The evolving value of older biomarkers in the clinical diagnosis of pediatric sepsis.

Sepsis remains the leading cause of childhood mortality worldwide. The evolving definition of pediatric sepsis is extrapolated from adult studies. Although lacking formal validation in the pediatric population, this working definition has historically proven its clinical utility. Prompt identification of pediatric sepsis is challenging as clinical picture is often variable. Timely intervention is crucial for optimal outcome, thus biomarkers are utilized to aid in immediate, yet judicious, diagnosis of sepsis. Over time, their use in sepsis has expanded with discovery of newer biomarkers that include genomic bio-signatures. Despite recent scientific advances, there is no biomarker that can accurately diagnose sepsis. Furthermore, older biomarkers are readily available in most institutions while newer biomarkers are not. Hence, the latter's clinical value in pediatric sepsis remains theoretical. Albeit promising, scarce data on newer biomarkers have been extracted from research settings making their clinical value unclear. As interest in newer biomarkers continue to proliferate despite their ambiguous clinical use, the literature on older biomarkers in clinical settings continue to diminish. Thus, revisiting the evolving value of these earliest biomarkers in optimizing pediatric sepsis diagnosis is warranted. This review focuses on the four most readily available biomarkers to bedside clinicians in diagnosing pediatric sepsis. IMPACT: The definition of pediatric sepsis remains an extrapolation from adult studies. Older biomarkers that include C-reactive protein, procalcitonin, ferritin, and lactate are the most readily available biomarkers in most pediatric institutions to aid in the diagnosis of pediatric sepsis. Older biomarkers, although in varying levels of reliability, remain to be useful clinical adjuncts in the diagnosis of pediatric sepsis if used in the appropriate clinical context. C-reactive protein and procalcitonin are more sensitive and specific among these older biomarkers in diagnosing pediatric sepsis although evidence varies in different age groups and clinical scenarios.

Monitoring Ceftazidime-Avibactam and Aztreonam Concentrations in the Treatment of a Bloodstream Infection Caused by a Multidrug-Resistant Enterobacter sp. Carrying Both Klebsiella pneumoniae Carbapenemase-4 and New Delhi Metallo-ß-Lactamase-1.

In an infection with an Enterobacter sp. isolate producing Klebsiella pneumoniae Carbapenemase-4 and New Delhi Metallo-ß-Lactamase-1 in the United States, recognition of the molecular basis of carbapenem resistance allowed for successful treatment by combining ceftazidime-avibactam and aztreonam. Antimicrobial synergy testing and therapeutic drug monitoring assessed treatment adequacy.

Adult and child automated immature granulocyte norms are inappropriate for evaluating early-onset sepsis in newborns.

AIM: Automated haematology analysers are increasingly being used. Normal ranges for automated immature granulocyte counts (IG%) are described in adults and children as <1%, but are not reported for newborns, who often have complete blood count with differential in evaluation for early-onset sepsis. Therefore, this study aimed to describe IG% during the first 48 hours of life (HOL) in newborns and determine the clinical factors affecting IG%. METHODS: We carried out retrospective chart reviews for newborns ≥35 weeks gestational age with one or more complete blood count with differential in the first 48 HOL. Clinical history and automated haematology results were reviewed. RESULTS: Forty-seven of 215 subjects had two or more complete blood counts within 48 h. In the first 48 HOL, IG% ranged from 0 to 8.4% (95th percentile 5.2%). At <12 h, 70% of samples had IG% >1%. IG% appears to decrease over time. Earlier hour of life and higher birth weight were independently associated with higher IG%. CONCLUSION: Immature granulocyte counts in newborns appeared to be higher than reported for other age groups. Use of adult and child norms for IG% would not be appropriate for newborns being evaluated for early-onset sepsis.

Evaluation of No-Touch Technologies for Decontamination of Toys in Pediatric Healthcare Settings.

No-touch technologies could be useful to decontaminate shared toys in healthcare settings. A high-level disinfection cabinet and electrostatic sprayer were effective against methicillin-resistant Staphylococcus aureus (MRSA), bacteriophage MS2, and Clostridioides difficile spores on toys. An ultraviolet-C light box was less effective but reduced MRSA and bacteriophage MS2 by >2 log10.

