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.

Comparative study showed that children faced a 78% higher risk of new-onset conditions after they had COVID-19.

AIM: Children have largely been unaffected by severe COVID-19 compared to adults, but data suggest that they may have experienced new conditions after developing the disease. We compared outcomes in children who had experienced COVID-19 and healthy controls. METHODS: A retrospective nested cohort study assessed the incidence rate of new-onset conditions after COVID-19 in children aged 0-14 years. Data were retrieved from an Italian paediatric primary care database linked to Veneto Region registries. Exposed children with a positive nasopharyngeal swab were matched 1:1 with unexposed children who had tested negative. Conditional Cox regression was fitted to estimate the adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for the exposure and outcome associations after adjusting for covariates. RESULTS: We compared 1656 exposed and 1656 unexposed children from 1 February 2020 to 30 November 2021. The overall excess risk for new-onset conditions after COVID-19 was 78% higher in the exposed than unexposed children. We found significantly higher risks for some new conditions in exposed children, including mental health issues (aHR 1.8, 95% CI 1.1-3.0) and neurological problems (aHR 2.4, 95% CI 1.4-4.1). CONCLUSION: Exposed children had a 78% higher risk of developing new conditions of interest after COVID-19 than unexposed children.

Clinical features of COVID-19 in Italian outpatient children and adolescents during Parental, Delta, and Omicron waves: a prospective, observational, cohort study.

Introduction: COVID-19 features changed with the Omicron variant of SARS-CoV-2 in adults. This study aims to describe COVID-19 symptoms in children and adolescents during the Parental, Delta, and Omicron eras. Methods: A single-centre, prospective observational study was conducted on individuals aged 0-20 years attending the University Hospital of Padua (Italy) from April 2020 to December 2022. COVID-19 cases were defined by positive SARS-CoV-2 molecular detection and/or serology; patient/family symptoms and virological positivity were considered to determine the infection onset. Variables were summarized and compared using appropriate tests of descriptive statistics. Results: A total of 509 cases [46% female, median age eight years (IQR: 4-12)] were studied. Three-hundred-eighty-seven (76%), 52 (10%), and 70 (14%) subjects experienced COVID-19 during the Parental, Delta, and Omicron waves, respectively. All subjects developed an asymptomatic/mild COVID-19. Overall, the most frequent symptoms were fever (47%) and rhinitis (21%), which showed a significant increasing incidence from the Parental to Omicron waves (p < 0.001). Conversely, diarrhea was most common during the pre-Omicron eras (p = 0.03). Stratifying symptoms according to the age group, fever, rhinitis, and skin rashes were observed more frequently among infants/toddlers; conversely, fatigue was more common in children older than five years. The duration of symptoms was similar across different SARS-CoV-2 variants of concern (VOCs); conversely, the number of symptoms varied according to the age group (p < 0.0001). Discussion: This study showed differences in COVID-19 clinical presentation among infants, children, and adolescents and confirmed Omicron infection is more likely to be associated with upper respiratory symptoms. However, further population-based studies are needed to support these findings. In addition, active surveillance will play a crucial role in assessing the disease severity of future VOCs.

Therapeutic Options and Outcomes for the Treatment of Children with Gram-Positive Bacteria with Resistances of Concern: A Systematic Review.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase-negative Staphylococci (MR-CoNS), and vancomycin-resistant Enterococci (VRE) are increasing worldwide and represent a threat for the limited treatment options in pediatric patients and neonates compared to adults. Recommendations in pediatrics are mainly extrapolated from adults' studies. METHODS: A literature search for the treatment of these pathogens in children (<18 years old) was conducted in Embase, MEDLINE, and Cochrane Library. Studies reporting data on single-patient-level outcomes related to a specific antibiotic treatment for multidrug resistant (MDR) Gram-positive bacterial infection in children were included. Studies reporting data from adults and children were included if single-pediatric-level information could be identified (PROSPERO registration: CRD42022383867). RESULTS: The search identified 11,740 studies (since January 2000), of which 48 fulfilled both the inclusion and the exclusion criteria and were included in the analysis: 29 for MRSA, 20 for VRE, and seven for MR-CoNS. Most studies were retrospective studies. Vancomycin was mainly used as a comparator, while linezolid and daptomycin were the most studied antimicrobials showing good efficacy. CONCLUSIONS: Linezolid showed a safety and efficacy profile in a neonatal setting; daptomycin is increasingly used for MRSA, but the evidence is scarce for VRE.

Early Treatments of Fragile Children with COVID-19-Results of CLEVER (Children COVID Early Treatment), a Retrospective, Observational Study.

