In Utero Exposure to Antibiotics and Risk of Serious Infections in the First Year of Life.

INTRODUCTION AND OBJECTIVE: Given the high prevalence of antibiotic prescription during pregnancy in France and previous studies suggesting an increased risk of infection in offspring with such exposures, our study aimed to investigate the association between prenatal exposure to systemic antibiotics and serious infections in full-term infants during their first year of life. METHODS: We conducted a retrospective population-based cohort study on singleton, full-term liveborn non-immunocompromised infants, using the French National Health Data System (SNDS) between 2012 and 2021. Systemic antibiotic dispensing in ambulatory care settings during pregnancy defined the exposure. Outcomes concerned serious infections (i.e., infections requiring hospitalization) in offspring identified between 3 and 12 months of life, hence excluding infections of maternal origin. Adjusted odds ratios (aORs) were estimated using logistic regression with multivariate models to control for potential confounders. RESULTS: Of 2,836,630 infants included, 39.6% were prenatally exposed to systemic antibiotics. Infants prenatally exposed to antibiotics had a higher incidence of serious infections compared with unexposed infants {aOR 1.12 [95% confidence interval (95% CI) 1.11-1.13]}. Similar associations were observed according to the timing of exposure during pregnancy, antibiotic class, and site of infections. The strongest association was observed when infants were prenatally exposed to three or more antibiotic courses during pregnancy [aOR 1.21 (95% CI 1.19-1.24)]. Limitations include residual confounders, such as genetic susceptibility to infections and the role of the underlying pathogen agent. CONCLUSION: Prenatal exposure to systemic antibiotics is very common and is associated with a weak yet significant associations with subsequent serious infectious events during the first year of life. While our study revealed associations, it is important to note that causation cannot be established, given the acknowledged limitations, including potential confounding by indication.

Lumacaftor/Ivacaftor Population Pharmacokinetics in Pediatric Patients with Cystic Fibrosis: A First Step Toward Personalized Therapy.

BACKGROUND: A major breakthrough in cystic fibrosis (CF) therapy was achievedAQ1 with CFTR modulators. The lumacaftor/ivacaftor combination is indicated for the treatment of CF in pediatric patients above 6 years old. Pharmacokinetic (PK) studies of lumacaftor/ivacaftor in these vulnerable pediatric populations are AQ2crucial to optimize treatment protocols. OBJECTIVES AND METHODS: The objectives of this study were to describe the population PK (PPK) of lumacaftor and ivacaftor in children with CF, and to identify factors associated with interindividual variability. The association between drug exposure and clinical response was also investigated. RESULTS: A total of 75 children were included in this PPK study, with 191 concentrations available for each compound and known metabolites (lumacaftor, ivacaftor, ivacaftor-M1, and ivacaftor-M6). PPK analysis was performed using Monolix software. A large interindividual variability was observed. The main sources of interpatient variability identified were patient bodyweight and hepatic function (aspartate aminotransferase). Forced expiratory volume in the first second (FEV1) was statistically associated with the level of exposure to ivacaftor after 48 weeks of treatment. CONCLUSIONS: This study is the first analysis of lumacaftor/ivacaftor PPK in children with CF. These data suggest that dose adjustment is required after identifying variability factors to optimize efficacy. The use of therapeutic drug monitoring as a basis for dose adjustment in children with CF may be useful.

Trends in harmful drug exposure during pregnancy in France between 2013 and 2019: A nationwide cohort study.

