Pharmacokinetics-Based Pediatric Dose Evaluation and Optimization Using Saliva - A Case Study.

Understanding pharmacokinetics (PK) in children is a prerequisite to determine optimal pediatric dosing. As plasma sampling in children is challenging, alternative PK sampling strategies are needed. In this case study we evaluated the suitability of saliva as alternative PK matrix to simplify studies in infants, investigating metamizole, an analgesic used off-label in infants. Six plasma and 6 saliva PK sample collections were scheduled after a single intravenous dose of 10 mg/kg metamizole. Plasma/saliva pharmacometric (PMX) modeling of the active metabolites 4-methylaminoantipyrine (4-MAA) and 4-aminoantipyrine (4-AA) was performed. Various reduced plasma sampling scenarios were evaluated by PMX simulations. Saliva and plasma samples from 25 children were included (age range, 5-70 months; weight range, 8.7-24.8 kg). Distribution of metamizole metabolites between plasma and saliva was without delay. Estimated mean (individual range) saliva/plasma fractions of 4-MAA and 4-AA were 0.32 (0.05-0.57) and 0.57 (0.25-0.70), respectively. Residual variability of 4-MAA (4-AA) in saliva was 47% (28%) versus 17% (11%) in plasma. A simplified sampling scenario with up to 6 saliva samples combined with 1 plasma sample was associated with similar PK parameter estimates as the full plasma sampling scenario. This case study with metamizole shows increased PK variability in saliva compared to plasma, compromising its suitability as single matrix for PK studies in infants. Nonetheless, rich saliva sampling can reduce the number of plasma samples required for PK characterization, thereby facilitating the conduct of PK studies to optimize dosing in pediatric patients.

COVID-19 Vaccine Acceptance Among Parents of Children With Multisystem Inflammatory Syndrome in Children.

Data on COVID-19 vaccine acceptability among parents of children with multisystem inflammatory syndrome (MIS-C) are limited. In this cohort of children with MIS-C, enrolled in the Swissped RECOVERY trial (NCT04826588), comparing intravenous immunoglobulins or methylprednisolone, who, in accordance with Swiss guidelines, were recommended for SARS-CoV-2 vaccination, 65% (73/112) of parents reported being vaccinated against SARS-CoV-2 before the MIS-C, while 70% were vaccinated after the MIS-C episode of their child. None of the children were vaccinated before the occurrence of the MIS-C, and only 9% (5/56) received the COVID-19 vaccine after the MIS-C. The predominant barriers to COVID-19 vaccination were concerns over potential side effects and insufficient support from their doctors. This emphasizes the crucial role of health care providers in promoting COVID-19 vaccination among children.

Association between perioperative prophylaxis with cefuroxime plus metronidazole or amoxicillin/clavulanic acid and surgical site infections in paediatric uncomplicated appendectomy: a Swiss retrospective cohort study.

OBJECTIVE: We aimed to evaluate the association between post-appendectomy SSI rates and the two most commonly used regimens for perioperative antimicrobial prophylaxis in Swiss children. METHODS: We conducted a retrospective cohort study, analysing data from the Swiss national SSI surveillance database with a study period from 2014 to 2018. All hospitals undertaking paediatric appendectomies in Switzerland participate in the surveillance. We compared the cumulative incidence and odds of post-appendectomy SSI within 30 days of surgery in children ≤ 16 years of age undergoing appendectomy for uncomplicated appendicitis and receiving perioperative antimicrobial prophylaxis with cefuroxime plus metronidazole or with amoxicillin/clavulanic acid using multivariable adjusted logistic regression and propensity-score matching. RESULTS: A total of 6207 cases were recorded in the study time frame. Overall SSI cumulative incidence was 1.9% (n = 119). 4256 children (54.9% male, median (IQR) age 12 [10, 14] years) received either cefuroxime plus metronidazole (n = 2348, 53.8% male) or amoxicillin/clavulanic acid (n = 1491, 57.0% male). SSI cumulative incidence was 1.1% (25/2348) among children receiving cefuroxime plus metronidazole and 2.8% (42/1491, p < 0.001) when receiving amoxicillin/clavulanic acid. The administration of cefuroxime plus metronidazole was associated with statistically significantly lower SSI odds compared to amoxicillin/clavulanic acid (aOR 0.35, 95%CI [0.20, 0.61], p < 0.001), and this was confirmed upon propensity-score matching. CONCLUSION: We found lower odds of post-appendectomy SSI in children receiving cefuroxime plus metronidazole compared to amoxicillin/clavulanic acid. Treating amoxicillin/clavulanic acid as the baseline, only 55 children need to receive cefuroxime plus metronidazole perioperative prophylaxis to avert one SSI. Existing guidelines recommending amoxicillin/clavulanic acid may need to be revised. Trial registration ISRCTN47727811, registered retrospectively.

