Quantifying antibiotic use in paediatrics: a proposal for neonatal DDDs

The defined daily dose (DDD) as defined by the World Health Organization (WHO) has been the most frequently used unit of measurement to measure antibiotic use. However, measuring antibiotic use in paediatrics is a problem as the WHO DDD methodology is not applicable in children (aged >1 month) due to the large variation in body weight within this population. Based on the narrow range of body weights in the neonatal population, we therefore aimed to develop a set of neonatal DDDs for antibiotics. Eight well-respected (inter)national sources for dosage recommendations of antibiotics in children and neonates were consulted for the assumed maintenance dose of the ten most frequently used antibiotics in neonatal intensive care units in its main indication for neonates. A set of neonatal DDDs for ten commonly used antibiotics in neonates based on an assumed neonatal weight of 2 kg was proposed. Primarily in children DDDs are not applicable to quantify antibiotic use since there is large variation in body weight. In the neonatal population, however, based on its narrow range of body weights and when access to patient level data is not available, neonatal DDDs can be used as a unit of measurement

Antibiotic use for community-acquired pneumonia in neonates and children: WHO evidence review.

Background Pneumonia is the most common cause of death in children worldwide, accounting for 15% of all deaths of children under 5 years of age. This review summarises the evidence for the empirical antibiotic treatment of community-acquired pneumonia in neonates and children and puts emphasis on publications since the release of the previous WHO Evidence Summary report published in 2014. Methods A systematic search for systematic reviews and meta-analyses of antibiotic therapy for community-acquired pneumonia was conducted between 1 January 2013 and 10 November 2016. Results The optimal dosing recommendation for amoxicillin remains unclear with limited pharmacological and clinical evidence. There is limited evidence from surveillance to indicate whether amoxicillin or broader spectrum antibiotics (e.g. third-generation cephalosporins) are being used most commonly for paediatric CAP in different WHO regions. Data are lacking on clinical efficacy in the context of pneumococcal, staphylococcal and mycoplasma disease and the relative contributions of varying first-line and step-down options to the selection of such resistance. Conclusion Further pragmatic trials are required to optimise management of hospitalised children with severe and very severe pneumonia

P3MC: A double blind parallel group randomised placebo controlled trial of Propranolol and Pizotifen in preventing migraine in children

<p>Abstract</p> <p>Background</p> <p>A recent Cochrane Review demonstrated the remarkable lack of reliable clinical trials of migraine treatments for children, especially for the two most prescribed preventative treatments in the UK, <it>Propranolol </it>and <it>Pizotifen</it>.</p> <p>Migraine trials in both children and adults have high placebo responder rates, e.g. of 23%, but for a trial's results to be generalisable "placebo responders" should not be excluded and for a drug to be worthwhile it should be clearly superior, both clinically and statistically, to placebo.</p> <p>Methods/Design</p> <p>Two multicentre, two arm double blind parallel group randomised controlled trials, with allocation ratio of 2:1 for each comparison, Propranolol versus placebo and Pizotifen versus placebo. The trial is designed to test whether Propranolol is superior to placebo and whether Pizotifen is superior to placebo for the prevention of migraine attacks in children aged 5 - 16 years referred to secondary care out-patient settings with frequent migraine (2-6/4 weeks). The primary outcome measure is the number of migraine attacks during trial weeks 11 to 14.</p> <p>Discussion</p> <p>A strength of this trial is the participation of clinically well defined migraine patients who will also be approached to help with future longer-term follow-up studies.</p> <p>Trial Registration</p> <p>ISRCTN97360154</p

Amelogenesis Imperfecta caused by N-Terminal Enamelin Point Mutations in Mice and Men is driven by Endoplasmic Reticulum Stress

‘Amelogenesis imperfecta’ (AI) describes a group of inherited diseases of dental enamel that have major clinical impact. Here, we identify the aetiology driving AI in mice carrying a p.S55I mutation in enamelin; one of the most commonly mutated proteins underlying AI in humans. Our data indicate that the mutation inhibits the ameloblast secretory pathway leading to ER stress and an activated unfolded protein response (UPR). Initially, with the support of the UPR acting in pro-survival mode, Enam(p.S55I) heterozygous mice secreted structurally normal enamel. However, enamel secreted thereafter was structurally abnormal; presumably due to the UPR modulating ameloblast behaviour and function in an attempt to relieve ER stress. Homozygous mutant mice failed to produce enamel. We also identified a novel heterozygous ENAM(p.L31R) mutation causing AI in humans. We hypothesize that ER stress is the aetiological factor in this case of human AI as it shared the characteristic phenotype described above for the Enam(p.S55I) mouse. We previously demonstrated that AI in mice carrying the Amelx(p.Y64H) mutation is a proteinopathy. The current data indicate that AI in Enam(p.S55I) mice is also a proteinopathy, and based on comparative phenotypic analysis, we suggest that human AI resulting from the ENAM(p.L31R) mutation is another proteinopathic disease. Identifying a common aetiology for AI resulting from mutations in two different genes opens the way for developing pharmaceutical interventions designed to relieve ER stress or modulate the UPR during enamel development to ameliorate the clinical phenotype

