Optimised versus standard dosing of vancomycin in infants with Gram-positive sepsis (NeoVanc): a multicentre, randomised, open-label, phase 2b, non-inferiority trial.

BACKGROUND: Vancomycin is the most widely used antibiotic for neonatal Gram-positive sepsis, but clinical outcome data of dosing strategies are scarce. The NeoVanc programme comprised extensive preclinical studies to inform a randomised controlled trial to assess optimised vancomycin dosing. We compared the efficacy of an optimised regimen to a standard regimen in infants with late onset sepsis that was known or suspected to be caused by Gram-positive microorganisms. METHODS: NeoVanc was an open-label, multicentre, phase 2b, parallel-group, randomised, non-inferiority trial comparing the efficacy and toxicity of an optimised regimen of vancomycin to a standard regimen in infants aged 90 days or younger. Infants with at least three clinical or laboratory sepsis criteria or confirmed Gram-positive sepsis with at least one clinical or laboratory criterion were enrolled from 22 neonatal intensive care units in Greece, Italy, Estonia, Spain, and the UK. Infants were randomly assigned (1:1) to either the optimised regimen (25 mg/kg loading dose, followed by 15 mg/kg every 12 h or 8 h dependent on postmenstrual age, for 5 ± 1 days) or the standard regimen (no loading dose; 15 mg/kg every 24 h, 12 h, or 8 h dependent on postmenstrual age for 10 ± 2 days). Vancomycin was administered intravenously via 60 min infusion. Group allocation was not masked to local investigators or parents. The primary endpoint was success at the test of cure visit (10 ± 1 days after the end of actual vancomycin therapy) in the per-protocol population, where success was defined as the participant being alive at the test of cure visit, having a successful outcome at the end of actual vancomycin therapy, and not having a clinically or microbiologically significant relapse or new infection requiring antistaphylococcal antibiotics for more than 24 h within 10 days of the end of actual vancomycin therapy. The non-inferiority margin was -10%. Safety was assessed in the intention-to-treat population. This trial is registered at ClinicalTrials.gov (NCT02790996). FINDINGS: Between March 3, 2017, and July 29, 2019, 242 infants were randomly assigned to the standard regimen group (n=122) or the optimised regimen group (n=120). Primary outcome data in the per-protocol population were available for 90 infants in the optimised group and 92 in the standard group. 64 (71%) of 90 infants in the optimised group and 73 (79%) of 92 in the standard group had success at test of cure visit; non-inferiority was not confirmed (adjusted risk difference -7% [95% CI -15 to 2]). Incomplete resolution of clinical or laboratory signs after 5 ± 1 days of vancomycin therapy was the main factor contributing to clinical failure in the optimised group. Abnormal hearing test results were recorded in 25 (30%) of 84 infants in the optimised group and 12 (15%) of 79 in the standard group (adjusted risk ratio 1·96 [95% CI 1·07 to 3·59], p=0·030). There were six vancomycin-related adverse events in the optimised group (one serious adverse event) and four in the standard group (two serious adverse events). 11 infants in the intention-to-treat population died (six [6%] of 102 infants in the optimised group and five [5%] of 98 in the standard group). INTERPRETATION: In the largest neonatal vancomycin efficacy trial yet conducted, no clear clinical impact of a shorter duration of treatment with a loading dose was demonstrated. The use of the optimised regimen cannot be recommended because a potential hearing safety signal was identified; long-term follow-up is being done. These results emphasise the importance of robust clinical safety assessments of novel antibiotic dosing regimens in infants. FUNDING: EU Seventh Framework Programme for research, technological development and demonstration.

Use of point-of-care molecular tests reduces hospitalization and oseltamivir administration in children presenting with influenza-like illness.

Influenza is associated with increased morbidity, healthcare costs, hospitalization rates, and mortality in children. Rapid immunochromatography assay (ICA), a test with low sensitivity, is often used as point-of-care (POC) test. Recently, the rapid syndromic molecular test FilmArray has become available. This observational study aims to evaluate whether the use of FilmArray would decrease the use of antivirals and hospitalization rates among children presenting to the emergency room (ER) with influenza-like illness (ILI) symptoms. Nasopharyngeal swabs were prospectively collected from children, aged 0-16 years, presenting with ILI at the ER of a tertiary hospital during the peak endemic period. Patients were allocated to be tested by either FilmArray or ICA. The use of antivirals and hospitalization rates were noted. Logistic regression models were used to investigate the impact of testing methods on decision-making. Overall, 80 children were included (mean age: 5 years). Admissions were more likely to occur if an ICA test was performed (OR, 3.16; 95% CI, 1.01-9.82; p = .046). Oseltamivir administration was more likely among children who had undergone the ICA test (OR, 4.67; 95% CI, 1.06-20.43; p = .041). The implementation of rapid molecular test had no impact on complementary diagnostic testing or antibacterial prescription. The use of FilmArray significantly reduced both hospitalization and oseltamivir administration in children. Further knowledge on the use of POC tests is required to improve current management of children presenting with ILI and decrease associated healthcare costs.