Detection of mostly viral pathogens and high proportion of antibiotic treatment initiation in hospitalised children with community-acquired pneumonia in Switzerland - baseline findings from the first two years of the KIDS-STEP trial.

AIMS OF THE STUDY: Globally, since the introduction of conjugate-vaccines against encapsulated bacteria, respiratory viruses have caused most hospitalisations for community-acquired pneumonia. The aim of this study was to describe pathogens detected and their association with clinical findings in Switzerland. METHODS: Baseline data were analysed for all trial participants enrolled between September 2018 and September 2020 into the KIDS-STEP Trial, a randomised controlled superiority trial on the effect of betamethasone on clinical stabilisation of children admitted with community-acquired pneumonia. Data included clinical presentation, antibiotic use and results of pathogen detection. In addition to routine sampling, nasopharyngeal specimens were analysed for respiratory pathogens using a panel polymerase chain reaction test covering 18 viral and 4 bacterial pathogens. RESULTS: 138 children with a median age of 3 years were enrolled at the eight trial sites. Fever (obligatory for enrolment) had been present for median 5 days before admission. Most common symptoms were reduced activity (129, 93.5%) and reduced oral intake (108, 78.3%). Oxygen saturation <92% was found in 43 (31.2%). Forty-three participants (29.0%) were already on antibiotic treatment prior to admission and 104 participants (75.4%) received antibiotic treatment on admission. Pathogen testing results were available from 132 children: 31 (23.5%) had respiratory syncytial virus detected, 21 (15.9%) human metapneumovirus. The pathogens detected showed expected seasonal and age preponderance and were not associated with chest X-ray findings. CONCLUSIONS: In the context of the predominantly viral pathogens detected, the majority of antibiotic treatment is probably unnecessary. The ongoing trial, as well as other studies, will be able to provide comparative pathogen detection data to compare pre- and post-COVID-19-pandemic settings.

Methylprednisolone versus intravenous immunoglobulins in children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS): an open-label, multicentre, randomised trial.

BACKGROUND: The emergence of paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) led to the widespread use of anti-inflammatory treatments in the absence of evidence from randomised controlled trials (RCTs). We aimed to assess the effectiveness of intravenous methylprednisolone compared with intravenous immunoglobulins. METHODS: This is an open-label, multicentre, two-arm RCT done at ten hospitals in Switzerland in children younger than 18 years hospitalised with PIMS-TS (defined as age <18 years; fever and biochemical evidence of inflammation, and single or multiorgan dysfunction; microbiologically proven or putative contact with SARS-CoV-2; and exclusion of any other probable disease). Patients were randomly assigned 1:1 to intravenous methylprednisolone (10 mg/kg per day for 3 days) or intravenous immunoglobulins (2 g/kg as a single dose). The primary outcome was length of hospital stay censored at day 28, death, or discharge. Secondary outcomes included proportion and duration of organ support. Analyses were done by intention-to-treat. The study was registered with Swiss National Clinical Trials Portal (SNCTP000004720) and ClinicalTrials.gov (NCT04826588). FINDINGS: Between May 21, 2021, and April 15, 2022, 75 patients with a median age of 9·1 years (IQR 6·2-12·2) were included in the intention-to-treat population (37 in the methylprednisolone group and 38 in the intravenous immunoglobulins group). The median length of hospital stay was 6·0 days (IQR 4·0-8·0) in the methylprednisolone group and 6·0 days (IQR 5·0-8·8) in the intravenous immunoglobulins group (estimated effect size -0·037 of the log10 transformed times, 95% CI -0·13 to 0·065, p=0·42). Fewer patients in the methylprednisolone group (ten [27%] of 37) required respiratory support compared with the intravenous immunoglobulin group (21 [55%] of 38, p=0·025). Need and duration of inotropes, admission to intensive care units, cardiac events after baseline, and major bleeding and thrombotic events were not significantly different between the study groups. INTERPRETATION: In this RCT, treatment with methylprednisolone in children with PIMS-TS did not significantly affect the length of hospital stay compared with intravenous immunoglobulins. Intravenous methylprednisolone could be an acceptable first-line treatment in children with PIMS-TS. FUNDING: NOMIS Foundation, Vontobel Foundation, and Gaydoul Foundation.

