Stratified Management for Bacterial Infections in Late Preterm and Term Neonates:Current Strategies and Future Opportunities Toward Precision Medicine

Bacterial infections remain a major cause of morbidity and mortality in the neonatal period. Therefore, many neonates, including late preterm and term neonates, are exposed to antibiotics in the first weeks of life. Data on the importance of inter-individual differences and disease signatures are accumulating. Differences that may potentially influence treatment requirement and success rate. However, currently, many neonates are treated following a “one size fits all” approach, based on general protocols and standard antibiotic treatment regimens. Precision medicine has emerged in the last years and is perceived as a new, holistic, way of stratifying patients based on large-scale data including patient characteristics and disease specific features. Specific to sepsis, differences in disease susceptibility, disease severity, immune response and pharmacokinetics and -dynamics can be used for the development of treatment algorithms helping clinicians decide when and how to treat a specific patient or a specific subpopulation. In this review, we highlight the current and future developments that could allow transition to a more precise manner of antibiotic treatment in late preterm and term neonates, and propose a research agenda toward precision medicine for neonatal bacterial infections.</p

Evaluation of a clinical decision rule to guide antibiotic prescription in children with suspected lower respiratory tract infection in The Netherlands

BACKGROUND: Optimising the use of antibiotics is a key component of antibiotic stewardship. Respiratory tract infections (RTIs) are the most common reason for antibiotic prescription in children, even though most of these infections in children under 5 years are viral. This study aims to safely reduce antibiotic prescriptions in children under 5 years with suspected lower RTI at the emergency department (ED), by implementing a clinical decision rule. METHODS AND FINDINGS: In a stepped-wedge cluster randomised trial, we included children aged 1-60 months presenting with fever and cough or dyspnoea to 8 EDs in The Netherlands. The EDs were of varying sizes, from diverse geographic and demographic regions, and of different hospital types (tertiary versus general). In the pre-intervention phase, children received usual care, according to the Dutch and NICE guidelines for febrile children. During the intervention phase, a validated clinical prediction model (Feverkidstool) including clinical characteristics and C-reactive protein (CRP) was implemented as a decision rule guiding antibiotic prescription. The intervention was that antibiotics were withheld in children with a low or intermediate predicted risk of bacterial pneumonia (≤10%, based on Feverkidstool). Co-primary outcomes were antibiotic prescription rate and strategy failure. Strategy failure was defined as secondary antibiotic prescriptions or hospitalisations, persistence of fever or oxygen dependency up to day 7, or complications. Hospitals were randomly allocated to 1 sequence of treatment each, using computer randomisation. The trial could not be blinded. We used multilevel logistic regression to estimate the effect of the intervention, clustered by hospital and adjusted for time period, age, sex, season, ill appearance, and fever duration; predicted risk was included in exploratory analysis. We included 999 children (61% male, median age 17 months [IQR 9 to 30]) between 1 January 2016 and 30 September 2018: 597 during the pre-intervention phase and 402 during the intervention phase. Most children (77%) were referred by a general practitioner, and half of children were hospitalised. Intention-to-treat analyses showed that overall antibiotic prescription was not reduced (30% to 25%, adjusted odds ratio [aOR] 1.07 [95% CI 0.57 to 2.01, p = 0.75]); strategy failure reduced from 23% to 16% (aOR 0.53 [95% CI 0.32 to 0.88, p = 0.01]). Exploratory analyses showed that the intervention influenced risk groups differently (p < 0.01), resulting in a reduction in antibiotic prescriptions in low/intermediate-risk children (17% to 6%; aOR 0.31 [95% CI 0.12 to 0.81, p = 0.02]) and a non-significant increase in the high-risk group (47% to 59%; aOR 2.28 [95% CI 0.84 to 6.17, p = 0.09]). Two complications occurred during the trial: 1 admission to the intensive care unit during follow-up and 1 pleural empyema at day 10 (both unrelated to the study intervention). Main limitations of the study were missing CRP values in the pre-intervention phase and a prolonged baseline period due to logistical issues, potentially affecting the power o

