The epidemiology of cephalosporin allergy labels in pediatric primary care.

Background: Recent studies have sought to understand the epidemiology and impact of beta-lactam allergy labels on children; however, most of these studies have focused on penicillin allergy labels. Fewer studies assess cephalosporin antibiotic allergy labels in children. The objective of this study was to determine the prevalence, factors associated with, and impact of cephalosporin allergy labels in children cared for in the primary care setting. Methods: Cephalosporin allergy labels were reviewed among children in a dual center, retrospective, birth cohort who were born between 2010 and 2020 and followed in 90 pediatric primary care practices. Antibiotic prescriptions for acute otitis media were compared in children with and without cephalosporin allergies. Results: 334,465 children comprised the birth cohort and 2,877 (0.9%) were labeled as cephalosporin allergic during the study period at a median age of 1.6 years. Third-generation cephalosporins were the most common class of cephalosporin allergy (83.0%). Cephalosporin allergy labels were more common in children with penicillin allergy labels than those without (5.8% vs. 0.6%). Other factors associated with a cephalosporin allergy label included white race, private insurance, presence of a chronic condition, and increased health care utilization. Children with third-generation cephalosporin allergy labels received more amoxicillin/clavulanate (28.8% vs. 10.2%) and macrolides (10.4% vs. 1.9%) and less amoxicillin (55.8% vs. 70.9%) for treatment of acute otitis media than non-allergic peers p < 0.001. Conclusions: One in 100 children is labeled as cephalosporin allergic, and these children receive different antibiotics for the treatment of acute otitis media compared to non-allergic peers.

Adjunctive Diagnostic Studies Completed Following Detection of Candidemia in Children: Secondary Analysis of Observed Practice From a Multicenter Cohort Study Conducted by the Pediatric Fungal Network.

BACKGROUND: Adjunctive diagnostic studies (aDS) are recommended to identify occult dissemination in patients with candidemia. Patterns of evaluation with aDS across pediatric settings are unknown. METHODS: Candidemia episodes were included in a secondary analysis of a multicenter comparative effectiveness study that prospectively enrolled participants age 120 days to 17 years with invasive candidiasis (predominantly candidemia) from 2014 to 2017. Ophthalmologic examination (OE), abdominal imaging (AbdImg), echocardiogram, neuroimaging, and lumbar puncture (LP) were performed per clinician discretion. Adjunctive diagnostic studies performance and positive results were determined per episode, within 30 days from candidemia onset. Associations of aDS performance with episode characteristics were evaluated via mixed-effects logistic regression. RESULTS: In 662 pediatric candidemia episodes, 490 (74%) underwent AbdImg, 450 (68%) OE, 426 (64%) echocardiogram, 160 (24%) neuroimaging, and 76 (11%) LP; performance of each aDS per episode varied across sites up to 16-fold. Longer durations of candidemia were associated with undergoing OE, AbdImg, and echocardiogram. Immunocompromised status (58% of episodes) was associated with undergoing AbdImg (adjusted odds ratio [aOR] 2.38; 95% confidence intervals [95% CI] 1.51-3.74). Intensive care at candidemia onset (30% of episodes) was associated with undergoing echocardiogram (aOR 2.42; 95% CI 1.51-3.88). Among evaluated episodes, positive OE was reported in 15 (3%), AbdImg in 30 (6%), echocardiogram in 14 (3%), neuroimaging in 9 (6%), and LP in 3 (4%). CONCLUSIONS: Our findings show heterogeneity in practice, with some clinicians performing aDS selectively, potentially influenced by clinical factors. The low frequency of positive results suggests that targeted application of aDS is warranted.

The Quality and Management of Penicillin Allergy Labels in Pediatric Primary Care.

BACKGROUND AND OBJECTIVES: Penicillin allergy labels are the most common drug allergy label. The objective of this study was to describe the quality and management of penicillin allergy labels in the pediatric primary care setting. METHODS: Retrospective chart review of 500 of 18 015 children with penicillin allergy labels born from January 1, 2010 to June 30, 2020 randomly selected from an outpatient birth cohort from Texas Children's Pediatrics and Children's Hospital of Philadelphia networks. Penicillin allergy risk classification ("not allergy," "low risk," "moderate or high risk," "severe risk," "unable to classify") was determined based on documentation within (1) the allergy tab and (2) electronic healthcare notes. Outcomes of allergy referrals and penicillin re-exposure were noted. RESULTS: Half of penicillin allergy labels were "unable to classify" based on allergy tab documentation. Risk classification agreement between allergy tabs and healthcare notes was fair (Cohen's ĸ = 0.35 ± 0.02). Primary care physicians referred 84 of 500 (16.8%) children to an allergist, but only 54 (10.8%) were seen in allergy clinic. All children who were challenged (25 of 25) passed skin testing. Removal of allergy labels was uncommon (69 of 500, 13.8%) but occurred more often following allergy appointments (26 of 54, 48%) than not (43 of 446, 9.6%, P < .001). Children delabeled by primary care physicians were as likely to tolerate subsequent penicillin-class antibiotics as those delabeled by an allergist (94% vs 93%, P = .87). CONCLUSIONS: Penicillin allergy documentation within the allergy tab was uninformative, and children were infrequently referred to allergists. Future quality improvement studies should improve penicillin allergy documentation and expand access to allergy services.

