Impact of Intravenous Fat Emulsion Choice on Candida Biofilm, Hyphal Growth, and Catheter-Related Bloodstream Infections in Pediatric Patients.

BACKGROUND: Use of mixed-oil (MO) intravenous fat emulsion (IFE) was shown to inhibit Candida albicans biofilm formation and overall rate of catheter-related bloodstream infections (CR-BSIs) compared with soybean-oil (SO) IFE). We aimed to delineate this inhibitory mechanism and impact of IFE choice on distribution of fungal CR-BSIs. METHODS: Transcriptional profiling was conducted on C. albicans grown in SO-IFE, MO-IFE, or SO-IFE with capric acid. Overexpression strains of shared down-regulated genes were constructed using a tetracycline-off system to assess hypha and biofilm formation in IFEs. A 5-year retrospective multicenter cohort study was performed to assess differences in CR-BSIs caused by Candida species based on the IFE formulation received in pediatric patients. RESULTS: Genes significantly down-regulated in MO-IFE and SO-IFE with capric acid included CDC11, HGC1, and UME6. Overexpression of HGC1 or UME6 enabled filamentation in capric acid and MO-IFE. Interestingly, only overexpression of UME6 was sufficient to rescue biofilm growth in MO-IFE. MO-IFE administration was associated with a higher proportion of non-albicans Candida versus C. albicans CR-BSIs (42% vs 33%; odds ratio, 1.22 [95% confidence interval, .46-3.26]). CONCLUSIONS: MO-IFE affects C. albicans biofilm formation and hyphal growth via a UME6-dependent mechanism. A numerical but not statistically significant difference in distribution of Candida spp. among CR-BSIs was observed.

Delivery of carbohydrates, amino acids, and lipids via intravenous catheters is necessary for some patients to supply daily caloric needs. These nutrient-dense parenteral solutions can promote microbial biofilm growth on the catheter surface, which may seed subsequent catheter-related bloodstream infection (CR-BSI). In fact, receipt of parenteral nutrition is an established risk factor for CR-BSI caused by the polymorphic fungal pathogen Candida albicans. New intravenous fat emulsions (IFEs) have gained market share and IFEs containing capric acid (mixed-oil [MO] IFE) compared with those without (soybean-oil [SO] IFE) impair the C. albicans yeast-to-hypha switch­a trait strongly associated with pathogenicity and biofilm formation. In this study, we found that MO-IFE and capric acid reduced expression of a transcriptional regulator involved in hyphal extension (UME6) and down-regulated genes involved in cell partitioning (HGC1). Overexpression of these genes enabled hyphal growth in MO-IFE. Secondly, we sought to determine whether the type of IFE administered was associated with the clinical incidence of CR-BSIs caused by C. albicans or other common non-albicans Candida species. There was a nonsignificant numerical reduction in C. albicans infections in patients administered MO-IFE compared with SO-IFE. Collectively, this work shows that IFEs differentially affect Candida biology with potential infectious consequences for the patient.

Monoclonal Antibody Use for Coronavirus Disease 2019 in Pediatric Patients: A Multicenter Retrospective Study.

Monoclonal antibodies for COVID-19 are authorized in high-risk patients aged ≥12 years, but evidence in pediatric patients is limited. In our cohort of 142 patients treated at seven pediatric hospitals between 12/1/20 and 7/31/21, 9% developed adverse events, 6% were admitted for COVID-19 within 30 days, and none received ventilatory support or died.

Impact of Severe Acute Respiratory Syndrome Coronavirus 2 Variants on Short- and Mid-term Cardiac Outcomes in Multisystem Inflammatory Syndrome in Children.

Cardiac outcomes of 131 children with multisystem inflammatory syndrome (MIS-C) were examined. The majority of the cohort was male (66.4%) and half were Black (49.6%). Cardiac involvement was evident in 25% of the cohort at diagnosis. Favorable short- and mid-term outcomes were documented on follow-up, irrespective of the severe acute respiratory syndrome coronavirus 2 variants causing the infection.

Increasing Prevalence of Pediatric Community-acquired UTI by Extended Spectrum ß-Lactamase-producing E. coli: Cause for Concern.