Antibiotics needed to treat multidrug-resistant infections in neonates.

Infections remain a leading cause of death in neonates. The sparse antibiotic development pipeline and challenges in conducting neonatal research have resulted in few effective antibiotics being adequately studied to treat multidrug-resistant (MDR) infections in neonates, despite the increasing global mortality burden caused by antimicrobial resistance. Of 40 antibiotics approved for use in adults since 2000, only four have included dosing information for neonates in their labelling. Currently, 43 adult antibiotic clinical trials are recruiting patients, compared with only six trials recruiting neonates. We review the World Health Organization (WHO) priority pathogens list relevant to neonatal sepsis and propose a WHO multiexpert stakeholder meeting to promote the development of a neonatal priority antibiotic development list. The goal is to develop international, interdisciplinary consensus for an accelerated neonatal antibiotic development programme. This programme would enable focused research on identified priority antibiotics for neonates to reduce the excess morbidity and mortality caused by MDR infections in this vulnerable population.

Les infections demeurent l'une des principales causes de décès chez les nouveau-nés. Les rares projets de développement d'antibiotiques et les défis posés par la recherche néonatale ont entraîné une pénurie d'antibiotiques efficaces spécialement étudiés pour traiter les infections multirésistantes (MR) chez les nouveau-nés, en dépit d'une mortalité galopante due à une résistance accrue aux antimicrobiens. Sur 40 antibiotiques autorisés pour les adultes depuis 2000, quatre à peine sont munis d'un étiquetage indiquant la posologie adaptée aux nouveau-nés. Actuellement, 43 essais cliniques portant sur des antibiotiques recrutent des patients du côté des adultes, contre six seulement du côté des nouveau-nés. Dans le présent document, nous passons en revue la liste prioritaire d'agents pathogènes établie par l'Organisation mondiale de la Santé (OMS) pour soigner la septicémie néonatale et proposons de réunir, sous l'égide de l'OMS, des parties prenantes issues de plusieurs domaines d'expertise afin de promouvoir la création d'une liste prioritaire de développement d'antibiotiques destinés aux nouveau-nés. Objectif: parvenir à un consensus international et interdisciplinaire visant à accélérer le programme de mise au point d'antibiotiques à usage néonatal. Ce programme permettrait d'orienter les recherches vers des antibiotiques identifiés comme prioritaires pour les nouveau-nés, en vue de faire baisser les taux de morbidité et de mortalité excessifs qu'engendrent les infections MR au sein de cette population vulnérable.

Las infecciones siguen siendo una de las principales causas de muerte en los recién nacidos. Debido al escaso desarrollo de los antibióticos y a las dificultades para llevar a cabo la investigación neonatal, son pocos los antibióticos eficaces que se estudian de manera adecuada para tratar las infecciones multirresistentes (MR) en los recién nacidos, a pesar de la creciente carga de mortalidad mundial causada por la resistencia a los antimicrobianos. De los 40 antibióticos aprobados para su uso en adultos desde el 2000, solo cuatro han incluido información sobre la dosis para recién nacidos en su etiquetado. En la actualidad, 43 ensayos clínicos con antibióticos para adultos están reclutando pacientes, en comparación con solo seis ensayos que reclutan recién nacidos. Se revisa la lista de patógenos prioritarios de la Organización Mundial de la Salud (OMS) relevantes para la sepsis neonatal y se propone una reunión de la OMS con múltiples expertos para promover el desarrollo de una lista de antibióticos prioritarios para los recién nacidos. El objetivo es desarrollar un consenso internacional e interdisciplinario para establecer un programa acelerado de desarrollo de antibióticos neonatales. Este programa permitiría centrar la investigación en los antibióticos prioritarios identificados para los recién nacidos con el fin de reducir el exceso de morbilidad y mortalidad causado por las infecciones MR en esta población vulnerable.

Antimicrobial stewardship programs in solid-organ transplant recipients in Switzerland.