Scalable in-hospital decontamination of N95 filtering face-piece respirator with a peracetic acid room disinfection system.

BACKGROUND: Critical shortages of personal protective equipment, especially N95 respirators, during the coronavirus disease 2019 (COVID-19) pandemic continues to be a source of concern. Novel methods of N95 filtering face-piece respirator decontamination that can be scaled-up for in-hospital use can help address this concern and keep healthcare workers (HCWs) safe. METHODS: A multidisciplinary pragmatic study was conducted to evaluate the use of an ultrasonic room high-level disinfection system (HLDS) that generates aerosolized peracetic acid (PAA) and hydrogen peroxide for decontamination of large numbers of N95 respirators. A cycle duration that consistently achieved disinfection of N95 respirators (defined as ≥6 log10 reductions in bacteriophage MS2 and Geobacillus stearothermophilus spores inoculated onto respirators) was identified. The treated masks were assessed for changes to their hydrophobicity, material structure, strap elasticity, and filtration efficiency. PAA and hydrogen peroxide off-gassing from treated masks were also assessed. RESULTS: The PAA room HLDS was effective for disinfection of bacteriophage MS2 and G. stearothermophilus spores on respirators in a 2,447 cubic-foot (69.6 cubic-meter) room with an aerosol deployment time of 16 minutes and a dwell time of 32 minutes. The total cycle time was 1 hour and 16 minutes. After 5 treatment cycles, no adverse effects were detected on filtration efficiency, structural integrity, or strap elasticity. There was no detectable off-gassing of PAA and hydrogen peroxide from the treated masks at 20 and 60 minutes after the disinfection cycle, respectively. CONCLUSION: The PAA room disinfection system provides a rapidly scalable solution for in-hospital decontamination of large numbers of N95 respirators during the COVID-19 pandemic.

Opportunities for Regulatory Changes to Promote Pediatric Device Innovation in the United States: Joint Recommendations From Pediatric Innovator Roundtables.

OBJECTIVE: The purpose of this report is to provide insight from pediatric stakeholders with a shared desire to facilitate a revision of the current United States regulatory pathways for the development of pediatric healthcare devices. METHODS: On August 5, 2020, a group of innovators, engineers, professors and clinicians met to discuss challenges and opportunities for the development of new medical devices for pediatric health and the importance of creating a regulatory environment that encourages and accelerates the research and development of such devices. On January 6, 2021, this group joined regulatory experts at a follow-up meeting. RESULTS: One of the primary issues identified was the need to present decision-makers with opportunities that change the return-on-investment balance between adult and pediatric devices to promote investment in pediatric devices. DISCUSSION/CONCLUSION: Several proposed strategies were discussed, and these strategies can be divided into two broad categories: 1. Removal of real and perceived barriers to pediatric device innovation; 2. Increasing incentives for pediatric device innovation.

Health impact and cost-effectiveness of a domestically-produced rotavirus vaccine in India: A model based analysis.

BACKGROUND: Currently, Indian officials are incorporating a domestically manufactured rotavirus vaccine (based on the 116E rotavirus strain) into the country's universal immunization program; this vaccine will cost significantly less than western rotavirus vaccines. Here, we examine the public health impact, cost, and cost-effectiveness of universal vaccination in India using the 116E vaccine. This work will allow comparison of universal 116E vaccination with other approaches to child mortality reduction, shed light on the future burden of rotavirus disease in India, and help stakeholders understand future resource needs. METHODS: Using information from published literature, we developed a dynamic simulation model of rotavirus transmission, natural history, and related utilization among Indian infants followed until age five. Infection risk depended on the degree of viral shedding in the population. Infection risk and severity were influenced by age, number of previous infections, and vaccination history. Probabilities of inpatient and outpatient health services utilization depended on symptom severity. With the model, we compared a strategy of nationwide 116E vaccination to one of no vaccination. Costs were considered from the perspective of all payers (including families) and from the societal perspective. RESULTS: We estimated that an established 116E vaccination program would reduce symptomatic rotavirus infection by 13.0%, while reducing population-wide rotavirus mortality by 34.6% (over 34,000 lives annually). Rotavirus outpatient visits would decline by 21.3%, and hospitalization would decline by 28.1%. The cost per disability-adjusted life year (DALY) averted was estimated at 3,429 Rupees (approximately $56). Predicted mortality reduction in children born during the first five years of vaccination implementation was nearly identical to that in children born in later years (34.4% versus 34.6%). CONCLUSIONS: 116E vaccination of Indian infants would likely substantially reduce rotavirus-related morbidity, mortality, and utilization at a cost considered highly cost-effective by standard criteria. Nearly the entire mortality reduction benefit of vaccination was attributable to direct protection of those vaccinated, as opposed to indirect "herd immunity" effects.