Oral and Intravenous Amoxicillin Dosing Recommendations in Neonates:A Pooled Population Pharmacokinetic Study

BACKGROUND: There is a lack of evidence on oral amoxicillin pharmacokinetics and exposure in neonates with possible serious bacterial infection (pSBI). We aimed to describe amoxicillin disposition following oral and intravenous administration and to provide dosing recommendations for preterm and term neonates treated for pSBI.METHODS: In this pooled-population pharmacokinetic study, 3 datasets were combined for nonlinear mixed-effects modeling. In order to evaluate amoxicillin exposure following oral and intravenous administration, pharmacokinetic profiles for different dosing regimens were simulated with the developed population pharmacokinetic model. A target of 50% time of the free fraction above the minimal inhibitory concentration (MIC) with an MICECOFF of 8 mg/L (to cover gram-negative bacteria such as Escherichia coli) was used.RESULTS: The cohort consisted of 261 (79 oral, 182 intravenous) neonates with a median (range) gestational age of 35.8 weeks (range, 24.9-42.4) and bodyweight of 2.6 kg (range, 0.5-5). A 1-compartment model with first-order absorption best described amoxicillin pharmacokinetics. Clearance (L/h/kg) in neonates born after 30 weeks' gestation increased with increasing postnatal age (PNA day 10, 1.25-fold; PNA day 20, 1.43-fold vs PNA day 3). Oral bioavailability was 87%. We found that a twice-daily regimen of 50 mg/kg/day is superior to a 3- or 4-times daily schedule in the first week of life for both oral and intravenous administration.CONCLUSIONS: This pooledpopulation pharmacokinetic description of intravenous and oral amoxicillin in neonates provides age-specific dosing recommendations. We conclude that neonates treated with oral amoxicillin in the first weeks of life reach adequate amoxicillin levels following a twice-daily dosing regimen. Oral amoxicillin therapy could therefore be an adequate, cost-effective, and more patient-friendly alternative for neonates worldwide.</p

Severe Pediatric COVID-19 and Multisystem Inflammatory Syndrome in Children From Wild-type to Population Immunity:A Prospective Multicenter Cohort Study With Real-time Reporting

BACKGROUND: SARS-CoV-2 variant evolution and increasing immunity altered the impact of pediatric SARS-CoV-2 infection. Public health decision-making relies on accurate and timely reporting of clinical data. METHODS: This international hospital-based multicenter, prospective cohort study with real-time reporting was active from March 2020 to December 2022. We evaluated longitudinal incident rates and risk factors for disease severity. RESULTS: We included 564 hospitalized children with acute COVID-19 (n = 375) or multisystem inflammatory syndrome in children (n = 189) from the Netherlands, Curaçao and Surinam. In COVID-19, 134/375 patients (36%) needed supplemental oxygen therapy and 35 (9.3%) required intensive care treatment. Age above 12 years and preexisting pulmonary conditions were predictors for severe COVID-19. During omicron, hospitalized children had milder disease. During population immunity, the incidence rate of pediatric COVID-19 infection declined for older children but was stable for children below 1 year. The incidence rate of multisystem inflammatory syndrome in children was highest during the delta wave and has decreased rapidly since omicron emerged. Real-time reporting of our data impacted national pediatric SARS-CoV-2 vaccination- and booster-policies. CONCLUSIONS: Our data supports the notion that similar to adults, prior immunity protects against severe sequelae of SARS-CoV-2 infections in children. Real-time reporting of accurate and high-quality data is feasible and impacts clinical and public health decision-making. The reporting framework of our consortium is readily accessible for future SARS-CoV-2 waves and other emerging infections.</p

Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection ar

Oral antibiotics for neonatal infections: a systematic review and meta-analysis

BACKGROUND: Worldwide many neonates suffer from bacterial infections. Adequate treatment is important but is associated with prolonged hospitalization for intravenous administration. In older children, oral switch therapy has been proven effective and safe for several indications and is now standard care. OBJECTIVES: To evaluate the currently available evidence on pharmacokinetics, safety and efficacy of oral antibiotics and oral switch therapy in neonates (0-28 days old). METHODS: We performed systematic searches in Medline, Embase.com, Cochrane, Google Scholar and Web of Science. Studies were eligible if they described the use of oral antibiotics in neonates (0-28 days old), including antibiotic switch studies and pharmacological studies. RESULTS: Thirty-one studies met the inclusion criteria. Compared with parenteral administration, oral antibiotics generally reach their maximum concentration later and have a lower bioavailability, but in the majority of cases adequate serum levels for bacterial killing are reached. Furthermore, studies on efficacy of oral antibiotics showed equal relapse rates (OR 0.95; 95% CI 0.79-1.16; I2 0%) or mortality (OR 1.11; 95% CI 0.72-1.72; I2 0%). Moreover, a reduction in hospital stay was observed. CONCLUSIONS: Oral antibiotics administered to neonates are absorbed and result in adequate serum levels, judged by MICs of relevant pathogens, over time. Efficacy studies are promising but robust evidence is lacking, most importantly because in many cases clinical efficacy and safety are not properly addressed. Early oral antibiotic switch therapy in neonates could be beneficial for both families and healthcare systems. There is a need for additional well-designed trials in different settings.status: publishe

Asthma patients experience increased symptoms of anxiety, depression and fear during the COVID-19 pandemic

Population studies showed a decrease in psychological wellbeing during the COVID-19 pandemic. Asthma is associated with a negative effect on anxiety and depression, which might worsen during the COVID-19 lockdown. The aim of the study was to compare fear, anxiety and depression between asthma patients and patients wit hout asthma pre-COVID-19 and during COVID-19 pandemic. This study compares fear, anxiety and depression in asthma patients and controls between pre-COVID-19 and during COVID-19 lockdown with a cross-sectional online survey. Participants were invited to fill out several questionnaires pertaining to fear, anxiety, depression, asthma control and quality of life. Asthma patients (N = 37) displayed, during the course of the pandemic, a clinically relevant increase in anxiety (3.32 ± 2.95 vs. 6.68 ± 3.78; p < 0.001) and depression (1.30 ± 1.15 vs. 3.65 ± 3.31; p < 0.001), according to the hospital anxiety and depression levels (HADS) compared to pre-COVID-19 assessment. This was not seen in controls. Also, asthma patients displayed more anxiety about acquiring COVID-19 disease compared to controls ((5.11 ± 1.99 vs. 3.50 ± 2.79), p = 0.006). Patients with asthma experienced an increase in anxiety and depression levels and were more afraid of acquiring COVID-19 disease compared to controls. Also, patients with asthma were more likely to avoid healthcare facilities due to fear of acquiring COVID-19 disease compared to controls. Therefore, we advise health care workers to address these possible negative effects on mental health by phone or e-consults

Bacterial lysate therapy for the prevention of wheezing episodes and asthma exacerbations: A systematic review and meta-analysis

Wheezing and asthma are a growing cause of morbidity in children and adults. Treatment is aimed at prevention of disease exacerbations and preservation of lung function. Respiratory viruses are involved in ∼40–60% of exacerbations. Bacterial lysates prevent recurrent respiratory tract infections and might reduce exacerbations. Moreover, immunomodulatory effects have been observed in human and animal studies. Here we aimed to assess the effects of bacterial lysate therapy on preschool wheezing episodes and asthma exacerbation frequency. We performed a systematic literature review based on the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) statement and a meta-analysis using Cochrane Review Manager. Out of 2016 retrieved articles, 22 studies were included, of which five provided sufficient data for a meta-analysis. The use of bacterial lysates showed a decrease of both wheezing episodes (mean difference −2.35 (−3.03– −1.67), p<0.001) and asthma exacerbations in children (mean difference −0.90 (−1.23– −0.57), p<0.001). Additionally, antibiotic use was reduced, and the duration of wheezing episodes was also decreased. No data for adults with asthma are currently available. The immunomodulatory effect seems to be dependent on increased T-helper (Th)1-cell activation and Th2-cell suppression. These favourable effects of bacterial lysates indicate that they show promise as add-on therapy in preschool wheezing and childhood asthma