BACKGROUND: Antimicrobial resistance and emerging spectrum-ß-lactamase (ESBL) infections are a rising concern in public health. Despite the increasing prevalence of community-acquired (CA) ESBL-E. coli UTIs, there is little data on the antibiotic resistance profiles of this bacterial strain in the pediatric population. We review antibiotic resistance profile and rising trend in pediatric ESBL-E. coli UTI presentation at our pediatric hospital. METHODS: This retrospective study reviewed data drawn from the infectious disease database at our pediatric hospital for all patients whose urine culture grew ESBL-E. coli from 01/2015 to 01/2021. Demographic information and antimicrobial susceptibility test results for ESBL-E. coli isolates from CA-UTIs were collected. Annual changes in resistance to antimicrobial agents and average annual percent change in ESBL-E. coli UTI presentation over the study period are reported. RESULTS: From 01/2015 to 01/2021, 6403 urine cultures at our hospital grew E. coli. Of these, 169 urine cultures from 135 children grew ESBL-E. coli. The study population was 57% male (77) with a mean age of 6.9 ± 6.2 years and multiethnic. CA-UTI by ESBL-producing E. coli accounted for 2.62% of total E. coli UTIs within the study period and increased from 0.97% in 2015 to 3.54% in 2020 by an average of 0.51% each year. CONCLUSIONS: These findings demonstrate an increase in CA-ESBL E. coli UTIs in children. We observed most isolates demonstrated multidrug resistance. As CA-ESBL E. coli UTIs are associated with prolonged hospitalization and increased morbidity, our findings highlight the rising trend in pediatric CA-ESBL E. coli UTI.

Risk factors for community acquired pediatric urinary tract infection with extended-spectrum-ß-lactamase Escherichia coli - A case-control study.

INTRODUCTION: Community-acquired (CA) infections caused by extended-spectrum ß-lactamase (ESBL) producing Escherichia coli urinary tract infections (UTI) have become increasingly prevalent, posing a serious threat to public health. Risk factors for ESBL UTI have not been extensively studied in the pediatric population. We report findings from a case control study to identify risk factors for CA ESBL-producing E. coli UTI in children. MATERIALS AND METHOD: A cohort of children with CA ESBL Escherichia coli UTI evaluated at a tertiary referral hospital from January 2014 through April 2021, were matched 1:3 with control group of non-ESBL CA E. coli UTI based on age at first episode of non-ESBL UTI. To identify potential risk factors for ESBL E. coli UTI, conditional logistic regression model was utilized accounting for age matching. Univariate models were fitted for each clinical risk factor. Factors found to be significantly associated with ESBL UTI were simultaneously included in a single model to check for associations adjusted for all other factors. RESULTS: On conditional multivariate analyses for univariate testing, male sex (P = 0.021), history of Urology care (P = 0.001), and antibiotic treatment within 30 days prior to positive culture (P = 0.004) were identified as independent risk factors for CA ESBL E. coli UTI. Comorbidity scores were assigned to each patient according to pediatric comorbidity index (PCI); children with ESBL UTI were more likely to have higher morbidity risk than non-ESBL UTI children (P < 0.001). From the logistic model, the higher the morbidity scores, the more likely children will have CA ESBL UTI (P < 0.001). DISCUSSION: Identifying risk factors for ESBL-producing E. coli UTI in children is important because of limited therapeutic options. This knowledge is essential for clinical decision making and to develop intervention strategies to reduce disease burden. Our study found that although females have an increased predisposition to UTIs, we observed that the male sex is an independent risk factor for ESBL E. coli UTI. This finding warrants further investigation to determine underlying cause. Because of the retrospective design of the study, collection of data from a single center, and differences in characteristics between patient populations, treatments, and prescribing patterns in the community, this study may not be generalizable. CONCLUSIONS: Findings from our case-control study suggest that the male sex, history of Urology care, and previous antibiotic exposure are independent risk factors for CA ESBL-GNB UTI. Children with ESBL E. coli UTI are more likely to have longer admission duration and higher comorbidity index.

SARS-CoV-2 infection in hospitalized children with type 1 and type 2 diabetes.