Antibiotic-resistant gram-negative organisms in pediatric chronic-care facilities.

This study was designed to define the prevalence of colonization with antibiotic-resistant gram-negative rectal specimens were obtained from subjects residing in 2 pediatric extended-care facilities and were processed to identify gram-negative organisms resistant to ceftazidime, gentamicin, meropenem, and piperacillin-tazobactam. Horizontal transmission was assessed by analyzing all resistant isolates by pulsed-field gel electrophoresis. Forty percent of subjects were colonized with >/=1 resistant bacillus; >60% of organisms were resistant to >/=2 of the antibiotics tested. Colonization was disproportionate among residents with a tracheostomy or other prosthesis. More than 65% of colonized subjects shared 1 organism with another resident, with cross-colonization occurring among both enteric and nonenteric species. Children residing in chronic-care facilities represent a large reservoir for resistant bacilli. Such colonization may be amenable to simple barrier infection-control procedures.

Recurrence of vancomycin-resistant Enterococcus stool colonization during antibiotic therapy.

OBJECTIVE: To test the hypothesis that antibiotic therapy may promote recurrence of vancomycin-resistant Enterococcus (VRE) stool colonization in patients who have previously had three consecutive negative stool cultures obtained at least 1 week apart. DESIGN: One-year prospective cohort study examining the effect of antibiotic therapy on recurrence and density of VRE stool colonization in patients who have cleared colonization. Pulsed-field gel electrophoresis (PFGE) was performed to determine whether recurrent VRE strains were the same clone as the previous colonizing strain. SETTING: A Department of Veterans Affairs medical center including an acute care hospital and nursing home. PATIENTS: All patients with at least one stool culture positive for VRE who subsequently had three consecutive negative stool cultures obtained at least 1 week apart. RESULTS: Of the 16 patients who cleared VRE colonization, 13 received antibiotic therapy during the study period. Eight (62%) of the 13 patients who received antibiotics developed recurrent high-density VRE stool colonization (range, 4.9 to 9.1 log10 colony-forming units per gram) during a course of therapy. Five patients had VRE strains available for PFGE analysis; recurrent strains were unrelated to the prior strain in 3 patients, closely related in 1 patient, and indistinguishable in 1 patient. CONCLUSIONS: Antibiotic therapy may be associated with recurrent high-density VRE stool colonization in many patients who have previously had three consecutive negative stool cultures. These patients should be screened for recurrent stool colonization when antibiotic therapy is administered.

Undetected vancomycin-resistant Enterococcus stool colonization in a Veterans Affairs Hospital using a Clostridium difficile-focused surveillance strategy.

We examined the point prevalence of undetected vancomycin-resistant Enterococcus (VRE) stool colonization in an institution that screens stool samples submitted for Clostridium difficile testing. Of 112 patients not known to be colonized, 10 (9%) had rectal VRE colonization. A prospective algorithm was effective for identification of colonized patients.

Antianaerobic antibiotic therapy promotes overgrowth of antibiotic-resistant, gram-negative bacilli and vancomycin-resistant enterococci in the stool of colonized patients.

