Implementation and impact of pediatric antimicrobial stewardship programs: a systematic scoping review.

Background: Antibiotics are the most common medicines prescribed to children in hospitals and the community, with a high proportion of potentially inappropriate use. Antibiotic misuse increases the risk of toxicity, raises healthcare costs, and selection of resistance. The primary aim of this systematic review is to summarize the current state of evidence of the implementation and outcomes of pediatric antimicrobial stewardship programs (ASPs) globally. Methods: MEDLINE, Embase and Cochrane Library databases were systematically searched to identify studies reporting on ASP in children aged 0-18 years and conducted in outpatient or in-hospital settings. Three investigators independently reviewed identified articles for inclusion and extracted relevant data. Results: Of the 41,916 studies screened, 113 were eligible for inclusion in this study. Most of the studies originated in the USA (52.2%), while a minority were conducted in Europe (24.7%) or Asia (17.7%). Seventy-four (65.5%) studies used a before-and-after design, and sixteen (14.1%) were randomized trials. The majority (81.4%) described in-hospital ASPs with half of interventions in mixed pediatric wards and ten (8.8%) in emergency departments. Only sixteen (14.1%) studies focused on the costs of ASPs. Almost all the studies (79.6%) showed a significant reduction in inappropriate prescriptions. Compliance after ASP implementation increased. Sixteen of the included studies quantified cost savings related to the intervention with most of the decreases due to lower rates of drug administration. Seven studies showed an increased susceptibility of the bacteria analysed with a decrease in extended spectrum beta-lactamase producers E. coli and K. pneumoniae; a reduction in the rate of P. aeruginosa carbapenem resistance subsequent to an observed reduction in the rate of antimicrobial days of therapy; and, in two studies set in outpatient setting, an increase in erythromycin-sensitive S. pyogenes following a reduction in the use of macrolides. Conclusions: Pediatric ASPs have a significant impact on the reduction of targeted and empiric antibiotic use, healthcare costs, and antimicrobial resistance in both inpatient and outpatient settings. Pediatric ASPs are now widely implemented in the USA, but considerable further adaptation is required to facilitate their uptake in Europe, Asia, Latin America and Africa

Standardising neonatal and paediatric antibiotic clinical trial design and conduct: the PENTA-ID network view.

Antimicrobial development for children remains challenging due to multiple barriers to conducting randomised clinical trials (CTs). There is currently considerable heterogeneity in the design and conduct of paediatric antibiotic studies, hampering comparison and meta-analytic approaches. The board of the European networks for paediatric research at the European Medicines Agency (EMA), in collaboration with the Paediatric European Network for Treatments of AIDS-Infectious Diseases network (www.penta-id.org), recently developed a Working Group on paediatric antibiotic CT design, involving academic, regulatory and industry representatives. The evidence base for any specific criteria for the design and conduct of efficacy and safety antibiotic trials for children is very limited and will evolve over time as further studies are conducted. The suggestions being put forward here are based on the adult EMA guidance, adapted for neonates and children. In particular, this document provides suggested guidance on the general principles of harmonisation between regulatory and strategic trials, including (1) standardised key inclusion/exclusion criteria and widely applicable outcome measures for specific clinical infectious syndromes (CIS) to be used in CTs on efficacy of antibiotic in children; (2) key components of safety that should be reported in paediatric antibiotic CTs; (3) standardised sample sizes for safety studies. Summarising views from a range of key stakeholders, specific criteria for the design and conduct of efficacy and safety antibiotic trials in specific CIS for children have been suggested. The recommended criteria are intended to be applicable to both regulatory and clinical investigator-led strategic trials and could be the basis for harmonisation in the design and conduct of CTs on antibiotics in children. The next step is further discussion internationally with investigators, paediatric CTs networks and regulators

Development of a Novel Multipenicillin Assay and Assessment of the Impact of Analyte Degradation: Lessons for Scavenged Sampling in Antimicrobial Pharmacokinetic Study Design