OBJECTIVE: Describe the trends of exposure to harmful drugs during pregnancy over recent years in France. DESIGN: Nationwide cohort study. SETTING: The French National administrative health Data System (SNDS). POPULATION: Pregnancies starting between 2013 and 2019 and outcomes corresponding to live births, medical terminations of pregnancy, and stillbirths. METHODS: Each pregnancy was divided into a preconceptional period of 90 days before conception and three trimesters from conception to birth. Harmful drugs were defined according to their risks to the fetus: teratogenicity or fetotoxicity. Exposure was defined using the critical period during pregnancy for each type of harmful drug: preconceptional period or first trimester for teratogenic drugs and second or third trimesters for fetotoxic drugs. MAIN OUTCOME MEASURES: Prevalence of pregnancies exposed to at least one harmful drug. RESULTS: Among 5,253,284 pregnancies, 204,402 (389 per 10,000) pregnancies were exposed to at least one harmful drug during the critical periods: 48,326 (92 per 10,000) pregnancies were exposed to teratogenic drugs during the preconceptional period or the first trimester, and 155,514 (299 per 10,000) pregnancies were exposed to fetotoxic drugs during the second or third trimesters. Teratogenic drugs were mainly retinoids for topical use (44 per 10,000 pregnancies), antiepileptics (13 per 10,000 pregnancies) and statins (13 per 10,000 pregnancies). Fetotoxic drugs were mainly non-steroidal anti-inflammatory drugs (NSAIDs), for systemic (128 per 10,000 pregnancies) and topical use (122 per 10,000 pregnancies). Exposure to teratogenic drugs decreased from the preconceptional period to the first trimester. Exposure to fetotoxic drugs decreased from the second to the third trimester. Between 2013 and 2019, we found a decrease in harmful drug exposure overall, mainly for topical and systemic NSAIDs and for topical retinoids. CONCLUSIONS: In this nationwide study, about one in 25 pregnancies was exposed to at least one harmful drug, mainly NSAIDs and topical retinoids. Although the prevalence of harmful drug exposure decreased over the study period, NSAID exposure in the second and third trimester remains of concern.

Prophylactic Intravenous Acetaminophen in Extremely Premature Infants: Minimum Effective Dose Research by Bayesian Approach.

BACKGROUND: Patent ductus arteriosus (PDA) in preterm infants is associated with increased morbidities and mortality. Prophylactic treatment with cyclooxygenase inhibitors, as indomethacin or ibuprofen, failed to demonstrate significant clinical benefits. Acetaminophen may represent an alternative treatment option. OBJECTIVE: This study evaluated the minimum effective dose of prophylactic acetaminophen to close the ductus and assessed the safety and tolerability profile in extremely preterm infants at 23-26 weeks of gestation. METHODS: A dose finding trial with Bayesian continual reassessment method was performed in a multicenter study with premature infants hospitalized in neonatal intensive care unit. Infants of 23-26 weeks of gestation and post-natal age ≤ 12 h were enrolled. Four intravenous acetaminophen dose levels were predefined. The primary outcome was the ductus arteriosus closing at two consecutive echocardiographies or at day 7. The main secondary objectives included the safety of acetaminophen on hemodynamics and biological hepatic function. RESULTS: A total of 29 patients were analyzed sequentially for the primary analysis with 20 infants assigned to the first dose level followed by 9 infants to the second dose level. No further dose level increase was necessary. The posterior probabilities of success, estimated from the Bayesian logistic model, were 46.1% [95% probability interval (PI), 24.9-63.9] and 67.6% (95% PI, 51.5-77.9) for dose level 1 and 2, respectively. A closing or closed pattern was observed among 19 patients at the end of treatment [65.5% (95% confidence interval (CI), 45.7-82.0)]. No change in alanine aminotransferase values was observed during treatment. A significant decrease in aspartate aminotransferase values was observed with postnatal age. No change in systolic and diastolic blood pressures was observed during treatment. CONCLUSIONS: Minimum effective dose to close the ductus was 25 mg/kg loading dose then 10 mg/kg/6 h for 5 days in extremely preterm infants. Acetaminophen was well tolerated in this study following these doses. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04459117.

Neutralizing Antibody Levels as a Correlate of Protection Against SARS-CoV-2 Infection: A Modeling Analysis.