Pediatric immunization-related safety incidents in primary care: A mixed methods analysis of a national database.

Background: Children are scheduled to receive 18–20 immunizations before their 18th birthday in England and Wales; this approximates to 13 million vaccines administered per annum. Each immunization represents a potential opportunity for immunization-related error and effective immunization is imperative to maintain the public health benefit from immunization. Using data from a national reporting system, this study aimed to characterize pediatric immunization-related safety incident reports from primary care in England and Wales between 2002 and 2013. Methods: A cross-sectional mixed methods study was undertaken. This comprised reading the free-text of incident reports and applying codes to describe incident type, potential contributory factors, harm severity, and incident outcomes. A subsequent thematic analysis was undertaken to interpret the most commonly occurring codes, such as those describing the incident, events leading up to it and reported contributory factors, within the contexts they were described. Results: We identified 1745 reports and most (n = 1077, 61.7%) described harm outcomes including three deaths, 67 reports of moderate harm and 1007 reports of low harm. Failure of timely vaccination was the potential cause of three child deaths from meningitis and pneumonia, and described in a further 113 reports. Vaccine administration incidents included the wrong number of doses (n = 476, 27.3%), wrong timing (n = 294, 16.8%), and wrong vaccine (n = 249, 14.3%). Documentation failures were frequently implicated. Socially and medically vulnerable children were commonly described. Conclusion: This is the largest examination of reported contributory factors for immunization-related patient safety incidents in children. Our findings suggest investments in IT infrastructure to support data linkage and identification of risk predictors, development of consultation models that promote the role of parents in mitigating safety incidents, and improvement efforts to adapt and adopt best practices from elsewhere, are needed to mitigate future immunization-related patient safety incidents. These priorities are particularly pressing for vulnerable patient groups.8 page(s

Protein hydrolysate versus standard formula for preterm infants

BACKGROUND: When human milk is not available for feeding preterm infants, protein hydrolysate rather than standard cow's milk formulas (with intact proteins) are often used because they are perceived as being tolerated better and less likely to lead to complications. However, protein hydrolysate formulas are more expensive than standard formulas, and concern exists that their use in practice is not supported by high-quality evidence. OBJECTIVES: To assess the effect of feeding preterm infants with hydrolysed formula (versus standard cow's milk formulas) on the risk of feed intolerance, necrotising enterocolitis, and other morbidity and mortality in preterm infants. SEARCH METHODS: We used the standard Cochrane Neonatal search strategy including electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 4), Ovid MEDLINE, Ovid Embase, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (to April 2017), as well as conference proceedings and previous reviews. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials that compared feeding preterm infants with protein hydrolysate versus standard (non-hydrolysed) cow's milk formula. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial eligibility and risk of bias and extracted data independently. We analysed treatment effects as described in the individual trials and reported risk ratios and risk differences for dichotomous data, and mean differences for continuous data, with respective 95% confidence intervals (CI). We used a fixed-effect model in meta-analyses and explored potential causes of heterogeneity in sensitivity analyses. We assessed quality of evidence at the outcome level using the GRADE approach. MAIN RESULTS: We identified 11 trials for inclusion in the review. All trials were small (total participants 665) and had various methodological limitations including uncertainty about methods to ensure allocation concealment and blinding. Most participants were clinically stable preterm infants of gestational age less than about 34 weeks or birth weight less than about 1750 g. Fewer participants were extremely preterm, extremely low birth weight, or growth-restricted. Most trials found no effects on feed intolerance assessed variously as mean prefeed gastric residual volume, incidence of abdominal distention or other concerning gastrointestinal signs, or time taken to achieve full enteral feeds (meta-analysis was limited because studies used different measures). Meta-analysis found no effect on the risk of necrotising enterocolitis (typical risk ratio 1.10, 95% CI 0.36 to 3.34; risk difference 0.00, 95% CI -0.03 to 0.04; 5 trials, 385 infants) (low quality evidence; downgraded for imprecision and design weaknesses). AUTHORS' CONCLUSIONS: The identified trials provide only low quality evidence about the effects of feeding preterm infants with protein hydrolysate versus standard formula. The existing data did not support conclusions that feeding with protein hydrolysate affects the risk of feed intolerance or necrotising enterocolitis. Further large, pragmatic trials are needed to provide more reliable and precise estimates of effectiveness and cost-effectiveness

