Efficacy and safety of switching from intravenous to oral antibiotics (amoxicillin-clavulanic acid) versus a full course of intravenous antibiotics in neonates with probable bacterial infection (RAIN): a multicentre, randomised, open-label, non-inferiority trial.

BACKGROUND: Switching from intravenous antibiotic therapy to oral antibiotic therapy among neonates is not yet practised in high-income settings due to uncertainties about exposure and safety. We aimed to assess the efficacy and safety of early intravenous-to-oral antibiotic switch therapy compared with a full course of intravenous antibiotics among neonates with probable bacterial infection. METHODS: In this multicentre, randomised, open-label, non-inferiority trial, patients were recruited at 17 hospitals in the Netherlands. Neonates (postmenstrual age ≥35 weeks, postnatal age 0-28 days, bodyweight ≥2 kg) in whom prolonged antibiotic treatment was indicated because of a probable bacterial infection, were randomly assigned (1:1) to switch to an oral suspension of amoxicillin 75 mg/kg plus clavulanic acid 18·75 mg/kg (in a 4:1 dosing ratio, given daily in three doses) or continue on intravenous antibiotics (according to the local protocol). Both groups were treated for 7 days. The primary outcome was cumulative bacterial reinfection rate 28 days after treatment completion. A margin of 3% was deemed to indicate non-inferiority, thus if the reinfection rate in the oral amoxicillin-clavulanic acid group was less than 3% higher than that in the intravenous antibiotic group the null hypothesis would be rejected. The primary outcome was assessed in the intention-to-treat population (ie, all patients who were randomly assigned and completed the final follow-up visit on day 35) and the per protocol population. Safety was analysed in all patients who received at least one administration of the allocated treatment and who completed at least one follow-up visit. Secondary outcomes included clinical deterioration and duration of hospitalisation. This trial was registered with ClinicalTrials.gov, NCT03247920, and EudraCT, 2016-004447-36. FINDINGS: Between Feb 8, 2018 and May 12, 2021, 510 neonates were randomly assigned (n=255 oral amoxicillin-clavulanic group; n=255 intravenous antibiotic group). After excluding those who withdrew consent (n=4), did not fulfil inclusion criteria (n=1), and lost to follow-up (n=1), 252 neonates in each group were included in the intention-to-treat population. The cumulative reinfection rate at day 28 was similar between groups (one [<1%] of 252 neonates in the amoxicillin-clavulanic acid group vs one [<1%] of 252 neonates in the intravenous antibiotics group; between-group difference 0 [95% CI -1·9 to 1·9]; pnon-inferiority<0·0001). No statistically significant differences were observed in reported adverse events (127 [50%] vs 113 [45%]; p=0·247). In the intention-to-treat population, median duration of hospitalisation was significantly shorter in the amoxicillin-clavulanic acid group than the intravenous antibiotics group (3·4 days [95% CI 3·0-4·1] vs 6·8 days [6·5-7·0]; p<0·0001). INTERPRETATION: An early intravenous-to-oral antibiotic switch with amoxicillin-clavulanic acid is non-inferior to a full course of intravenous antibiotics in neonates with probable bacterial infection and is not associated with an increased incidence of adverse events. FUNDING: The Netherlands Organization for Health Research and Development, Innovatiefonds Zorgverzekeraars, and the Sophia Foundation for Scientific Research.

Rotavirus Vaccine Safety and Effectiveness in Infants With High-Risk Medical Conditions.

OBJECTIVES: Rotavirus vaccination has 87% to 100% effectiveness against severe rotavirus acute gastroenteritis (AGE) in healthy infants in high-income countries. Little is known whether infants with medical risk conditions (MRCs) are equally protected and if the vaccine is equally well tolerated. We conducted a quasi-experimental prospective multicenter before-after cohort study to assess the vaccine effectiveness (VE) and safety profile of the human rotavirus vaccine (HRV) among MRC infants that required prolonged or frequent postnatal care. METHODS: The Netherlands has no national rotavirus immunization program, but HRV was implemented in routine care for MRC infants in 13 Dutch hospitals. Participants in the before and after cohort, HRV unvaccinated and vaccinated, respectively, were followed for occurrence of (rotavirus) AGE. VE of at least 1 dose was estimated by using time-to-event analysis for severe rotavirus AGE. Vaccine-related serious adverse event (AEs) after HRV were retrieved systematically from medical charts. Solicited AEs after vaccinations were prospectively collected and compared between vaccination time points with or without HRV. RESULTS: In total, 1482 high-risk infants with MRC were enrolled, including 631 in the before and 851 in the after cohorts; 1302 infants were premature (88.3%), 447 were small for gestational age (30.2%), and 251 had at least 1 congenital disorder (17.0%). VE against severe rotavirus AGE was 30% (95% confidence interval [CI]: -36% to 65%). Overall, the observed number of rotavirus hospitalizations was low and not significantly different between the cohorts (2 and 2, respectively). The rate of vaccine-related serious AE was 0.24 per 100 vaccine doses. The adjusted risk ratio for any AE after HRV vaccination compared with other routine vaccinations was 1.09 (95% CI: 1.05 to 1.12) for concomitant administration and 0.91 (95% CI: 0.81 to 0.99) for single HRV administration. Gastrointestinal AEs were 10% more frequent after HRV. CONCLUSIONS: In contrast to previous findings among healthy term infants, in routine use, HRV offered limited protection to vulnerable medical risk infants. HRV is generally well tolerated in this group in single administration, but when coadministered with routine vaccines, it is associated with higher risk of (mostly gastrointestinal) AE. Our study highlights the importance of studying vaccine performance in subgroups of medically vulnerable infants.