BACKGROUND AND OBJECTIVE: Antianaerobic antibiotic therapy promotes persistent high-density growth of vancomycin-resistant enterococci (VRE) in the stool of colonized patients. We tested the hypothesis that antibiotic regimens with potent antianaerobic activity promote overgrowth of coexisting antibiotic-resistant, gram-negative bacilli in the stool of VRE-colonized patients. DESIGN: Eight-month prospective study examining the effect of antibiotic therapy on the stool density of gram-negative bacilli resistant to ceftazidime, ciprofloxacin, or piperacillin/tazobactam. SETTING: A Department of Veterans Affairs medical center including an acute care hospital and nursing home. PATIENTS: All VRE-colonized patients with at least 3 stool samples available for analysis. RESULTS: One-hundred forty stool samples were obtained from 37 study patients. Forty-nine (61%) of 80 stool samples obtained during therapy with an antianaerobic regimen were positive for an antibiotic-resistant, gram-negative bacillus, where-as only 14 (23%) of 60 samples obtained 4 or more weeks after completion of such therapy were positive (P < .001). Twenty-four (65%) of the 37 patients had one or more stool cultures positive for a gram-negative bacillus resistant to ciprofloxacin, ceftazidime, or piperacillin/tazobactam. The density of these organisms was higher during therapy with antianaerobic regimens than in the absence of such therapy for at least 2 weeks (mean +/- standard deviation, 5.6 +/- 1.4 and 3.9 +/- 0.71 log10 organisms/g; P < .001). CONCLUSION: Limiting the use of antianaerobic antibiotics in VRE-colonized patients may reduce the density of colonization with coexisting antibiotic-resistant, gram-negative bacilli.

Colonization and infection with multiple nosocomial pathogens among patients colonized with vancomycin-resistant Enterococcus.

OBJECTIVE: To test the hypothesis that patients colonized with vancomycin-resistant Enterococcus (VRE) have a higher frequency of colonization or infection with other nosocomial pathogens than do patients who are not colonized with VRE. DESIGN: A rectal swab culture survey was conducted to determine the point-prevalence of stool colonization with ceftazidime-resistant gram-negative bacilli in hospitalized patients with or without VRE stool colonization. For a 6-month period, the frequency of Clostridium difficile diarrhea and isolation of antibiotic-resistant (ie, ceftazidime-, piperacillin/tazobactam-, levofloxacin-, or trimethoprim/sulfamethoxazole-resistant) gram-negative bacilli, methicillin-resistant Staphylococcus aureus (MRSA), and non-albicans Candida species from clinical specimens other than stool was examined. SETTING: A Department of Veterans Affairs medical center. PATIENTS: All patients hospitalized in the acute care facility and one nursing home unit during a 1-week period in February 2001. RESULTS: VRE-colonized patients had a higher point-prevalence of rectal colonization with ceftazidime-resistant gram-negative bacilli than did patients not colonized with VRE (17% vs 4%; P = .026). During a 6-month period,the VRE-colonized patients were more likely to have Clostridium difficile-associated diarrhea (26% vs 2%; P = .001), MRSA infection (17% vs 4%; P = .017), or colonization or infection with gram-negative bacilli resistant to 4 different antibiotics. CONCLUSION: VRE-colonized patients in our institution have a higher frequency of colonization or infection with other nosocomial pathogens than do patients who are not colonized with VRE. This suggests that isolation measures implemented to control VRE could help limit the dissemination of other, coexisting pathogens.

Role of fecal incontinence in contamination of the environment with vancomycin-resistant enterococci.

BACKGROUND: We tested the hypothesis that patients with vancomycin-resistant Enterococcus (VRE) stool colonization who are continent of feces contaminate the environment less frequently than patients who are colonized and incontinent. METHODS: We prospectively examined the frequency of environmental VRE contamination in the rooms of 15 patients who were continent and 15 who were incontinent and VRE-colonized. Broth-enrichment cultures of bed rails, bedside table, and call buttons were performed at baseline, and 2 and 5 days after environmental disinfection. The numbers of VRE colonies isolated after directly plating environmental swabs onto agar were compared for the continent and incontinent groups. RESULTS: The percentages of patients with 1 or more positive environmental cultures for VRE were not significantly different for the groups of patients who were continent and incontinent at baseline (60% vs 73%, P =.45) or 2 days after disinfection (60% vs 80%, P =.24). The numbers of VRE colonies isolated by direct plating were not significantly different for the continent and incontinent groups (P =.42). CONCLUSIONS: Environmental contamination occurs frequently in the rooms of patients who are continent, and those who are incontinent and VRE-colonized. Our findings suggest that similar infection control measures should be implemented for patients who are continent and incontinent.

