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Introduction: Large variability in neonatal amoxicillin dosing recommendations may reflect uncertainty about appropriate efficacy and toxicity targets. Objective: The aim of this study was to model efficacious and safe exposure for current neonatal amoxicillin dosing regimens, given a range of assumptions for minimal inhibitory concentration (MIC), targeted %fT > MIC, and potential for aminopenicillin-related neurotoxicity. Methods: Individual intravenous amoxicillin exposures based on 6 international and 9 Swiss neonatal dosing recommendations, reflecting the range of current dosing approaches, were assessed by a previously developed population pharmacokinetic model informed by neonatal data from an international cohort. Exposure was simulated by attributing each dosing regimen to each patient cohort. End points of interest were %fT > MIC and potential neurotoxicity using C_max > 140 mg/L as threshold. Results: None of the dosing regimens achieved targets of ≥100%fT > MIC at any of the relevant MICs for a desired probability of target attainment (PTA) of ≥90%. All regimens achieved a PTA ≥90% for Streptococcus agalactiae (MIC 0.25 mg/L) and Listeria monocytogenes (MIC 1 mg/L) when targeting ≤70%fT > MIC. In contrast, none of the regimens resulted in a PTA ≥90% targeting ≥70%fT > MIC for enterococci (MIC 4 mg/L). The maximum amoxicillin concentration associated with potential neurotoxicity was exceeded using 4 dosing regimens (100 mg/kg q12, 60/30 mg/kg q12/8, 50 mg/kg q12/8/6, and 50 mg/kg q12/8/4) for ≥10% of neonates. Conclusions: The acceptability of regimens is highly influenced by efficacy and toxicity targets, the selection of which is challenging. Novel randomized trial designs combined with pharmacometric modeling and simulation could assist in selecting optimal dosing regimens in this understudied population.

Background: The definition of late-onset bacterial sepsis (LOS) in very preterm infants is not unified. The objective was to assess the concordance of LOS diagnosis between experts in neonatal infection and international classifications and to evaluate the potential impact on heart rate variability and rate of “bronchopulmonary dysplasia or death”. Methods: A retrospective (2017–2020) multicenter study including hospitalized infants born before 31 weeks of gestation with intention to treat at least 5-days with antibiotics was performed. LOS was classified as “certain or probable” or “doubtful” independently by five experts and according to four international classifications with concordance assessed by Fleiss’s kappa test. Results: LOS was suspected at seven days (IQR: 5–11) of life in 48 infants. Following expert classification, 36 of them (75%) were considered as “certain or probable” (kappa = 0.41). Following international classification, this number varied from 13 to 46 (kappa = −0.08). Using the expert classification, “bronchopulmonary dysplasia or death” occurred less frequently in the doubtful group (25% vs. 78%, p < 0.001). Differences existed in HRV changes between the two groups. Conclusion: The definition of LOS is not consensual with a low international and moderate inter-observer agreement. This affects the evaluation of associated organ dysfunction and prognosis.

Long-gap esophageal atresia (LGEA) represents a surgical challenge. Despite the increasing use of thoracoscopy over the past decades, its application in LGEAs remains limited. This study aimed to evaluate the morbidity and mortality rates of LGEA thoracoscopic repair in the early and mid-term in France over the study period. After institutional ethical approval (#23.76), we conducted a multicenter, retrospective analysis of all patients who underwent a thoracoscopic repair for LGEA in France from 2010 to 2022. LGEA was defined following ERNICA 2021 consensus. We collected data related to the initial treatment and up to 1-year follow-up. Postoperative complications were categorized into early (30 days) and were classified according to the Clavien-Dindo classification. Fifty patients were included: 24 Delayed Primary Anastomosis (DPA) and 26 tractions. The overall rate of post-operative complication was 82%. The primary early complications included anastomotic leaks 56%, prolonged drainage 40%, pneumothorax 20%, pneumonia 20% and stricture 16% with no difference between DPA and traction. The traction method had a longer postoperative length of stay (69 vs. 31 days, p < 0,002). The nutritional evolution of tractions was poorer, with 30,8% exclusive oral nutrition at one year (vs. 66,7% DPA, p = 0.018). This is the largest cohort of patients who underwent thoracoscopic surgery for LGEA. Although thoracoscopic management of LGEAs is associated with a high complication rate, DPA management was associated with a shorter postoperative hospital stay and better mid-term nutritional outcomes. We believe that LGEAs remain a surgical challenge and thoracoscopy should be reserved for expert surgeons.

L'infection est une cause importante de morbidité et mortalité néonatales. L'évaluation néonatale des antibiotiques est indispensable pour optimiser la dose, assurer efficacité et sécurité du traitement, et limiter les risques de sélection de résistances bactériennes. Or, en raison de difficultés techniques et éthiques spécifiques, de nombreux antibiotiques sont utilisés en l'absence de données pharmacologiques néonatales suffisantes. Cette thèse pose donc les questions suivantes : quel impact sur les prescriptions posologiques néonatales des antibiotiques ? Comment faciliter la conduite d'études pharmacocinétiques néonatales et le transfert de leurs résultats vers la pratique clinique quotidienne? Les travaux réalisés ont permis de 1) révéler une hétérogénéité considérable au sein des protocoles posologiques de prescription néonatale des antibiotiques en France, 2) révéler, grâce à l'analyse de Plans d'Investigation Pédiatriques soumis à l'Agence Européenne du Médicament, l'hétérogénéité du design des études intégrées au développement des antibiotiques chez le nouveau-né, 3) démontrer, avec l'exemple de la ciprofloxacine, les performances d'une stratégie d'échantillonnage pharmacocinétique non invasive pour la modélisation pharmacocinétique de population et l'optimisation posologique néonatale, 4) établir, grâce à l'application de cette stratégie, un schéma posologique néonatal optimisé pour le céfotaxime, 5) démontrer, avec l'exemple de la vancomycine, les performances d'un outil informatique de prescription néonatale personnalisée à l'usage du clinicien. Les stratégies proposées ici pourront être appliquées pour optimiser la prescription posologique d'autres classes thérapeutiques en néonatologie.