Julia Bielicki

The worldwide antibiotic resistance and prescribing in european children (ARPEC) point prevalence survey: Developing hospital-quality indicators of antibiotic prescribing for children

OBJECTIVES Previously, web-based tools for cross-sectional antimicrobial point prevalence surveys (PPSs) have been used in adults to develop indicators of quality improvement. We aimed to determine the feasibility of developing similar quality indicators of improved antimicrobial prescribing focusing specifically on hospitalized neonates and children worldwide. METHODS A standardized antimicrobial PPS method was employed. Included were all inpatient children and neonates receiving an antimicrobial at 8:00 am on the day of the PPS. Denominators included the total number of inpatients. A web-based application was used for data entry, validation and reporting. We analysed 2012 data from 226 hospitals (H) in 41 countries (C) from Europe (174H; 24C), Africa (6H; 4C), Asia (25H; 8C), Australia (6H), Latin America (11H; 3C) and North America (4H). RESULTS Of 17,693 admissions, 6499 (36.7%) inpatients received at least one antimicrobial, but this varied considerably between wards and regions. Potential indicators included very high broad-spectrum antibiotic prescribing in children of mainly ceftriaxone (ranked first in Eastern Europe, 31.3%; Asia, 13.0%; Southern Europe, 9.8%), cefepime (ranked third in North America, 7.8%) and meropenem (ranked first in Latin America, 13.1%). The survey identified worryingly high use of critically important antibiotics for hospital-acquired infections in neonates (34.9%; range from 14.2% in Africa to 68.0% in Latin America) compared with children (28.3%; range from 14.5% in Africa to 48.9% in Latin America). Parenteral administration was very common among children in Asia (88%), Latin America (81%) and Europe (67%). Documentation of the reasons for antibiotic prescribing was lowest in Latin America (52%). Prolonged surgical prophylaxis rates ranged from 78% (Europe) to 84% (Latin America). CONCLUSIONS Simple web-based PPS tools provide a feasible method to identify areas for improvement of antibiotic use, to set benchmarks and to monitor future interventions in hospitalized neonates and children. To our knowledge, this study has derived the first global quality indicators for antibiotic use in hospitalized neonates and children.

Systematic Review of Antibiotic Resistance Rates Among Gram-Negative Bacteria in Children With Sepsis in Resource-Limited Countries

BACKGROUND Gram-negative antimicrobial resistance (AMR) is of global concern, yet there are few reports from low- and low-middle-income countries, where antimicrobial choices are often limited. METHODS This study offers a systematic review of PubMed, Embase, and World Health Organization (WHO) regional databases of Gram-negative bacteremia in children in low- and low-middle-income countries reporting AMR since 2001. RESULTS Data included 30 studies comprising 71 326 children, of whom 7056 had positive blood cultures, and Gram-negative organisms were isolated in 4710 (66.8%). In neonates, Klebsiella pneumoniae median resistance to ampicillin was 94% and cephalosporins 84% in Asia; 100% and 50% in Africa. Large regional variations in resistance rates to commonly prescribed antibiotics for Salmonella spp. were identified. Multidrug resistance (resistance to ampicillin, chloramphenicol, and cotrimoxazole) was present in 30% (interquartile range [IQR], 0-59.6) in Asia and 75% (IQR, 30-85.4) in Africa. CONCLUSIONS There is a need for an international pediatric antimicrobial resistance surveillance system that collects local epidemiological data to improve the evidence base for the WHO guidance for childhood Gram-negative bacteremia.

Epidemiology and clinical outcomes of multidrug-resistant, gram-negative bloodstream infections in a European tertiary pediatric hospital during a 12-month period.