Penicillins are widely used to treat infections in children, however the evidence is continuing to evolve in defining optimal dosing. Modern paediatric pharmacokinetic study protocols frequently favour opportunistic, “scavenged” sampling. This study aimed to develop a small volume single assay for five major penicillins and to assess the influence of sample degradation on inferences made using pharmacokinetic modelling, to investigate the suitability of scavenged sampling strategies. Using a rapid ultra-high performance liquid chromatographic-tandem mass spectrometric method, an assay for five penicillins (amoxicillin, ampicillin, benzylpenicillin, piperacillin and flucloxacillin) in blood plasma was developed and validated. Penicillin stabilities were evaluated under different conditions. Using these data, the impact of drug degradation on inferences made during pharmacokinetic modelling was evaluated. All evaluated penicillins indicated good stability at room temperature (23 ± 2°C) over 1 hour remaining in the range of 98-103% of the original concentration. More rapid analyte degradation had already occurred after 4 hours with stability ranging from 68% to 99%. Stability over longer periods declined: degradation of up to 60% was observed with delayed sample processing of up to 24 hours. Modelling showed that analyte degradation can lead to a 30% and 28% bias in clearance and volume of distribution, respectively, and falsely show nonlinearity in clearance. Five common penicillins can now be measured in a single low volume blood sample. Beta-lactam chemical instability in plasma can cause misleading pharmacokinetic modelling results, which could impact upon model-based dosing recommendations and the forthcoming era of beta-lactam therapeutic drug monitoring

Refining pathological evaluation of neoadjuvant therapy for adenocarcinoma of the esophagus

AIM: To assess tumour regression grade (TRG) and lymph node downstaging to help define patients who benefit from neoadjuvant chemotherapy.METHODS: Two hundred and eighteen consecutive patients with adenocarcinoma of the esophagus or gastro-esophageal junction treated with surgery alone or neoadjuvant chemotherapy and surgery between 2005 and 2011 at a single institution were reviewed. Triplet neoadjuvant chemotherapy consisting of platinum, fluoropyrimidine and anthracycline was considered for operable patients (World Health Organization performance status ? 2) with clinical stage T2-4 N0-1. Response to neoadjuvant chemotherapy (NAC) was assessed using TRG, as described by Mandard et al. In addition lymph node downstaging was also assessed. Lymph node downstaging was defined by cN1 at diagnosis: assessed radiologically (computed tomography, positron emission tomography, endoscopic ultrasonography), then pathologically recorded as N0 after surgery; ypN0 if NAC given prior to surgery, or pN0 if surgery alone. Patients were followed up for 5 years post surgery. Recurrence was defined radiologically, with or without pathological confirmation. An association was examined between t TRG and lymph node downstaging with disease free survival (DFS) and a comprehensive range of clinicopathological characteristics.RESULTS: Two hundred and eighteen patients underwent esophageal resection during the study interval with a mean follow up of 3 years (median follow up: 2.552, 95%CI: 2.022-3.081). There was a 1.8% (n = 4) inpatient mortality rate. One hundred and thirty-six (62.4%) patients received NAC, with 74.3% (n = 101) of patients demonstrating some signs of pathological tumour regression (TRG 1-4) and 5.9% (n = 8) having a complete pathological response. Forty four point one percent (n = 60) had downstaging of their nodal disease (cN1 to ypN0), compared to only 15.9% (n = 13) that underwent surgery alone (pre-operatively overstaged: cN1 to pN0), (P < 0.0001). Response to NAC was associated with significantly increased DFS (mean DFS; TRG 1-2: 5.1 years, 95%CI: 4.6-5.6 vs TRG 3-5: 2.8 years, 95%CI: 2.2-3.3, P < 0.0001). Nodal down-staging conferred a significant DFS advantage for those patients with a poor primary tumour response to NAC (median DFS; TRG 3-5 and nodal down-staging: 5.533 years, 95%CI: 3.558-7.531 vs TRG 3-5 and no nodal down-staging: 1.114 years, 95%CI: 0.961-1.267, P < 0.0001).CONCLUSION: Response to NAC in the primary tumour and in the lymph nodes are both independently associated with improved DFS

Consumption of oral antibiotic formulations for young children according to the WHO Access, Watch, Reserve (AWaRe) antibiotic groups: an analysis of sales data from 70 middle-income and high-income countries

