Engaging School Communities During COVID-19: The Role of School Nurses.

We explored the role of school nurses during the COVID-19 pandemic by conducting interviews and focus groups with them in 2022 and 2023 in an urban public school district. Findings indicated that school nurses played an essential public health role in engaging the school community, overseeing COVID-19 testing, and enforcing risk mitigation strategies during the pandemic. Our results contribute to understanding school nurses' experiences during the pandemic and highlight the need for training and support for their vital role. (Am J Public Health. 2024;114(S5):S402-S404. https://doi.org/10.2105/AJPH.2024.307591).

Guideline-Concordant Antiviral Treatment in Children at High Risk for Influenza Complications.

BACKGROUND: National guidelines recommend antiviral treatment for children with influenza at high risk for complications regardless of symptom duration. Little is known about concordance of clinical practice with this recommendation. METHODS: We performed a cross-sectional study of outpatient children (aged 1-18 years) at high risk for complications who were diagnosed with influenza during the 2016-2019 influenza seasons. High-risk status was determined using an existing definition that includes age, comorbidities, and residence in a long-term care facility. The primary outcome was influenza antiviral dispensing within 2 days of influenza diagnosis. We determined patient- and provider-level factors associated with guideline-concordant treatment using multivariable logistic regression. RESULTS: Of the 274 213 children with influenza at high risk for influenza complications, 159 350 (58.1%) received antiviral treatment. Antiviral treatment was associated with the presence of asthma (aOR, 1.13; 95% confidence interval [CI], 1.11-1.16), immunosuppression (aOR, 1.10; 95% CI, 1.05-1.16), complex chronic conditions (aOR, 1.04; 95% CI, 1.01-1.07), and index encounter in the urgent care setting (aOR, 1.3; 95% CI, 1.26-1.34). Factors associated with decreased odds of antiviral treatment include age 2-5 years compared with 6-17 years (aOR, 0.95; 95% CI, .93-.97), residing in a chronic care facility (aOR, .61; 95% CI, .46-.81), and index encounter in an emergency department (aOR, 0.66; 95% CI, .63-.71). CONCLUSIONS: Among children with influenza at high risk for complications, 42% did not receive guideline-concordant antiviral treatment. Further study is needed to elucidate barriers to appropriate use of antivirals in this vulnerable population.

Pharmacokinetics and safety of a single dose of telavancin in pediatric subjects 2-17 years of age.

Antimicrobial resistance increases infection morbidity in both adults and children, necessitating the development of new therapeutic options. Telavancin, an antibiotic approved in the United States for certain bacterial infections in adults, has not been examined in pediatric patients. The objectives of this study were to evaluate the short-term safety and pharmacokinetics (PK) of a single intravenous infusion of telavancin in pediatric patients. Single-dose safety and PK of 10 mg/kg telavancin was investigated in pediatric subjects >12 months to ≤17 years of age with known or suspected bacterial infection. Plasma was collected up to 24-h post-infusion and analyzed for concentrations of telavancin and its metabolite for noncompartmental PK analysis. Safety was monitored by physical exams, vital signs, laboratory values, and adverse events following telavancin administration. Twenty-two subjects were enrolled: 14 subjects in Cohort 1 (12-17 years), 7 subjects in Cohort 2 (6-11 years), and 1 subject in Cohort 3 (2-5 years). A single dose of telavancin was well-tolerated in all pediatric age cohorts without clinically significant effects. All age groups exhibited increased clearance of telavancin and reduced exposure to telavancin compared to adults, with mean peak plasma concentrations of 58.3 µg/mL (Cohort 1), 60.1 µg/mL (Cohort 2), and 53.1 µg/mL (Cohort 3). A 10 mg/kg dose of telavancin was well tolerated in pediatric subjects. Telavancin exposure was lower in pediatric subjects compared to adult subjects. Further studies are needed to determine the dose required in phase 3 clinical trials in pediatrics.

HLA-B*07:02 and HLA-C*07:02 are associated with trimethoprim-sulfamethoxazole respiratory failure.