Length of stay, cost, and mortality of healthcare-acquired bloodstream infections in children and neonates: A systematic review and meta-analysis.

OBJECTIVE: To estimate the attributable mortality, length of stay (LOS), and healthcare cost of pediatric and neonatal healthcare-acquired bloodstream infections (HA-BSIs). DESIGN: A systematic review and meta-analysis. METHODS: A systematic search (January 2000-September 2018) was conducted in PubMed, Cochrane, and CINAHL databases. Reference lists of selected articles were screened to identify additional studies. Case-control or cohort studies were eligible for inclusion when full text was available in English and data for at least 1 of the following criteria were provided: attributable or excess LOS, healthcare cost, or mortality rate due to HA-BSI. Study quality was evaluated using the Critical Appraisal Skills Programme Tool (CASP). Study selection and quality assessment were conducted by 2 independent researchers, and a third researcher was consulted to resolve any disagreements. Fixed- or random-effect models, as appropriate, were used to synthesize data. Heterogeneity and publication bias were evaluated. RESULTS: In total, 21 studies were included in the systematic review and 13 studies were included in the meta-analysis. Attributable mean LOS ranged between 4 and 27.8 days; healthcare cost ranged between $1,642.16 and $160,804 (2019 USD) per patient with HA-BSI; and mortality rate ranged between 1.43% and 24%. The pooled mean attributable hospital LOS was 16.91 days (95% confidence interval [CI], 13.70-20.11) and the pooled attributable mortality rate was 8% (95% CI, 6-9). A meta-analysis was not conducted for cost due to lack of eligible studies. CONCLUSIONS: Pediatric HA-BSIs have a significant impact on mortality, LOS, and healthcare cost, further highlighting the need for implementation of HA-BSI prevention strategies.

Attributable length of stay and cost for pediatric and neonatal central line-associated bloodstream infections in Greece.

BACKGROUND AND OBJECTIVE: Central line-associated bloodstream infections (CLABSIs) are the most frequent pediatric hospital-acquired infections and are associated with significant morbidity and healthcare costs. The aim of our study was to determine the attributable length of stay (LOS) and cost for CLABSIs in pediatric patients in Greece, for which there is currently a paucity of data. METHODS: A retrospective matched-cohort study was performed in two tertiary pediatric hospitals. Inpatients with a central line in neonatal and pediatric intensive care units, hematology/oncology units, and a bone marrow transplantation unit between June 2012 and June 2015 were eligible. Patients with confirmed CLABSI were enrolled on the day of the event and were matched (1:1) to patients without CLABSI (non-CLABSIs) by hospital, unit, and LOS prior to study enrollment (188 children enrolled, 94 CLABSIs). The primary outcome measure was the attributable LOS and cost. Baseline demographic and clinical characteristics were recorded. Attributable outcomes were calculated as the differences in estimates of outcomes between CLABSIs and non-CLABSIs, after adjustment for propensity score and potential confounders. RESULTS: There were no differences between the two groups regarding their baseline characteristics. After adjustment for age, gender, matching characteristics, central line management after study enrollment, and propensity score, the mean LOS and cost were 57.5days and €31,302 in CLABSIs versus 36.6days and €17,788 in non-CLABSIs. Overall, a CLABSI was associated with a mean (95% CI) adjusted attributable LOS and cost of 21days (7.3-34.8) and €13,727 (5,758-21,695), respectively. No significant difference was detected in LOS and cost by hospitalization unit. CONCLUSIONS: CLABSIs were found to impose a significant economic burden in Greece, a finding that highlights the importance of implementing CLABSI prevention strategies.

Overweight and obesity decreased in Greek schoolchildren from 2009 to 2012 during the early phase of the economic crisis.

AIM: We examined the weight status of Greek schoolchildren from November 2009 to May 2012, shortly before, and during the early years, of the Greek economic crisis. METHODS: This was a mixed longitudinal study that formed part of the West Attica Growth Study and followed children at the ages of 6-7, 9-10, 12-13 and 15-16 years every six months for 2.5 years. Each child's height and weight were measured and their body mass index calculated. We were able to determine the weight status of 1327 children (53% boys) based on their first and last measurements. Overweight, obesity and underweight were defined using the International Obesity Task Force criteria. RESULTS: During the 2.5-year study period, there was a decrease in the total prevalence of overweight and obesity, which reached a statistical significance for both sexes. It decreased from 43% to 37.3% (p = 0.02) in boys and from 33.4% to 26.9% (p = 0.0056) in girls. There was also a statistically significant increase in normal weight children and a slight but insignificant increase in underweight children of both sexes. CONCLUSION: During the initial years of the Greek economic crisis, there was a statistically significant reduction in overweight and obesity in children from six to 16 years of age.

Considerations on the current universal vaccination policy against hepatitis A in Greece after recent outbreaks.

