Application of the Weighted-Incidence Syndromic Combination Antibiogram (WISCA) to guide the empiric antibiotic treatment of febrile neutropenia in oncological paediatric patients: experience from two paediatric hospitals in Northern Italy.

BACKGROUND: Guidelines about febrile neutropenia in paediatric patients are not homogeneous; the best empiric treatment of this condition should be driven by local epidemiology. The Weighted-Incidence Syndromic Combination Antibiogram (WISCA) addresses the need for disease-specific local susceptibility evidence that could guide empiric antibiotic prescriptions based on outcome estimates of treatment regimens obtained as a weighted average of pathogen susceptibilities. This study developed a WISCA model to inform empirical antibiotic regimen selection for febrile neutropenia (FN) episodes in onco-haematological paediatric patients treated at two Italian paediatric tertiary centres. METHODS: We included blood cultures from patients with a bloodstream infection and neutropenia admitted to the Paediatric Haematology-Oncology wards in Padua and Genoa Hospitals from 2016 to 2021. WISCAs were developed by estimating the coverage of 20 antibiotics as monotherapy and of 21 combined regimens with a Bayesian probability distribution. RESULTS: We collected 350 blood cultures, including 196 g-negative and 154 g-positive bacteria. Considering the most used antibiotic combinations, such as piperacillin-tazobactam plus amikacin, the median coverage for the pool of bacteria collected in the study was 78%. When adding a glycopeptide, the median coverage increased to 89%, while the replacement of piperacillin-tazobactam with meropenem did not provide benefits. The developed WISCAs showed that no monotherapy offered an adequate coverage rate for the identified pathogens. CONCLUSIONS: The application of WISCA offers the possibility of maximizing the clinical utility of microbiological surveillance data derived from large hospitals to inform the choice of the best empiric treatment while contributing to spare broad-spectrum antibiotics.

Multistep antimicrobial stewardship intervention on antibiotic prescriptions and treatment duration in children with pneumonia.

INTRODUCTION: The Italian antimicrobial prescription rate is one of the highest in Europe, and antibiotic resistance has become a serious problem with high costs and severe consequences, including prolonged illnesses, the increased period of hospitalization and mortality. Inadequate antibiotic prescriptions have been frequently reported, especially for lower respiratory tract infections (LRTI); many patients receive antibiotics for viral pneumonia or bronchiolitis or broad-spectrum antibiotics for not complicated community-acquired pneumonia. For this reason, healthcare organizations need to implement strategies to raise physicians' awareness about this kind of drug and their overall effect on the population. The implementation of antibiotic stewardship programs and the use of Clinical Pathways (CPs) are excellent solutions because they have proven to be effective tools at diagnostic and therapeutic levels. AIMS: This study evaluates the impact of CPs implementation in a Pediatric Emergency Department (PED), analyzing antibiotic prescriptions before and after the publication in 2015 and 2019. The CP developed in 2019 represents an update of the previous one with the introduction of serum procalcitonin. The study aims to evaluate the antibiotic prescriptions in patients with community-acquired pneumonia (CAP) before and after both CPs (2015 and 2019). METHODS: The periods analyzed are seven semesters (one before CP-2015 called PRE period, five post CP-2015 called POST 1-5 and 1 post CP-2019 called POST6). The patients have been split into two groups: (i) children admitted to the Pediatric Acute Care Unit (INPATIENTS), and (ii) patients evaluated in the PED and sent back home (OUTPATIENTS). We have analyzed all descriptive diagnosis of CAP (the assessment of episodes with a descriptive diagnosis were conducted independently by two pediatricians) and CAP with ICD9 classification. All antibiotic prescriptions for pediatric patients with CAP were analyzed. RESULTS: A drastic reduction of broad-spectrum antibiotics prescription for inpatients has been noticed; from 100.0% in the PRE-period to 66.7% in POST1, and up to 38.5% in POST6. Simultaneously, an increase in amoxicillin use from 33.3% in the PRE-period to 76.1% in POST1 (p-value 0.078 and 0.018) has been seen. The outpatients' group's broad-spectrum antibiotics prescriptions decreased from 54.6% PRE to 17.4% in POST6. Both for outpatients and inpatients, there was a decrease of macrolides. The inpatient group's antibiotic therapy duration decreased from 13.5 days (PRE-period) to 7.0 days in the POST6. Antibiotic therapy duration in the outpatient group decreased from 9.0 days (PRE) to 7.0 days (POST1), maintaining the same value in subsequent periods. Overlapping results were seen in the ICD9 group for both inpatients and outpatients. CONCLUSIONS: This study shows that CPs are effective tools for an antibiotic stewardship program. Indeed, broad-spectrum antibiotics usage has dropped and amoxicillin prescriptions have increased after implementing the CAP CP-2015 and the 2019 update.