Background: Bloodstream infections caused by multidrug-resistant, Gram-negative (MDRGN) bacteria represent a significant cause of morbidity and mortality. Prompt diagnosis and appropriate empiric treatment are the most important determinants of patient outcome. The objective of our study was to assess the epidemiology and clinical outcome of MDRGN sepsis in a tertiary-care pediatric hospital during a 12-month period. Methods: It was a retrospective, observational study of MDRGN bacteremia including all patients <18 years of age, hospitalized during 2011, with documented bacteremia caused by Enterobacteriaceae or non-fermentative bacteria. Results: Overall, 136 blood cultures in 119 patients were included. The median age of patients was 1.1 years; 86.3% of patients had an underlying disease. The cumulative incidence of Gram-negative bloodstream infections was 5.4/1000 hospital admissions and the infection rate was 0.65/1000 hospital days. Most frequently isolated strains were Klebsiella pneumoniae, Escherichia coli and Pseudomonas aeruginosa; 67.6% of infections were hospital acquired. The percentage of multidrug-resistant (MDR) organisms among isolated species was 39%. The crude rate of mortality was 16% and sepsis-related mortality was 9.2%. The mortality rate among patients with an antibiotic-resistant isolate was 22.6%. Factors significantly associated with sepsis-related mortality were antibiotic resistance (odds ratio: 4.26, 95% confidence interval: 1.07–16.9) and hospital acquisition of infection (odds ratio: 1.13, 95% confidence interval: 1.05–1.22). Conclusions: This study demonstrates the high mortality of hospital-acquired MDRGN bacteremia in children. International networks focusing on clinical management and outcomes of MDRGN in children are required. Study of novel antibiotics active against Gram-negative bacteria should include children early in the clinical trial development programs.

Comparing neonatal and paediatric antibiotic prescribing between hospitals: a new algorithm to help international benchmarking

OBJECTIVES The WHO anatomical therapeutic chemical (ATC)/defined daily dose (DDD) methodology is a standardized method of comparing antimicrobial use. The ATC/DDD is defined as the average maintenance daily dose of a drug used in a 70 kg adult, ignoring the considerable differences in body weight of neonates and children. The aim of this study was to develop a new standardized way of comparing rates of antimicrobial prescribing between European childrens hospitals. METHODS This pilot study at four European childrens hospitals (in the UK, Greece and Italy) collected data including demographics, antibiotic use, dosing and indication in children and neonates over a 14 day period. RESULTS A total of 1217 antibiotic prescriptions were issued with 47 different antibiotics used. Approximately half of all children and a third of all neonates received antibiotics, with wide variation between centres in the type and dose of antibiotic used. We propose a new pragmatic three-step algorithm. The first step includes a simple comparison of the proportion of hospitalized children on antibiotics by weight bands and the number of antimicrobials that account for 90% of total DDD drug usage (DU90%). The second step is a comparison of the dosing used (mg/kg/day). The third step is to compare overall drug exposure using DDD/100 bed days for standardized weight bands between centres. CONCLUSIONS This novel method has the potential to be a useful tool to provide antibiotic use comparator data and requires validation in a large prospective point prevalence study.

Antibiotic Resistance Prevalence in Routine Bloodstream Isolates from Children’s Hospitals Varies Substantially from Adult Surveillance Data in Europe

Background: Surveillance of antimicrobial resistance (AMR) is central for defining appropriate strategies to deal with changing AMR levels. It is unclear whether childhood AMR patterns differ from those detected in isolates from adult patients. Methods: Resistance percentages of nonduplicate Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis, Enterococcus faecium, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa bloodstream isolates from children less than 18 years of age reported to the Antibiotic Resistance and Prescribing in European Children (ARPEC) project were compared with all-age resistance percentages reported by the European Antimicrobial Resistance Surveillance Network (EARS-Net) for the same pathogen–antibiotic class combinations, period and countries. In addition, resistance percentages were compared between ARPEC isolates from children less than 1 year of age and children greater than or equal to1 year of age. Results: Resistance percentages for many important pathogen–antibiotic class combinations were different for ARPEC isolates compared with EARS-Net. E. coli and K. pneumoniae fluoroquinolone resistance percentages were substantially lower in ARPEC (13.4% and 17.9%) than in EARS-Net (23.0% and 30.7%), whereas the reverse was true for all pathogen–antibiotic class combinations in P. aeruginosa (for example, 27.3% aminoglycoside resistance in ARPEC, 19.3% in EARS-Net, 32.8% carbapenem resistance in ARPEC and 20.5% in EARS-Net), and for S. pneumoniae and macrolide resistance. For many Gram-negative pathogen–antibiotic class combinations, isolates from children greater than or equal to 1 year of age showed higher resistance percentages than isolates from children less than 1 year of age. Conclusions: Age-stratified presentation of resistance percentage estimates by surveillance programs will allow identification of important variations in resistance patterns between different patient groups for targeted intervention.