We have identified an underrecognized severe adverse drug reaction (ADR) of trimethoprim-sulfamethoxazole (TMP-SMX) associated respiratory failure in previously healthy children and young adults. We investigated potential genetic risk factors associated with TMP-SMX induced respiratory failure in a cohort of seven patients. We explored whole genome sequence among seven patients representing nearly half of all reported cases worldwide and 63 unrelated control individuals in two stages: (1) human leukocyte antigen (HLA) locus variation as several other ADRs have been associated HLA genetic variants and (2) coding variation to catalog and explore potential rare variants contributing to this devastating reaction. All cases were either heterozygous (carriers) or homozygous for the common HLA-B*07:02-HLA-C*07:02 haplotype. Despite the small sample size, this observation is statistically significant both in conservative comparison to maximum reported population frequencies (binomial P = 0.00017 for HLA-B and P = 0.00028 for HLA-C) and to our control population assessed by same HLA genotyping approach (binomial P = 0.000001 for HLA-B and P = 0.000018 for HLA-C). No gene elsewhere in the genome harnessed shared rare case enriched coding variation. Our results suggests that HLA-B*07:02 and HLA-C*07:02 are necessary for a patient to develop respiratory failure due to TMP-SMX.

Precision dosing of vancomycin: in defence of AUC-guided therapy in children.

In 2020, new vancomycin guidelines were released, recommending the transition from trough-based to AUC24 monitoring for adult and paediatric patients. Given the resources required to achieve this transition, there has been debate about the costs and benefits of AUC24-based monitoring. A recent narrative review of vancomycin therapeutic drug monitoring in paediatrics claims to have uncovered the methodological weaknesses of the data that informed the guidelines and advises against premature adoption of AUC24-guided monitoring. In this article, we present supporting arguments for AUC24-guided monitoring in children, which include that: (i) troughs alone are inadequate surrogates for AUC24; (ii) vancomycin-associated nephrotoxicity has significant consequences that warrant optimization of dosing; (iii) a substantial portion of children receiving vancomycin are at high risk for poor outcomes and deserve targeted monitoring; and (iv) limited efficacy data in support of AUC24 is not a justification to revert to a less supported monitoring approach.

Screening Trimethoprim Primary Metabolites for Covalent Binding to Albumin.

Modification of endogenous proteins by drugs and drug metabolites are thought to be a cause of idiosyncratic adverse drug reactions (IADRs). Trimethoprim (TMP) is a commonly prescribed antibiotic that has been implicated in IADRs; however, there is no known mechanism by which this drug or its metabolites modify proteins. This study describes the results of screening trimethoprim and its primary metabolites for the ability to covalently modify human serum albumin (HSA). The first step of the screen was in vitro reactions of the compounds with HSA followed by western blotting with antisera specific to drug-modified proteins. Compounds with positive signal in the western blot were then screened using an untargeted peptide profiling method to discover modified peptides. This strategy identified two sites in HSA that are modified by incubation with a TMP metabolite, α-hydroxy trimethoprim (Cα-OH-TMP).

Adverse drug reaction causality assessment tools for drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: room for improvement.

PURPOSE: Establishment of causality between drug exposure and adverse drug reactions (ADR) is challenging even for serious ADRs such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Several causality assessment tools (CAT) exist, but the reliability and validity of such tools is variable. The objective of this study was to compare the reliability and validity of existing ADR CATs on SJS/TEN cases. METHODS: Seven investigators completed three CAT (ALDEN, Naranjo, Liverpool) for 10 SJS/TEN cases. Each CAT categorized the causality of 30 potential drugs as definite/very probable, probable, possible, or doubtful/unlikely. An additional reviewer provided expert opinion by designating the implicated drug(s) for each case. A Kappa score was generated to compare CAT responses both by method (reliability of all 7 reviewers, by CATs) and by reviewer (reliability of the 3 CAT, by reviewer). A c statistic was calculated to assess validity. RESULTS: Inter-rater reliability by CAT was poor to fair: ALDEN 0.22, Naranjo 0.11, and Liverpool 0.12. Reliability was highest when causality classification was definite/very probable (0.16-0.41). Similarly, intra-rater reliability by reviewer was poor. When comparing the validity of the overall CAT to expert reviewer, area under the curve was highest for ALDEN (c statistic 0.65) as compared to Liverpool (0.55) or Naranjo (0.54). CONCLUSION: Available CAT have poor reliability and validity for drug-induced SJS/TEN. Due to the importance of determining ADR causality for research, industry, and regulatory purposes, development of an enhanced tool that can incorporate data from immunological testing and pharmacogenetic results may strengthen CAT usefulness and applicability for drug-induced SJS/TEN.

Correction to: Adverse drug reaction causality assessment tools for drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: room for improvement.

The correct name of the 9th Author is David J. Margolis. The original article was corrected.

Incidence, outcomes, and resource use in children with Stevens-Johnson syndrome and toxic epidermal necrolysis.

