Racial, ethnic and socioeconomic disparities in SARS-CoV-2 infection amongst children.

BACKGROUND: COVID-19 disproportionately affects racial and ethnic minority populations, but comparatively few epidemiologic studies have been performed on children as compared to adults. OBJECTIVES: To characterise factors associated with SARS-CoV-2 infections amongst children from Chicago, Illinois, USA. METHODS: A test-negative case-control study of children tested for SARS-CoV-2 (0-18 years) at three medical centres of the Rush University System for Health between 12 March and 7 December 2020 was conducted. Of 8462 children, 1,302 tested positive by real-time PCR or rapid (NAAT) testing. Infection with SARS-CoV-2 was analysed as the outcome variable; effects of predictors were assessed by logistic regression analysis. A Paediatric Risk Score Index with a concordance index of 72% of accuracy was created to predict SARS-CoV-2 infection. RESULTS: The median age of cases was 13 years. On multivariable analysis, factors associated with SARS-CoV-2 infection were being Hispanic/Latinx (odds ratio [OR] 2.45, 95% CI 1.99, 3.03); Black/African-American (OR 1.31, 95% CI 1.03, 1.66); overweight/obese (OR 1.27, 95% CI 1.02, 1.58); older age, 10-14 years (OR 1.70, 95% CI 1.39, 2.08), 15-18 years (OR 2.06, 95% CI 1.71, 2.47); from households with income <$50,000 (OR 1.36, 95% CI 1.17, 1.60); or residing in predominantly minority neighbourhoods (OR 1.45, 95% CI 1.17, 1.80). Infections were higher during the second "fall" wave (5 October 2020 onward) compared with the first "spring" wave (OR 2.30, 95% CI 2.01, 2.63). Within Chicago, racial/ethnic minority neighbourhoods had striking positivity rates, as high as 39% in majority Hispanic/Latinx West Lawn neighbourhood. In suburban Chicago, highest positivity rates (20%-28%) were in zip codes within Hispanic/Latinx communities. CONCLUSIONS: Infection with SARS-CoV-2 is more likely amongst children of Hispanic/Latinx ethnicity, Black/African-American race, aged 10-18 years, who are overweight/obese, from lower income households, and from minority neighbourhoods. Future studies should focus on the prevention of COVID-19 infection in children of highest risk.

A Pilot Study of Chicago Waterways as Reservoirs of Multidrug-Resistant Enterobacteriaceae (MDR-Ent) in a High-Risk Region for Community-Acquired MDR-Ent Infection in Children.

Community-acquired multidrug resistant Enterobacteriaceae (MDR-Ent) infections continue to increase in the United States. In prior studies, we identified neighboring regions in Chicago, Illinois, where children have 5 to 6 times greater odds of MDR-Ent infections. To prevent community spread of MDR-Ent, we need to identify the MDR-Ent reservoirs. A pilot study of 4 Chicago waterways for MDR-Ent and associated antibiotic resistance genes (ARGs) was conducted. Three waterways (A1 to A3) are labeled safe for "incidental contact recreation" (e.g., kayaking), and A4 is a nonrecreational waterway that carries nondisinfected water. Surface water samples were collected and processed for standard bacterial culture and shotgun metagenomic sequencing. Generally, A3 and A4 (neighboring waterways which are not hydraulically connected) were strikingly similar in bacterial taxa, ARG profiles, and abundances of corresponding clades and genera within the Enterobacteriaceae Additionally, total ARG abundances recovered from the full microbial community were strongly correlated between A3 and A4 (R2 = 0.97). Escherichia coli numbers (per 100 ml water) were highest in A4 (783 most probable number [MPN]) and A3 (200 MPN) relative to A2 (84 MPN) and A1 (32 MPN). We found concerning ARGs in Enterobacteriaceae such as MCR-1 (colistin), Qnr and OqxA/B (quinolones), CTX-M, OXA and ACT/MIR (beta-lactams), and AAC (aminoglycosides). We found significant correlations in microbial community composition between nearby waterways that are not hydraulically connected, suggesting cross-seeding and the potential for mobility of ARGs. Enterobacteriaceae and ARG profiles support the hypothesized concerns that recreational waterways are a potential source of community-acquired MDR-Ent.