Development of a Weighted-Incidence Syndromic Combination Antibiogram (WISCA) to guide the choice of the empiric antibiotic treatment for urinary tract infection in paediatric patients: a Bayesian approach.

BACKGROUND: To evaluate the ability of Weighted-Incidence Syndromic Combination Antibiograms (WISCA) to inform the selection of empirical antibiotic regimens for suspected paediatric community-acquired urinary tract infections. METHODS: Data were collected from outpatients (< 15 years) accessing the emergency rooms of Padua University-Hospital and Mestre Dell' Angelo-Hospital (Venice) between January 1st, 2016, and December 31st, 2018. WISCAs were developed by estimating the coverage of eight regimens using a Bayesian hierarchical model adjusted for age, sex, and previous antibiotic treatment or renal/urological comorbidities. RESULTS: 385 of 620 urine culture requests were included in the model analysis. The most frequently observed bacterium was E. coli (85% and 87%, Centre A and B). No centre effect on coverage estimates was found, and data were successfully pooled together. Coverage ranged from 77.8% (Co-trimoxazole) to 97.6% (Carbapenems). Complex cases and males had significantly lower odds of being covered by a regimen than non-complex cases and females (odds ratio (OR) 0.49 [95% HDI, 0.38-0.65], and OR: 0.73 [95% HDIs, 0.56-0.96] respectively). Children aged 3-5 years had lower odds of being covered by a regimen than other age groups, except for neonates. CONCLUSIONS: The developed WISCAs provide highly informative estimates on coverage patterns overcoming the limitation of combination antibiograms and expanding the framework of previous Bayesian WISCA algorithm.

Preventing recurrent acute otitis media with Streptococcus salivarius 24SMB and Streptococcus oralis 89a five months intermittent treatment: An observational prospective cohort study.

INTRODUCTION: Acute otitis media (AOM) is the most common childhood disease leading to antibiotic use. More than 80% of children under three years of age experience at least one episode, and about one-third of these report significant recurrence of episodes. In recent years, several studies reported that normal nasopharyngeal flora inhibits growth of common otopathogens, suggesting that maintenance of an "adequate" nasopharyngeal flora might prevent occurrence of upper respiratory tract infections, including AOM. This study aims to determine whether five-month treatment with Streptococcus salivarius 24SMB and Streptococcus oralis 89a nasal spray prevents recurrence of AOM and prescription of antibiotics in children with diagnosis of recurrent AOM. METHODS: Observational prospective cohort study including children aged 1-6 years with diagnosis of recurrent AOM registered with 31 Italian family pediatricians. 81 children were enrolled in the study from September 2016 to the end of the five therapeutic cycles of the Streptococcus salivarius 24SMB and Streptococcus oralis 89a supplied 7 days each month for 5 consecutive months. For each treated child, one untreated control was randomly selected, 1:1 matched for gender, age, and follow-up. RESULTS: 158 children (79 treated and 70 untreated) were included into the analysis (mean age, 3.9 years; 47% female). Univariate analysis showed a statistically significant 34% (95% CI 1%-56%) reduction in number of AOM episodes in treated children compared with those not treated. Significantly fewer antibiotics were dispensed among treated children (24%, 95% CI 1%-41%). CONCLUSIONS: Our findings suggest that intermittent treatment of children with diagnosis of recurrent AOM with nasal spray containing Streptococcus salivarius 24SMB and Streptococcus oralis 89a for a period of five months might be effective in preventing antibiotic use associated with recurrent episodes of AOM. Additional larger studies to address this important clinical problem are recommended.

