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.

Risk Factors for Retinopathy of Prematurity in the Netherlands: A Comparison of Two Cohorts.

INTRODUCTION: Retinopathy of prematurity (ROP) remains an important cause for preventable blindness. Aside from gestational age (GA) and birth weight, risk factor assessment can be important for determination of infants at risk of (severe) ROP. METHODS: Prospective, multivariable risk-analysis study (NEDROP-2) was conducted, including all infants born in 2017 in the Netherlands considered eligible for ROP screening by pediatricians. Ophthalmologists provided data of screened infants, which were combined with risk factors from the national perinatal database (Perined). Clinical data and potential risk factors were compared to the first national ROP inventory (NEDROP-1, 2009). During the second period, more strict risk factor-based screening inclusion criteria were applied. RESULTS: Of 1,287 eligible infants, 933 (72.5%) were screened for ROP and matched with the Perined data. Any ROP was found in 264 infants (28.3% of screened population, 2009: 21.9%) and severe ROP (sROP) (stage ≥3) in 41 infants (4.4%, 2009: 2.1%). The risk for any ROP is decreased with a higher GA (odds ratio [OR] 0.59 and 95% confidence interval [CI] 0.54-0.66) and increased for small for GA (SGA) (1.73, 1.11-2.62), mechanical ventilation >7 days (2.13, 1.35-3.37) and postnatal corticosteroids (2.57, 1.44-4.66). For sROP, significant factors were GA (OR 0.37 and CI 0.27-0.50), SGA (OR 5.65 and CI 2.17-14.92), postnatal corticosteroids (OR 3.81 and CI 1.72-8.40), and perforated necrotizing enterocolitis (OR 7.55 and CI 2.29-24.48). CONCLUSION: In the Netherlands, sROP was diagnosed more frequently since 2009. No new risk factors for ROP were determined in the present study, apart from those already included in the current screening guideline.

Neonatal microbiota development and the effect of early life antibiotics are determined by two distinct settler types.

The neonatal period, during which the initial gut microbiota is acquired, is a critical phase. The healthy development of the infant's microbiome can be interrupted by external perturbations, like antibiotics, which are associated with profound effects on the gut microbiome and various disorders later in life. The aim of this study was to investigate the development of intestinal microbiota and the effect of antibiotic exposure during the first three months of life in term infants. Fecal samples were collected from healthy infants and infants who received antibiotics in the first week of life at one week, one month, and three months after birth. Microbial composition was analyzed using IS-pro and compared between antibiotics-treated and untreated infants. In total, 98 infants, divided into four groups based on feeding type and delivery mode, were analyzed. At one week of age, samples clustered into two distinct groups, which were termed "settler types", based on their Bacteroidetes abundance. Caesarean-born infants belonged to the low-Bacteroidetes settler type, but vaginally-born infants were divided between the two groups. The antibiotics effect was assessed within a subgroup of 45 infants, vaginally-born and exclusively breastfed, to minimize the effect of other confounders. Antibiotics administration resulted in lower Bacteroidetes diversity and/or a delay in Bacteroidetes colonization, which persisted for three months, and in a differential development of the microbiota. Antibiotics resulted in pronounced effects on the Bacteroidetes composition and dynamics. Finally, we hypothesize that stratification of children's cohorts based on settler types may reveal group effects that might otherwise be masked.

Expert panel diagnosis demonstrated high reproducibility as reference standard in infectious diseases.

