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Infants admitted to the neonatal intensive care unit, particularly those born preterm, are at high risk for infection due to the combination of an immature immune system, prolonged hospitalization, and frequent use of invasive devices. Emerging evidence suggests that multidrug-resistant gram-negative (MDR-GN) infections are increasing in neonatal settings, which directly threatens recent and ongoing advances in contemporary neonatal care. A rising prevalence of antibiotic resistance among common neonatal pathogens compounds the challenge of optimal management of suspected and confirmed neonatal infection. We review the epidemiology of MDR-GN infections in neonates in the United States and internationally, with a focus on extended-spectrum β-lactamase (ESBL)-producing Enterobacterales and carbapenem-resistant Enterobacterales (CRE). We include published single-center studies, neonatal collaborative reports, and national surveillance data. Risk factors for and mechanisms of resistance are discussed. In addition, we discuss current recommendations for empiric antibiotic therapy for suspected infections, as well as definitive treatment options for key MDR organisms. Finally, we review best practices for prevention and identify current knowledge gaps and areas for future research.ImpactSurveillance and prevention of MDR-GN infections is a pediatric research priority.A rising prevalence of MDR-GN neonatal infections, specifically ESBL-producing Enterobacterales and CRE, compounds the challenge of optimal management of suspected and confirmed neonatal infection.Future studies are needed to understand the impacts of MDR-GN infection on neonatal morbidity and mortality, and studies of current and novel antibiotic therapies should include a focus on the pharmacokinetics of such agents among neonates.

Background: The prevalence of multidrug-resistant organisms (MDROs) in the post-acute care setting is well-documented in adults. Few studies have investigated the prevalence in children. Methods: We performed a prospective, single-center study including children with tracheostomy tubes age 2 months to 17 years admitted to a 24-bed post-acute care unit within a quaternary care children’s hospital. Index respiratory and stool specimens were obtained within two weeks of admission. Subsequent specimens were obtained weekly thereafter for up to eight weeks. MDROs were identified using methicillin-resistant Staphylococcus aureus (MRSA), extended-spectrum beta-lactamase Enterobacterales (ESBL-E), and carbapenem-resistant Enterobacterales (CRE) selective media (CHROMagar, Hardy Diagnostics). ESBL-E and CRE colonies were additionally plated onto MacConkey agar and only lactose fermenting organisms were considered positive. Index MDRO status was defined using week one samples; if not available, week two results were substituted. New MDRO acquisition was defined as a negative index MDRO culture with a subsequent positive culture. Results: A total of 47 children were enrolled. Median age was 9 months (interquartile range [IQR], 5-31 months) and median hospital length of stay prior to post-acute care admission was 89 days (IQR 27, 158). The most common pre-existing medical conditions were congenital heart disease (19, 40%), severe neurologic impairment (19, 40%), and prematurity Conclusion: MDROs are common in children hospitalized in the post-acute care unit. Nearly half of this cohort acquired CRE following admission, highlighting the need for strict infection prevention and control measures and tailored empiric antibiotic strategies.

Background: Feedback reports summarizing clinician performance are effective tools to improve antibiotic stewardship in the ambulatory setting, but few studies have evaluated their effectiveness for pediatric inpatients. We developed and implemented feedback reports reflecting electronically-derived measures of appropriate antibiotic choice and duration for community acquired pneumonia (CAP) and measured their impact on appropriate antibiotic use in children hospitalized for CAP. Methods: We performed a single center quasi-experimental study including children 6 months to 17 years hospitalized for CAP between 12/1/2021-11/30/2023. Children with chronic medical conditions, ICU stays >48 hours, and outside transfers were excluded. The intervention occurred in 11/2022 and included clinician education, a monthly group-level feedback report disseminated by email (Figure 1), and a monthly review of clinician performance during a virtual quality improvement meeting. Patient characteristics were compared using chi-square or Wilcoxon rank sum tests. Interrupted time series analysis (ITSA) was used to measure the immediate change in the proportion of CAP encounters receiving both the appropriate antibiotic choice and duration, as well as the change in slope from the preintervention to the postintervention periods. Choice and duration were analyzed separately using ITSA as a secondary analysis. Results: There were 817 CAP encounters, including 420 preintervention and 397 postintervention. Patients admitted in the postintervention period were older (median age 2 years vs 3 years, P=0.03), but otherwise there were no differences in race, ethnicity, sex, ICU admission, or complicated pneumonia. Preintervention, 52% of encounters received both the appropriate antibiotic choice and duration; 96% of encounters received the appropriate antibiotic choice and 54% received the appropriate duration. The ITSA demonstrated an immediate 16% increase in the proportion of patients receiving both appropriate antibiotic choice and duration (95% confidence interval, 1-31%; P = 0.047) and no significant further increase over time following the intervention (P = 0.84) (Figure 2). When antibiotic choice was analyzed separately by ITSA, there was no immediate change or change over time in the proportion of patients receiving the appropriate antibiotic choice. In the ITSA of duration alone, there was an immediate 17% increase in the proportion receiving the appropriate duration (95% confidence interval, 2-33%; P = 0.03) and no change over time. Conclusion: Feedback reports generated from electronically-derived metrics of antibiotic choice and duration, combined with ongoing clinician education, increased the proportion of children with CAP treated with the appropriate antibiotic duration. Electronic feedback reports are a scalable and impactful intervention to improve antibiotic use in children hospitalized with CAP.