The Epidemiology of Carbapenem-Resistant Enterobacteriaceae: The Impact and Evolution of a Global Menace.

Carbapenem-resistant Enterobacteriaceae (CRE) are a serious public health threat. Infections due to these organisms are associated with significant morbidity and mortality. Mechanisms of drug resistance in gram-negative bacteria (GNB) are numerous; ß-lactamase genes carried on mobile genetic elements are a key mechanism for the rapid spread of antibiotic-resistant GNB worldwide. Transmissible carbapenem-resistance in Enterobacteriaceae has been recognized for the last 2 decades, but global dissemination of carbapenemase-producing Enterobacteriaceae (CPE) is a more recent problem that, once initiated, has been occurring at an alarming pace. In this article, we discuss the evolution of CRE, with a focus on the epidemiology of the CPE pandemic; review risk factors for colonization and infection with the most common transmissible CPE worldwide, Klebsiella pneumoniae carbapenemase-producing K. pneumoniae; and present strategies used to halt the striking spread of these deadly pathogens.

Factors Associated With Pediatric Ventilator-Associated Conditions in Six U.S. Hospitals: A Nested Case-Control Study.

OBJECTIVES: A newly proposed surveillance definition for ventilator-associated conditions among neonatal and pediatric patients has been associated with increased morbidity and mortality among ventilated patients in cardiac ICU, neonatal ICU, and PICU. This study aimed to identify potential risk factors associated with pediatric ventilator-associated conditions. DESIGN: Retrospective cohort. SETTING: Six U.S. hospitals PATIENTS:: Children less than or equal to 18 years old ventilated for greater than or equal to 1 day. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We identified children with pediatric ventilator-associated conditions and matched them to children without ventilator-associated conditions. Medical records were reviewed for comorbidities and acute care factors. We used bivariate and multivariate conditional logistic regression models to identify factors associated with ventilator-associated conditions. We studied 192 pairs of ventilator-associated conditions cases and matched controls (113 in the PICU and cardiac ICU combined; 79 in the neonatal ICU). In the PICU/cardiac ICU, potential risk factors for ventilator-associated conditions included neuromuscular blockade (odds ratio, 2.29; 95% CI, 1.08-4.87), positive fluid balance (highest quartile compared with the lowest, odds ratio, 7.76; 95% CI, 2.10-28.6), and blood product use (odds ratio, 1.52; 95% CI, 0.70-3.28). Weaning from sedation (i.e., decreasing sedation) or interruption of sedation may be protective (odds ratio, 0.44; 95% CI, 0.18-1.11). In the neonatal ICU, potential risk factors included blood product use (odds ratio, 2.99; 95% CI, 1.02-8.78), neuromuscular blockade use (odds ratio, 3.96; 95% CI, 0.93-16.9), and recent surgical procedures (odds ratio, 2.19; 95% CI, 0.77-6.28). Weaning or interrupting sedation was protective (odds ratio, 0.07; 95% CI, 0.01-0.79). CONCLUSIONS: In mechanically ventilated neonates and children, we identified several possible risk factors associated with ventilator-associated conditions. Next steps include studying propensity-matched cohorts and prospectively testing whether changes in sedation management, transfusion thresholds, and fluid management can decrease pediatric ventilator-associated conditions rates and improve patient outcomes.

Analysis of ß-Lactamase Resistance Determinants in Enterobacteriaceae from Chicago Children: a Multicenter Survey.