OBJECTIVE: If a gold standard is lacking in a diagnostic test accuracy study, expert diagnosis is frequently used as reference standard. However, interobserver and intraobserver agreements are imperfect. The aim of this study was to quantify the reproducibility of a panel diagnosis for pediatric infectious diseases. STUDY DESIGN AND SETTING: Pediatricians from six countries adjudicated a diagnosis (i.e., bacterial infection, viral infection, or indeterminate) for febrile children. Diagnosis was reached when the majority of panel members came to the same diagnosis, leaving others inconclusive. We evaluated intraobserver and intrapanel agreement with 6 weeks and 3 years' time intervals. We calculated the proportion of inconclusive diagnosis for a three-, five-, and seven-expert panel. RESULTS: For both time intervals (i.e., 6 weeks and 3 years), intrapanel agreement was higher (kappa 0.88, 95%CI: 0.81-0.94 and 0.80, 95%CI: NA) compared to intraobserver agreement (kappa 0.77, 95%CI: 0.71-0.83 and 0.65, 95%CI: 0.52-0.78). After expanding the three-expert panel to five or seven experts, the proportion of inconclusive diagnoses (11%) remained the same. CONCLUSION: A panel consisting of three experts provides more reproducible diagnoses than an individual expert in children with lower respiratory tract infection or fever without source. Increasing the size of a panel beyond three experts has no major advantage for diagnosis reproducibility.

Antibiotic Overuse in Children with Respiratory Syncytial Virus Lower Respiratory Tract Infection.

BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections (LRTI) during the first year of life. Antibiotic treatment is recommended in cases suspected of bacterial coinfection. The aim of this prospective study was to estimate the incidence of bacterial coinfections and the amount of antibiotic overuse in children infected with RSV using expert panel diagnosis. METHODS: Children 1 month of age and over with LRTI or fever without source were prospectively recruited in hospitals in the Netherlands and Israel. Children with confirmed RSV infection by Polymerase Chain Reaction (PCR) on nasal swabs were evaluated by an expert panel as reference standard diagnosis. Three experienced pediatricians distinguished bacterial coinfection from simple viral infection using all available clinical information, including all microbiologic evaluations and a 28-day follow-up evaluation. RESULTS: A total of 188 children (24% of all 784 recruited patients) were positive for RSV. From these, 92 (49%) were treated with antibiotics. All 27 children (29%) with bacterial coinfection were treated with antibiotics. Fifty-seven patients (62%) were treated with antibiotics without a diagnosis of bacterial coinfection. In 8 of the 92 (9%), the expert panel could not distinguish simple viral infection from bacterial coinfection. CONCLUSION: This is the first prospective international multicenter RSV study using an expert panel as reference standard to identify children with and without bacterial coinfection. All cases of bacterial coinfections are treated, whereas as many as one-third of all children with RSV LRTI are treated unnecessarily with antibiotics.

Wheezing and infantile colic are associated with neonatal antibiotic treatment.

BACKGROUND: Cohort studies have suggested that early-life antibiotic treatment is associated with increased risk of atopy. We determined whether antibiotic treatment already in the first week of life increases the risk of atopic and non-atopic disorders. METHODS: The INCA study is a prospective observational birth cohort study of 436 term infants, with follow-up of 1 year; 151 neonates received broad-spectrum antibiotics for suspected neonatal infection (AB+), vs a healthy untreated control group (N = 285; AB-). In the first year, parents recorded daily (non-) allergic symptoms. At 1 year, doctors' diagnoses were registered and a blood sample was taken (n = 205). RESULTS: Incidence of wheezing in the first year was higher in AB+ than AB- (41.0% vs 30.5%, P = .026; aOR 1.56 [95%CI 0.99-2.46, P = .06]). Infantile colics were more prevalent in AB+ compared to AB- (21.9% and 14.4% P = .048), and antibiotic treatment was an independent risk factor for infantile colics (aOR 1.66 (95%CI 1.00-2.77) P = .05). Allergic sensitization (Phadiatop >0.70kUA/L) showed a trend toward a higher risk in AB+ (aOR 3.26 (95%CI 0.95-11.13) P = .06). Incidence of eczema, infections, and GP visits in the first year were similar in AB+ and AB-. CONCLUSION: Antibiotic treatment in the first week of life is associated with an increased risk of wheezing and infantile colics. This study may provide a rationale for early cessation of antibiotics in neonates without proven or probable infection.

A host-protein based assay to differentiate between bacterial and viral infections in preschool children (OPPORTUNITY): a double-blind, multicentre, validation study.