Background: Community-acquired pneumonia (CAP) is a common indication for antibiotic use in hospitalized children and is a key target for pediatric antimicrobial stewardship programs (ASPs). Building upon prior work, we developed and refined an electronic algorithm to identify children hospitalized with CAP and to evaluate the appropriateness of initial antibiotic choice and duration. Methods: We performed a cross-sectional study including children 6 months to 17 years hospitalized for CAP between January 1, 2019, and October 31, 2022, at a tertiary-care children’s hospital. CAP was defined electronically as an International Classification of Disease, Tenth Revision (ICD-10) code for pneumonia, a chest radiograph or chest computed tomography scan (CT) performed within 48 hours of admission, and systemic antibiotics administered within the first 48 hours of hospitalization and continued for at least 2 days. We applied the following exclusion criteria: patients transferred from another healthcare setting, those who died within 48 hours of hospitalization, children with complex chronic conditions, and those with intensive care unit stays >48 hours. Criteria for appropriate antibiotic choice and duration were defined based on established guidelines. Two physicians performed independent medical record reviews of 80 randomly selected patients (10% sample) to evaluate the performance of the electronic algorithm in (1) identifying patients treated for clinician-diagnosed CAP and (2) classifying antibiotic choice and duration as appropriate. A third physician resolved discrepancies. The electronic algorithm was compared to this medical record review, which served as the reference standard. Results: Of 80 children identified by the electronic algorithm, 79 (99%) were diagnosed with CAP based on medical record review. Antibiotic use was classified as the appropriate choice in 75 (94%) of 80 cases, and appropriate duration in 16 (20%) of 80 cases. The sensitivity of the electronic algorithm for identifying appropriate initial antibiotic choice was 94%; specificity could not be calculated because no events of inappropriate antibiotic choice were identified based on chart review. The sensitivity and specificity for determining appropriate duration were 88% and 97%, respectively (Table 1). Conclusions: The electronic algorithm accurately identified children hospitalized with CAP and demonstrated acceptable performance for identifying appropriate antibiotic choice and duration. Use of this electronic algorithm may improve the efficiency of stewardship activities and could facilitate alignment with updated accreditation standards. Future studies validating this algorithm at other centers are needed. Disclosures: None

BACKGROUNDInitial reports from the severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic described children as being less susceptible to coronavirus disease 2019 (COVID-19) than adults. Subsequently, a severe and novel pediatric disorder termed multisystem inflammatory syndrome in children (MIS-C) emerged. We report on unique hematologic and immunologic parameters that distinguish between COVID-19 and MIS-C and provide insight into pathophysiology.METHODSWe prospectively enrolled hospitalized patients with evidence of SARS-CoV-2 infection and classified them as having MIS-C or COVID-19. Patients with COVID-19 were classified as having either minimal or severe disease. Cytokine profiles, viral cycle thresholds (Cts), blood smears, and soluble C5b-9 values were analyzed with clinical data.RESULTSTwenty patients were enrolled (9 severe COVID-19, 5 minimal COVID-19, and 6 MIS-C). Five cytokines (IFN-γ, IL-10, IL-6, IL-8, and TNF-α) contributed to the analysis. TNF-α and IL-10 discriminated between patients with MIS-C and severe COVID-19. The presence of burr cells on blood smears, as well as Cts, differentiated between patients with severe COVID-19 and those with MIS-C.CONCLUSIONPediatric patients with SARS-CoV-2 are at risk for critical illness with severe COVID-19 and MIS-C. Cytokine profiling and examination of peripheral blood smears may distinguish between patients with MIS-C and those with severe COVID-19.FUNDINGFinancial support for this project was provided by CHOP Frontiers Program Immune Dysregulation Team; National Institute of Allergy and Infectious Diseases; National Cancer Institute; the Leukemia and Lymphoma Society; Cookies for Kids Cancer; Alex's Lemonade Stand Foundation for Childhood Cancer; Children's Oncology Group; Stand UP 2 Cancer; Team Connor; the Kate Amato Foundations; Burroughs Wellcome Fund CAMS; the Clinical Immunology Society; the American Academy of Allergy, Asthma, and Immunology; and the Institute for Translational Medicine and Therapeutics.