INTRODUCTION: Antimicrobial stewardship programs (ASPs) are essential for minimizing the emergence of antimicrobial resistance, while improving patient outcomes. The current status of ASP in the field of organ transplantation in Switzerland has not been well characterized. METHODS: We describe in this article the current status of ASP and discuss challenges and opportunities of implementing ASP dedicated to solid-organ transplant (SOT) recipients in Switzerland. RESULTS: ASP have been implemented in the Swiss healthcare system over the last years, although specific strategies for SOT recipients are mostly based on transplant infectious diseases (TID) consultations rather than structured institutional interventions. Even so, there is a unique opportunity for developing a successful ASP in Switzerland that also specifically addresses areas of practice relevant to SOT recipients. This is due to the existent network of TID specialists in close collaboration with transplant physicians, the small number of centers involved in the care of transplant recipients, and the development of the Swiss Transplant Cohort Study (STCS), a prospective nationwide cohort of SOT recipients in Switzerland. The STCS can identify actual challenges through the updated reports on the epidemiology on transplant infections, accurately monitor the impact of potential antimicrobial stewardship interventions, and represent an opportunity for nesting of pragmatic randomized controlled trials to address key questions about optimized antibiotic use for SOT recipients. CONCLUSIONS: Although ASP in SOT recipients rely more on specific TID consultations than in general antimicrobial stewardship teams, we identified several opportunities for the implementation of a successful ASP in Switzerland.

Profiling of humoral immune responses to norovirus in children across Europe.

Norovirus is a leading cause of epidemic acute gastroenteritis. More than 30 genotypes circulate in humans, some are common, and others are only sporadically detected. Here, we investigated whether serology can be used to determine which genotypes infect children. We established a multiplex protein microarray with structural and non-structural norovirus antigens that allowed simultaneous antibody testing against 30 human GI and GII genotypes. Antibody responses of sera obtained from 287 children aged < 1 month to 5.5 years were profiled. Most specific IgG and IgA responses were directed against the GII.2, GII.3, GII.4, and GII.6 capsid genotypes. While we detected antibody responses against rare genotypes, we found no evidence for wide circulation. We also detected genotype-specific antibodies against the non-structural proteins p48 and p22 in sera of older children. In this study, we show the age-dependent antibody responses to a broad range of norovirus capsid and polymerase genotypes, which will aid in the development of vaccines.

Pharmacogenetic Analysis of Voriconazole Treatment in Children.

Voriconazole is among the first-line antifungal drugs to treat invasive fungal infections in children and known for its pronounced inter- and intraindividual pharmacokinetic variability. Polymorphisms in genes involved in the metabolism and transport of voriconazole are thought to influence serum concentrations and eventually the therapeutic outcome. To investigate the impact of these genetic variants and other covariates on voriconazole trough concentrations, we performed a retrospective data analysis, where we used medication data from 36 children suffering from invasive fungal infections treated with voriconazole. Data were extracted from clinical information systems with the new infrastructure SwissPKcdw, and linear mixed effects modelling was performed using R. Samples from 23 children were available for DNA extraction, from which 12 selected polymorphism were genotyped by real-time PCR. 192 (49.1%) of 391 trough serum concentrations measured were outside the recommended range. Voriconazole trough concentrations were influenced by polymorphisms within the metabolizing enzymes CYP2C19 and CYP3A4, and within the drug transporters ABCC2 and ABCG2, as well as by the co-medications ciprofloxacin, levetiracetam, and propranolol. In order to prescribe an optimal drug dosage, pre-emptive pharmacogenetic testing and careful consideration of co-medications in addition to therapeutic drug monitoring might improve voriconazole treatment outcome of children with invasive fungal infections.

Transmission of SARS-CoV-2 within households: a remote prospective cohort study in European countries.

Household transmission studies are useful to quantify SARS-CoV-2 transmission dynamics. We conducted a remote prospective household study to quantify transmission, and the effects of subject characteristics, household characteristics, and implemented infection control measures on transmission. Households with a laboratory-confirmed SARS-CoV-2 index case were enrolled < 48 h following test result. Follow-up included digitally daily symptom recording, regular nose-throat self-sampling and paired dried blood spots from all household members. Samples were tested for virus detection and SARS-CoV-2 antibodies. Secondary attack rates (SARs) and associated factors were estimated using logistic regression. In 276 households with 920 participants (276 index cases and 644 household members) daily symptom diaries and questionnaires were completed by 95%, and > 85% completed sample collection. 200 secondary SARS-CoV-2 infections were detected, yielding a household SAR of 45.7% (95% CI 39.7-51.7%) and per-person SAR of 32.6% (95%CI: 28.1-37.4%). 126 (63%) secondary cases were detected at enrollment. Mild (aRR = 0.57) and asymptomatic index cases (aRR = 0.29) were less likely to transmit SARS-CoV-2, compared to index cases with an acute respiratory illness (p = 0.03 for trend), and child index cases (< 12 years aRR = 0.60 and 12-18 years aRR = 0.85) compared to adults (p = 0.03 for trend). Infection control interventions in households had no significant effect on transmission. We found high SARs with the majority of transmissions occuring early after SARS-CoV-2 introduction into the household. This may explain the futile effect of implemented household measures. Age and symptom status of the index case influence secondary transmission. Remote, digitally-supported study designs with self-sampling are feasible for studying transmission under pandemic restrictions.