The clinical effectiveness and cost-effectiveness of abatacept, adalimumab, etanercept and tocilizumab for treating juvenile idiopathic arthritis: a systematic review and economic evaluation

Background: Juvenile idiopathic arthritis (JIA) is characterised by joint pain, swelling and limitation of movement caused by inflammation. Subsequent joint damage can lead to disability and growth restriction. Treatment commonly includes disease modifying anti-rheumatic drugs (DMARD) such as methotrexate. Clinical practice now favours newer drugs termed biologic DMARDs where indicated.Objective: To assess the clinical and cost-effectiveness of four biologic DMARDs (etanercept, abatacept, adalimumab and tocilizumab - with or without methotrexate where indicated) for the treatment of JIA (systemic or oligoarticular JIA excluded).Data sources: Electronic bibliographic databases including MEDLINE, EMBASE, The Cochrane Library and DARE were searched for published studies from inception to May 2015 for English language articles. Bibliographies of related papers, systematic reviews and company submissions were screened and experts were contacted to identify additional evidence.Review methods: Systematic reviews of clinical-effectiveness, health-related quality of life and cost-effectiveness were undertaken according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. A cost-utility decision analytic model was developed to compare estimated cost-effectiveness of biologic DMARDs versus methotrexate. The base case time horizon was 30 years and the model took a National Health Service (NHS) perspective, with costs and benefits discounted at 3.5%.Results: Four placebo-controlled RCTs met the inclusion criteria for the clinical-effectiveness review (one RCT evaluating each biologic DMARD). Only one RCT included UK participants. Participants had to achieve an American College of Rheumatology Pediatric (ACR Pedi) 30 response to open-label lead-in treatment in order to be randomised. An exploratory adjusted indirect comparison suggests that the four biologic DMARDs are similar with fewer disease flares and greater proportions with ACR Pedi 50 and 70 responses among participants randomised to continued biologic DMARD. However, confidence intervals were wide, the number of trials was low and there was clinical heterogeneity between trials. Open-label extensions of the trials showed that generally ACR responses remained constant or even increased after the double-blind phase. The proportions of adverse events and serious adverse events were generally similar between treatment and placebo groups. Four economic evaluations of biologic DMARDs for patients with JIA were identified but all had limitations. Two quality of life studies were included, one of which informed the cost-utility model. The incremental cost-effectiveness ratio (ICER) for adalimumab, etanercept and tocilizumab versus methotrexate was £38,127, £32,526 and £38,656 per QALY, respectively. The ICER for abatacept versus methotrexate as a second line biologic was £39,536 per QALY.Limitations: The model does not incorporate the natural history of JIA in terms of long-term disease progression, as the current evidence is limited. There are no head-to-head trials of biologic DMARDs and clinical evidence for specific JIA subtypes is limited.Conclusions: Biologic DMARDs are superior to placebo (with methotrexate where permitted) in children with (predominantly) polyarticular course JIA, and an insufficient response to previous treatment. Randomised comparisons of biologic DMARDs with long-term efficacy and safety follow- are needed to establish comparative effectiveness. RCTs for JIA subtypes where evidence is lacking are also required.Funding: The National Institute for Health Research Health Technology Assessment programme. <br/

Bronchiolitis of Infancy Discharge Study (BIDS):a multicentre, parallel-group, double-blind, randomised controlled, equivalence trial with economic evaluation