Multidrug-resistant (MDR) Enterobacteriaceae infections are increasing in U.S. children; however, there is a paucity of multicentered analyses of antibiotic resistance genes responsible for MDR phenotypes among pediatric Enterobacteriaceae isolates. In this study, 225 isolates phenotypically identified as extended-spectrum ß-lactamase (ESBL) or carbapenemase producers, recovered from children ages 0 to 18 years hospitalized between January 2011 and April 2015 at three Chicago area hospitals, were analyzed. We used DNA microarray platforms to detect ESBL, plasmid-mediated AmpC (pAmpC), and carbapenemase type ß-lactamase (bla) genes. Repetitive-sequence-based PCR and multilocus sequence typing (MLST) were performed to assess isolate similarity. Plasmid replicon typing was conducted to classify plasmids. The median patient age was 4.2 years, 56% were female, and 44% presented in the outpatient setting. The majority (60.9%) of isolates were Escherichia coli and from urinary sources (69.8%). Of 225 isolates exhibiting ESBL- or carbapenemase-producing phenotypes, 90.7% contained a bla gene. The most common genotype was the blaCTX-M-1 group (49.8%); 1.8% were carbapenem-resistant Enterobacteriaceae (three blaKPC and one blaIMP). Overall, pAmpC (blaACT/MIR and blaCMY) were present in 14.2%. The predominant E. coli phylogenetic group was the virulent B2 group (67.6%) associated with ST43/ST131 (Pasteur/Achtman MLST scheme) containing the blaCTX-M-1 group (84%), and plasmid replicon types FIA, FII, and FIB. K. pneumoniae harboring blaKPC were non-ST258 with replicon types I1 and A/C. Enterobacter spp. carrying blaACT/MIR contained plasmid replicon FIIA. We found that ß-lactam resistance in children is diverse and that certain resistance mechanisms differ from known circulating genotypes in adults in an endemic area. The potential impact of complex molecular types and the silent dissemination of MDR Enterobacteriaceae in a vulnerable population needs to be studied further.

Ventilator-Associated Events in Neonates and Children--A New Paradigm.

OBJECTIVES: To identify a pediatric ventilator-associated condition definition for use in neonates and children by exploring whether potential ventilator-associated condition definitions identify patients with worse outcomes. DESIGN: Retrospective cohort study and a matched cohort analysis. SETTING: Pediatric, cardiac, and neonatal ICUs in five U.S. hospitals. PATIENTS: Children 18 years old or younger ventilated for at least 1 day. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We evaluated the evidence of worsening oxygenation via a range of thresholds for increases in daily minimum fraction of inspired oxygen (by 0.20, 0.25, and 0.30) and daily minimum mean airway pressure (by 4, 5, 6, and 7 cm H2O). We required worsening oxygenation be sustained for at least 2 days after at least 2 days of stability. We matched patients with a ventilator-associated condition to those without and used Cox proportional hazard models with frailties to examine associations with hospital mortality, hospital and ICU length of stay, and duration of ventilation. The cohort included 8,862 children with 10,209 hospitalizations and 77,751 ventilator days. For the fraction of inspired oxygen 0.25/mean airway pressure 4 definition (i.e., increase in minimum daily fraction of inspired oxygen by 0.25 or mean airway pressure by 4), rates ranged from 2.9 to 3.2 per 1,000 ventilator days depending on ICU type; the fraction of inspired oxygen 0.30/mean airway pressure 7 definition yielded ventilator-associated condition rates of 1.1-1.3 per 1,000 ventilator days. All definitions were significantly associated with greater risk of hospital death, with hazard ratios ranging from 1.6 (95% CI, 0.7-3.4) to 6.8 (2.9-16.0), depending on thresholds and ICU type. Each definition was associated with prolonged hospitalization, time in ICU, and duration of ventilation, among survivors. The advisory board of the study proposed using the fraction of inspired oxygen 0.25/mean airway pressure 4 thresholds to identify pediatric ventilator-associated conditions in ICUs. CONCLUSIONS: Pediatric patients with ventilator-associated conditions are at substantially higher risk for mortality and morbidity across ICUs, regardless of thresholds used. Next steps include identification of risk factors, etiologies, and preventative measures for pediatric ventilator-associated conditions.