BACKGROUND: A physician is frequently unable to distinguish bacterial from viral infections. ImmunoXpert is a novel assay combining three proteins: tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), interferon gamma induced protein-10 (IP-10), and C-reactive protein (CRP). We aimed to externally validate the diagnostic accuracy of this assay in differentiating between bacterial and viral infections and to compare this test with commonly used biomarkers. METHODS: In this prospective, double-blind, international, multicentre study, we recruited children aged 2-60 months with lower respiratory tract infection or clinical presentation of fever without source at four hospitals in the Netherlands and two hospitals in Israel. A panel of three experienced paediatricians adjudicated a reference standard diagnosis for all patients (ie, bacterial or viral infection) using all available clinical and laboratory information, including a 28-day follow-up assessment. The panel was masked to the assay results. We identified majority diagnosis when two of three panel members agreed on a diagnosis and unanimous diagnosis when all three panel members agreed on the diagnosis. We calculated the diagnostic performance (ie, sensitivity, specificity, positive predictive value, and negative predictive value) of the index test in differentiating between bacterial (index test positive) and viral (index test negative) infection by comparing the test classification with the reference standard outcome. FINDINGS: Between Oct 16, 2013 and March 1, 2015, we recruited 777 children, of whom 577 (mean age 21 months, 56% male) were assessed. The majority of the panel diagnosed 71 cases as bacterial infections and 435 as viral infections. In another 71 patients there was an inconclusive panel diagnosis. The assay distinguished bacterial from viral infections with a sensitivity of 86·7% (95% CI 75·8-93·1), a specificity of 91·1% (87·9-93·6), a positive predictive value of 60·5% (49·9-70·1), and a negative predictive value of 97·8% (95·6-98·9). In the more clear cases with unanimous panel diagnosis (n=354), sensitivity was 87·8% (74·5-94·7), specificity 93·0% (89·6-95·3), positive predictive value 62·1% (49·2-73·4), and negative predictive value 98·3% (96·1-99·3). INTERPRETATION: This external validation study shows the diagnostic value of a three-host protein-based assay to differentiate between bacterial and viral infections in children with lower respiratory tract infection or fever without source. This diagnostic based on CRP, TRAIL, and IP-10 has the potential to reduce antibiotic misuse in young children. FUNDING: MeMed Diagnostics.

Behaviour and development in 24-month-old moderately preterm toddlers.

OBJECTIVE: Moderately preterm children (gestational age 32-36+6 weeks) are at risk of cognitive and behaviour problems at school age. The aim of this study was to investigate if these problems are already present at the age of 2 years. STUDY DESIGN: Developmental outcome was assessed at 24-months (corrected age) with the Bayley-III-NL in 116 moderately preterm (M=34.66 ± 1.35 weeks gestation) and 99 term born children (M=39.45 ± 0.98 weeks gestation). Behaviour problems were assessed with the Child Behaviour Checklist. RESULTS: With age corrected for prematurity, moderately preterm children scored below term peers on Receptive Communication skills (11.05 ± 2.58 vs 12.02 ± 2.74, p=0.02). Without correcting age for prematurity, moderately preterm children scored below term born peers on Cognition (8.97 ± 2.11 vs 10.68 ± 2.35, p<0.001), Fine Motor (10.33 ± 2.15 vs 11.96 ± 2.15, p<0.001), Gross Motor (8.47 ± 2.55 vs 9.39±2.80, p=0.05), Receptive Communication (10.09 ± 2.48 vs 12.02 ± 2.74, p<0.001) and Expressive Communication (10.33 ± 2.43 vs 11.49 ± 2.51, p=0.005) skills. Compared with term peers, more moderately preterm children showed a (mild) delay (ie, scaled score <7) in gross motor skills with age uncorrected for prematurity (20.7% vs 11.2%, p=0.04). Moderately preterm children had more internalising behaviour problems than term children (44.76 ± 8.94 vs 41.54 ± 8.56, p=0.03). No group differences were found in percentages of (sub)clinical scores. CONCLUSIONS: At the age of 2 years, uncorrected for prematurity, differences in cognition, communication, and motor development were present in moderately preterm children compared with term born peers. After correcting age for prematurity, a difference was only found for receptive communication skills. In addition, moderately preterm children show more internalising behaviour problems.