Continuous-Infusion Vancomycin in Neonates: Assessment of a Dosing Regimen and Therapeutic Proposal

Introduction: Vancomycin remains the reference antibiotic in neonates for care-related infections caused by ß-lactam–resistant Gram-positive bacteria. Achieving the optimal serum vancomycin level is challenging because of high inter-individual variability and the drug's narrow therapeutic window. Continuous infusion might offer pharmacokinetic and practical advantages, but we lack consensus on the dosing regimen. The aim was to determine the proportion of neonates achieving an optimal therapeutic vancomycin level at the first vancomycin concentration assay and which dosing regimen is the most suitable for neonates.Methods: All neonates receiving continuous-infusion vancomycin (loading dose 15 mg/kg and maintenance dose 30 mg/kg/d) in a neonatal intensive care unit were retrospectively analyzed. The proportion of neonates reaching the target serum vancomycin level was calculated. After reviewing the literature to identify all published articles proposing a dosing regimen for continuous-infusion vancomycin for neonates, regimens were theoretically applied to our population by using maintenance doses according to covariate(s) proposed in the original publication.Results: Between January 2013 and December 2014, 75 neonates received 91 vancomycin courses by continuous infusion. Median gestational age, birth weight, and postnatal age were 27 weeks (interquartile range 26–30.5), 815 g (685–1,240), and 15 days (9–33). At the first assay, only 28/91 (30.8%) courses resulted in vancomycin levels between 20 and 30 mg/L (target level), 23/91 (25.3%) >30 mg/L and 40/91 (43.9%) <20 mg/L. We applied six published dosing regimens to our patients. One of these dosing regimens based on corrected gestational age (CGA) and serum creatinine level (SCR) would have allowed us to prescribe lower doses to neonates with high vancomycin levels and higher doses to neonates with low levels.Conclusions: A simplified dosing regimen of continuous-infusion vancomycin did not achieve therapeutic ranges in neonates; a patient-tailored dosing regimen taking into account CGA and SCR level or an individualized pharmacokinetic model can help to anticipate the inter-individual variability in neonates and would have been more suitable

Humidity during high‐frequency oscillatory ventilation compared to intermittent positive pressure ventilation in extremely preterm neonates: An in vitro and in vivo observational study

International audienceBackground: Inappropriate humidification of inspired gas during mechanical ventilation can impair lung development in extremely low birthweight (ELBW) infants. Humidification depends on multiple factors, such as the heater-humidifier device used, type of ventilation, and environmental factors. Few studies have examined inspired gas humidification in these infants, especially during high-frequency oscillatory ventilation (HFOV). Our objective was to compare humidity during HFOV and intermittent positive pressure ventilation (IPPV), in vitro and in vivo.Methods: In vitro and in vivo studies used the same ventilator during both HFOV and IPPV. The bench study used a neonatal test lung and two heater-humidifiers with their specific circuits; the in vivo study prospectively included preterm infants born before 28 weeks of gestation.Results: On bench testing, mean absolute (AH) and relative (RH) humidity values were significantly lower during HFOV than IPPV (RH = 79.4 ± 8.1% vs. 89.0 ± 6.2%, p < 0.001). Regardless of the ventilatory mode, mean RH significantly differed between the two heater-humidifiers (89.6 ± 6.7% vs 78.7 ± 6.8%, p = 0.003). The in vivo study included 10 neonates (mean ± SD gestational age: 25.7 ± 0.9 weeks and birthweight: 624.4 ± 96.1 g). Mean RH during HFOV was significantly lower than during IPPV (74.6 ± 5.7% vs. 83.0 ± 6.7%, p = 0.004).Conclusion: RH was significantly lower during HFOV than IPPV, both in vitro and in vivo. The type of heater-humidifier also influenced humidification. More systematic measurements of humidity of inspired gas, especially during HFOV, should be considered to optimize humidification and consequently lung protection in ELBW infants

Patient-Ventilator Synchrony in Extremely Premature Neonates during Non-Invasive Neurally Adjusted Ventilatory Assist or Synchronized Intermittent Positive Airway Pressure: A Randomized Crossover Pilot Trial

International audienceIntroduction: Synchronization of non-invasive ventilation is challenging in extremely premature infants. We compared patient-ventilator synchrony between non-invasive neurally adjusted ventilatory assist (NIV-NAVA) using transdiaphragmatic (Edi) catheter and synchronized intermittent positive airway pressure (SiPAP) using an abdominal trigger. Methods: This study was a monocentric, randomized, crossover trial in premature infants born before 28 weeks of gestation, aged 3 days or more, and below 32 weeks postmenstrual age. NIV-NAVA and SiPAP were applied in a random order for 2 h with analysis of data from the second hour. The primary outcome was the asynchrony index. Results: Fourteen patients were included (median [IQR] gestational age at birth 25.6 (25.3–26.4) weeks, median [IQR] birth weight 755 [680–824] g, median [IQR] postnatal age 26.5 [19.8–33.8] days). The median (IQR) asynchrony index was significantly lower in NIV-NAVA versus SiPAP (49.9% [44.1–52.6] vs. 85.8% [74.2–90.9], p &#x3c; 0.001). Ineffective efforts and auto-triggering were significantly less frequent in NIV-NAVA versus SiPAP (3.0% vs. 32.0% p &#x3c; 0.001 and 10.0% vs. 26.6%, p = 0.004, respectively). Double triggering was significantly less frequent in SiPAP versus NIV-NAVA (0.0% vs. 9.0%, p &#x3c; 0.001). No significant difference was observed for premature cycling and late cycling. Peak Edi and swing Edi were significantly lower in NIV-NAVA as compared to SiPAP (7.7 [6.1–9.9] vs. 11.0 [6.7–14.5] μV, p = 0.006; 5.4 [4.2–7.6] vs. 7.6 [4.3–10.8] μV, p = 0.007, respectively). No significant difference was observed between NIV-NAVA and SiPAP for heart rate, respiratory rate, COMFORTneo scores, apnoea, desaturations, or bradycardias. Discussion/Conclusion: NIV-NAVA markedly improves patient-ventilator synchrony as compared to SiPAP in extremely premature infants