Extended-spectrum ß-lactamase-producing Enterobacteriaceae in children: old foe, emerging threat.

Extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae present an ever-growing burden in the hospital and community settings, across all ages and demographics. Infections due to ESBL-containing pathogens continue to be associated with significant morbidity and mortality worldwide. With widespread empiric broad-spectrum ß-lactam use creating selective pressure, and the resultant emergence of stable, rapidly proliferating ESBL-producing clones with continued horizontal gene transfer across genera, addressing this issue remains imperative. Although well characterized in adults, the epidemiology, risk factors, outcomes, therapies, and control measures for ESBL-producing bacteria are less appreciated in children. This analysis provides a brief summary of ESBL-producing Enterobacteriaceae in children, with a focus on recent clinical and molecular data regarding colonization and infection in nonoutbreak settings.

Carbapenem-Resistant Enterobacteriaceae in Children, United States, 1999-2012.

The prevalence of carbapenem-resistant Enterobacteriaceae (CRE) infections is increasing in the United States. However, few studies have addressed their epidemiology in children. To phenotypically identify CRE isolates cultured from patients 1-17 years of age, we used antimicrobial susceptibilities of Enterobacteriaceae reported to 300 laboratories participating in The Surveillance Network-USA database during January 1999-July 2012. Of 316,253 isolates analyzed, 266 (0.08%) were identified as CRE. CRE infection rate increases were highest for Enterobacter species, blood culture isolates, and isolates from intensive care units, increasing from 0.0% in 1999-2000 to 5.2%, 4.5%, and 3.2%, respectively, in 2011-2012. CRE occurrence in children is increasing but remains low and is less common than that for extended-spectrum ß-lactamase-producing Enterobacteriaceae. The molecular characterization of CRE isolates from children and clinical epidemiology of infection are essential for development of effective prevention strategies.

Selection and horizontal gene transfer underlie microdiversity-level heterogeneity in resistance gene fate during wastewater treatment.

Activated sludge is the centerpiece of biological wastewater treatment, as it facilitates removal of sewage-associated pollutants, fecal bacteria, and pathogens from wastewater through semi-controlled microbial ecology. It has been hypothesized that horizontal gene transfer facilitates the spread of antibiotic resistance genes within the wastewater treatment plant, in part because of the presence of residual antibiotics in sewage. However, there has been surprisingly little evidence to suggest that sewage-associated antibiotics select for resistance at wastewater treatment plants via horizontal gene transfer or otherwise. We addressed the role of sewage-associated antibiotics in promoting antibiotic resistance using lab-scale sequencing batch reactors fed field-collected wastewater, metagenomic sequencing, and our recently developed bioinformatic tool Kairos. Here, we found confirmatory evidence that fluctuating levels of antibiotics in sewage are associated with horizontal gene transfer of antibiotic resistance genes, microbial ecology, and microdiversity-level differences in resistance gene fate in activated sludge.

Monitoring health disparities in healthcare-associated infection surveillance: A Society for Healthcare Epidemiology of America (SHEA) Research Network (SRN) Survey.

We investigated whether and how infection prevention programs monitor for health disparities as part of healthcare-associated infection (HAI) surveillance through a survey of healthcare epidemiology leaders. Most facilities are not assessing for disparities in HAI rates. Professional society and national guidance should focus on addressing this gap.

Asymptomatic screening for severe acute respiratory coronavirus virus 2 (SARS-CoV-2) as an infection prevention measure in healthcare facilities: Challenges and considerations.