Multicenter Randomized Trial of Methylprednisolone vs. Intravenous Immunoglobulins to Treat the Pediatric Inflammatory Multisystem Syndrome-Temporally Associated With SARS-CoV-2 (PIMS-TS): Protocol of the Swissped RECOVERY Trial.

Introduction: In 2020, a new disease entitled Pediatric Inflammatory Multisystem Syndrome temporally associated with COVID-19 (PIMS-TS), or Multisystem Inflammatory Syndrome in Children (MIS-C), emerged, with thousands of children affected globally. There is no available evidence based on randomized controlled trials (RCT) to date on the two most commonly used immunomodulatory treatments, intravenous immunoglobulins (IVIG) and corticosteroids. Therefore, the Swissped RECOVERY trial was conducted to assess whether intravenous (IV) methylprednisolone shortens hospital length of stay compared with IVIG. Methods and Analysis: Swissped RECOVERY is an ongoing investigator-initiated, open-label, multicenter two-arm RCT in children and adolescents <18 years hospitalized with a diagnosis of PIMS-TS. The trial is recruiting at 10 sites across Switzerland. Patients diagnosed with PIMS-TS are randomized 1:1 to methylprednisolone IV (10 mg/kg/day for 3 days) or IVIG (2 g/kg as a single dose). The primary outcome is hospital length of stay censored at day 28, death, or discharge (whichever is first). The target total sample size is ~80 patients 1:1 randomized to each study arm. Ancillary and exploratory studies on inflammation, vaccination acceptance and coverage, long-term outcomes, and healthcare costs are pre-planned. Significance: Currently, robust trial evidence for the treatment of PIMS-TS is lacking, with a controversy surrounding the use of corticosteroids vs. IVIG. This trial will provide evidence for the effectiveness and safety of these two treatments. Ethics and Dissemination: The study protocol, which was designed based on the U.K. RECOVERY trial, the patient information and consent forms, and other study-specific study documents were approved by the local ethics committees (Project ID: 2021-00362). Registration Details: The study is registered on the Swiss National Clinical Trials Portal (SNCTP000004720) and Clinicaltrials.gov (NCT04826588).

Amoxicillin duration and dose for community-acquired pneumonia in children: the CAP-IT factorial non-inferiority RCT.