Background The 2017 WHO Model List of Essential Medicines for Children (EMLc) groups antibiotics as Access, Watch, or Reserve, based on recommendations of their use as first-choice and second-choice empirical treatment for the most common infections. This grouping provides an opportunity to review country-level antibiotic consumption and a potential for stewardship. Therefore, we aimed to review 2015 levels of oral antibiotic consumption by young children globally. Methods We analysed wholesale antibiotic sales in 70 middle-income and high-income countries in 2015. We identified oral antibiotic formulations appropriate for use in young children (defined as child-appropriate formulations [CAFs]) using wholesale data from the IQVIA-Multinational Integrated Data Analysis System database, and we estimated 2015 antibiotic consumption in reference to the 2017 WHO EMLc Access, Watch, Reserve (AWaRe) antibiotic groups. We used three metrics for assessment of intra-country patterns: access percentage, defined as the number of CAF standard units of Access antibiotics divided by the total number of CAF standard units; amoxicillin index, defined as the number of amoxicillin CAF standard units divided by the total number of CAF standard units; and access-to-watch index, defined as the ratio of Access-to-Watch CAF standard units. Findings The overall median volume of CAF antibiotic standard units sold in 2015 per country was 74·5 million (IQR 12·4–210·7 million). The median access percentage among the 70 countries was 76·3% (IQR 62·6–84·2). The amoxicillin index was low (median 30·7%, IQR 14·3–47·3). The median access-to-watch index was 6·0 (IQR 3·1–9·8). CAF antibiotic consumption patterns were highly variable between the 70 countries, without a clear difference between high-income and middle-income countries. Interpretation Antibiotics in the Access group have a key role in treating young children globally. A simple combination of metrics based on the AWaRe groups can be informative on individual countries' patterns of antibiotic consumption and stewardship opportunities. These metrics could support countries in the development of programmes to improve access to core Access antibiotics, particularly amoxicillin. Funding Global Antibiotic R&D Partnership (German Federal Ministry of Health, Médecins Sans Frontières, Netherlands Ministry of Health, Welfare and Sport, and UK Department for International Development)

Global sales of oral antibiotics formulated for children.

Objective: To investigate international consumption patterns of child-appropriate oral formulations of antibiotics by formulation type, with a focus on dispersible tablets, using data from a global sales database. Method: Antibiotic sales data for 2015 covering 74 countries and regional country groups were obtained from the MIDAS® pharmaceutical sales database, which includes samples of pharmacy wholesalers and retailers. The focus was on sales of child-appropriate oral formulations of Access antibiotics in the 2017 World Health Organization's WHO Model list of essential medicines for children. Sales volumes are expressed using a standard unit (i.e. one tablet, capsule, ampoule or vial or 5 mL of liquid). Sales were analysed by antibiotic, WHO region and antibiotic formulation. Findings: Globally, 17.7 billion standard units of child-appropriate oral antibiotic formulations were sold in 2015, representing 24% of total antibiotic sales of 74.4 billion units (both oral and parenteral) in the database. The top five child-appropriate Access antibiotics by sales volume were amoxicillin, amoxicillin with clavulanic acid, trimethoprim-sulfamethoxazole, cefalexin and ampicillin. The proportion of the top five sold for use as a syrup varied between 42% and 99%. Dispersible tablets represented only 22% of all child-appropriate oral formulation sales and made up only 15% of sales of 10 selected Access antibiotics on the model list for children. Conclusion: Globally most child-appropriate oral antibiotics were not sold as dispersible tablets in 2015, as recommended by WHO. There is a clear need for novel solid forms of antibiotics suitable for use in children

Antibiotic prescriptions in Italian hospitalised children after serial point prevalence surveys (or pointless prevalence surveys): has anything actually changed over the years?

BACKGROUND: Point prevalence surveys have been used in several studies to provide immediate and easily comparable information about antibiotic use and showed that about one third of hospitalised children had on ongoing antimicrobial prescription during their hospital admission. The aim of this study, as part of the Global Antimicrobial Resistance, Prescribing and Efficacy in Neonates and Children project, is to describe antimicrobial prescriptions among hospitalised children in four tertiary care hospitals in Italy to show if something has changed over the years. METHODS: Four tertiary care Italian's hospitals joined three Point Prevalence Surveys (PPSs) in three different period of the year. All children under 18 years of age with an ongoing antimicrobial prescription, admitted on the participating wards at 8 o'clock in the morning of the selecting day were enrolled. RESULTS: A total of 1412 patients (475 neonates and 937 children) were admitted in the days of three PPSs. Overall, among the total admitted patients, 565 patients (40%) had an ongoing antimicrobial prescription in the days of the survey A total of 718 antibiotics were administered in the 485 admitted children and 133 in neonates. The most common indications for antibiotic therapy in children was Lower respiratory tract infections (244/718, 34%), while in neonates were prophylaxis for medical problems (35/133, 26.3%), newborn prophylaxis for newborn risk factors (29/133, 21.8%) and prophylaxis for surgical disease (15/133, 11.3%). CONCLUSIONS: Based on our results, it appears that nothing has changed since the last PPS and that the quality improved targets, underlyined in previous studies, are always the same. Serial PPSs can be part of AMS strategies but they are not sufficient alone to produce changes in clinical practice