Testing of asymptomatic patients for severe acute respiratory coronavirus virus 2 (SARS-CoV-2) (ie, "asymptomatic screening) to attempt to reduce the risk of nosocomial transmission has been extensive and resource intensive, and such testing is of unclear benefit when added to other layers of infection prevention mitigation controls. In addition, the logistic challenges and costs related to screening program implementation, data noting the lack of substantial aerosol generation with elective controlled intubation, extubation, and other procedures, and the adverse patient and facility consequences of asymptomatic screening call into question the utility of this infection prevention intervention. Consequently, the Society for Healthcare Epidemiology of America (SHEA) recommends against routine universal use of asymptomatic screening for SARS-CoV-2 in healthcare facilities. Specifically, preprocedure asymptomatic screening is unlikely to provide incremental benefit in preventing SARS-CoV-2 transmission in the procedural and perioperative environment when other infection prevention strategies are in place, and it should not be considered a requirement for all patients. Admission screening may be beneficial during times of increased virus transmission in some settings where other layers of controls are limited (eg, behavioral health, congregate care, or shared patient rooms), but widespread routine use of admission asymptomatic screening is not recommended over strengthening other infection prevention controls. In this commentary, we outline the challenges surrounding the use of asymptomatic screening, including logistics and costs of implementing a screening program, and adverse patient and facility consequences. We review data pertaining to the lack of substantial aerosol generation during elective controlled intubation, extubation, and other procedures, and we provide guidance for when asymptomatic screening for SARS-CoV-2 may be considered in a limited scope.

The role of the plasmid-mediated fluoroquinolone resistance genes as resistance mechanisms in pediatric infections due to Enterobacterales.

Introduction: Fluoroquinolones (FQs) are not commonly prescribed in children, yet the increasing incidence of multidrug-resistant (MDR) Enterobacterales (Ent) infections in this population often reveals FQ resistance. We sought to define the role of FQ resistance in the epidemiology of MDR Ent in children, with an overall goal to devise treatment and prevention strategies. Methods: A case-control study of children (0-18 years) at three Chicago hospitals was performed. Cases had infections by FQ-susceptible, ß-lactamase-producing (bla) Ent harboring a non- or low-level expression of PMFQR genes (PMFQS Ent). Controls had FQR infections due to bla Ent with expressed PMFQR genes (PMFQR Ent). We sought bla genes by PCR or DNA (BD Max Check-Points assay®) and PMFQR genes by PCR. We performed rep-PCR, MLST, and E. coli phylogenetic grouping. Whole genome sequencing was additionally performed on PMFQS Ent positive isolates. Demographics, comorbidities, and device, antibiotic, and healthcare exposures were evaluated. Predictors of infection were assessed. Results: Of 170 ß-lactamase-producing Ent isolates, 85 (50%) were FQS; 23 (27%) had PMFQR genes (PMFQS cases). Eighty-five (50%) were FQR; 53 (62%) had PMFQR genes (PMFQR controls). The median age for children with PMFQS Ent and PMFQR Ent was 4.3 and 6.2 years, respectively (p = NS). Of 23 PMFQS Ent, 56% were Klebsiella spp., and of 53 PMFQR Ent, 76% were E. coli. The most common bla and PMFQR genes detected in PMFQS Ent were bla SHV ESBL (44%) and oqxAB (57%), and the corresponding genes detected in PMFQR Ent were bla CTX-M-1-group ESBL (79%) and aac(6')-Ib-cr (83%). Whole genome sequencing of PMFQS Ent revealed the additional presence of mcr-9, a transferable polymyxin resistance gene, in 47% of isolates, along with multiple plasmids and mobile genetic elements propagating drug resistance. Multivariable regression analysis showed that children with PMFQS Ent infections were more likely to have hospital onset infection (OR 5.7, 95% CI 1.6-22) and isolates containing multiple bla genes (OR 3.8, 95% CI 1.1-14.5). The presence of invasive devices mediated the effects of healthcare setting in the final model. Differences in demographics, comorbidities, or antibiotic use were not found. Conclusions: Paradoxically, PMFQS Ent infections were often hospital onset and PMFQR Ent infections were community onset. PMFQS Ent commonly co-harbored multiple bla and PMFQR genes, and additional silent, yet transferrable antibiotic resistance genes such as mcr-9, affecting therapeutic options and suggesting the need to address infection prevention strategies to control spread. Control of PMFQS Ent infections will require validating community and healthcare-based sources and risk factors associated with acquisition.