CONTEXT: While diabetes is a risk factor for severe illness from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in adults, there is conflicting data surrounding the relationship between the virus and diabetic disease process in children. OBJECTIVE: This case series aims to illustrate an increase in the incidence of types 1 and 2 diabetes mellitus (T1DM, T2DM) between April - November 2020 at a large tertiary care children's hospital and examine the characteristics and adverse outcomes in these children. In addition, two children with significant complications from coronavirus disease 2019 (COVID-19) and diabetes are highlighted. METHODS: Hospitalized children with T1DM or T2DM and SARS-CoV-2 infection were identified, and electronic medical records were reviewed. RESULTS: We observed a 16.3% increased rate of new-onset T1DM and 205.3% increased rate of new-onset insulin-dependent T2DM between April and November 2020 when compared to the same observational time frame in 2019. Among children with new-onset T1DM, 56.9% presented with DKA in 2019 and 47.1% in 2018 compared to 64.3% in 2020, which was higher than the national average. Twenty-eight children were diagnosed with COVID-19 and diabetes during this time. The 2 described cases with significant complications from COVID-19 and DKA required large doses of intravenous insulin over a prolonged duration. CONCLUSION: This study highlights that the COVID-19 pandemic might have led to an increased rate of new-onset T1DM, T2DM, and DKA in children and adolescents compared to a similar time frame in the prior 2 years. The clinical phenotypes and outcomes in children with diabetes to COVID-19 infection may be distinct and therefore, future pediatric specific studies are needed to define the role of SARS-CoV-2.

Challenges of Antibiotic Stewardship in the Pediatric and Neonatal Intensive Care Units.

The goals of antimicrobial stewardship programs (ASPs) are to optimize antimicrobial prescribing habits in order to improve patient outcomes, reduce antimicrobial resistance, and reduce hospital costs. Multiple society-endorsed guidelines and government policies reinforce the importance of ASP implementation. Effective antimicrobial stewardship can impact unique patients, hospitals, and societal antibiotic-resistance burden. The role and subsequent success of these programs has largely been reported in the adult population. Pediatric and neonatal intensive care units present unique challenges for traditional antimicrobial stewardship approaches. The purpose of this review article is to explore the challenges of appropriate antibiotic use in the pediatric and neonatal intensive care units and to summarize strategies ASPs can use to overcome these challenges. These problems include non-specific disease presentations, limited evidence for definitive treatment durations in many pediatric infections, fewer pediatric-trained infectious disease physicians, and applicability of intensive laboratory obtainment, collection, and interpretation. Additionally, many ASP implementation studies evaluating the efficacy of ASPs exclude the PICU and NICU. Areas of focus for pediatric ASPs should likely include appropriate antibiotic initiation, appropriate antibiotic duration, and appropriate antibiotic de-escalation.

Virological Characteristics of Hospitalized Children With SARS-CoV-2 Infection.

BACKGROUND AND OBJECTIVES: In children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, virological characteristics and correlation with disease severity have not been extensively studied. The primary objective in this study is to determine the correlation between SARS-CoV-2 viral load (VL) in infected children with age, disease severity, and underlying comorbidities. METHODS: Children <21 years, screened for SARS-CoV-2 at the time of hospitalization, who tested positive by polymerase chain reaction were included in this study. VL at different sites was determined and compared between groups. RESULTS: Of the 102 children included in this study, 44% of the cohort had asymptomatic infection, and children with >1 comorbidity were the most at risk for severe disease. VL in children with symptomatic infection was significantly higher than in children with asymptomatic infection (3.0 × 105 vs 7.2 × 103 copies per mL; P = .001). VL in the respiratory tract was significantly higher in children <1 year, compared with older children (3.3 × 107 vs 1.3 × 104 copies per mL respectively; P < .0001), despite most infants presenting with milder illness. Besides the respiratory tract, SARS-CoV-2 RNA was also detectable in samples from the gastrointestinal tract (saliva and rectum) and blood. In 13 children for whom data on duration of polymerase chain reaction positivity was available, 12 of 13 tested positive 2 weeks after initial diagnosis, and 6 of 13 continued to test positive 4 weeks after initial diagnosis. CONCLUSIONS: In hospitalized children with SARS-CoV-2, those with >1 comorbid condition experienced severe disease. SARS-CoV-2 VL in the respiratory tract is significantly higher in children with symptomatic disease and children <1 year of age.

Initial Guidance on Use of Monoclonal Antibody Therapy for Treatment of Coronavirus Disease 2019 in Children and Adolescents.