Greece is the only European Union member state that in 2008 included hepatitis A (HAV) vaccine in the routine national childhood immunization program (NCIP). Given that the resources allocated to public health have dramatically decreased since 2008 and that Greece is a low endemicity country for the disease, the benefit from universal vaccination has been questioned. The aim of this paper is to summarize the available epidemiological data of the disease for 1982-2013, and discuss the effects of universal vaccination on disease morbidity. Descriptive analysis, ARIMA modeling and time series intervention analysis were conducted using surveillance data of acute HAV. A decreasing trend of HAV notification rate over the years was identified (p<0.001). However, universal vaccination (~ 80% vaccine coverage of children) had no significant effect on the annual number of reported cases (p = 0.261) and has resulted to a progressive increase of the average age of infection in the general population. The mean age of cases before the inclusion of the vaccine to NCIP (24.1 years, SD = 1.5) was significantly lower than the mean age of cases after 2008 (31.7 years, SD = 2.1) (p<0.001). In the last decade, one third of all reported cases were Roma (a population accounting for 1.5% of the country's total population) and in 2013 three outbreaks with 16, 9 and 25 Roma cases respectively, were recorded, indicating the decreased effectiveness of the current immunization strategy in this group. Data suggest that universal vaccination may need to be re-considered. Probably a more cost effective approach would be to implement a program that will include: a) vaccination of high risk groups, b) universal vaccination of Roma children and improving conditions at Roma camps, c) education of the population and travel advice, and d) enhancement of the control measures to increase safety of shellfish and other foods.

Vaccination coverage among adolescents and risk factors associated with incomplete immunization.

The compliance with vaccination recommendations in adolescence has not been well documented in Greece. The aims of the present study were to estimate the vaccination coverage in a sample of adolescents and to identify risk factors associated with incomplete immunization. Α total of 1,005 adolescents aged 11 to 19 years who were outpatient visitors at an Adolescent Health Unit were included in this study. Participation required parental presence and consent and presentation of the official Child Health Booklet, from which immunizations were transcribed. The highest coverage rates were observed for childhood immunizations: poliomyelitis and hepatitis B (both 96%), measles/mumps/rubella (MMR; 93.1%), and meningitidis C (MenC; 83.4%). By contrast, lower rates were shown for the booster dose of tetanus/diphtheria/pertussis (39.6%), for hepatitis A (HAV; 59.1%), for the varicella vaccine (13.8% among adolescents without disease history), and among girls for the human papillomavirus vaccine (11.9%). We found a significant association between age and series completion for MMR, MenC, and HAV, with lower uptake among older adolescents . Overall, 22.7% of study participants were fully vaccinated according to criteria employed. In particular, non-urban residents, non-nationals, and females had lower likelihood of being fully vaccinated. In conclusion, our findings suggest suboptimal vaccination coverage among our sample's adolescents, mandating that every effort should be made to increase uptake, particularly among the geographically dispersed and the culturally diverse and female adolescents.

Development and assessment of a questionnaire for a descriptive cross-sectional study concerning parents' knowledge, attitudes and practises in antibiotic use in Greece.

BACKGROUND: Upper Respiratory Infections (URIs) are common in children. The cause is usually viral, but parents' attitude often contributes to inappropriate antibiotic prescribing, promoting antibiotic resistance. The objective is to describe the process of developing a questionnaire to assess parents' Knowledge, Attitude and Practices (KAP) concerning the role of antibiotics when children suffer from URIs, as well as to evaluate the response rates, the completeness and the reliability (Cronbach) of the questionnaires. Finally, to note any limitations of the study. METHODS: Literature review, along with pre-testing yielded a questionnaire designed to assess the parents' KAP-level. A postal survey was set, in a national sample of 200 schools stratified by geographical region. The participants consist of a multistage geographical cluster sample of 8000 parents. The influence of demographic characteristics (i.e. sex, age, education) was analyzed. Cronbach index test and factor analysis were used to assess the reliability of the questionnaire. RESULTS: The response rate of the parents was 69%. Islands presented the lowest response rate while in Northern Greece the response rate was the highest. Sixty-eight point nine percent of the sample returned questionnaires fully completed, while 91.5% completed 95% of the questions. Three questions out of 70 were answered in a very low rate which was associated mostly with immigrant respondents. The section describing parents' attitude toward antibiotic use was not completed as much as the sections of knowledge or practices. The questions were factor analyzed and 10 out of the 21 extracted factors were finally evaluated, reducing the number of independent variables to 46. The reliability of the questionnaire was 0.55. However, only items that increased the Cronbach when added were eventually included in the final scales raising the internal consistency to 0.68. Limitations of the study, such as the vocabulary and form of the questionnaire and the idiocycrancy of the respondents, emerged during the analysis. CONCLUSION: The response rate and the completeness of the questionnaires were higher than expected, probably attributed to the involvement of the teachers. The study findings were satisfactory regarding the development of a reliable instrument capable to measure parents' KAP characteristics.