Trends in C-Reactive Protein Use in Early-Onset Sepsis Evaluations and Associated Antibiotic Use.

OBJECTIVES: To determine the prevalence of C-reactive protein (CRP) use in early-onset sepsis (EOS) evaluations in neonatal intensive care units (NICUs) across the United States over time and to determine the association between CRP use and antibiotic use. STUDY DESIGN: A retrospective cohort study of NICUs contributing data to Premier Healthcare Database from 2009 through 2021. EOS evaluation was defined as a blood culture charge <3 days after birth. CRP use for each NICU was calculated as the proportion of infants with a CRP test obtained <3 days after birth among those undergoing an EOS evaluation and categorized as, low (<25%); medium-low (25 to <50%), medium-high (50 to <75%), and high (≥75%). Outcomes included antibiotic use and mortality ≤7 days after birth. RESULTS: Among 572 NICUs, CRP use varied widely and was associated with time. The proportion of NICUs with high CRP use decreased from 2009 to 2021 (24.7% vs. 17.4%, P <0.001), and low CRP use NICUs increased (47.9% vs. 64.8%, P <0.001). Compared with low use NICUs, high use NICUs more frequently continued antibiotics >3 days (10% vs. 25%, P<0.001). This association persisted in multivariable-adjusted regression analyses (aRR 1.95, 95%CI 1.54, 2.48). Risk of mortality was not different in high use NICUs (adjusted risk difference -0.02%, 95%CI -0.04%, 0.0008%). CONCLUSIONS: CRP use in EOS evaluations varied widely across NICUs. High CRP use was associated with prolonged antibiotic therapy but not mortality ≤7 days after birth. Reducing routine CRP use in EOS evaluations may be a target for neonatal antibiotic stewardship efforts.

Transmission, seroprevalence, and maternal-fetal impact of lymphocytic choriomeningitis virus.

Congenital infections can have devastating short- and long-term impacts on the developing fetus. Lymphocytic choriomeningitis virus (LCMV) is a zoonotic pathogen of concern that causes a severe congenital syndrome but is under-recognized and under-studied. Herein we review data on the natural animal reservoirs of LCMV, modes of transmission to humans, seroprevalence of LCMV worldwide in both pregnant and non-pregnant individuals, mechanisms of viral dissemination to placenta and fetus, and impact of climate change on viral transmission. We highlight opportunities to enhance awareness of congenital LCMV and provide recommendations for prevention and monitoring among at-risk pregnant people. IMPACT: Key message of the article: LCMV is a zoonotic virus that poses a major threat to maternal-fetal health. Adds to the existing literature: We comprehensively address transmission of LCMV from the natural reservoir to the pregnant individual, placenta, and fetus. Impact: Available data call for enhanced patient and provider awareness about congenital LCMV during pregnancy, as well as a need for efforts to better define the seroprevalence and impact of congenital LCMV worldwide.

Antibiotic Stewardship in the Neonatal Intensive Care Unit.

Antibiotic stewardship is a multidisciplinary, evidence-based approach to optimize antibiotic use and mitigate development of antibiotic resistance. Neonates have high rates of antibiotic exposure, particularly those born preterm and admitted to the NICU, and mounting evidence describes the adverse consequences of such exposures in the absence of infection. Here, we review the general principles of antibiotic stewardship and how they can be applied in NICUs. The unique characteristics of NICUs and patients cared for in this setting, which warrant unique implementation strategies and special considerations are discussed. We summarize current antibiotic use metrics for assessment of responses to stewardship interventions and changes over time, and review evidence-based infection prevention practices in the NICU. Current recommendations for empiric antibiotic use in the NICU and the utility of infection biomarkers are summarized. Lastly, given the growing global threat of increasing antibiotic resistance, specific threats in the NICU are highlighted.

Diagnostic Performance and Patient Outcomes With C-Reactive Protein Use in Early-Onset Sepsis Evaluations.