Variation in paediatric hospital antibiotic guidelines in Europe

Objective To assess the availability and source of guidelines for common infections in European paediatric hospitals and determine their content and characteristics. Design Participating hospitals completed an online questionnaire on the availability and characteristics of antibiotic prescribing guidelines and on empirical antibiotic treatment including duration of therapy for 5 common infection syndromes: respiratory tract, urinary tract, skin and soft tissue, osteoarticular and sepsis in neonates and children. Results 84 hospitals from 19 European countries participated in the survey of which 74 confirmed the existence of guidelines. Complete guidelines (existing guidelines for all requested infection syndromes) were reported by 20% of hospitals and the majority (71%) used a range of different sources. Guidelines most commonly available were those for urinary tract infection (UTI) (74%), neonatal sepsis (71%) and sepsis in children (65%). Penicillin and amoxicillin were the antibiotics most commonly recommended for respiratory tract infections (RTIs) (up to 76%), cephalosporin for UTI (up to 50%) and for skin and soft tissue infection (SSTI) and bone infection (20% and 30%, respectively). Antistaphylococcal penicillins were recommended for SSTIs and bone infections in 43% and 36%, respectively. Recommendations for neonatal sepsis included 20 different antibiotic combinations. Duration of therapy guidelines was mostly available for RTI and UTI (82%). A third of hospitals with guidelines for sepsis provided recommendations for length of therapy. Conclusions Comprehensive antibiotic guideline recommendations are generally lacking from European paediatric hospitals. We documented multiple antibiotics and combinations for most infections. Considerable improvement in the quality of guidelines and their evidence base is required, linking empirical therapy to resistance rates.

Timing of Measles Immunization and Effective Population Vaccine Coverage

OBJECTIVE: To describe measles vaccination patterns in a cohort of Swiss children aged up to 3 years insured with a single health insurer. METHODS: A dynamic cohort study evaluating measles immunizations patterns in children born between 2006 and 2008 was conducted. Time-to-event analysis was used to describe timing of measles immunization. Effective vaccine coverage was calculated by using an area under the curve approach. RESULTS: In the study cohort, 62.6% of 13-month-old children were up-to-date for the first measles immunization (recommended at 12 months of age). Approximately 59% of 25-month-old children were up-to-date for the second measles immunization (recommended at 15–24 months of age). Most doses were delivered during months in a child’s life when well-child visits are recommended (eg, 12 months of age). For second measles vaccine dose, accelerations in vaccine delivery occurred at time points for well-child visits during the months 19 and 25 of age but with lower final uptake than for the first measles vaccine dose. Until their second birthday, children in our cohort spent on average 177 days and 89 days susceptible to measles due to policy recommendations and additional delays, respectively. In a group of children aged 6 months to 2 years reflecting the age distribution in our cohort, effective vaccine coverage was only 48.6%. CONCLUSIONS: Timing and timeliness of measles immunizations influence effective population vaccine coverage and should be routinely reported in addition to coverage whenever possible. Proposed timing and relation of recommended vaccinations to well-child visits could be relevant aspects in optimizing measles vaccine coverage to reach measles elimination.

Antimicrobial stewardship for neonates and children: a global approach.