Carbapenem-resistant enterobacteriaceae: an emerging problem in children.

Antibiotic resistance among gram-negative bacteria has reached critical levels. The rise of carbapenem resistance in Enterobacteriaceae carrying additional resistance genes to multiple antibiotic classes has created a generation of organisms nearly resistant to all available therapy. Carbapenem-resistant Enterobacteriaceae (CRE) infections are known to be associated with significant morbidity and mortality, and these pathogens have now made their way to the most vulnerable populations, including children. This review provides a brief overview of CRE, with a focus on CRE infections in children, and highlights available data on the epidemiology, clinical characteristics, carbapenemase types, risk factors, treatment, and outcomes of these multi-drug resistant infections in the pediatric population.

Whole-genome sequencing for neonatal intensive care unit outbreak investigations: Insights and lessons learned.

Infectious diseases outbreaks are a cause of significant morbidity and mortality among hospitalized patients. Infants admitted to the neonatal intensive care unit (NICU) are particularly vulnerable to infectious complications during hospitalization. Thus, rapid recognition of and response to outbreaks in the NICU is essential. At Rush University Medical Center, whole-genome sequencing (WGS) has been utilized since early 2016 as an adjunctive method for outbreak investigations. The use of WGS and potential lessons learned are illustrated for 3 different NICU outbreak investigations involving methicillin-resistant Staphylococcus aureus (MRSA), group B Streptococcus (GBS), and Serratia marcescens. WGS has contributed to the understanding of the epidemiology of outbreaks in our NICU, and it has also provided further insight in settings of unusual diseases or when lower-resolution typing methods have been inadequate. WGS has emerged as the new gold standard for evaluating strain relatedness. As barriers to implementation are overcome, WGS has the potential to transform outbreak investigation in healthcare settings.

A Previously Healthy 18-Year-Old Male With Fever, Arrhythmia, and Shock.

A male individual aged 18 years with no significant past medical history presented with fever, headache, dry cough, and chest pain. On clinical examination, he had tachycardia and hypotension needing intravenous fluid resuscitation and inotropic support. A chest radiograph revealed streaky lung opacities, and he was treated with antibiotics for suspected community-acquired pneumonia complicated by septic shock. Significant elevation of cardiac enzymes was noted, and there was a continued need for inotropes to maintain normotension. He also developed intermittent bradycardia, with serial electrocardiograms showing first-degree atrioventricular block, low-voltage QRS complexes, and ST-T wave changes and telemetry demonstrating junctional and ventricular escape rhythm. A complete workup for sepsis and acute myocarditis were performed to find the etiologic agent. Intravenous immunoglobulins were started to treat myocarditis, with eventual clinical improvement. He was eventually diagnosed with an unusual etiology for his illness. He was noted to still have intermittent ventricular escape rhythm on electrocardiograms on follow-up 2 weeks after discharge but continues to remain asymptomatic and in good health.

A Multicentered Study of the Clinical and Molecular Epidemiology of TEM- and SHV-type Extended-Spectrum Beta-Lactamase Producing Enterobacterales Infections in Children.