BACKGROUND: Data are limited regarding the optimal dose and duration of amoxicillin treatment for community-acquired pneumonia in children. OBJECTIVES: To determine the efficacy, safety and impact on antimicrobial resistance of shorter (3-day) and longer (7-day) treatment with amoxicillin at both a lower and a higher dose at hospital discharge in children with uncomplicated community-acquired pneumonia. DESIGN: A multicentre randomised double-blind 2 × 2 factorial non-inferiority trial in secondary care in the UK and Ireland. SETTING: Paediatric emergency departments, paediatric assessment/observation units and inpatient wards. PARTICIPANTS: Children aged > 6 months, weighing 6-24 kg, with a clinical diagnosis of community-acquired pneumonia, in whom treatment with amoxicillin as the sole antibiotic was planned on discharge. INTERVENTIONS: Oral amoxicillin syrup at a dose of 35-50 mg/kg/day compared with a dose of 70-90 mg/kg/day, and 3 compared with 7 days' duration. Children were randomised simultaneously to each of the two factorial arms in a 1 : 1 ratio. MAIN OUTCOME MEASURES: The primary outcome was clinically indicated systemic antibacterial treatment prescribed for respiratory tract infection (including community-acquired pneumonia), other than trial medication, up to 28 days after randomisation. Secondary outcomes included severity and duration of parent/guardian-reported community-acquired pneumonia symptoms, drug-related adverse events (including thrush, skin rashes and diarrhoea), antimicrobial resistance and adherence to trial medication. RESULTS: A total of 824 children were recruited from 29 hospitals. Ten participants received no trial medication and were excluded. Participants [median age 2.5 (interquartile range 1.6-2.7) years; 52% male] were randomised to either 3 (n = 413) or 7 days (n = 401) of trial medication at either lower (n = 410) or higher (n = 404) doses. There were 51 (12.5%) and 49 (12.5%) primary end points in the 3- and 7-day arms, respectively (difference 0.1%, 90% confidence interval -3.8% to 3.9%) and 51 (12.6%) and 49 (12.4%) primary end points in the low- and high-dose arms, respectively (difference 0.2%, 90% confidence interval -3.7% to 4.0%), both demonstrating non-inferiority. Resolution of cough was faster in the 7-day arm than in the 3-day arm for cough (10 days vs. 12 days) (p = 0.040), with no difference in time to resolution of other symptoms. The type and frequency of adverse events and rate of colonisation by penicillin-non-susceptible pneumococci were comparable between arms. LIMITATIONS: End-of-treatment swabs were not taken, and 28-day swabs were collected in only 53% of children. We focused on phenotypic penicillin resistance testing in pneumococci in the nasopharynx, which does not describe the global impact on the microflora. Although 21% of children did not attend the final 28-day visit, we obtained data from general practitioners for the primary end point on all but 3% of children. CONCLUSIONS: Antibiotic retreatment, adverse events and nasopharyngeal colonisation by penicillin-non-susceptible pneumococci were similar with the higher and lower amoxicillin doses and the 3- and 7-day treatments. Time to resolution of cough and sleep disturbance was slightly longer in children taking 3 days' amoxicillin, but time to resolution of all other symptoms was similar in both arms. FUTURE WORK: Antimicrobial resistance genotypic studies are ongoing, including whole-genome sequencing and shotgun metagenomics, to fully characterise the effect of amoxicillin dose and duration on antimicrobial resistance. The analysis of a randomised substudy comparing parental electronic and paper diary entry is also ongoing. TRIAL REGISTRATION: Current Controlled Trials ISRCTN76888927, EudraCT 2016-000809-36 and CTA 00316/0246/001-0006. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 60. See the NIHR Journals Library website for further project information.

Pneumonia (an acute lung infection) is a common diagnosis in young children worldwide. To cure this, some children are given antibiotics, but we do not currently know the best amount (dose) to give and the ideal number of days (duration) of treatment. Taking antibiotics causes changes in bacteria, making them more resistant to treatment. This may be affected by the dose and duration, and is important because resistant bacteria are harder to treat and could spread to other people. Amoxicillin is the most common antibiotic treatment for children with pneumonia. CAP-IT (Community-Acquired Pneumonia: a protocol for a randomIsed controlled Trial) tested if lower doses and shorter durations of amoxicillin are as good as higher doses and longer durations, and whether or not these affect the presence of resistant bacteria. In total, 824 children in the UK and Ireland with pneumonia participated. They received either high- or low-dose amoxicillin for 3 or 7 days following discharge from hospital. To ensure that neither doctors nor parents were influenced by knowing which group a child was in, we included dummy drugs (placebo). We measured how often children were given more antibiotics for respiratory infections in the 4 weeks after starting the trial medicine. To check for resistant bacteria, a nose swab was collected before starting treatment and again after 4 weeks. One in every eight participating children was given additional antibiotics. We found no important difference in this proportion between 3 days and 7 days of amoxicillin treatment, or between lower or higher doses. Although children's coughs took slightly longer to go away when they received only 3 days of antibiotics, rash was reported slightly more often in children taking 7 days of antibiotics. There was no effect of dose of amoxicillin on any of the symptom measurements. No effect of duration of treatment or dose was observed for antibiotic resistance in bacteria living in the nose and throat.

Effect of Amoxicillin Dose and Treatment Duration on the Need for Antibiotic Re-treatment in Children With Community-Acquired Pneumonia: The CAP-IT Randomized Clinical Trial.