Evolution of Anti-RBD IgG Avidity following SARS-CoV-2 Infection

SARS-CoV-2 infection rapidly elicits anti-Spike antibodies whose quantity in plasma gradually declines upon resolution of symptoms. This decline is part of the evolution of an immune response leading to B cell differentiation into short-lived antibody-secreting cells or resting memory B cells. At the same time, the ongoing class switch and antibody maturation processes occurring in germinal centers lead to the selection of B cell clones secreting antibodies with higher affinity for their cognate antigen, thereby improving their functional activity. To determine whether the decline in SARS-CoV-2 antibodies is paralleled with an increase in avidity of the anti-viral antibodies produced, we developed a simple assay to measure the avidity of anti-receptor binding domain (RBD) IgG elicited by SARS-CoV-2 infection. We longitudinally followed a cohort of 29 convalescent donors with blood samples collected between 6- and 32-weeks post-symptoms onset. We observed that, while the level of antibodies declines over time, the anti-RBD avidity progressively increases and correlates with the B cell class switch. Additionally, we observed that anti-RBD avidity increased similarly after SARS-CoV-2 mRNA vaccination and after SARS-CoV-2 infection. Our results suggest that anti-RBD IgG avidity determination could be a surrogate assay for antibody affinity maturation and, thus, suitable for studying humoral responses elicited by natural infection and/or vaccination

Neurodevelopmental Outcomes after Premedication with Atropine/Propofol vs Atropine/Atracurium/Sufentanil for Neonatal Intubation: 2-Year Follow-Up of a Randomized Clinical Trial

International audienceThis study followed 173 newborn infants in the PREmedication Trial for Tracheal Intubation of the NEOnate multicenter, double-blind, randomized controlled trial of atropine-propofol vs atropine-atracurium-sufentanil for premedication before nonemergency intubation. At 2 years of corrected age, there was no significant difference between the groups in death or risk of neurodevelopmental delay assessed with the Ages and Stages Questionnaire

Predictive Performance of Population Pharmacokinetic Models of Levetiracetam in Children and Evaluation of Dosing Regimen

International audienceLevetiracetam is a broad-spectrum antiepileptic drug that exhibits high interindividual variability in serum concentrations in children. A population pharmacokinetic approach can be used to explain this variability and optimize dosing schemes. The objectives are to identify the best predictive population pharmacokinetic model for children and to evaluate recommended doses using simulations and Bayesian forecasting. A validation cohort included children treated with levetiracetam who had a serum drug concentration assayed during therapeutic drug monitoring. We assessed the predictive performance of all the population pharmacokinetic models published in the literature using mean prediction errors, root mean squared errors, and visual predictive checks. A population model was finally constructed on the data, and dose simulations were performed to evaluate doses. We included 267 levetiracetam concentrations ranging from 2 to 69 mg/L from 194 children in the validation cohort. Six published models were externally evaluated. Most of the models underestimated the variability of our population. A 1-compartment model with first-order absorption and elimination with allometric scaling was finally fitted on our data. In our cohort, 57% of patients had a trough concentration 5 mg/L, doses ≥30 mg/kg/d for patients ≤50 kg and ≥2000 mg/d for patients >50 kg are required. In our population, a high percentage of children had low trough concentrations. Our population pharmacokinetic model could be used for therapeutic drug monitoring of levetiracetam in children

Humoral Responses Elicited after a Fifth Dose of SARS-CoV-2 mRNA Bivalent Vaccine

While an important part of the world’s population is vaccinated against SARS-CoV-2, new variants continue to emerge. We observe that even after a fifth dose of the mRNA bivalent vaccine, most vaccinated individuals have antibodies that poorly neutralize several Omicron subvariants, including BQ.1.1, XBB, XBB.1.5, FD.1.1, and CH.1.1. However, Fc-effector functions remain strong and stable over time against new variants, which may partially explain why vaccines continue to be effective. We also observe that donors who have been recently infected have stronger antibody functional activities, including neutralization and Fc-effector functions, supporting the observations that hybrid immunity leads to better humoral responses

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

Peer reviewe

An extended SARS-CoV-2 mRNA vaccine prime-boost interval enhances B cell immunity with limited impact on T cells

Summary: Spacing the first two doses of SARS-CoV-2 mRNA vaccines beyond 3–4 weeks raised initial concerns about vaccine efficacy. While studies have since shown that long-interval regimens induce robust antibody responses, their impact on B and T cell immunity is poorly known. Here, we compare SARS-CoV-2 naive donors B and T cell responses to two mRNA vaccine doses administered 3–4 versus 16 weeks apart. After boost, the longer interval results in a higher magnitude and a more mature phenotype of RBD-specific B cells. While the two geographically distinct cohorts present quantitative and qualitative differences in T cell responses at baseline and after priming, the second dose led to convergent features with overall similar magnitude, phenotype, and function of CD4+ and CD8+ T cell responses at post-boost memory time points. Therefore, compared to standard regimens, a 16-week interval has a favorable impact on the B cell compartment but minimally affects T cell immunity