OBJECTIVES: To determine performance of C-reactive protein (CRP) in the diagnosis of early-onset sepsis, and to assess patient outcomes with and without routine use of CRP. STUDY DESIGN: This was a retrospective cohort study of infants admitted to 2 neonatal intensive care units. CRP was used routinely in early-onset sepsis evaluations during 2009-2014; this period was used to determine CRP performance at a cut-off of ≥10 mg/L in diagnosis of culture-confirmed early-onset sepsis. Routine CRP use was discontinued during 2018-2020; outcomes among infants admitted during this period were compared with those in 2012-2014. RESULTS: From 2009 to 2014, 10 134 infants were admitted; 9103 (89.8%) had CRP and 7549 (74.5%) had blood culture obtained within 3 days of birth. CRP obtained ±4 hours from blood culture had a sensitivity of 41.7%, specificity 89.9%, and positive likelihood ratio 4.12 in diagnosis of early-onset sepsis. When obtained 24-72 hours after blood culture, sensitivity of CRP increased (89.5%), but specificity (55.7%) and positive likelihood ratio (2.02) decreased. Comparing the periods with (n = 4977) and without (n = 5135) routine use of CRP, we observed lower rates of early-onset sepsis evaluation (74.5% vs 50.5%), antibiotic initiation (65.0% vs 50.8%), and antibiotic prolongation in the absence of early-onset sepsis (17.3% vs 7.2%) in the later period. Rate and timing of early-onset sepsis detection, transfer to a greater level of care, and in-hospital mortality were not different between periods. CONCLUSIONS: CRP diagnostic performance was not sufficient to guide decision-making in early-onset sepsis. Discontinuation of routine CRP use was not associated with differences in patient outcomes despite lower rates of antibiotic administration.

Group B Streptococcus Infection in Extremely Preterm Neonates and Neurodevelopmental Outcomes at 2 Years.

BACKGROUND: This study was performed to determine the incidence of group B Streptococcus (GBS) disease among extremely preterm infants and assess to risk of death or neurodevelopmental impairment (NDI) at a corrected age of 18-26 months. METHODS: In this observational cohort study of infants enrolled in a multicenter registry, the incidence of GBS disease was assessed in infants born in 1998-2016 at 22-28 weeks' gestation and surviving for >12 hours. The composite outcome, death or NDI, was assessed in infants born in 1998-2014 at 22-26 weeks' gestation. Infection was defined as GBS isolation in blood or cerebrospinal fluid culture at ≤72 hours (early-onset disease [EOD]) or >72 hours (late-onset disease [LOD]) after birth. Using Poisson regression models, the outcome was compared in infants with GBS disease, infants infected with other pathogens, and uninfected infants. RESULTS: The incidence of GBS EOD (2.70/1000 births [95% confidence interval (CI), 2.15-3.36]) and LOD (8.47/1000 infants [7.45-9.59]) did not change significantly over time. The adjusted relative risk of death/NDI was higher among infants with GBS EOD than in those with other infections (adjusted relative risk, 1.22 [95% CI, 1.02-1.45]) and uninfected infants (1.44 [1.23-1.69]). Risk of death/NDI did not differ between infants with GBS LOD and comparator groups. GBS LOD occurred at a significantly later age than non-GBS late-onset infection. Among infants surviving >30 days, the risk of death was higher with GBS LOD (adjusted relative risk, 1.90 [95% CI, 1.36-2.67]), compared with uninfected infants. CONCLUSIONS: In a cohort of extremely preterm infants, the incidence of GBS disease did not change during the study period. The increased risk of death or NDI with GBS EOD, and of death among some infants with GBS LOD, supports the need for novel preventive strategies for disease reduction. CLINICAL TRIALS REGISTRATION: NCT00063063.

Neonatal multidrug-resistant gram-negative infection: epidemiology, mechanisms of resistance, and management.

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 ß-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. IMPACT: Surveillance 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.

Perinatal COVID-19: guideline development, implementation, and challenges.

PURPOSE OF REVIEW: The aim of this review was to describe the process of and challenges in developing national guidance for management of infants born to mothers with COVID-19. RECENT FINDINGS: Beginning in January 2020, infection with the novel coronavirus SARS-CoV-2 spread across the USA, causing the illness COVID-19. As pregnant women began to present for delivery while sick with COVID-19, the American Academy of Pediatrics (AAP) convened a writing group in March 2020 to develop guidance for the management of their newborns. The initial guidance was developed emergently and was forced to rely on extremely limited data from China. The initial guidance advocated for a conservative approach that included temporary physical separation of infected mother and newborn. To address the knowledge deficit, the AAP sponsored a volunteer registry to collect data on perinatal infection and management. As data have emerged informing the natural history of COVID-19, the performance of PCR-based diagnostics, the value of infection control measures and the risk of infant disease, AAP has issued serial updates to newborn guidance. SUMMARY: Evolving knowledge on the epidemiology of perinatal COVID-19 has informed newborn guidance. The most recent guidance focuses on the use of infection control measures to support maternal-newborn contact and breastfeeding.

Derivation of a metabolic signature associated with bacterial meningitis in infants.