RAIN study: a protocol for a randomised controlled trial evaluating efficacy, safety and cost-effectiveness of intravenous-to-oral antibiotic switch therapy in neonates with a probable bacterial infection

INTRODUCTION: High morbidity and mortality rates of proven bacterial infection are the main reason for substantial use of intravenous antibiotics in neonates during the first week of life. In older children, intravenous-to-oral switch after 48 hours of intravenous therapy has been shown to have many advantages and is nowadays commonly practised. We, therefore, aim to evaluate the effectiveness, safety and cost-effectiveness of an early intravenous-to-oral switch in neonates with a probable bacterial infection. METHODS AND ANALYSIS: We present a protocol for a multicentre randomised controlled trial assessing the non-inferiority of an early intravenous-to-oral antibiotic switch compared with a full course of intravenous antibiotics in neonates (0-28 days of age) with a probable bacterial infection. Five hundred and fifty patients will be recruited in 17 hospitals in the Netherlands. After 48 hours of intravenous treatment, they will be assigned to either continue with intravenous therapy for another 5 days (control) or switch to amoxicillin/clavulanic acid suspension (intervention). Both groups will be treated for a total of 7 days. The primary outcome will be bacterial (re)infection within 28 days after treatment completion. Secondary outcomes are the pharmacokinetic profile of oral amoxicillin/clavulanic acid, the impact on quality of life, cost-effectiveness, impact on microbiome development and additional yield of molecular techniques in diagnosis of probable bacterial infection. ETHICS AND DISSEMINATION: This study has been approved by the Medical Ethics Committee of the Erasmus Medical Centre. Results will be presented in peer-reviewed journals and at international conferences. TRIAL REGISTRATION NUMBER: NCT03247920.status: publishe

Pharmacokinetics of Clavulanic Acid in the Pediatric Population: A Systematic Literature Review

BACKGROUND AND OBJECTIVE: Clavulanic acid is a commonly used β-lactam inhibitor in pediatrics for a variety of infections. Clear insight into its mode of action is lacking, however, and a target has not been identified. The dosing of clavulanic acid is currently based on that of the partner drug (amoxicillin or ticarcillin). Still, proper dosing of the compound is needed because clavulanic acid has been associated with adverse effects. In this systematic review, we aim to describe the current literature on the pharmacokinetics of clavulanic acid in the pediatric population METHODS: We performed a systematic search in MEDLINE, Embase.com, Cochrane Central, Google Scholar, and Web of Science. We included all published studies reporting pharmacokinetic data on clavulanic acid in neonates and children 0-18 years of age. RESULTS: The search resulted in 18 original studies that met the inclusion criteria. In general, the variation in drug exposure was large, which can be partly explained by differences in disease state, route of administration, or age. Unfortunately, the studies' limited background information hampered in-depth assessment of the observed variability. CONCLUSION: The pharmacokinetics of clavulanic acid in pediatric patients is highly variable, similar to reports in adults, but more pronounced. Significant knowledge gaps remain with regard to the population-specific explanation for this variability. Model-based pharmacokinetic studies that address both maturational and disease-specific changes in the pediatric population are therefore needed. Furthermore, additional pharmacodynamic studies are needed to define a clear target. The combined outcomes will eventually lead to pharmacokinetic-pharmacodynamic modeling of clavulanic acid and targeted exposure. CLINICAL TRIAL REGISTRATION: PROSPERO CRD42020137253