Importance: The optimal dose and duration of oral amoxicillin for children with community-acquired pneumonia (CAP) are unclear. Objective: To determine whether lower-dose amoxicillin is noninferior to higher dose and whether 3-day treatment is noninferior to 7 days. Design, Setting, and Participants: Multicenter, randomized, 2 × 2 factorial noninferiority trial enrolling 824 children, aged 6 months and older, with clinically diagnosed CAP, treated with amoxicillin on discharge from emergency departments and inpatient wards of 28 hospitals in the UK and 1 in Ireland between February 2017 and April 2019, with last trial visit on May 21, 2019. Interventions: Children were randomized 1:1 to receive oral amoxicillin at a lower dose (35-50 mg/kg/d; n = 410) or higher dose (70-90 mg/kg/d; n = 404), for a shorter duration (3 days; n = 413) or a longer duration (7 days; n = 401). Main Outcomes and Measures: The primary outcome was clinically indicated antibiotic re-treatment for respiratory infection within 28 days after randomization. The noninferiority margin was 8%. Secondary outcomes included severity/duration of 9 parent-reported CAP symptoms, 3 antibiotic-related adverse events, and phenotypic resistance in colonizing Streptococcus pneumoniae isolates. Results: Of 824 participants randomized into 1 of the 4 groups, 814 received at least 1 dose of trial medication (median [IQR] age, 2.5 years [1.6-2.7]; 421 [52%] males and 393 [48%] females), and the primary outcome was available for 789 (97%). For lower vs higher dose, the primary outcome occurred in 12.6% with lower dose vs 12.4% with higher dose (difference, 0.2% [1-sided 95% CI -∞ to 4.0%]), and in 12.5% with 3-day treatment vs 12.5% with 7-day treatment (difference, 0.1% [1-sided 95% CI -∞ to 3.9]). Both groups demonstrated noninferiority with no significant interaction between dose and duration (P = .63). Of the 14 prespecified secondary end points, the only significant differences were 3-day vs 7-day treatment for cough duration (median 12 days vs 10 days; hazard ratio [HR], 1.2 [95% CI, 1.0 to 1.4]; P = .04) and sleep disturbed by cough (median, 4 days vs 4 days; HR, 1.2 [95% CI, 1.0 to 1.4]; P = .03). Among the subgroup of children with severe CAP, the primary end point occurred in 17.3% of lower-dose recipients vs 13.5% of higher-dose recipients (difference, 3.8% [1-sided 95% CI, -∞ to10%]; P value for interaction = .18) and in 16.0% with 3-day treatment vs 14.8% with 7-day treatment (difference, 1.2% [1-sided 95% CI, -∞ to 7.4%]; P value for interaction = .73). Conclusions and Relevance: Among children with CAP discharged from an emergency department or hospital ward (within 48 hours), lower-dose outpatient oral amoxicillin was noninferior to higher dose, and 3-day duration was noninferior to 7 days, with regard to need for antibiotic re-treatment. However, disease severity, treatment setting, prior antibiotics received, and acceptability of the noninferiority margin require consideration when interpreting the findings. Trial Registration: ISRCTN Identifier: ISRCTN76888927.

Aetiology of acute respiratory infection in preschool children requiring hospitalisation in Europe-results from the PED-MERMAIDS multicentre case-control study.

BACKGROUND: Both pathogenic bacteria and viruses are frequently detected in the nasopharynx (NP) of children in the absence of acute respiratory infection (ARI) symptoms. The aim of this study was to estimate the aetiological fractions for ARI hospitalisation in children for respiratory syncytial virus (RSV) and influenza virus and to determine whether detection of specific respiratory pathogens on NP samples was associated with ARI hospitalisation. METHODS: 349 children up to 5 years of age hospitalised for ARI (following a symptom-based case definition) and 306 hospital controls were prospectively enrolled in 16 centres across seven European Union countries between 2016 and 2019. Admission day NP swabs were analysed by multiplex PCR for 25 targets. RESULTS: RSV was the leading single cause of ARI hospitalisations, with an overall population attributable fraction (PAF) of 33.4% and high seasonality as well as preponderance in younger children. Detection of RSV on NP swabs was strongly associated with ARI hospitalisation (OR adjusted for age and season: 20.6, 95% CI: 9.4 to 45.3). Detection of three other viral pathogens showed strong associations with ARI hospitalisation: influenza viruses had an adjusted OR of 6.1 (95% CI: 2.5 to 14.9), parainfluenza viruses (PIVs) an adjusted OR of 4.6 (95% CI: 1.8 to 11.3) and metapneumoviruses an adjusted OR of 4.5 (95% CI: 1.3 to 16.1). Influenza viruses had a PAF of 7.9%, PIVs of 6.5% and metapneumoviruses of 3.0%. In contrast, most other pathogens were found in similar proportions in cases and controls, including Streptococcus pneumoniae, which was weakly associated with case status, and endemic coronaviruses. CONCLUSION: RSV is the predominant cause of ARI hospitalisations in young children in Europe and its detection, as well as detection of influenza virus, PIV or metapneumovirus, on NP swabs can establish aetiology with high probability. PAFs for RSV and influenza virus are highly seasonal and age dependent.

Global antibiotic dosing strategies in hospitalised children: Characterising variation and implications for harmonisation of international guidelines.