Although anti-severe acute respiratory syndrome-coronavirus 2 antibody kinetics have been described in large populations of vaccinated individuals, we still poorly understand how they evolve during a natural infection and how this impacts viral clearance. For that purpose, we analyzed the kinetics of both viral load and neutralizing antibody levels in a prospective cohort of individuals during acute infection with alpha variant. Using a mathematical model, we show that the progressive increase in neutralizing antibodies leads to a shortening of the half-life of both infected cells and infectious viral particles. We estimated that the neutralizing activity reached 90% of its maximal level within 11 days after symptom onset and could reduce the half-life of both infected cells and circulating virus by a 6-fold factor, thus playing a key role to achieve rapid viral clearance. Using this model, we conducted a simulation study to predict in a more general context the protection conferred by pre-existing neutralization titers, due to either vaccination or prior infection. We predicted that a neutralizing activity, as measured by 50% effective dose > 103 , could reduce by 46% the risk of having viral load detectable by standard polymerase chain reaction assays and by 98% the risk of having viral load above the threshold of infectiousness. Our model shows that neutralizing activity could be used to define correlates of protection against infection and transmission.

Simultaneous pharmacokinetic modeling of unbound and total darunavir with ritonavir in adolescents: a substudy of the SMILE trial.

Darunavir (DRV) is an HIV protease inhibitor commonly used as part of antiretroviral treatment regimens globally for children and adolescents. It requires a pharmacological booster, such as ritonavir (RTV) or cobicistat. To better understand the pharmacokinetics (PK) of DRV in this younger population and the importance of the RTV boosting effect, a population PK substudy was conducted within SMILE trial, where the maintenance of HIV suppression with once daily integrate inhibitor + darunavir/ritonavir in children and adolescents is evaluated. A joint population PK model that simultaneously used total DRV, unbound DRV, and total RTV concentrations was developed. Competitive and non-competitive models were examined to define RTV's influence on DRV pharmacokinetics. Linear and non-linear equations were tested to assess DRV protein binding. A total of 443 plasma samples from 152 adolescents were included in this analysis. Darunavir PK was best described by a one-compartment model first-order absorption and elimination. The influence of RTV on DRV pharmacokinetics was best characterized by ritonavir area under the curve on DRV clearance using a power function. The association of non-linear and linear equations was used to describe DRV protein binding to alpha-1 glycoprotein and albumin, respectively. In our population, simulations indicate that 86.8% of total and unbound DRV trough concentrations were above 0.55 mg/L [10 times protein binding-adjusted EC50 for wild-type (WT) HIV-1] and 0.0243 mg/L (10 times EC90 for WT HIV-1) targets, respectively. Predictions were also in agreement with observed outcomes from adults receiving 800/100 mg DRV/r once a day. Administration of 800/100 mg of DRV/r once daily provides satisfactory concentrations and exposures for adolescents aged 12 years and older.

Drug-induced fetal and offspring disorders, beyond birth defects.

Studies on drug utilization in western countries disclosed that about nine over ten women use at least one or more drugs during pregnancy. Determining whether a drug is safe or not in pregnant women is a challenge of all times. As a developing organism, the fetus is particularly vulnerable to effects of drugs used by the mother. Historically, research has predominantly focused on birth defects, which represent the most studied adverse pregnancy outcomes. However, drugs can also alter the ongoing process of pregnancy and impede the general growth of the fetus. Finally, adverse drug reactions can theoretically damage all developing systems, organs or tissues, such as the central nervous system or the immune system. This extensive review focuses on different aspects of drug-induced damages affecting the fetus or the newborn/infant, beyond birth defects, which are not addressed here.

Predictive Factors of Response to Immunotherapy in Lymphomas: A Multicentre Clinical Data Warehouse Study (PRONOSTIM).