BACKGROUND: In November 2020, the US Food and Drug Administration (FDA) provided Emergency Use Authorizations (EUA) for 2 novel virus-neutralizing monoclonal antibody therapies, bamlanivimab and REGN-COV2 (casirivimab plus imdevimab), for the treatment of mild to moderate coronavirus disease 2019 (COVID-19) in adolescents and adults in specified high-risk groups. This has challenged clinicians to determine the best approach to use of these products. METHODS: A panel of experts in pediatric infectious diseases, pediatric infectious diseases pharmacy, pediatric intensive care medicine, and pediatric hematology from 29 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a guidance statement was developed and refined based on review of the best available evidence and expert opinion. RESULTS: The course of COVID-19 in children and adolescents is typically mild and there is no high-quality evidence supporting any high-risk groups. There is no evidence for safety and efficacy of monoclonal antibody therapy for treatment of COVID-19 in children or adolescents, limited evidence of modest benefit in adults, and evidence for potential harm associated with infusion reactions or anaphylaxis. CONCLUSIONS: Based on evidence available as of December 20, 2020, the panel suggests against routine administration of monoclonal antibody therapy (bamlanivimab, or casirivimab and imdevimab), for treatment of COVID-19 in children or adolescents, including those designated by the FDA as at high risk of progression to hospitalization or severe disease. Clinicians and health systems choosing to use these agents on an individualized basis should consider risk factors supported by pediatric-specific evidence and ensure the implementation of a system for safe and timely administration that does not exacerbate existing healthcare disparities.

Multicenter Interim Guidance on Use of Antivirals for Children With Coronavirus Disease 2019/Severe Acute Respiratory Syndrome Coronavirus 2.

BACKGROUND: Although coronavirus disease 2019 (COVID-19) is a mild infection in most children, a small proportion develop severe or critical illness. Data describing agents with potential antiviral activity continue to expand such that updated guidance is needed regarding use of these agents in children. METHODS: A panel of pediatric infectious diseases physicians and pharmacists from 20 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a set of guidance statements was developed and refined based on review of the best available evidence and expert opinion. RESULTS: Given the typically mild course of COVID-19 in children, supportive care alone is suggested for most cases. For children with severe illness, defined as a supplemental oxygen requirement without need for noninvasive or invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO), remdesivir is suggested, preferably as part of a clinical trial if available. Remdesivir should also be considered for critically ill children requiring invasive or noninvasive mechanical ventilation or ECMO. A duration of 5 days is appropriate for most patients. The panel recommends against the use of hydroxychloroquine or lopinavir-ritonavir (or other protease inhibitors) for COVID-19 in children. CONCLUSIONS: Antiviral therapy for COVID-19 is not necessary for the great majority of pediatric patients. For children with severe or critical disease, this guidance offers an approach for decision-making regarding use of remdesivir.

Management of Cepacia Syndrome With a Combination of Intravenous and Inhaled Antimicrobials in a Non-Cystic Fibrosis Pediatric Patient.

Burkholderia cepacia complex (Bcc) is an opportunistic pathogen, posing little risk to healthy individuals. The presentation of Bcc can vary from a virtually asymptomatic chronic infection, to an acute, life-threatening necrotizing pneumonia, acute respiratory distress syndrome, and bacteremia (cepacia syndrome) associated with a mortality rate up to 75%. We present the successful treatment of a 17-year-old male with chronic granulomatous disorder who presented with cepacia syndrome and confirmed Bcc pneumonia using a novel antimicrobial approach. Despite initial IV antimicrobial therapy, our patient continued to decline, developing hypotension requiring pressor support and eventually extracorporeal membrane oxygenation. An aggressive, multimechanistic approach including the combination of nebulized tobramycin, IV sulfamethoxazole-trimethoprim, ceftazidime, enteral minocycline, and corticosteroids was implemented. This multimechanistic antimicrobial approach in combination with systemic corticosteroids led to the successful treatment of cepacia syndrome in the setting of necrotizing pneumonia due to B cepacia with full respiratory recovery. We suggest that in patients with cepacia syndrome who continue to decline despite IV antimicrobial therapy, using multiple antimicrobial mechanisms of action may improve clinical outcomes.

Multidisciplinary Guidance Regarding the Use of Immunomodulatory Therapies for Acute Coronavirus Disease 2019 in Pediatric Patients.