Accuracy of the Diagnosis of Bronchopulmonary Dysplasia in a Referral-Based Health Care System.

OBJECTIVE: To evaluate the accuracy of the diagnosis of bronchopulmonary dysplasia (BPD) in a national database of a referral-based health care system, where preterm infants are often transferred back to regional hospitals before 36 weeks postmenstrual age (PMA). STUDY DESIGN: We evaluated preterm infants <32 weeks, born between 2004 and 2008 in the Academic Medical Center in Amsterdam with a high-risk profile for BPD. In addition to patient characteristics and outcomes, we collected data on respiratory support at 36 weeks PMA. True incidence of BPD, defined as needing supplemental oxygen and/or positive pressure support at 36 weeks PMA, was compared with the diagnosis registered in the National Perinatal Registry. Two imputation algorithms for patients transferred before 36 weeks PMA were validated. RESULTS: We identified 243 preterm infants with a high-risk BPD profile. Sixty-seven percent of these infants had a correct BPD diagnosis recorded in the National Perinatal Registry, 2% had a false positive, and 31% a false negative diagnosis. Infants with a false negative diagnosis of BPD were twice as often transferred to a regional hospital before 36 weeks PMA compared with a true positive diagnosis. Imputation algorithms did not improve the accuracy of BPD registration. CONCLUSIONS: Registration of the diagnosis BPD in a national database in countries with a referral-based health care system may not be accurate. Optimizing data collection and monitoring data entry is necessary to improve BPD registration before data can be used for national and international benchmarking.

Postoperative course in the cardiac intensive care unit following the first stage of Norwood reconstruction.

The medical records of all patients born between 1 September, 2000, and 31 August, 2002, and undergoing the first stage of Norwood reconstruction, were retrospectively reviewed for details of the perioperative course. We found 99 consecutive patients who met the criterions for inclusion. Hospital mortality for the entire cohort was 15.2%, but was 7.3%, with 4 of 55 dying, in the setting of a "standard" risk profile, as opposed to 25.0% for those with a "high" risk profile, 11 of 44 patients dying in this group. Extracorporeal membrane oxygenation was utilized in 7 patients, with 6 deaths. Median postoperative length of stay in the hospital was 14 days, with a range from 2 to 85 days, and stay in the cardiac intensive care unit was 11 days, with a range from 2 to 85 days. Delayed sternal closure was performed in 18.2%, with a median of 1 day until closure, with a range from zero to 5 days. Excluding isolated delayed sternal closure, and cannulation and decannulation for extracorporeal support, 24 patients underwent 33 cardiothoracic reoperations, including exploration for bleeding in 12, diaphragmatic plication in 4; shunt revision in 4, and other procedures in 13. The median duration of total mechanical ventilation was 4.0 days, with a range from 0.7 to 80.5 days. Excluding those who died, the median total duration of mechanical ventilation was 3.8 days, with a range from 0.9 to 46.3 days. Reintubation for cardiorespiratory failure or upper airway obstruction was performed in 31 patients. Postoperative electroencephalographic and/or clinical seizures occurred in 13 patients, with 7 discharged on anti-convulsant medications. Postoperative renal failure, defined as a level of creatinine greater than 1.5 mg/dl, was present in 13 patients. Eleven had significant thrombocytopenia, with fewer than 20,000 platelets per microl, and injury to the vocal cords was identified in eight patients. Risk factors for longer length of stay included lower Apgar scores, preoperative intubation, early reoperations, reintubation and sepsis, but not weight at birth, genetic syndromes, the specific surgeon, or the duration of surgery. Although mortality rates after the first stage of reconstruction continue to fall, the course in the intensive care unit is remarkable for significant morbidity, especially involving the cardiac, pulmonary and central nervous systems. These patients utilize significant resources during the first hospitalization. Further studies are necessary to stratify the risks faced by patients with hypoplasia of the left heart in whom the first stage of Norwood reconstruction is planned, to determine methods to reduce perioperative morbidity, and to determine the long-term implications of short-term complications, such as diaphragmatic paresis, injury to the vocal cords, prolonged mechanical ventilation, and postoperative seizures.