PII-111 - ESTABLISHING EVIDENCE-BASED, ANTENATAL DOSE RECOMMENDATIONS FOR AMOXICILLIN (WITH AND WITHOUT CLAVULANIC ACID)

A. Dibbets^1,2,3, I. Slaats⁴, A. Colbers⁵, H. Scheepers^2,3, S. de Wildt^4,6,7; ¹Department of Pharmacy, Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands, Nijmegen, Gelderland, The Netherlands, ²Department of Gynaecology and Obstetrics, Maastricht University Medical Center, Maastricht, Limburg, The Netherlands, ³GROW, Institute for Oncology and Reproduction, Maastricht University, Maastricht, Limburg, The Netherlands, ⁴Department of Pharmacy, Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, Gelderland, The Netherlands, ⁵Department of Pharmacy, Radboud University Medical Center, Nijmegen, Gelderland, The Netherlands, ⁶Department of Paediatric and Neonatal Intensive Care, Erasmus MC Sophia's Children Hospital, Rotterdam, Zuid-Holland, The Netherlands, ⁷Department of Intensive Care, Radboud University Medical Center, Nijmegen, Gelderland, The Netherlands.

Background: Amoxicillin and its combination with clavulanic acid (amoxi-clav) are commonly used antibiotics in pregnancy. Dutch dosing guidelines often advise higher doses for non-pregnant individuals than for pregnant individuals. However, physiological alterations in pregnancy may lead to subtherapeutic plasma concentrations, which may necessitate dose adjustments. This evidence review aimed to establish evidence-based antenatal dose recommendations for amoxicillin and amoxi-clav, for implementation into clinical practice.

Methods: Data on the safety and efficacy of amoxicillin and amoxi-clav was collected, along with evidence from pharmacokinetic models from existing literature, to develop antenatal dose recommendations using our previously developed Framework for Dose Selection in Pregnancy (FDSP). The FDSP and the proposed doses were reviewed by a multidisciplinary working committee of project MADAM, including healthcare practitioners, experts from other disciplines including pharmacology, reproductive toxicology and medical ethics, alongside patient representatives.

Results: Model simulations show slightly lower concentrations of amoxicillin in the second and third trimester compared to non-pregnant individuals, due to an increase in renal clearance and expanded volume of distribution. No information was found on the pharmacokinetics of clavulanic acid alone during pregnancy. Aligning pregnancy doses with non-pregnant doses for treating mild-to-moderate infections may mitigate the risk of antimicrobial resistance and underdosing. Recommending the highest dose within a dose range during pregnancy is also advisable. For prophylaxis during preterm prelabor rupture of the membranes, increasing the daily dose from three oral doses of 500 mg to three oral doses of 750 mg may be warranted. Model simulations suggest that the current dosing regimen (2000 mg iv bolus followed by 1000 mg q6h) for prophylaxis during childbirth for prevention of early-onset neonatal sepsis is adequate. The proposed doses were endorsed by the working committee and will be integrated into clinical practice.

Conclusion: This evidence review underscores the current risk of underdosing of amoxicillin and amoxi-clav during pregnancy for most indications and the need to adjust doses accordingly.