The Impact of Clinical Pathways on Antibiotic Prescribing for Acute Otitis Media and Pharyngitis in the Emergency Department.

BACKGROUND: Although Italian pediatric antimicrobial prescription rates are among the highest in Europe, little action has been taken to improve the appropriateness of antimicrobial prescriptions. The primary aim of this study was to assess changes in antibiotic prescription before and after acute otitis media (AOM) and group A streptococcus (GAS) pharyngitis Clinical Pathway (CP) implementation; secondary aims were to compare treatment failures and to assess change in the total antibiotics costs before and after CP implementation. METHODS: Pre-post quasi-experimental study comparing the 6-month period before CP implementation (baseline period: October 15, 2014, through April 15, 2015) to the 6 months after intervention (postintervention: October 15, 2015, through April 15, 2016). RESULTS: Two hundred ninety-five pre- and 278 postintervention emergency department visits were associated with AOM. After CP implementation, there was an increase in "wait and see" approach and a decrease in overall prescription of broad-spectrum antibiotics from 53.2% to 32.4% (P < 0.001). One hundred fifty-one pre- and 166 postimplementation clinic visits were associated with GAS pharyngitis, with a decrease in broad-spectrum prescription after CP implementation (46.4% vs. 6.6%; P < 0.001). For both conditions, no difference was found in treatment failure, and total antibiotics cost was significantly reduced after CP implementation, with a decrease especially in broad-spectrum antibiotics costs. CONCLUSIONS: A reduction in broad-spectrum antibiotic prescriptions and a reduction in the total cost of antibiotics for AOM and GAS pharyngitis along with an increase in "wait and see" prescribing for AOM indicate effectiveness of CP for antimicrobial stewardship in this setting.

Effects of clinical pathway implementation on antibiotic prescriptions for pediatric community-acquired pneumonia.

BACKGROUND: Italian pediatric antimicrobial prescription rates are among the highest in Europe. As a first step in an Antimicrobial Stewardship Program, we implemented a Clinical Pathway (CP) for Community Acquired Pneumonia with the aim of decreasing overall prescription of antibiotics, especially broad-spectrum. MATERIALS AND METHODS: The CP was implemented on 10/01/2015. We collected antibiotic prescribing and outcomes data from children aged 3 months-15 years diagnosed with CAP from 10/15/2014 to 04/15/2015 (pre-intervention period) and from 10/15/2015 to 04/15/2016 (post-intervention period). We assessed antibiotic prescription differences pre- and post-CP, including rates, breadth of spectrum, and duration of therapy. We also compared length of hospital stay for inpatients and treatment failure for inpatients and outpatients. Chi-square and Fisher's exact test were used to compare categorical variables and Wilcoxon rank sum test was used to compare quantitative outcomes. RESULTS: 120 pre- and 86 post-intervention clinic visits were identified with a diagnosis of CAP. In outpatients, we observed a decrease in broad-spectrum regimens (50% pre-CP vs. 26.8% post-CP, p = 0.02), in particular macrolides, and an increase in narrow-spectrum (amoxicillin) post-CP. Post-CP children received fewer antibiotic courses (median DOT from 10 pre-CP to 8 post-CP, p<0.0001) for fewer days (median LOT from 10 pre-CP to 8 post-CP, p<0.0001) than their pre-CP counterparts. Physicians prescribed narrow-spectrum monotherapy more frequently than broad-spectrum combination therapy (DOT/LOT ratio 1.157 pre-CP vs. 1.065 post-CP). No difference in treatment failure was reported before and after implementation (2.3% pre-CP vs. 11.8% post-CP, p = 0.29). Among inpatients we also noted a decrease in broad-spectrum regimens (100% pre-CP vs. 66.7% post-CP, p = 0.02) and the introduction of narrow-spectrum regimens (0% pre-CP vs. 33.3% post-CP, p = 0.02) post-CP. Hospitalized patients received fewer antibiotic courses post-CP (median DOT from 18.5 pre-CP to 10 post-CP, p = 0.004), while there was no statistical difference in length of therapy (median LOT from 11 pre-CP to 10 post-CP, p = 0.06). Days of broad spectrum therapy were notably lower post-CP (median bsDOT from 17 pre-CP to 4.5 post-CP, p <0.0001). No difference in treatment failure was reported before and after CP implementation (16.7% pre-CP vs. 15.4% post-CP, p = 1). CONCLUSIONS: Introduction of a CP for CAP in a Pediatric Emergency Department led to reduction of broad-spectrum antibiotic prescriptions, of combination therapy and of duration of treatment both for outpatients and inpatients.