(1) Background: SARS-CoV-2 infection is notably mild in children, though comorbidities may increase the risk of hospitalization and may represent a risk for increased disease severity. There is an urgent need for targeted therapies with an acceptable efficacy and safety profile. To date, most of the medicines for COVID-19-specific treatment are prescribed off-label for children due to a lack of clinical trials and consequent evidence in this population. (2) Methods: This was a retrospective, observational study investigating the safety of treatments for the prevention of severe COVID-19 in fragile pediatric patients who received monoclonal antibodies and antivirals for mild-to-moderate symptoms between December 2021 and July 2022. (3) Results: Thirty-two patients were included. Monoclonal antibodies were prescribed to 62%, intravenous antivirals to 22%, and oral antivirals to 16% of children. Sotrovimab was the most frequently prescribed drug among monoclonal antibodies and overall (59%). The second most prescribed drug was remdesivir (22%). No severe adverse drug reaction was reported. There was no progression to severe disease and no death cases due to COVID-19 or drug administration. At drug-type stratification, resolution of symptoms and swab positivity time showed no difference between the two groups at 7 and 28 days. Off-label prescriptions were 84% overall, and in similar proportions between the two groups. (4) Conclusions: in this small sample, antivirals seemed safe and showed no differences in efficacy as compared to MAbs for the early treatment of COVID-19 in fragile children, thus representing a valuable choice, even when administered off-label.

Perceived Psychological Impact on Children and Parents of Experiencing COVID-19 Infection in One or More Family Members.

SARS-CoV-2 infection may impair behavior and mental health; we explored the psychological impact on parents and children who experienced COVID-19 within their families. A cross-sectional web-based survey was conducted on families attending the COVID-19 Follow-up Clinic at the Department for Women's and Children's Health, Padua (Italy). From April 2020 to August 2021, 75 surveys were collected from 66 families (97 parents and 129 children); almost 70% of participants had COVID-19, mostly asymptomatic/mildly symptomatic, and the median time from infection to survey compilation was 164.7 days (SD 56). Most parents (>87%) reported positive relationships with family members either before, during, or after COVID-19. More than one-third of children and adolescents were unable to adapt to isolation. Among 31 pre-school children with a median age of 3 (SD 1.7), a change of one or more functions was reported for 74.2% of cases irrespective of COVID-19 status, particularly a change in circadian rhythm (25%), in relationship with parents (42.8%), and poor emotional control (36%). Among 74 children with a median age of 10.9 years (SD 2.7), 8.1% had a score indicating a disease; however, significant impairment in attention was reported for 16.7%, along with anxiety/depression and problems with conduct in 5.6% and 6.5% of cases, respectively.

Therapeutic Options and Outcomes for the Treatment of Neonates and Preterms with Gram-Negative Multidrug-Resistant Bacteria: A Systematic Review.

(1) Background: Infections caused by multidrug-resistant (MDR) or extensively drug-resistant (XDR) bacteria represent a challenge in the neonatal population due to disease severity and limited therapeutic possibilities compared to adults. The spread of antimicrobial resistance and drug availability differ significantly worldwide. The incidence of MDR bacteria has constantly risen, causing an increase in morbidity, mortality, and healthcare costs in both high-income (HIC) and low- and middle-income countries (LMIC). Therefore, more evidence is needed to define the possible use of newer molecules and to optimize combination regimens for the oldest antimicrobials in neonates. This systematic review aims to identify and critically appraise the current antimicrobial treatment options and the relative outcomes for MDR and XDR Gram-negative bacterial infections in the neonatal population. (2) Methods: A literature search for the treatment of MDR Gram-negative bacterial infections in neonates (term and preterm) was conducted in Embase, MEDLINE, and Cochrane Library. Studies reporting data on single-patient-level outcomes related to a specific antibiotic treatment for MDR Gram-negative bacterial infection in children were included. Studies reporting data from adults and children were included if single-neonate-level information could be identified. We focused our research on four MDROs: Enterobacterales producing extended-spectrum beta-lactamase (ESBL) or carbapenemase (CRE), Pseudomonas aeruginosa, and Acinetobacter baumannii. PROSPERO registration: CRD42022346739 (3) Results: The search identified 11,740 studies (since January 2000), of which 22 fulfilled both the inclusion and exclusion criteria and were included in the analysis. Twenty of these studies were conducted in LMIC. Colistin is the main studied and used molecule to treat Gram-negative MDR bacteria for neonate patients in the last two decades, especially in LMIC, with variable evidence of efficacy. Carbapenems are still the leading antibiotics for ESBL Enterobacterales, while newer molecules (i.e., beta-lactam agents/beta-lactamase inhibitor combination) are promising across all analyzed categories, but data are few and limited to HICs. (4) Conclusions: Data about the treatment of Gram-negative MDR bacteria in the neonatal population are heterogeneous and limited mainly to older antimicrobials. Newer drugs are promising but not affordable yet for many LMICs. Therefore, strategies cannot be generalized but will differ according to the country's epidemiology and resources. More extensive studies are needed to include new antimicrobials and optimize the combination strategies for the older ones.

Long-term Immune Response to SARS-CoV-2 Infection Among Children and Adults After Mild Infection.