A clinical strain of Escherichia coli possessing CMY-2 plasmid-mediated amp C beta-lactamase: an emerging concern in pediatrics?

A 5-year-old child was colonized by an isolate of Escherichia coli that transferred resistance to third-generation cephalosporins and cefoxitin. This resistance phenotype was encoded on a >75-kb plasmid pLRM 22. The transferable plasmid contained both blaCMY-2 and blaTEM-1b. Increasing reports of CMY-2 beta-lactamase in clinical isolates in children raise concerns about the empiric use of third-generation cephalosporins in this patient group.

Inhibition of methicillin-resistant Staphylococcus aureus by an in vitro continuous-flow culture containing human stool microflora.

We used an in vitro continuous-flow culture model of human stool microflora to examine the ability of human stool microflora to inhibit growth of two methicillin-resistant S. aureus (MRSA) strains. Continuous-flow cultures consistently eliminated MRSA inocula of 10(6) cfu/mL within 4 days, and addition of continuous-flow culture resulted in elimination of a pre-established MRSA culture ( approximately 10(8) cfu/mL) within 6-8 days. Anaerobic or "aerobic" (i.e., continuous bubbling of room air to eliminate obligate anaerobes) cultures eliminated MRSA at similar rates. The MRSA strains were unable to replicate under anaerobic conditions in sterile filtrates produced from the continuous-flow culture, but rapid growth occurred when glucose was added. These data demonstrate that indigenous stool microflora efficiently eliminate MRSA colonization and obligate anaerobes are not essential for inhibition. Our findings also suggest that inhibition of MRSA in continuous-flow cultures is due to depletion of nutrients rather than production of inhibitory conditions.

First reported case of Neisseria meningitidis periorbital cellulitis associated with meningitis.

Cellulitis is a rare manifestation of meningococcal disease. We describe the case of a previously healthy 4-month-old female infant who developed periorbital cellulitis associated with meningococcal meningitis.

Effect of parenteral antibiotic administration on establishment of intestinal colonization in mice by Klebsiella pneumoniae strains producing extended-spectrum beta-lactamases.

A mouse model was used to test the hypothesis that antibiotics with activity against anaerobes promote overgrowth of extended-spectrum beta-lactamase-producing Klebsiella pneumoniae strains in stool. Subcutaneous clindamycin consistently promoted establishment of high-density colonization, whereas piperacillin-tazobactam, ceftriaxone, and ceftazidime promoted colonization only when a large inoculum and/or more resistant strain was administered.

The effect of antibiotic rotation on colonization with antibiotic-resistant bacilli in a neonatal intensive care unit.

OBJECTIVE: This study was designed to test whether rotation of antibiotics can reduce colonization with resistant Gram-negative bacilli in a neonatal intensive care unit (NICU). METHODS: A monthly rotation of gentamicin, piperacillin-tazobactam, and ceftazidime was compared with unrestricted antibiotic use in side-by-side NICU populations (rotation team vs control team). Pharyngeal and rectal samples were obtained 3 times a week and tested for Gram-negative bacilli resistant to each of the rotation antibiotics. Pulsed-field gel electrophoresis analysis determined the numbers of genetically discordant resistant organisms on each team. The association between colonization with a resistant bacillus (the primary outcome) and team assignment was tested. RESULTS: A total of 1062 infants were studied during a 1-year period. A total of 10.7% infants on the rotation team versus 7.7% on the control team were colonized with a resistant bacillus. No interteam differences were distinguishable when the numbers of genetically discordant resistant organisms were normalized to the total number of team admissions. The incidence of nosocomial infection and mortality also were similar across teams. CONCLUSION: These data indicate that rotation of parenteral antibiotics according to the applied protocol has no detectable effect in decreasing the reservoir of resistant Gram-negative bacilli in a tertiary-care NICU.