BACKGROUND: Paediatric global antibiotic guidelines are inconsistent, most likely due to the limited pharmacokinetic and efficacy data in this population. We investigated factors underlying variation in antibiotic dosing using data from five global point prevalence surveys. METHODS & FINDINGS: Data from 3,367 doses of the 16 most frequent intravenous antibiotics administered to children 1 month-12 years across 23 countries were analysed. For each antibiotic, we identified standard doses given as either weight-based doses (in mg/kg/day) or fixed daily doses (in mg/day), and investigated the pattern of dosing using each strategy. Factors underlying observed variation in weight-based doses were investigated using linear mixed effects models. Weight-based dosing (in mg/kg/day) clustered around a small number of peaks, and all antibiotics had 1-3 standard weight-based doses used in 5%-48% of doses. Dosing strategy was more often weight-based than fixed daily dosing for all antibiotics apart from teicoplanin, which had approximately equal proportions of dosing attributable to each strategy. No strong consistent patterns emerged to explain the historical variation in actual weight-based doses used apart from higher dosing seen in central nervous system infections, and lower in skin and soft tissue infections compared to lower respiratory tract infections. Higher dosing was noted in the Americas compared to the European region. CONCLUSIONS: Antibiotic dosing in children clusters around a small number of doses, although variation remains. There is a clear opportunity for the clinical, scientific and public health communities to consolidate behind a consistent set of global antibiotic dosing guidelines to harmonise current practice and prioritise future research.

Experiences and needs of persons living with a household member infected with SARS-CoV-2: A mixed method study.

BACKGROUND: Households are important sites for transmission of SARS-CoV-2 and preventive measures are recommended. This study aimed to 1) investigate the impact of living with a person infected with SARS-CoV-2; 2) understand how household members implemented infection control recommendations in their home; and 3) identify the information and support needs of household members. METHODS: For this observational mixed-methods study, households with a person with confirmed SARS-CoV-2 infection were recruited via drive-through testing sites of Municipal Health Services, healthcare worker screening or hospital emergency visits in the University Medical Centre Utrecht, the Netherlands and via primary care physicians, hospital emergency visits or preoperative screening in the University Hospital of Antwerp, Belgium. We recorded household characteristics, including characteristics of all household members, together with their views on prevention measures. In a subset of households one adult household member was asked to participate in an interview investigating their views on preventive measures. Survey data were analysed using descriptive statistics and interview data by rapid framework analysis. A triangulation protocol was used to integrate findings. RESULTS: Thirty-four households (120 household members) were included in the quantitative survey. Twenty-two households were invited to be interviewed, of which 18 completed an interview (response 81.8%). Survey data showed that almost all households implemented some preventive measures, the use of face masks being least frequently reported. Measures taken depended on what was physically possible, the perceived severity of illness of the index patient and to what extent household members were willing to limit social interaction. Respondents did not believe in the effectiveness of wearing face masks within the house, and from the interviews this was explained by media coverage of face masks, impracticality and the stigma associated with wearing masks. Interviewees reported that quarantine had a high emotional burden and wished to have more information about the exact duration of quarantine, their own COVID-19 status, symptoms and when to seek medical help. CONCLUSION: People were willing to implement prevention measures, however actual adherence depended on perceived severity of illness and the perceived risk of becoming infected. Homes are social environments and recommendations for infection prevention should account for this context. Incorporating our findings into policy making could provide households with more relevant and actionable advice.

SARS-CoV-2 testing and infection control strategies in European paediatric emergency departments during the first wave of the pandemic.

Between February and May 2020, during the first wave of the COVID-19 pandemic, paediatric emergency departments in 12 European countries were prospectively surveyed on their implementation of SARS-CoV-2 disease (COVID-19) testing and infection control strategies. All participating departments (23) implemented standardised case definitions, testing guidelines, early triage and infection control strategies early in the outbreak. Patient testing criteria initially focused on suspect cases and later began to include screening, mainly for hospital admissions. Long turnaround times for test results likely put additional strain on healthcare resources.Conclusion: Shortening turnaround times for SARS-CoV-2 tests should be a priority. Specific paediatric testing criteria are needed. What is Known: • WHO and public health authorities issued case definitions, testing and infection control recommendations for COVID-19 in January. • SARS-CoV-2 testing was made available across Europe in February. What is New: • Paediatric emergency departments implemented COVID-19-specific procedures rapidly, including case definitions, testing guidelines and early triage. • A third of surveyed departments waited more than 24 h for SARS-CoV-2 test to be reported, resulting in additional strain on resources.