Immunotherapy (IT) is a major therapeutic strategy for lymphoma, significantly improving patient prognosis. IT remains ineffective for a significant number of patients, however, and exposes them to specific toxicities. The identification predictive factors around efficacy and toxicity would allow better targeting of patients with a higher ratio of benefit to risk. PRONOSTIM is a multicenter and retrospective study using the Clinical Data Warehouse (CDW) of the Greater Paris University Hospitals network. Adult patients with Hodgkin lymphoma or diffuse large-cell B lymphoma treated with immune checkpoint inhibitors or CAR T (Chimeric antigen receptor T) cells between 2017 and 2022 were included. Analysis of covariates influencing progression-free survival (PFS) or the occurrence of grade ≥3 toxicity was performed. In total, 249 patients were included. From this study, already known predictors for response or toxicity of CAR T cells such as age, elevated lactate dehydrogenase, and elevated C-Reactive Protein at the time of infusion were confirmed. In addition, male gender, low hemoglobin, and hypo- or hyperkalemia were demonstrated to be potential predictive factors for progression after CAR T cell therapy. These findings prove the attractiveness of CDW in generating real-world data, and show its essential contribution to identifying new predictors for decision support before starting IT.

Local anesthetics systemic toxicity in children: analysis of the French pharmacovigilance database.

PURPOSE: To characterize clinical profile of pediatric local anesthetic (LA) systemic toxicity (LAST) and to identify determinants of life-threatening outcomes. METHODS: Spontaneous reports notified to the French Pharmacovigilance Network were retrieved and followed by a case-by-case review, according to the following criteria: LA as suspected drug, age < 18 years, adverse drug reactions related to nervous system, cardiac, respiratory, psychiatric or general disorders. Multivariate logistic regression analysis was performed to identify factors leading to life-threatening reaction (i.e. continuous seizures or cardiorespiratory arrest). RESULTS: Among 512 cases retrieved, 64 LAST cases were included (neonates 11%, infants 30%, children 36%, adolescents 23%) mainly involving lidocaine (47%), lidocaine + prilocaine (22%) and ropivacaine (14%). Toxicity profiles were neurological (58%), cardiac (11%) or mixed (20%) and 7 patients (11%) developed methemoglobinemia. LAST was life-threatening for 23 patients (36%) and 2 patients died. Doses were above recommendations in 26 patients (41%) and were not different between life-threatening and non-life-threatening cases. The context of use (general and orthopedic surgery, p = 0.006) and the type of LA agent (lidocaine, p = 0.016) were independently associated with a life-threatening outcome. CONCLUSION: In this national retrospective analysis, LAST in children appear to be a rare event. Neurological and cardiac signs were the most frequently reported reactions. LAST in children can be life-threatening, even at therapeutic doses. Although a fatal outcome may anecdotally occur, the vast majority of patients recovered after appropriate medical care.

Association of depression and suicidal behaviour reporting with HIV integrase inhibitors: a global pharmacovigilance study.

OBJECTIVES: Concerns have been raised regarding neuropsychiatric adverse drug reactions of integrase inhibitors (INSTIs) in patients living with HIV. The aim of this study was to assess the risk of depression and suicidality reporting with INSTIs based on a global pharmacovigilance database. METHODS: Depression and suicidality cases in patients treated with INSTIs were identified within the WHO global database of individual case safety reports, VigiBase. Risk of depression and suicidality reporting with INSTIs compared with other ART was assessed using disproportionality analyses (case/non-case statistical approach). RESULTS: Of 19 991 410 reports over the study period, 124 184 reports concerned patients exposed to ART, including 22 661 patients exposed to an INSTI. Among patients treated with an INSTI, 547 cases of depression and 357 cases of suicidality were identified. Disproportionality analyses showed that depression [reporting OR (ROR) 3.6; 95% CI: 3.2-4.0] and suicidality (ROR 4.7; 95% CI: 4.1-5.4) were more reported with the use of INSTIs compared with other ART. Amongst INSTIs, depression reporting was significantly greater for bictegravir and dolutegravir, whereas suicidality reporting was significantly greater for dolutegravir only. CONCLUSIONS: Our findings suggest that depression and suicidality are adverse drug reactions of all INSTI agents, especially dolutegravir, which may occur within the first months of therapy.