I antimicrobial resistance (AMR) is directly linked with intense use of antimicrobials (AMs). This has led to the development of an antimicrobial stewardship (AS) movement aimed at the rational use of AMs. Neonates and children are prescribed AMs very frequently and exhibit different AMR patterns compared with other patient groups. AS has proved successful in reducing AM use without negatively affecting patient mortality, for example, in neonatal intensive care, and there are now clear opportunities to improve its global applicability. Although there has been progress in the implementation of AS activities in wellresourced settings, AS remains rudimentary in many resource-limited settings. Traditional AS approaches have evolved in the context of clearly structured and regulated healthcare systems, with high initial and ongoing costs, even if ultimately cost effective. The aim of this review is to outline the basic principles and strategies of pediatric AS and to discuss how these may be applied in a range of different settings. This has been framed within the consideration of access to AMs versus their excess use. Specific recommendations for the implementation of AS programs are available elsewhere and will only be touched on to illustrate the importance of local integration of AS activities.

Neonatal and pediatric antimicrobial stewardship programs in Europe-defining the research agenda.

The relationship between suboptimal use of antimicrobials and antimicrobial resistance has become increasingly clear. Despite significant international effort aimed at reducing inappropriate antimicrobial prescribing in hospitals, antimicrobial resistance remains a major public health threat. Antimicrobial Stewardship Programs (ASPs) comprise a series of measures aimed at optimizing the use of antimicrobials, while improving the quality of patient care and promoting cost-effectiveness. This discussion article aims to summarize some of the approaches that have been used in neonatal and pediatric ASPs, with a particular focus on the European healthcare setting. Current evidence demonstrates neonatal and pediatric ASPs to be safe, practical to implement, generally cost-effective and possibly associated with a reduction in antimicrobial resistance rates. This review identified that, despite the recognized need for additional evidence and information on implementation, published data on pediatric ASPs derives mainly from the United States, with very few published reports on formal ASPs in European children’s hospitals. Consequently, the optimal method of implementation remains unknown within a European setting. Future research needs to include novel study designs on how best to introduce ASPs, monitoring of clinically relevant outcomes and cost-effectiveness with improved measurement of the impact on antimicrobial resistance.

Using a simple point-prevalence survey to define appropriate antibiotic prescribing in hospitalised children across the UK

Background The National Health Service England, Commissioning for Quality and Innovation for Antimicrobial Resistance (CQUIN AMR) aims to reduce the total antibiotic consumption and the use of certain broad-spectrum antibiotics in secondary care. However, robust baseline antibiotic use data are lacking for hospitalised children. In this study, we aim to describe, compare and explain the prescription patterns of antibiotics within and between paediatric units in the UK and to provide a baseline for antibiotic prescribing for future improvement using CQUIN AMR guidance. Methods We conducted a cross-sectional study using a point prevalence survey (PPS) in 61 paediatric units across the UK. The standardised study protocol from the Antibiotic Resistance and Prescribing in European Children (ARPEC) project was used. All inpatients under 18 years of age present in the participating hospital on the day of the study were included except neonates. Results A total of 1247 (40.9%) of 3047 children hospitalised on the day of the PPS were on antibiotics. The proportion of children receiving antibiotics showed a wide variation between both district general and tertiary hospitals, with 36.4% ( 95% CI 33.4% to 39.4%) and 43.0% (95% CI 40.9% to 45.1%) of children prescribed antibiotics, respectively. About a quarter of children on antibiotic therapy received either a medical or surgical prophylaxis with parenteral administration being the main prescribed route for antibiotics (>60% of the prescriptions for both types of hospitals). General paediatrics units were surprisingly high prescribers of critical broad-spectrum antibiotics, that is, carbapenems and piperacillin-tazobactam. Conclusions We provide a robust baseline for antibiotic prescribing in hospitalised children in relation to current national stewardship efforts in the UK. Repeated PPS with further linkage to resistance data needs to be part of the antibiotic stewardship strategy to tackle the issue of suboptimal antibiotic use in hospitalised children.