Importance: Understanding the long-term immune response against SARS-CoV-2 infection in children is crucial to optimize vaccination strategies. Although it is known that SARS-CoV-2 antibodies may persist in adults 12 months after infection, data are limited in the pediatric population. Objective: To examine long-term anti-SARS-CoV-2 spike receptor-binding domain (S-RBD) IgG kinetics in children after SARS-CoV-2 infection. Design, Setting, and Participants: In this single-center, prospective cohort study, patients were enrolled consecutively from April 1, 2020, to August 31, 2021, at the COVID-19 Family Cluster Follow-up Clinic, Department of Women's and Children's Health, University Hospital of Padua. A cohort of 252 COVID-19 family clusters underwent serologic follow-up at 1 to 4, 5 to 10, and more than 10 months after infection with quantification of anti-S-RBD IgG by chemiluminescent immunoassay. Exposures: SARS-CoV-2 infection. Results: Among 902 study participants, 697 had confirmed SARS-CoV-2 infection, including 351 children or older siblings (mean [SD] age, 8.6 [5.1] years) and 346 parents (mean [SD] age, 42.5 [7.1] years). Among 697 cases, 674 (96.7%) were asymptomatic or mild. Children had significantly higher S-RBD IgG titers than older patients across all follow-up time points, with an overall median S-RBD IgG titer in patients younger than 3 years 5-fold higher than adults (304.8 [IQR, 139.0-516.6] kBAU/L vs 55.6 [24.2-136.0] kBAU/L, P < .001). Longitudinal analysis of 56 study participants sampled at least twice during follow-up demonstrated the persistence of antibodies up to 10 months from infection in all age classes, despite a progressive decline over time. Conclusions and Relevance: In this cohort study of Italian children and adults following SARS-CoV-2 infection different kinetics of SARS-CoV-2 antibodies were found across several age classes of individuals with asymptomatic or mild COVID-19, which could help in optimizing COVID-19 vaccination strategies and prevention policies. This work provides further evidence of sustained immune response in children up to 1 year after primary SARS-CoV-2 infection.

Antibiotic Prescription Patterns in the Paediatric Primary Care Setting before and after the COVID-19 Pandemic in Italy: An Analysis Using the AWaRe Metrics.

The containment measures following COVID-19 pandemic drastically reduced airway infections, but they also limited the access of patients to healthcare services. We aimed to assess the antibiotic prescription patterns in the Italian paediatric primary care setting before and after the containment measures implementation. For this retrospective analysis, we used a population database, Pedianet, collecting data of patients aged 0-14 years enrolled with family paediatricians (FP) from March 2019 to March 2021. Antibiotic prescriptions were classified according to WHO AWaRe classification. An interrupted time series evaluating the impact of the containment measures implementation on the monthly antibiotic index, on the access to watch index, and on the amoxicillin to co-amoxiclav index stratified by diagnosis was performed. Overall, 121,304 antibiotic prescriptions were retrieved from 134 FP, for a total of 162,260 children. From March 2020, the antibiotic index dropped by more than 80% for respiratory infections. The Access to Watch trend did not change after the containment measures, reflecting the propensity to prescribe more broad-spectrum antibiotics for respiratory infections even during the pandemic. Similarly, co-amoxiclav was prescribed more often than amoxicillin alone for all the diagnoses, with a significant variation in the trend slope for upper respiratory tract infections prescriptions.

Treatment for Severe Malaria: Post-Artesunate Delayed Haemolysis and Neutropenia.

Parenteral artesunate (AS) is the WHO first-line treatment recommended in adults and children for severe malaria. Post-artesunate delayed haemolysis (PADH) is an uncommon adverse reaction to AS with a mechanism that is not fully understood, occurring in adults and children. Neutropenia is another possible finding after AS treatment, albeit rare. We present the case of a child who experienced both effects after treatment with AS for imported severe Falciparum malaria with very high parasitaemia. In addition, thirty-five paediatric cases of PADH, five cases of delayed anaemia without known haemolysis, and fourteen cases of neutropenia after artesunate treatment were identified from the literature review. PADH seems to be a dose-independent reaction and is not strongly related to hyperparasitaemia, although it is more frequent in this case. To date, the benefits of AS outweigh its potential side effects. However, haematological follow-up is mandatory to avoid possible complications from anaemia and neutropenia, especially in children treated with other contemporary drugs.

Enteral Linezolid as an Effective Option to Treat an Extremely Preterm Infant with Bacillus cereus Sepsis.

We report the safe and effective use of oral linezolid for treatment of Bacillus cereus sepsis in an extremely preterm neonate, previously fed with human donor milk, in which a Brevibacillus sp. was eventually found. Due to several predisposing factors, premature, very low birth weight newborns are extremely vulnerable to invasive infections by environmental pathogens. After vancomycin microbiologic treatment failure (despite adequate blood concentrations and clinical response), linezolid was chosen for its optimal enteral absorption and bioavailability, also after exhaustion of peripheral venous heritage. No adverse events were recorded, with clinical cure. We reviewed the literature on B. cereus infections in newborns, together with the available evidence on the use of linezolid in similar contexts.