BACKGROUND: Immune-mediated lung injury and systemic hyperinflammation are characteristic of severe and critical coronavirus disease 2019 (COVID-19) in adults. Although the majority of severe acute respiratory syndrome coronavirus 2 infections in pediatric populations result in minimal or mild COVID-19 in the acute phase of infection, a small subset of children develop severe and even critical disease in this phase with concomitant inflammation that may benefit from immunomodulation. Therefore, guidance is needed regarding immunomodulatory therapies in the setting of acute pediatric COVID-19. This document does not provide guidance regarding the recently emergent multisystem inflammatory syndrome in children (MIS-C). METHODS: A multidisciplinary panel of pediatric subspecialty physicians and pharmacists with expertise in infectious diseases, rheumatology, hematology/oncology, and critical care medicine was convened. Guidance statements were developed based on best available evidence and expert opinion. RESULTS: The panel devised a framework for considering the use of immunomodulatory therapy based on an assessment of clinical disease severity and degree of multiorgan involvement combined with evidence of hyperinflammation. Additionally, the known rationale for consideration of each immunomodulatory approach and the associated risks and benefits was summarized. CONCLUSIONS: Immunomodulatory therapy is not recommended for the majority of pediatric patients, who typically develop mild or moderate COVID-19. For children with severe or critical illness, the use of immunomodulatory agents may be beneficial. The risks and benefits of such therapies are variable and should be evaluated on a case-by-case basis with input from appropriate specialty services. When available, the panel strongly favors immunomodulatory agent use within the context of clinical trials. The framework presented herein offers an approach to decision-making regarding immunomodulatory therapy for severe or critical pediatric COVID-19 and is informed by currently available data, while awaiting results of placebo-controlled randomized clinical trials.

Ceftaroline vs vancomycin for the treatment of acute pulmonary exacerbations in pediatric patients with cystic fibrosis.

INTRODUCTION: Respiratory infection with methicillin-resistant Staphylococcus aureus (MRSA) is an increasing complication in cystic fibrosis (CF) that results in accelerated lung function decline and mortality. Vancomycin is considered a first-line intravenous treatment agent for MRSA associated acute pulmonary exacerbations (APEs); however, rates of vancomycin intolerance and resistance have been observed. These factors have led to the exploration of additional treatment options for treating MRSA associated APEs. METHODS: This is a retrospective chart review conducted at a CF center including patients 0 to 21 years of age with CF admitted for an APE and treated with either vancomycin or ceftaroline between January 2016 and August 2018. The primary endpoint was to determine ceftaroline efficacy compared to vancomycin in the treatment of MRSA associated APEs. RESULTS: There were 180 patients included in the study with 90 patients in each antibiotic group. Admission to discharge forced expiratory volume in 1 second (FEV1 ) improved in the ceftaroline (66.5% vs 81.1%; P < .001) and vancomycin (65.5% vs 77.3%; P < .001) treatment groups. No difference existed in mean change in FEV1 (14.1% vs 13.5%; P = .25) or readmissions (15% vs 22; P = .27) between ceftaroline and vancomycin groups, respectively. DISCUSSION: In this retrospective study, no difference existed between ceftaroline and vancomycin with regard to observed improvement in lung function from admission to discharge. Additionally, no difference was observed in mean FEV1 or readmission rate between the two groups. Ceftaroline may represent an effective and safe intravenous antimicrobial option for targeting MRSA in pediatric CF patients with APEs.

Multicenter Initial Guidance on Use of Antivirals for Children With Coronavirus Disease 2019/Severe Acute Respiratory Syndrome Coronavirus 2.

BACKGROUND: Although coronavirus disease 2019 (COVID-19) is mild in nearly all children, a small proportion of pediatric patients develop severe or critical illness. Guidance is therefore needed regarding use of agents with potential activity against severe acute respiratory syndrome coronavirus 2 in pediatrics. METHODS: A panel of pediatric infectious diseases physicians and pharmacists from 18 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a set of guidance statements was developed and refined based on review of best available evidence and expert opinion. RESULTS: Given the typically mild course of pediatric COVID-19, supportive care alone is suggested for the overwhelming majority of cases. The panel suggests a decision-making framework for antiviral therapy that weighs risks and benefits based on disease severity as indicated by respiratory support needs, with consideration on a case-by-case basis of potential pediatric risk factors for disease progression. If an antiviral is used, the panel suggests remdesivir as the preferred agent. Hydroxychloroquine could be considered for patients who are not candidates for remdesivir or when remdesivir is not available. Antivirals should preferably be used as part of a clinical trial if available. CONCLUSIONS: Antiviral therapy for COVID-19 is not necessary for the great majority of pediatric patients. For those rare cases of severe or critical disease, this guidance offers an approach for decision-making regarding antivirals, informed by available data. As evidence continues to evolve rapidly, the need for updates to the guidance is anticipated.