Management of Gastro-Intestinal Toxicity of the Pi3 Kinase Inhibitor: Optimizing Future Dosing Strategies.

The phosphatidylinositol 3-kinase (PI3K) pathway plays a key role in cancer progression and in host immunity. Idelalisib was the first of this class to be approved with the second-generation Pi3 kinase inhibitors copanlisib, duvelisib and umbralisib, subsequently being approved in the United States. Real-world data are lacking, however, in relation to the incidence and toxicity of Pi3 kinase inhibitor-induced colitis. We here review, in the first instance, the general landscape of the Pi3K inhibitors in the context of hematological malignancies, with a focus on the adverse gastrointestinal side effects reported by various clinical trials. We further review the available worldwide pharmacovigilance data in relation to these drugs. Finally, we describe our own real-world experience with idelalisib-induced colitis management in our center and in a national setting.

Azathioprine-induced vanishing bile duct syndrome: The value of early thiopurine metabolism assessment.

About 15% to 28% of patients treated with thiopurines experienced adverse drug reactions, such as haematological and hepatic toxicities. Some of these related to the polymorphic activity of the thiopurine S-methyltransferase (TPMT), the key detoxifying enzyme of thiopurine metabolism. We report here a case of thiopurine-induced ductopenia with a comprehensive pharmacological analysis on thiopurine metabolism. A 34-year-old woman, with a medical history of severe systemic lupus erythematosus with recent introduction of azathioprine therapy, presented with mild fluctuating transaminase blood levels consistent with a hepatocellular pattern, which evolved to a cholestatic pattern over the next weeks. A blood thiopurine metabolite assay revealed low 6-thioguanine nucleotides (6-TGN) level and a dramatically increased 6-methylmercaptopurine ribonucleotides (6-MMPN) level, together with an unfavourable [6-MMPN:6-TGN] metabolite ratio and a high TPMT activity. After a total of about 6 months of thiopurine therapy, a transjugular liver biopsy revealed a ductopenia, and azathioprine discontinuation led to further clinical improvement. In line with previous reports from the literature, our case supports the fact that ductopenia is a rare adverse drug reaction of azathioprine. The mechanism of reaction is unknown but may involve high 6-MMPN blood level, due to unusual thiopurine metabolism (switched metabolism). Early therapeutic drug monitoring with measurement of 6-TGN and 6-MMPN blood levels may help physicians to identify patients at risk of similar duct injury.

Evaluation of the effectiveness of potassium chloride in the management of out-of hospital cardiac arrest by refractory ventricular fibrillation: Study protocol of the POTACREH study.

PURPOSE: Out-of-hospital cardiac arrest (OHCA) has a poor prognosis, with an overall survival rate of about 5% at discharge. Shockable rhythm cardiac arrests (ventricular fibrillation (VF) and pulseless ventricular tachycardia (VT)) have a better prognosis. In case of shockable rhythm, treatment is based on defibrillation, and thereafter, in case of failure of 3 external electric shocks (EES), on direct intravenous administration of 300 mg amiodarone, or lidocaine when amiodarone is unavailable or inefficient. During surgical procedures under extracorporeal circulation, a high potassium cardioplegia solution is administered to interrupt cardiac activity and facilitate surgical procedure. By extension, direct intravenous administration of potassium chloride (KCl) has been shown to convert VF, resulting in return to a hemodynamically efficient organized heart rate within a few minutes. The aim of this study is to provide clinical evidence that direct intravenous injection of KCl, into a patient presenting with OHCA due to refractory VF although 3 EES, should interrupt this VF and then allow rapid restauration of an organized heart rhythm, and thus return of spontaneous circulation (ROSC). METHODS: A multicenter, prospective, single group, phase 2 study will be conducted on 81 patients presenting with refractory VF. After failure of 3 EES, each patient will receive direct intravenous injection of 20 mmol KCl instead of amiodarone. The primary outcome will be survival rate at hospital admission. Major secondary outcomes will include ROSC and time to ROSC in the prehospital setting, number of VF recidivism after KCl injection, survival rate at hospital discharge with a good neurologic prognostic, and survival rate 3 months after hospital discharge with a good neurologic prognostic. RESULTS: No patient is currently included in the study. DISCUSSION: Conventional guideline strategy based on antiarrhythmic drug administration, i.e. amiodarone or lidocaine, for OHCA due to shockable rhythm, has not yet demonstrated an increase in survival at hospital admission or at hospital discharge. This may be related to the major cardiodepressant effect of those drugs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04316611. Registered on March 2020. AP-HP180577 / N° EUDRACT: 2019-002544-24. Funded by the French Health Ministry. https://clinicaltrials.gov/ct2/show/NCT04316611.