Galacto-Oligosaccharide/Polidextrose Enriched Formula Protects against Respiratory Infections in Infants at High Risk of Atopy: A Randomized Clinical Trial.

BACKGROUND: Early nutrition affects the risk of atopy and infections through modifications of intestinal microbiota. The Prebiotics in the Prevention of Atopy (PIPA) study was a 24-month randomised, double-blind, placebo-controlled trial. It aimed to evaluate the effects of a galacto-oligosaccharide/polydextrose (GOS/PDX)-formula (PF) on atopic dermatitis (AD) and common infections in infants who were born to atopic parents and to investigate the relationship among early nutrition, gut microbiota and clinical outcomes. METHODS: A total of 201 and 199 infants were randomized to receive a PF and standard formula (SF), respectively; 140 infants remained on exclusive breastfeeding (BF). RESULTS: The cumulative incidence of AD and its intensity and duration were not statistically different among the three groups. The number of infants with at least one episode of respiratory infection (RI) and the mean number of episodes until 48 weeks of age were significantly lower in the PF group than in the SF group. The number of patients with recurrent RIs and incidence of wheezing lower RIs until 96 weeks were lower in the PF group than the SF group, but similar to the BF group. Bifidobacteria and Clostridium cluster I colonization increased over time in the PF group but decreased in the SF and BF groups. Bifidobacteria had a protective role in RIs, whereas Clostridium cluster I was associated with atopy protection. CONCLUSION: The early administration of PF protects against RIs and mediates a species-specific modulation of the intestinal microbiota. TRIAL REGISTRATION: clinicaltrial.gov Identifier: NCT02116452.

Current management of late onset neonatal bacterial sepsis in five European countries.

UNLABELLED: Late onset neonatal sepsis (LOS) has a high mortality and the optimal management is poorly defined. We aimed to evaluate new expert panel-derived criteria to define LOS and characterize the current management and antibiotic susceptibility of LOS-causing organisms in Europe. A prospective observational study enrolled infants aged 4 to 90 days in five European countries. Clinical and laboratory findings as well as empiric treatment were recorded and patients were followed until the end of antibiotic therapy. Failure was defined as a change of primary antibiotic, no resolution of clinical signs, appearance of new signs/pathogens or death. Antibiotic therapy was considered appropriate if the organism was susceptible to at least one empiric antibiotic. 113 infants (median age 14 days, 62 % ≤1500 g) were recruited; 61 % were culture proven cases (28 CoNS, 24 Enterobacteriaceae, 11 other Gram-positives and 6 Gram-negative non-fermentative organisms). The predictive value of the expert-panel criteria to identify patients with a culture proven LOS was 61 % (95 % CI 52 % to 70 %). Around one third of Enterobacteriaceae were resistant to ampicillin + or cefotaxime + gentamicin but only 10 % to meropenem. Empiric treatment contained a total of 43 different antibiotic regimens. All-cause mortality was 8 % with an additional 45 % classified as failure of empiric therapy, mainly due to change of primary antibiotics (42/60). CONCLUSIONS: The expert panel-derived diagnostic criteria performed well identifying a high rate of culture proven sepsis. Current management of LOS in Europe is extremely variable suggesting an urgent need of evidence-based guidelines.

Intussusception among young children in Europe.