BACKGROUND: Extended-spectrum ß-lactamase (ESBL)-producing Enterobacterales-(Ent) infections are increasing in pediatrics. Before CTX-M ESBL emerged, the most common infection-associated ESBL genes were TEM and SHV-type ESBLs. We sought to define the current epidemiology of Ent infections in children due to blaTEM and blaSHV (TEM-SHV-Ent). METHODS: A retrospective case-control analysis of children with TEM-SHV-Ent infections at 3 Chicago-area hospitals was performed. Cases had extended-spectrum-cephalosporin (ESC)-resistant infections due to blaTEM or blaSHV. DNA analysis assessed ß-lactamase (bla) genes, multilocus sequence types, and E. coli phylogenetic grouping. Controls had ESC-susceptible Ent infections, matched 3:1 to cases by age, source, and hospital. Clinical-epidemiologic infection predictors were assessed. RESULTS: Of 356 ESC-R-Ent isolates from children (median 4.3 years), 38 (10.7%) were positive solely for blaTEM-ESBL (26%) or blaSHV-ESBL genes (74%). Predominant organisms were Klebsiella (34.2%) and E. coli (31.6%); 67% of E. coli were phylogroup B2. Multilocus sequence types revealed multiple strains, 58% resistant to ≥3 antibiotic classes. On multivariable analysis, children with TEM-SHV-Ent infections more often had recent inpatient care (OR, 8.2), yet were diagnosed mostly as outpatients (OR, 25.6) and less in Neonatal Intensive Care Units (OR, 0.036) than controls. TEM-SHV-Ent patients had more gastrointestinal (OR, 23.7) and renal comorbidities (OR, 4.2). Differences in demographics, antibiotic exposure, and foreign bodies were not found. CONCLUSION: TEM-SHV-Ent are commonly linked to inpatient exposures in children with chronic conditions but most often present in outpatient settings. Clinicians should be aware of the potential increased risk for TEM-SHV-Ent infections in outpatients with gastrointestinal and renal comorbidities and histories of prolonged hospital stays.

Pediatric research priorities in healthcare-associated infections and antimicrobial stewardship.

OBJECTIVE: To develop a pediatric research agenda focused on pediatric healthcare-associated infections and antimicrobial stewardship topics that will yield the highest impact on child health. PARTICIPANTS: The study included 26 geographically diverse adult and pediatric infectious diseases clinicians with expertise in healthcare-associated infection prevention and/or antimicrobial stewardship (topic identification and ranking of priorities), as well as members of the Division of Healthcare Quality and Promotion at the Centers for Disease Control and Prevention (topic identification). METHODS: Using a modified Delphi approach, expert recommendations were generated through an iterative process for identifying pediatric research priorities in healthcare associated infection prevention and antimicrobial stewardship. The multistep, 7-month process included a literature review, interactive teleconferences, web-based surveys, and 2 in-person meetings. RESULTS: A final list of 12 high-priority research topics were generated in the 2 domains. High-priority healthcare-associated infection topics included judicious testing for Clostridioides difficile infection, chlorhexidine (CHG) bathing, measuring and preventing hospital-onset bloodstream infection rates, surgical site infection prevention, surveillance and prevention of multidrug resistant gram-negative rod infections. Antimicrobial stewardship topics included ß-lactam allergy de-labeling, judicious use of perioperative antibiotics, intravenous to oral conversion of antimicrobial therapy, developing a patient-level "harm index" for antibiotic exposure, and benchmarking and or peer comparison of antibiotic use for common inpatient conditions. CONCLUSIONS: We identified 6 healthcare-associated infection topics and 6 antimicrobial stewardship topics as potentially high-impact targets for pediatric research.

A γ-Lactam Siderophore Antibiotic Effective against Multidrug-Resistant Gram-Negative Bacilli.

Treatment of multidrug-resistant Gram-negative bacterial pathogens represents a critical clinical need. Here, we report a novel γ-lactam pyrazolidinone that targets penicillin-binding proteins (PBPs) and incorporates a siderophore moiety to facilitate uptake into the periplasm. The MIC values of γ-lactam YU253434, 1, are reported along with the finding that 1 is resistant to hydrolysis by all four classes of ß-lactamases. The druglike characteristics and mouse PK data are described along with the X-ray crystal structure of 1 binding to its target PBP3.