Population pharmacokinetics of unbound and total dolutegravir concentrations in children aged 12†years and older: a PK substudy of the SMILE trial.

BACKGROUND: SMILE, a multicentre randomized trial, compared the efficacy and safety of switching virologically suppressed children and adolescents with HIV to a once-daily dual regimen of dolutegravir plus ritonavir-boosted darunavir versus continuing standard ART. Within a nested pharmacokinetic (PK) substudy, we performed a population PK analysis to describe total and unbound dolutegravir plasma concentrations in children and adolescents receiving this dual therapy. METHODS: Sparse blood samples were obtained during follow-up for dolutegravir quantification. A population PK model was developed to simultaneously describe total and unbound dolutegravir concentrations. Simulations were performed and were compared with the protein-adjusted 90% inhibitory concentration (IC90) and the in vitro IC50, respectively. Dolutegravir exposures in children aged ≥12 years were also compared with values in treatment-experienced adults. RESULTS: Four hundred and fifty-five samples from 153 participants aged between 12 and 18 years were collected for this PK analysis. A one-compartment model with first-order absorption and elimination best described unbound dolutegravir concentrations. The relationship between unbound and total dolutegravir concentrations was best characterized by a non-linear model. Unbound dolutegravir apparent clearance was significantly influenced by total bilirubin concentrations and by Asian ethnicity. All children and adolescents had trough concentrations well above the protein-adjusted IC90 and the in vitro IC50 values. Dolutegravir concentrations and exposures were also similar to those obtained in adults receiving dolutegravir 50 mg once daily. CONCLUSIONS: A once-daily 50 mg dolutegravir dose for children and adolescents produces adequate total and unbound concentrations when used as part of dual therapy with ritonavir-boosted darunavir.

Assessing the risk of adverse pregnancy outcomes and birth defects reporting in women exposed to ganciclovir or valganciclovir during pregnancy: a pharmacovigilance study.

OBJECTIVES: Cytomegalovirus (CMV) is the leading cause of congenital infection worldwide. Reference anti-CMV treatment is valganciclovir/ganciclovir, which is contraindicated in pregnancy given questions about teratogenicity. METHODS: We analysed reports from VigiBase, the world's largest safety database, and performed a disproportionality analysis of adverse pregnancy outcomes associated with (val)ganciclovir compared with any other drugs or with (val)aciclovir as comparators. RESULTS: Among 3 104 984 reports related to childbearing-age women or to pregnancy topics, 6186 were exposed to (val)ganciclovir or (val)aciclovir including 251 adverse pregnancy outcomes with (val)ganciclovir (n = 34) or (val)aciclovir (n = 217). We did not evidence any increased reporting of any adverse pregnancy outcome [miscarriage, stillbirth, small weight for gestational age, preterm birth (<37 weeks of gestation)] or birth defects with (val)ganciclovir compared with the use of (val)aciclovir during pregnancy. Four cases of oesophageal and anorectal atresia were identified with (val)ganciclovir, which may be related to concomitant drugs/medical conditions and require further analyses. CONCLUSIONS: These preliminary results require confirmation but suggest the possibility for trial evaluation of val(ganciclovir) in severe maternal or fetal CMV infections.

Paediatric drug development and evaluation: Existing challenges and recommendations.