BACKGROUND: Diagnosis of bacterial meningitis (BM) is challenging in newborn infants. Presently, biomarkers of BM have limited diagnostic accuracy. Analysis of cerebrospinal fluid (CSF) metabolites may be a useful diagnostic tool in BM. METHODS: In a nested case-control study, we examined >400 metabolites in CSF of uninfected infants and infants with culture-confirmed BM using gas and liquid chromatography mass spectrometry. Preterm and full-term infants in a Level III or IV Neonatal Intensive Care Unit were prospectively enrolled when evaluated for serious bacterial infection. RESULTS: Over 200 CSF metabolites significantly differed in uninfected infants and infants with BM. Using machine learning, we found that as few as 6 metabolites distinguished infants with BM from uninfected infants in this pilot cohort. Further analysis demonstrated three metabolites associated with Group B Streptococcal meningitis. CONCLUSIONS: We report the first comprehensive metabolic analysis of CSF in infants with BM. In our pilot cohort, we derived a metabolic signature that predicted the presence or absence of BM, irrespective of gestational age, postnatal age, sex, race and ethnicity, presence of neurosurgical hardware, white blood cell count in CSF, and red blood cell contamination in CSF. Metabolic analysis may aid diagnosis of BM and facilitate clinical decision-making in infants. IMPACT: In a pilot cohort, metabolites in cerebrospinal fluid distinguished infants with bacterial meningitis from uninfected infants.We report the first comprehensive metabolic analysis of cerebrospinal fluid in infants with bacterial meningitis.Our findings may be used to improve diagnosis of bacterial meningitis and to offer mechanistic insights into the pathophysiology of bacterial meningitis in infants.

Protocol adherence rates in superiority and noninferiority randomized clinical trials published in high impact medical journals.

BACKGROUND/AIMS: Noninferiority clinical trials are susceptible to false confirmation of noninferiority when the intention-to-treat principle is applied in the setting of incomplete trial protocol adherence. The risk increases as protocol adherence rates decrease. The objective of this study was to compare protocol adherence and hypothesis confirmation between superiority and noninferiority randomized clinical trials published in three high impact medical journals. We hypothesized that noninferiority trials have lower protocol adherence and greater hypothesis confirmation. METHODS: We conducted an observational study using published clinical trial data. We searched PubMed for active control, two-arm parallel group randomized clinical trials published in JAMA: The Journal of the American Medical Association, The New England Journal of Medicine, and The Lancet between 2007 and 2017. The primary exposure was trial type, superiority versus noninferiority, as determined by the hypothesis testing framework of the primary trial outcome. The primary outcome was trial protocol adherence rate, defined as the number of randomized subjects receiving the allocated intervention as described by the trial protocol and followed to primary outcome ascertainment (numerator), over the total number of subjects randomized (denominator). Hypothesis confirmation was defined as affirmation of noninferiority or the alternative hypothesis for noninferiority and superiority trials, respectively. RESULTS: Among 120 superiority and 120 noninferiority trials, median and interquartile protocol adherence rates were 91.5 [81.4-96.7] and 89.8 [83.6-95.2], respectively; P = 0.47. Hypothesis confirmation was observed in 107/120 (89.2%) of noninferiority and 64/120 (53.3%) of superiority trials, risk difference (95% confidence interval): 35.8 (25.3-46.3), P < 0.001. CONCLUSION: Protocol adherence rates are similar between superiority and noninferiority trials published in three high impact medical journals. Despite this, we observed greater hypothesis confirmation among noninferiority trials. We speculate that publication bias, lenient noninferiority margins and other sources of bias may contribute to this finding. Further study is needed to identify the reasons for this observed difference.

Measles Serostatus Among Parturient Patients at 2 Philadelphia Hospitals in 2021.

This observational study explores whether rubella serostatus, which is routinely assessed during pregnancy, can serve as a proxy for measles serostatus in parturient persons.

Continuous Positive Airway Pressure versus Mechanical Ventilation on the First Day of Life in Very Low-Birth-Weight Infants.

Objective The objective of this study was to determine differences in the incidence of bronchopulmonary dysplasia (BPD) or death in very low-birth-weight (VLBW) infants managed successfully on continuous positive airway pressure (CPAP) versus mechanical ventilation on the first day of life (DOL). Study Design This is a retrospective analysis of the Alere neonatal database for infants born between January 2009 and December 2014, weighing ≤ 1,500 g. Baseline demographics, clinical characteristics, and outcomes were compared between the two groups. Multivariable regression analysis was performed to control the variables that differ in bivariate analysis. Results In this study, 4,629 infants (birth weight 1,034 ± 290 g, gestational age 28.1 ± 2.5 weeks) met the inclusion criteria. The successful use of early CPAP was associated with a significant reduction in BPD or death (p < 0.001), as well as days to room air, decreased oxygen use at discharge, lower risk for severe intraventricular hemorrhage, and patent ductus arteriosus requiring surgical ligation (p < 0.001 for all outcomes). Conclusion Successful use of early CPAP on the first DOL in VLBW infants is associated with a reduced risk of BPD or death.