Background: There are no randomised trials of peripheral capillary oxygen saturation (SpO2) targets in acute respiratory infection. Two national guidelines recommended different targets for the management of acute viral bronchiolitis. Objectives: To compare the American Academy of Pediatrics guideline target of SpO2 ≥ 90% with the Scottish Intercollegiate Guidelines Network target of SpO2 ≥ 94%. Design: A multicentre, parallel-group, double-blind, randomised controlled, equivalence trial with economic evaluation. Setting: Eight paediatric hospital departments in the UK. Participants: Infants > 6 weeks and ≤ 12 months of age (corrected for prematurity) with physician-diagnosed bronchiolitis admitted to hospital from a paediatric emergency assessment area. Follow-up for 6 months by standardised telephone contacts. Intervention: Infants were randomised to a target oxygen saturation of ≥ 94% (standard care) or ≥ 90% (modified care) displayed by a pulse saturation oximeter (Masimo Corporation Limited, CA, USA). Routine care: All infants received routine care in addition to the study intervention. Infants were eligible for discharge when they exhibited a SpO2 of ≥ 94% in room air for 4 hours including a period of sleep and were also feeding adequately (≥ 75% usual volume). Primary outcome: A total of 615 infants were recruited, of whom 308 were allocated to the standard care group and 307 to the modified care group. The primary outcome was time to cough resolution. There was equivalence at the prespecified variance of ± 2 days [time to cough resolution: standard care group, 15 days; modified care group, 15 days; median difference 1 day (benefit modified), 95% confidence interval (CI) –1 to 2 days]. Secondary results: Return to adequate feeding occurred sooner in infants in the modified care group than in those in the standard care group (19.5 vs. 24.1 hours). This difference was non-equivalent [median difference 2.7 hours (95% CI –0.3 to 7.0 hours) versus prespecified ± 4 hours; post-hoc hazard ratio 1.22 (95% CI 1.04 to 1.44 (p-value = 0.015)]. Parent perspective of the time taken to return to normal was not equivalent, being 12 days in the standard care group compared with 11 days in the modified care group [median difference 1.0 day (95% CI 0.0 to 3.0 days) versus prespecified ± 2 days; post-hoc hazard ratio 1.19 (95% CI 1.00 to 1.41); p-value = 0.043]. At 28 days, SpO2 was equivalent [mean difference 0.11% (95% CI –0.35% to 0.57%), within the 1% prespecified]. The modified care group (55.6%) required oxygen less than the standard care group (73.1%), and for a shorter period (5.7 hours vs. 27.6 hours). Infants in the modified care group were fit for discharge (30.2 hours vs. 44.2 hours, hazard ratio 1.46, 95% CI 1.23 to 1.73; p-value < 0.001) and were discharged (40.9 hours vs. 50.9 hours; hazard ratio 1.28, 95% CI 1.06 to 1.50; p-value < 0.003) sooner than those in the standard care group. There were 35 serious adverse events in the standard care group, compared with 25 in the modified care group. Eight infants in the standard care group and 12 in the modified care group were admitted to a high-dependency unit. By 28 days, 23 infants had been readmitted to hospital in the standard care group and 12 infants in the modified care group. Parents of infants in the modified care group did not experience higher levels of anxiety and, by 14 days, had lost 28% fewer hours to usual activities. NHS costs were £290 lower in the modified care group than in the standard care group, with additional societal costs also being lower in the modified care group. Conclusions: Management of infants to a SpO2 target of ≥ 90% is as clinically effective as ≥ 94%, gives rise to no additional safety concerns, and appears to be cost-effective. Future work could focus on the safety and effectiveness of using intermittent oxygen saturation monitoring in secondary care, and to consider what are safe and effective oxygen saturation targets for children with bronchiolitis managed in primary care. Trial registration: This trial is registered as ISRCTN28405428. Funding: This project was funded by the NIHR Health Technology Assessment programme. Masimo Corporation Limited, CA, USA, kindly provided oxygen saturation monitors with standard and altered algorithms

A prospective study of the use of antibiotics in the Emergency Department of a Chinese University Hospital

Background: Antibiotics are one of the most widely misused group of medicines. The aim of this study was to investigate the use of antibiotics in one of the paediatric emergency departments in China. Methods: We performed a prospective, cross-sectional study of antibiotic use in the paediatric emergency room of West China Second University Hospital. A total of 500 consecutive patients from March 25 to April 3 2013 were included. Clinical details of the patients were also collected in order to analyse antibiotic use. Key findings: The median age of patients was 2 years 2 months. The five most common conditions seen in the emergency department were wheezy bronchitis, upper respiratory tract infections, tonsillitis, pneumonia and diarrhoea. A total of 311 children (62%) received antibiotics. The antibiotics prescribed were predominantly cephalosporins and penicillins. More than one antibiotic was used in 51 patients. In total, 75% of the antibiotics prescribed were cephalosporins. More than three-quarters of the young children with wheezy bronchitis received antibiotics. Antibiotic use for children with an upper respiratory tract infections or tonsillitis was greater than the 20% maximum recommended by the European Surveillance of Antimicrobial Consumption. Conclusions: The majority of children attending the emergency department received antibiotics. For many of the conditions, the use of antibiotics was inappropriate