Intussusception, a potentially lethal condition with poorly understood etiology, is the most common cause of acute intestinal obstruction in children younger than 5 years old. In some cases, the condition has been associated with administration of the first licensed rotavirus vaccine, the reassortant rhesus-human tetravalent rotavirus vaccine (RRV-TV; RotaShield). No such association has to date been reported from large phase III safety trials with new rotavirus vaccines. As 2 new, live-attenuated oral rotavirus vaccines are currently under review for approval by the European Union regulatory authorities, a review of the clinical, etiologic and epidemiologic aspects of intussusception in Europe is urgently needed. We conducted a review of Medline literature, published from 1995 onwards on intussusception in the World Health Organization's European Region. The results are compared with data from previous reviews and other regions. The classic triad of intussusception symptoms (abdominal pain, abdominal mass, bloody stools) was present in 29-33% of patients according to the medical literature reviewed. Conservative treatment (barium, air or saline enema) was the rule (81% of cases), and few complications were observed during treatment. Treatment outcome was generally favorable, with recurrence occurring in approximately 1 in 10 patients, and only 1 death reported. Structural lead points were seen in 3% of patients; no other reliable data on the etiology of intussusception were found. The incidence of acute intussusception in young children in Europe, according to 6 heterogeneous hospital-based studies, ranged from 0.66 to 2.24 per 1000 children in inpatient departments and from 0.75 to 1.00 per 1000 children in emergency departments. Peak incidences were found in children 3-9 months of age. There are still gaps in our knowledge of intussusception with respect to its etiology and especially by which mechanisms RRV-TV might have caused it to occur. Data from regions outside Europe showed that rotavirus infection and disease are not associated with intussusception. As new rotavirus vaccines become available for use in Europe, postlicensure surveillance for intussusception is indicated and may be instrumental in further understanding the epidemiology of this condition and in further assessing the safety of future vaccines.

Varicella vaccination in Italy : an economic evaluation of different scenarios.

AIM: To determine the economic impact (cost-benefit analysis) of childhood varicella vaccination, with the Oka/Merck varicella zoster virus vaccine live (Varivax) in Italy. METHODS: This analysis is based on an epidemiological model of varicella zoster virus (VZV) dynamics adapted to the Italian situation. Cost data (Euro, 2002 values) were collected through a literature review. Several vaccination scenarios were analysed: (i) routine vaccination programme for children aged 1-2 years with different levels of vaccination coverage (90%, 70% and 45%) without any catch-up programme; (ii) routine vaccination programme for children aged 1-2 years with different levels of vaccination coverage (90%, 70% and 45%) completed by a catch-up programme for 6-year-old children over the first 5 years of vaccine marketing; and (iii) routine vaccination programme for children aged 1-2 years with different levels of vaccination coverage (90%, 70% and 45%) completed by a catch-up programme during the first year of vaccine marketing for children aged 2-11 years. PERSPECTIVES: A societal perspective, including both direct and indirect costs, and a health-system perspective, limited to costs supported by Italian Health Authorities, were considered. RESULTS: A routine vaccination programme has a clearly positive impact on chickenpox morbidity. Respectively, 68% and 57% of chickenpox-related hospitalisations and deaths could be prevented with a 90% coverage rate. With vaccination costs being more than offset by a reduction in chickenpox treatment costs in the base case, such a programme could also induce savings from both a societal and a health-system perspective (40% and 12% savings, respectively for a 90% coverage rate). A lower coverage rate reduces cost savings, but there is still a 9% decrease in overall societal costs for a 45% coverage rate. Although the reduction in total societal costs was robust to the sensitivity analyses performed, a slight uncertainty remains regarding cost reduction from a health-system perspective. However, in this latter perspective, even in the worst-case scenario of the sensitivity analysis, routine vaccination programmes may be cost effective, the worst-case scenario for cost parameters leading to cost per life-year gained of Euro2853. Catch-up programmes combined with routine vaccination should lead to further cost reductions from a societal perspective: 15% for a massive catch-up during the first year of vaccine marketing compared with toddlers' vaccination alone, and 11% for a catch-up focused on 6-year-old children for a period of 5 years. However, the impact of catch-up programmes on the costs from an Italian health-system perspective remains close to zero (+/-1%). CONCLUSION: This model suggests, with its underlying assumptions and data, that routine ZVZ vaccination may be cost saving from both a societal and a health system perspective in the base case. In the worst-case scenario of the sensitivity analysis, vaccination remains cost effective.