The Impact of High-Profile Sexual Abuse Cases in the Media on a Pediatric Emergency Department.

High-profile media cases of sexual abuse may encourage disclosures of abuse from victims of unrelated assaults and also influence parental concerns, leading to increased emergency department visits. In the region of the study authors' institution, there are two recent high-profile sexual abuse cases with media coverage: Earl Bradley, a Delaware pediatrician, and Jerry Sandusky, a Pennsylvania college football coach. This is a retrospective cohort study of children evaluated for sexual abuse at a pediatric emergency department. Patients were classified as either presenting during a media period or non-media period. The media periods were one-month periods immediately following breaking news reports, when the cases were highly publicized in the media. The non-media periods were the 12-month periods directly preceding the first reports. The median number of emergency department visits per month during a non-media period was 9 visits (interquartile range 6-10). There were 11 visits in the month following the Sandusky case and 13 visits following the Bradley case. There was no statistical difference in number of emergency department visits for sexual abuse between the periods (p = .09). These finding have implications regarding use of resources in pediatric EDs after high-profile sexual abuse cases.

Perinatal COVID-19: Implications for care of the newborn.

The maternal/newborn dyad presents special challenges to infection management. Early in the COVID-19 pandemic, lack of information regarding SARS-CoV-2 transmission and virulence made it difficult to develop appropriate care guidance when pregnant persons had COVID-19 at the time of presentation for childbirth. We will review the considerations for the parturient, newborn, and care team, and describe the evolution of perinatal COVID management guidance.

Utility of Anaerobic Blood Cultures in Neonatal Sepsis Evaluation.

BACKGROUND: Clinicians variably obtain anaerobic blood cultures as part of sepsis evaluations in the neonatal intensive care unit (NICU). Our objective was to determine if anaerobic blood culture bottles yielded clinically relevant information by either recovering pathogens exclusively or more rapidly than the concurrently obtained aerobic culture bottle in the NICU. METHODS: A retrospective cohort study of blood cultures obtained from infants admitted to the NICU from 08/01/2015-08/31/2023. Standard practice was to inoculate 2 mL of blood divided equally between an aerobic and an anaerobic culture bottle. We analyzed positive blood cultures where both aerobic and anaerobic bottles were obtained and compared pathogen recovery and time to positivity between the bottles. RESULTS: During the study period, 4599 blood cultures were obtained from 3665 infants, and 265 (5.8%) were positive. Of these, 182 cultures were sent as aerobic-anaerobic pairs and recovered pathogenic organisms. Organisms were recovered exclusively from the anaerobic bottle in 32 (17.6%) cultures. Three organisms were obligate anaerobes; the rest were facultative anaerobes including Coagulase-negative staphylococci (40.6%), Escherichia coli (15.6%), and Staphylococcus aureus (15.6%). Cultures with exclusive recovery in the anaerobic bottle were more frequently obtained ≤3 days after birth, compared to other cultures (31.3% vs. 15.3%, p=0.03). When both bottles recovered the pathogen (n=113), the anaerobic bottle had a shorter time to positivity in 76 (67.3%) cultures. CONCLUSIONS: Including anaerobic culture bottles could lead to identification of pathogens not recovered in the aerobic bottle, as well as earlier identification of pathogens.

Hospital-Onset Bacteremia Among Neonatal Intensive Care Unit Patients.