Developing Consensus on Clinical Outcomes for Children with Mild Pneumonia: A Delphi Study.

BACKGROUND: The absence of consensus for outcomes in pediatric antibiotic trials is a major barrier to research harmonization and clinical translation. We sought to develop expert consensus on study outcomes for clinical trials of children with mild community-acquired pneumonia (CAP). METHODS: Applying the Delphi method, a multispecialty expert panel ranked the importance of various components of clinical response and treatment failure outcomes in children with mild CAP for use in research. During Round 1, panelists suggested additional outcomes in open-ended responses that were added to subsequent rounds of consensus building. For Rounds 2 and 3, panelists were provided their own prior responses and summary statistics for each item in the previous round. The consensus was defined by >70% agreement. RESULTS: The expert panel determined that response to and failure of treatment should be addressed at a median of 3 days after initiation. Complete or substantial improvement in fever, work of breathing, dyspnea, tachypnea when afebrile, oral intake, and activity should be included as components of adequate clinical response outcomes. Clinical signs and symptoms including persistent or worsening fever, work of breathing, and reduced oral intake should be included in treatment failure outcomes. Interventions including receipt of parenteral fluids, supplemental oxygen, need for high-flow nasal cannula oxygen therapy, and change in prescription of antibiotics should also be considered in treatment failure outcomes. CONCLUSIONS: Clinical response and treatment failure outcomes determined by the consensus of this multidisciplinary expert panel can be used for pediatric CAP studies to provide objective data translatable to clinical practice.

Impact of Penicillin Allergy Labels on Children Treated for Outpatient Respiratory Infections.

BACKGROUND: Penicillin allergy is the most common antibiotic allergy, yet most children labeled as allergic tolerate penicillin. The impact of inaccurate penicillin allergy labels (PALs) on pediatric outpatients is unknown. The objective of this study was to compare outcomes between children with and without a PAL after treatment for outpatient respiratory tract infections (RTI). METHODS: A retrospective, longitudinal birth cohort study was performed in children who received care in 90 pediatric primary care practices in Philadelphia and Houston metropolitan areas. Prescribing and clinical outcomes of children with a PAL at the time of an RTI were compared to non-allergic children, adjusting for potential confounders. RESULTS: Antibiotics were prescribed for 663,473 non-recurrent RTIs among 200,977 children. Children with a PAL (5% of cohort) were more likely than non-allergic children to receive broad-spectrum antibiotics (adjusted relative risk (aRR) 3.24, 95% CI 3.22-3.26) and second-line antibiotics (aRR 4.87, 95% CI 4.83, 4.89). Compared to non-allergic children receiving first-line antibiotics, children with a PAL were more likely to return with adverse drug events (aRR 1.28, 95% CI 1.18-1.39). There was no difference in treatment failure between groups (aRR 0.95, 95% CI 0.90-1.00). CONCLUSIONS: PALs lead to higher rates of broad-spectrum and second-line antibiotic prescribing in children treated for RTIs in primary care and contribute to unnecessary healthcare utilization through increased adverse events. Given the frequency of PALs, efforts to prevent inappropriate penicillin allergy labeling and promote de-labeling of existing inaccurate allergy labels may improve care of children treated for common bacterial infections.

Antibiotic Indications and Appropriateness in the Pediatric Intensive Care Unit: A 10-Center Point Prevalence Study.

