Sarah Baklouti1, Virginie Rigourd2, Alice Panchaud3, Hedvig Nordeng4, Karel Allegaert5, Pieter Annaert6, Mia-Chun HUANG6, Anaelle Monfort7, Monia Guidi8, Peggy Gandia1
1UMR1436-INTHERES, ENVT/INRAe, 2Milkbank, Ile de France, Necker-Enfants Malades Hospital, AP-HP, 3Institute of Primary Health Care (BIHAM), University of Bern, 4Pharmacoepidemiology and Drug Safety Research Group, Department of Pharmacy, University of Oslo, 5Department of Development and Regeneration, KU Leuven, 6Drug Delivery and Disposition Lab, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 7CHU Sainte-Justine, 8Center for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital and University of Lausanne
Introduction Amoxicillin, a widely used ß-lactam antibiotic, requires better pharmacokinetic characterization during breastfeeding. Few studies have assessed the risks associated with amoxicillin exposure in breastfed infants. In these studies, the relative infant dose (RID) — a commonly used metric to estimate the infant’s daily intake relative to the maternal dose — was reported to be below 1.3% [1]. The WHO Working Group on Drugs and Human Lactation considers medications compatible with breastfeeding when the RID is below 10% [2-5], except for highly toxic drugs such as cytostatic agents or psychotropic medications with long half-lives, which may accumulate and pose risks to the infant. However, the methodology currently used to determine the RID remains rudimentary. First, it does not account for the continuous exchange of amoxicillin between maternal blood and milk compartments. Second, it assumes a fully breastfed infant consumes 0.15 L of milk per kilogram of body weight daily, which may not be accurate for every individual. A pharmacokinetic modeling approach offers a more comprehensive characterization of amoxicillin distribution in maternal blood and breast milk. This approach is particularly valuable when only limited biological samples can be collected per individual, as is often the case with breastfeeding mothers. Our primary objective was to quantify the daily amoxicillin intake by infants and assess inter-individual variability using a modeling approach. A secondary objective was to investigate the relationship between maternal amoxicillin use and clinical outcomes in newborns. Cases of diarrhea, skin rashes, and candidiasis in breastfed infants have been reported [6-8]. Therefore, we also aimed to monitor side effects in infants and evaluate any potential impact on breast milk production. Methods Twenty-five breastfeeding French mothers treated with amoxicillin for at least two days were included in the study. The study was approved by the French Committee for Medical and Health Research Ethics (N°21.01446.000014) (EudraCT: 2021-002247-30, approved on July 13, 2022). Breastfeeding mothers received amoxicillin according to an infection-specific dosing regimen, following the recommendations of the Marketing Authorization. Three blood and three milk samples were collected on a single day, during the interval between two consecutive oral administrations. The same time slots were applied for both matrices: (i) 15-30 minutes, (ii) 1-2 hours, and (iii) 3-4 hours after amoxicillin intake. Blood and milk samples were analyzed using a validated LC-MS/MS method. Clinical data were recorded for both mothers and infants for one week following blood and milk sampling. The milk-to-plasma ratio and RID were calculated using two distinct approaches: 1.Traditional approach: amoxicillin concentrations measured in maternal plasma and breast milk were used to determine the milk-to-plasma ratio at each sampling time point (i.e., the first blood sample was paired with the first milk collection, and so on). The RID was then calculated using each measured amoxicillin concentration in breast milk, assuming an infant milk intake of 150 mL per kg of body weight per day, while accounting for the actual maternal dose and weight. 2.Pharmacokinetic modeling approach: a population pharmacokinetic (PopPK) model was developed with Monolix. Using the final PopPK model, plasma and milk kinetic profiles were simulated at steady state in R. A maintenance oral dose of 6 g/day (2 g every 8 hours) was selected as the highest clinically applicable dose to assess the worst-case scenario. The mean breastfeeding frequency was set at 11 feedings per day (range: 6–18 feedings) [9]. Amoxicillin concentrations in plasma and breast milk were used to determine the milk-to-plasma ratio, drug intake per feeding, and total daily intake over 24 hours adjusted for feeding frequency. The RID was then calculated relative to a maternal body weight of 65 ± 12 kg (SD). Since amoxicillin is also prescribed for infants, the RID was additionally calculated using the pediatric dose of 100 mg/kg/day for both approaches. For both approaches and for both maternal and pediatric doses, the mean (SD) and min-max range of RID values were determined. Results The participating mothers had an average age of 35 years and a mean weight of 65 kg, receiving a daily amoxicillin dose of 2760 mg. They breastfed an average of nine times per day, with five mothers reporting a decrease in milk production unrelated to amoxicillin use. The study included 12 male and 13 female infants, with an average age of 5.5 months and a mean weight of 6.7 kg. No adverse events were reported in the infants. A two-compartment PopPK model was selected, with no transfer rate constant from milk to plasma. No covariates were included in the final model. The milk-to-plasma ratio was <10%, and all RID values, both relative to the adult and pediatric doses, remained below 0.1%. Conclusion The RID values for amoxicillin were well within recommended thresholds for breastfeeding mothers, regardless of whether they were calculated based on the maximum adult dose or the pediatric dose. These findings suggest that the daily amount of amoxicillin ingested by breastfed infants is unlikely to cause significant short-term effects. However, the primary concern is not only the amount of antibiotic transferred into breast milk but also its potential impact on the infant’s gut microbiota. Amoxicillin, a commonly prescribed ß-lactam antibiotic in pediatrics, has been shown to influence gut microbiota composition in children, though studies remain limited. Research on Bifidobacterium populations—which play a beneficial role in gut health—indicates that amoxicillin can alter species composition and reduce microbial diversity [10-12]. Given that microbiota disruptions have been linked to various diseases, including inflammatory bowel disease, type 1 diabetes, and obesity [13], an important question remains: what are the consequences of low-level amoxicillin exposure on the newborn’s gut microbiota over a few days? To date, this question remains unanswered, warranting further investigation.
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Reference: PAGE 33 (2025) Abstr 11438 [www.page-meeting.org/?abstract=11438]
Poster: Clinical Applications