Importance: The Centers for Disease Control and Prevention plans to introduce hospital-onset bacteremia (HOB) as a health care-associated infection measure. The epidemiology and clinical characteristics of HOB among infants admitted to the neonatal intensive care unit (NICU) are unknown. Objective: To estimate the rate of HOB among infants admitted to the NICU, measure the association of HOB risk with birth weight group and postnatal age, and estimate HOB-attributable mortality. Design, Setting, and Participants: This retrospective multicenter cohort study and emulated trial from 2016 to 2021 included a convenience sample of 322 NICUs in the United States. Participants were infants admitted to participating NICUs for 4 or more days. Exposures: The primary exposures were birth weight and postnatal age. Additional exposures included small for gestational age and central line presence. Main Outcomes and Measures: The primary study outcomes were HOB and HOB-attributable mortality. Results: Of 451 443 included infants, 250 763 (55.6%) were male, 200 680 (44.4%) were female, and 62 091 (13.8%) were born 1500 g or less. Of 9015 HOB events that occurred among 8356 infants (2%) during 8 163 432 days at risk (unadjusted incidence rate, 1.1 per 1000 patient-days; 95% CI, 1.0-1.2), 4888 HOB events (54.2%) occurred in the absence of a central line. Within the first 2 weeks after birth, the HOB rate was 14.2 per 1000 patient-days (95% CI, 12.6-16.1) among infants born 750 g or less, to 0.4 events per 1000 patient-days among infants born more than 2500 g (95% CI, 0.4-0.5). Among infants born 750 g or less, the relative HOB risk decreased by 90% after day 42 compared with days 4 to 14 (incidence rate ratio [IRR], 0.10; 95% CI, 0.1-0.1). Conversely, among infants born more than 2500 g, the relative HOB risk increased by 50% after day 42 compared with days 4 to 14 (IRR, 1.5, 95% CI, 1.2-1.9). Compared with otherwise similar infants without HOB, infants with HOB had an absolute difference in attributable mortality of 5.5% (95% CI, 4.7-6.3). Conclusions and Relevance: This study found that HOB events in the NICU are associated with increased mortality. Birth weight is an important risk factor for HOB; however, the relative rate of HOB decreases over postnatal age among low-birth-weight infants and increases among infants born more than 2500 g. Identifying strategies to prevent HOB and programs to decrease HOB risk are urgently needed to reduce infant mortality.

Septic arthritis and concern for osteomyelitis in a child with rat bite fever.

Rat bite fever is a rare infection usually caused by Streptobacillus moniliformis. A case of septic arthritis and possible osteomyelitis as sequelae of rat bite fever in a pediatric patient is described.

Serratia Infection Epidemiology Among Very Preterm Infants in the Neonatal Intensive Care Unit.

BACKGROUND: Serratia spp. are opportunistic, multidrug resistant, Gram-negative pathogens, previously described among preterm infants in case reports or outbreaks of infection. We describe Serratia late-onset infection (LOI) in very preterm infants in a large, contemporary, nationally representative cohort. METHODS: In this secondary analysis of prospectively collected data of preterm infants born 401-1500 grams and/or 22-29 weeks gestational age from 2018 to 2020 at 774 Vermont Oxford Network members, LOI was defined as culture-confirmed blood and/or cerebrospinal fluid infection > 3 days after birth. The primary outcome was incidence of Serratia LOI. Secondary outcomes compared rates of survival and discharge morbidities between infants with Serratia and non-Serratia LOI. RESULTS: Among 119,565 infants, LOI occurred in 10,687 (8.9%). Serratia was isolated in 279 cases (2.6% of all LOI; 2.3 Serratia infections per 1000 infants). Of 774 hospitals, 161 (21%) reported at least one Serratia LOI; 170 of 271 (63%) cases occurred at hospitals reporting 1 or 2 Serratia infections, and 53 of 271 (20%) occurred at hospitals reporting ≥5 Serratia infections. Serratia LOI was associated with a lower rate of survival to discharge compared with those with non-Serratia LOI (adjusted relative risk 0.88, 95% CI: 0.82-0.95). Among survivors, infants with Serratia LOI had higher rates of tracheostomy, gastrostomy and home oxygen use compared with those with non-Serratia LOI. CONCLUSIONS: The incidence of Serratia LOI was 2.3 infections per 1000 very preterm infants in this cohort. Lower survival and significant morbidity among Serratia LOI survivors highlight the need for recognition and targeted prevention strategies for this opportunistic nosocomial infection.

Critical care among newborns with and without a COVID-19 diagnosis, May 2020-February 2022.

OBJECTIVE: To assess COVID-19 association with newborn critical care outcomes, including nursery level of care and ventilation, during three time periods: Pre-delta (May 2020-June 2021), Delta (July-November 2021), and Omicron (December 2021-February 2022). STUDY DESIGN: In a retrospective cohort of newborns born May 2020-February 2022 using the Premier Healthcare Database, we classified COVID-19 status and critical care using International Classification of Diseases 10th Revision and Current Procedural Terminology codes, laboratory data, and billing records and assessed for variation during three time periods. RESULTS: Of 1,388,712 newborns, 0.06% had COVID-19 during the birth hospitalization (Pre-delta period: 0.03%; Delta: 0.07%; Omicron: 0.21%). Among newborns with COVID-19, the risks for admission to a higher-level nursery and for invasive or non-invasive ventilation were lower in the Omicron period compared to Pre-delta and Delta periods. CONCLUSION: From May 2020-February 2022, COVID-19 in newborns was rare and cases were less severe during the period of Omicron predominance.