BACKGROUND: Antibiotics are prescribed to most pediatric intensive care unit (PICU) patients, but data describing indications and appropriateness of antibiotic orders in this population are lacking. METHODS: We performed a multicenter point prevalence study that included children admitted to 10 geographically diverse PICUs over 4 study days in 2019. Antibiotic orders were reviewed for indication, and appropriateness was assessed using a standardized rubric. RESULTS: Of 1462 patients admitted to participating PICUs, 843 (58%) had at least 1 antibiotic order. A total of 1277 antibiotic orders were reviewed. Common indications were empiric therapy for suspected bacterial infections without sepsis or septic shock (260 orders, 21%), nonoperative prophylaxis (164 orders, 13%), empiric therapy for sepsis or septic shock (155 orders, 12%), community-acquired pneumonia (CAP; 118 orders, 9%), and post-operative prophylaxis (94 orders, 8%). Appropriateness was assessed for 985 orders for which an evidence-based rubric for appropriateness could be created. Of these, 331 (34%) were classified as inappropriate. Indications with the most orders classified as inappropriate were empiric therapy for suspected bacterial infection without sepsis or septic shock (78 orders, 24%), sepsis or septic shock (55 orders, 17%), CAP (51 orders, 15%), ventilator-associated infections (47 orders, 14%), and post-operative prophylaxis (44 orders, 14%). The proportion of antibiotics classified as inappropriate varied across institutions (range, 19%-43%). CONCLUSIONS: Most PICU patients receive antibiotics. Based on our study, we estimate that one-third of antibiotic orders are inappropriate. Improved antibiotic stewardship and research focused on strategies to optimize antibiotic use in critically ill children are needed.

Antimicrobial Stewardship in the Pediatric Primary Care Setting.

Antibiotics are the most commonly prescribed medications in the pediatric outpatient setting, yet 30% to 50% of these prescriptions are deemed to be unnecessary. Outpatient antimicrobial stewardship is the concerted effort to monitor and improve antibiotic use in the community setting. The best methods of conducting antimicrobial stewardship in the outpatient setting are currently unknown, and an individualized approach is likely needed. In this review, we discuss the importance of, resources for, and research supporting outpatient antimicrobial stewardship and review ways an individual pediatric provider can further steward efforts. [Pediatr Ann. 2022;51(5):e196-e201.].

Factors Associated With Penicillin Allergy Labels in Electronic Health Records of Children in 2 Large US Pediatric Primary Care Networks.

Importance: Penicillin allergy labels influence clinical decision-making, yet most children who are labeled do not have type 1 hypersensitivity allergic reactions and instead have a history of predictable adverse reactions or unspecified illness symptoms while receiving penicillin for viral infections. Studies describing penicillin allergy labeling in the pediatric outpatient setting are lacking. Objective: To describe the epidemiology and factors associated with penicillin allergy labels across 2 large US pediatric primary care networks. Design, Setting, and Participants: This retrospective, longitudinal birth cohort study was conducted in 90 primary care pediatric practices serving a diverse population of children across Houston, Texas, Austin, Texas, Philadelphia, Pennsylvania, and parts of New Jersey. Participants were children born between January 2010 and June 2020 who had a health care visit in the first 14 days of life and at least 2 additional visits in the first year of life at one of 90 primary care pediatric practices. Censoring criteria were additionally applied to exclude data from children no longer seeking health care in the 90 clinics over time. Statistical analysis was performed from February to May 2021. Exposures: Basic patient demographics, health care utilization, penicillin exposure, and primary clinic location. Main Outcomes and Measures: Addition of penicillin allergy label in the electronic medical record. Results: Among 334 465 children in the birth cohort, 164 173 (49.1%) were female; 72 831 (21.8%) were Hispanic, 59 598 (17.8%) were non-Hispanic Black, and 148 534 (44.4%) were non-Hispanic White; the median (IQR) age at censoring was 3.8 (1.7-6.6) years; 18 015 (5.4%) were labeled as penicillin allergic, but the prevalence of penicillin allergy labeling ranged from 0.9% to 10.2% across practices. Children were labeled at a median (IQR) age of 1.3 (0.9-2.3) years. Non-Hispanic White children were more likely to be labeled compared with non-Hispanic Black children after controlling for potential confounders (adjusted odds ratio, 1.7 [95% CI, 1.6-1.8]). There were 6797 allergic children (37.7%) labeled after receiving 1 penicillin prescription and 1423 (7.9%) labeled after receiving 0 penicillin prescriptions. Conclusions and Relevance: In this cohort study of more than 330 000 children, penicillin allergy labeling was common and varied widely across practices. Children were labeled early in life, and almost half were labeled after receiving 1 or 0 penicillin prescriptions. These findings raise questions regarding the validity of penicillin allergy labels. Future work exploring the fidelity of and outcomes associated with penicillin allergy-labeling in children is warranted.

Clinical Impact of Plasma Metagenomic Next-generation Sequencing in a Large Pediatric Cohort.