Despite various international regulatory initiatives over the last 20 years, many challenges remain in the field of paediatric drug development and evaluation. Indeed, drug research and development is still focused essentially on adult indications, thereby excluding many paediatric patients, limiting the feasibility of trials and favouring competing developments. Off-label prescribing persists and the development of age-appropriate dosage forms for children remains limited. Against this background, the members of this panel (TR) recommend the launch of multi-partner exchange forums on specific topics in order to focus new drug research and development on the real, unmet medical needs of children and adolescents, and in keeping with the underlying mechanisms of action. Scientific information sharing and cooperation between stakeholders are also essential for defining reference evaluation methods in each medical field. These forums can be organised through existing paediatric facilities and research networks at the French and European level. The latter are specifically dedicated to paediatric research and can facilitate clinical trial implementation and patient enrolment. Moreover, specific grants and public/private partnerships are still needed to support studies on the repositioning of drugs in paediatric indications, and pharmacokinetic studies aimed at defining appropriate dosages. The development of new pharmaceutical forms, better suited for paediatric use, and the promotion of resulting innovations will stimulate future investments. Initiatives to gather observational safety and efficacy data following off-label and/or derogatory early access should also be encouraged to compensate for the lack of information available in these situations. Finally, the creation of Ethics Committees (EC) with a specific "mother-child" advisory expertise should be promoted to ensure that the current regulation (Jardé law in France) is implemented whilst also taking into account the paediatric specificities in medical trials.

Beta-lactam exposure and safety in intermittent or continuous infusion in critically ill children: an observational monocenter study.

The aim of this study was to assess the pharmacokinetic (PK) exposure and clinical toxicity for three beta-lactams: cefotaxime, piperacillin/tazobactam, and meropenem, depending on two lengths of infusion: continuous and intermittent, in critically ill children. This single center observational prospective study was conducted in a pediatric intensive care unit. All hospitalized children who had one measured plasma concentration of the investigated antibiotics were included. Plasma antibiotic concentrations were interpreted by a pharmacologist, using a Bayesian approach based on previously published population pharmacokinetic models in critically ill children. Exposure was considered optimal, low, or high according to the PK target 100% fT> 4 × MIC and a trough concentration below the toxic concentration (50 mg.L-1 for cefotaxime, 150 mg.L-1 for piperacillin, and 44 mg.L-1 for meropenem). Between May 2019 and January 2020, 80 patients were included and received 106 antibiotic courses: 74 (70%) were administered in intermittent infusion (II) and 32 (30%) in continuous infusion (CI). Compared to II, CI provided more optimal PK exposure (n = 22/32, 69% for CI versus n = 35/74, 47% for II, OR 1.2, 95%CI 1.01-1.5, p = 0.04), less underexposure (n = 4/32, 13% for CI versus n = 36/74, 49% for II, OR 0.7, 95%CI 0.6-0.84, p < 0.001), and more overexposure (n = 6/32, 19% for CI versus n = 3/74, 4% for II, OR 1.2, 95%CI 1.03-1.3, p = 0.01). Five adverse events have been reported during the study period, although none has been attributed to beta-lactam treatment. CONCLUSION: CI provided a higher probability to attain an optimal PK target compared to II, but also a higher risk for overexposure. Regular therapeutic drug monitoring is recommended in critically ill children receiving beta-lactams, regardless of the length of infusion. WHAT IS KNOWN: • Since beta-lactams are time-dependent antibiotics, the probability to attain the pharmacokinetic target is higher with continuous infusion compared to that with intermittent infusion. • In daily practice, continuous or extended infusions are rarely used despite recent guidelines, and toxicity is hardly reported. WHAT IS NEW: • Continuous infusion provided a higher probability to attain an optimal pharmacokinetic target compared to intermittent infusion, but also a higher risk of overexposure. • Regular therapeutic drug monitoring is recommended in critically ill children receiving beta-lactams, regardless of the length of infusion.