

7}, Jeffrey Lipman^{8

9

10}, Andrew Rhodes¹¹, Marina Basarab¹², Mike Sharland¹, Sarraa Almahdi¹³, Rachel M Wake^{1

14}, Joseph F Standing^{1

15

16}, Dagan O Lonsdale^{1

2

11}

Affiliations

¹ Institute for Infection and Immunity, St George's, University of London, London SW17 0RE, UK.
² Department of Clinical Pharmacology & Therapeutics, St George's University Hospitals NHS Foundation Trust, London SW17 0QT, UK.
³ Institute of Chemistry, University of Tartu, 50411 Tartu, Estonia.
⁴ Analytical Services International Ltd., London SW17 0RE, UK.
⁵ Department of Medical and Molecular Genetics, King's College London, London WC2R 2LS, UK.
⁶ Brighton and Sussex Medical School, Brighton BN1 9PX, UK.
⁷ Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London WC1E 7HU, UK.
⁸ Jamieson Trauma Institute, Royal Brisbane and Women's Hospital, Brisbane, QLD 4029, Australia.
⁹ The University of Queensland Centre for Clinical Research, Brisbane, QLD 4029, Australia.
¹⁰ Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nimes University Hospital, University of Montpellier, 30029 Nimes, France.
¹¹ Department of Critical Care, St George's University Hospitals NHS Foundation Trust, London SW17 0QT, UK.
¹² Infection Care Group, St George's University Hospitals NHS Foundation Trust, London SW17 0QT, UK.
¹³ London North West University Healthcare NHS Trust, London HA1 3UJ, UK.
¹⁴ Clinical Academic Group in Infection and Immunity, St George's University Hospitals NHS Foundation Trust, London SW17 0QT, UK.
¹⁵ Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.
¹⁶ UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK.

Abstract

Pharmacokinetics are highly variable in critical illness, and suboptimal antibiotic exposure is associated with treatment failure. Benzylpenicillin is a commonly used beta-lactam antibiotic, and pharmacokinetic data of its use in critically ill adults are lacking. We performed a pharmacokinetic study of critically unwell patients receiving benzylpenicillin, using data from the ABDose study. Population pharmacokinetic modelling was undertaken using NONMEM version 7.5, and simulations using the final model were undertaken to optimize the pharmacokinetic profile. We included 77 samples from 12 participants. A two-compartment structural model provided the best fit, with allometric weight scaling for all parameters and a creatinine covariate effect on clearance. Simulations (n = 10,000) demonstrated that 25% of simulated patients receiving 2.4 g 4-hourly failed to achieve a conservative target of 50% of the dosing interval with free drug above the clinical breakpoint MIC (2 mg/L). Simulations demonstrated that target attainment was improved with continuous or extended dosing. To our knowledge, this study represents the first full population PK analysis of benzylpenicillin in critically ill adults.

Keywords: NONMEM; antibiotic; benzylpenicillin; beta-lactam; critical illness; pharmacokinetics.

Abstract

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