BACKGROUND: Plasma metagenomic next-generation sequencing (mNGS) has the potential to detect thousands of different organisms with a single test. There are limited data on the real-world impact of mNGS and even less guidance on the types of patients and clinical scenarios in which mNGS testing is beneficial. METHODS: A retrospective review of patients who had mNGS testing as part of routine clinical care at Texas Children's Hospital from June 2018-August 2019 was performed. Medical records were reviewed for pertinent data. An expert panel of infectious disease physicians adjudicated each unique organism identified by mNGS for clinical impact. RESULTS: There were 169 patients with at least one mNGS test. mNGS identified a definitive, probable or possible infection in 49.7% of patients. mNGS led to no clinical impact in 139 patients (82.2%), a positive impact in 21 patients (12.4%), and a negative impact in 9 patients (5.3%). mNGS identified a plausible cause for infection more often in immunocompromised patients than in immunocompetent patients (55.8% vs. 30.0%, P = 0.006). Positive clinical impact was highest in patients with multiple indications for testing (37.5%, P = 0.006) with deep-seated infections, overall, being most often associated with a positive impact. CONCLUSION: mNGS testing has a limited real-world clinical impact when ordered indiscriminately. Immunocompromised patients with well-defined deep-seated infections are likely to benefit most from testing. Further studies are needed to evaluate the full spectrum of clinical scenarios for which mNGS testing is impactful.

Risk factors for microbiologic failure in children with Enterobacter species bacteremia.

BACKGROUND: Enterobacter species are an important cause of healthcare-associated bloodstream infections (BSI) in children. Up to 19% of adult patients with Enterobacter BSI have recurrence of infection resistant to third-generation cephalosporins (3GCs) while on therapy with a 3GC. Data are lacking regarding the incidence of and risk factors for recurrence of infection in children with Enterobacter BSI. METHODS: We conducted a retrospective case-control study of patients aged ≤21 years old admitted to Texas Children's Hospital from January 2012 through December 2018 with Enterobacter BSI. The primary outcome was microbiologic failure from 72 hours to 30 days after the initial BSI (cases). The secondary outcome was isolation of a 3GC non-susceptible Enterobacter sp. from a patient with an initial 3GC-susceptible isolate. RESULTS: Twelve patients (6.7%) had microbiologic failure compared to 167 controls without microbiologic failure. Of the 138 patients (77.1%) with an Enterobacter sp. isolate that was initially susceptible to 3GCs, 3 (2.2%) developed a subsequent infection with a non-susceptible isolate. Predictors of microbiologic failure were having an alternative primary site of infection besides bacteremia without a focus or an urinary tract infection (OR, 9.64; 95% CI, 1.77-52.31; P < 0.01) and inadequate source control (OR, 22.16; 95% CI, 5.26-93.36; P < 0.001). CONCLUSIONS: Source of infection and adequacy of source control are important considerations in preventing microbiologic failure. In-vitro susceptibilities can be used to select an antibiotic regimen for the treatment of Enterobacter BSI in children.

Comparative Effectiveness of Echinocandins vs Triazoles or Amphotericin B Formulations as Initial Directed Therapy for Invasive Candidiasis in Children and Adolescents.

BACKGROUND: Invasive candidiasis is the most common invasive fungal disease in children and adolescents, but there are limited pediatric-specific antifungal effectiveness data. We compared the effectiveness of echinocandins to triazoles or amphotericin B formulations (triazole/amphotericin B) as initial directed therapy for invasive candidiasis. METHODS: This multinational observational cohort study enrolled patients aged >120 days and <18 years with proven invasive candidiasis from January 1, 2014, to November 28, 2017, at 43 International Pediatric Fungal Network sites. Primary exposure was initial directed therapy administered at the time qualifying culture became positive for yeast. Exposure groups were categorized by receipt of an echinocandin vs receipt of triazole/amphotericin B. Primary outcome was global response at 14 days following invasive candidiasis onset, adjudicated by a centralized data review committee. Stratified Mantel-Haenszel analyses estimated risk difference between exposure groups. RESULTS: Seven-hundred and fifty invasive candidiasis episodes were identified. After exclusions, 541 participants (235 in the echinocandin group and 306 in the triazole/amphotericin B group) remained. Crude failure rates at 14 days for echinocandin and triazole/amphotericin B groups were 9.8% (95% confidence intervals [CI]: 6.0% to 13.6%) and 13.1% (95% CI: 9.3% to 16.8%), respectively. The adjusted 14-day risk difference between echinocandin and triazole/amphotericin B groups was -7.1% points (95% CI: -13.1% to -2.4%), favoring echinocandins. The risk difference was -0.4% (95% CI: -7.5% to 6.7%) at 30 days. CONCLUSIONS: In children with invasive candidiasis, initial directed therapy with an echinocandin was associated with reduced failure rate at 14 days but not 30 days. These results may support echinocandins as initial directed therapy for invasive candidiasis in children and adolescents. CLINICAL TRIALS REGISTRATION: NCT01869829.