In this study evaluating BNT162b2, vaccine effectiveness against hospitalization for Covid-19 in the delta-predominant period among adolescents 12 to 18 years of age was more than 90%; during the omicron period, vaccine effectiveness was 40% against hospitalization and 79% against critical illness. Vaccine effectiveness against hospitalization was 68% among children 5 to 11 years of age.

In this study, maternal vaccination with an mRNA vaccine during pregnancy was less common among infants hospitalized for Covid-19 than among controls. The effectiveness of maternal vaccination against Covid-19 hospitalization of infants was 52% overall and was greater when delta, rather than omicron, was predominant.

Infections due to antibiotic-resistant organisms are increasing in prevalence and represent a major public health threat. Antibiotic overuse is a major driver of this epidemic, and antibiotic stewardship an important means of limiting antibiotic resistance. The intensive care unit (ICU) setting presents an intersection of opportunities and challenges for effective antibiotic stewardship, but limited data inform optimal stewardship interventions in this setting. In this review, we present unique considerations for stewardship interventions the ICU setting and summarize available data evaluating the impact of prospective audit and feedback, diagnostic test stewardship, rapid molecular diagnostic tests, and procalcitonin-guided algorithms for antibiotic discontinuation. The existing knowledge gaps ripe for future research are emphasized.

Background: Conditionally immortalized podocytes are valuable research tools but are difficult to efficiently transfect and do not provide graded transgene expression. Methods: Conditionally immortalized mouse podocyte cell lines were established employing a tetracycline-inducible system. Glomerular cells, isolated from transgenic mice bear- ing two transgenes, NPHS2-reverse tetracycline-controlled transactivator, rtTA (A transgene) and H2-Kb-thermosensitive SV40 T, ts58A (I transgene), were cloned. One clone (AI podocytes) expressing WT1 and synaptopodin was transfected with pBI-EGFP (enhanced green fluorescent protein, G transgene) and separately with ptTS-Neo (transcriptional suppressor, T transgene) to produce stable transformants, AIG podocytes and AIT podocytes. Results: AIG podocytes expressed EGFP at 33 and 37°C after doxycycline treatment, and retained podocin and rtTA mRNA expression and temperature-sensitive growth regulation. AIT podocytes, transiently transfected with luciferase-BI-EGFP (LG transgene), showed reduced background expression of EGFP and luciferase in the absence of doxycycline. In AITLG podocytes, generated by stable transfection of AIT podocytes with the LG transgene, luciferase expression was tightly regulated by doxycycline in a time- and concentration-dependent manner both at 33 and 37°C, although background expression was not entirely eliminated. These podocytes retained temperature-sensitive growth regulation and expression of podocyte differentiation markers. Conclusion: Mouse podocytes expressed tetracycline-induced transgenes efficiently while retaining differentiation markers.

To assess the impact of a diagnostic test stewardship intervention focused on tracheal aspirate cultures. Quality improvement intervention. Tertiary care pediatric intensive care unit (PICU). Mechanically ventilated children admitted between 9/2018 and 8/2022. We developed and implemented a consensus guideline for obtaining tracheal aspirate cultures through a series of Plan-Do-Study-Act cycles. Change in culture rates and broad-spectrum antibiotic days of therapy (DOT) per 100 ventilator days were analyzed using statistical process control charts. A secondary analysis comparing the preintervention baseline (9/2018-8/2020) to the postintervention period (9/2020-8/2021) was performed using Poisson regression. The monthly tracheal aspirate culture rate prior to the COVID-19 pandemic (9/2018-3/2020) was 4.6 per 100 ventilator days. A centerline shift to 3.1 cultures per 100 ventilator days occurred in 4/2020, followed by a second shift to 2.0 cultures per 100 ventilator days in 12/2020 after guideline implementation. In our secondary analysis, the monthly tracheal aspirate culture rate decreased from 4.3 cultures preintervention (9/2018-8/2020) to 2.3 cultures per 100 ventilator days postintervention (9/2020-8/2021) (IRR 0.52, 95% CI 0.47-0.59, < 0.01). Decreases in tracheal aspirate culture use were driven by decreases in inappropriate cultures. Treatment of ventilator-associated infections decreased from 1.0 to 0.7 antibiotic courses per 100 ventilator days ( = 0.03). There was no increase in mortality, length of stay, readmissions, or ventilator-associated pneumonia postintervention. A diagnostic test stewardship intervention was both safe and effective in reducing the rate of tracheal aspirate cultures and treatment of ventilator-associated infections in a tertiary PICU.