An evidence-based, risk-adapted algorithm for antifungal prophylaxis reduces risk for invasive mold infections in children with hematologic malignancies.

BACKGROUND: Children with hematologic malignancies, especially those who receive intensive chemotherapy, are at high risk for invasive mold infections (IMI) that confer substantial mortality. Randomized controlled trials support the use of antifungal prophylaxis with antimold activity as an optimal strategy for risk reduction in this population, but studies outlining the practical application of evidence-based recommendations are lacking. PROCEDURE: We conducted a 15-year, single-institution retrospective review in a diverse cohort of children with hematologic malignancies treated with chemotherapy to determine the incidence of proven or probable IMI diagnosed between 2006 and 2020. Multivariable logistic regression was used to identify host and disease factors associated with IMI risk. We then compared the incidence and type of IMI and related factors before and after 2016 implementation of an evidence-based, risk-adapted antifungal prophylaxis algorithm that broadened coverage to include molds in patients at highest risk for IMI. RESULTS: We identified 61 cases of proven or probable IMI in 1456 patients diagnosed with hematologic malignancies during the study period (4.2%). Implementation of an antifungal prophylaxis algorithm reduced the IMI incidence in this population from 4.8% to 2.9%. Both Hispanic ethnicity and cancer diagnosis prior to 2016 were associated with risk for IMI. CONCLUSION: An evidence-based, risk-adapted approach to antifungal prophylaxis for children with hematologic malignancies is an effective strategy to reduce incidence of IMI.

Unconfirmed penicillin allergy labels in the paediatric outpatient setting: A call for research and quality improvement initiatives.

Over the last 10 years, the electronic medical record has redefined medical documentation, and physicians rely on accurate records to make clinical decisions. Penicillin allergy labels (PALs) are important pieces of the medical history that guide physicians in selecting specific antibiotic classes for the treatment of infectious diseases. However, most children labelled as penicillin-allergic do not have an IgE-mediated (immediate) allergic reaction to penicillin or its derivatives. In the absence of confirmatory penicillin allergy testing or additional history, these children receive alternative, often broad-spectrum and second-line, antibiotics. Addressing unconfirmed PALs requires an understanding of how and why labels get added to the electronic medical record. This viewpoint highlights the knowledge gaps in paediatric outpatient penicillin allergy labelling and proposes an acronym ('LABEL') that primary care providers and antimicrobial stewards can utilise when designing initiatives to address unconfirmed PALs in the community.

Intermittent Education and Audit and Feedback Reduce Inappropriate Prescribing of Oral Third-Generation Cephalosporins for Pediatric Upper Respiratory Tract Infections.

OBJECTIVE: In June 2017, leaders within a pediatric ambulatory care network in Houston approached the antimicrobial stewardship team at Texas Children's Hospital with concerns for high oral third-generation cephalosporin (oTGC) use in their clinics. An outpatient quality improvement (QI) team was formed. The specific aim was to reduce inappropriate oTGC prescribing at one clinic ("Clinic A") by 15% in one year. METHODS: Following a benchmark analysis of oTGC use at Clinic A, Plan-Do-Study-Act (PDSA) cycles were designed and conducted over one year: one educational session, three individual audit and feedback sessions, and one group feedback session. The primary outcome was the percentage of oTGCs not aligning with American Academy of Pediatrics (AAP) guidelines for bacterial upper respiratory tract infections. Monthly oTGC prescribing at Clinic A was also compared to four control clinics. RESULTS: In June 2017, 72% (231/322) of oTGCs prescriptions at Clinic A did not align with AAP guidelines. The most common diagnosis was primary/nonrecurrent acute otitis media. Following interventions, the mean percentage inappropriate oTGCs decreased from 72% to 45% (absolute reduction 27%, p < 0.001), which was sustained the year following the last PDSA cycle (absolute reduction 26%, p < 0.001). Total monthly oTGC prescribing at Clinic A decreased over time, but not in four control clinics. Provider active participation in stewardship activities decreased over time. CONCLUSION: Intermittent education and audit and feedback were associated with reduced oTGC misuse at Clinic A but not at four control clinics. Improvements were maintained despite decreased participation in stewardship activities, suggesting that perceptions of ongoing antibiotic audits can help sustain prescribing improvements.

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.