BACKGROUND/OBJECTIVES: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening cutaneous reactions, typically to drugs or infection. The incidence and outcomes of these conditions in children are unknown. The objective of this study was to report the overall burden of Stevens-Johnson syndrome and toxic epidermal necrolysis in children in the United States. METHODS: We performed a retrospective cohort analysis of children and adolescents younger than 18 years of age using the 2009 and 2012 Kids' Inpatient Database. RESULTS: We identified 1486 children and adolescents hospitalized with a diagnosis of Stevens-Johnson syndrome or toxic epidermal necrolysis. The national incidence per 100 000 was 6.3 for Stevens-Johnson syndrome, 0.7 for Stevens-Johnson syndrome/toxic epidermal necrolysis overlap syndrome, and 0.5 for toxic epidermal necrolysis. The highest incidence in children was in those aged 11-15 years (38.4 per 100 000). Toxic epidermal necrolysis and Stevens-Johnson syndrome/toxic epidermal necrolysis overlap syndrome were associated with longer stay, greater mortality, and higher hospital charges than those with Stevens-Johnson syndrome. Hospital mortality was highest in children with toxic epidermal necrolysis and in children aged 0-5 years. CONCLUSIONS: The incidence of Stevens-Johnson syndrome and toxic epidermal necrolysis in children is higher than reported in adults, and there are significant age-based variations in incidence and outcomes across the pediatric population. Further study is needed to determine the most effective treatment strategies to reduce costs and improve outcomes in children hospitalized with severe cutaneous reactions.

Pharmacokinetics of Clindamycin in Obese and Nonobese Children.

Although obesity is prevalent among children in the United States, pharmacokinetic (PK) data for obese children are limited. Clindamycin is a commonly used antibiotic that may require dose adjustment in obese children due to its lipophilic properties. We performed a clindamycin population PK analysis using data from three separate trials. A total of 420 samples from 220 children, 76 of whom had a body mass index greater than or equal to the 95th percentile for age, were included in the analysis. Compared to other metrics, total body weight (TBW) was the most robust measure of body size. The final model included TBW and a sigmoidal maturation relationship between postmenstrual age (PMA) and clearance (CL): CL (liters/hour) = 13.8 × (TBW/70)0.75 × [PMA2.83/(39.52.83+PMA2.83)]; volume of distribution (V) was associated with TBW, albumin (ALB), and alpha-1 acid glycoprotein (AAG): V (liters) = 63.6 × (TBW/70) × (ALB/3.3)-0.83 × (AAG/2.4)-0.25 After accounting for differences in TBW, obesity status did not explain additional interindividual variability in model parameters. Our findings support TBW-based dosing for obese and nonobese children.

Bioactivation of Trimethoprim to Protein-Reactive Metabolites in Human Liver Microsomes.

The formation of drug-protein adducts via metabolic activation and covalent binding may stimulate an immune response or may result in direct cell toxicity. Protein covalent binding is a potentially pivotal step in the development of idiosyncratic adverse drug reactions (IADRs). Trimethoprim (TMP)-sulfamethoxazole (SMX) is a combination antibiotic that commonly causes IADRs. Recent data suggest that the contribution of the TMP component of TMP-SMX to IADRs may be underappreciated. We previously demonstrated that TMP is bioactivated to chemically reactive intermediates that can be trapped in vitro by N-acetyl cysteine (NAC), and we have detected TMP-NAC adducts (i.e., mercapturic acids) in the urine of patients taking TMP-SMX. However, the occurrence and extent of TMP covalent binding to proteins was unknown. To determine the ability of TMP to form protein adducts, we incubated [(14)C]TMP with human liver microsomes in the presence and absence of NADPH. We observed protein covalent binding that was NADPH dependent and increased with incubation time and concentration of both protein and TMP. The estimated covalent binding was 0.8 nmol Eq TMP/mg protein, which is comparable to the level of covalent binding for several other drugs that have been associated with covalent binding-induced toxicity and/or IADRs. NAC and selective inhibitors of CYP2B6 and CYP3A4 significantly reduced TMP covalent binding. These results demonstrate for the first time that TMP bioactivation can lead directly to protein adduct formation, suggesting that TMP has been overlooked as a potential contributor of TMP-SMX IADRs.

In Vitro Hepatic Oxidative Biotransformation of Trimethoprim.

Trimethoprim (TMP) has been widely used since the 1960s, both alone and in combination with sulfamethoxazole. Unfortunately, information regarding the role that cytochrome P450 enzymes (P450s) play in the formation of TMP primary metabolites is scarce. Hence, we undertook in vitro studies to identify and more fully characterize the P450s that catalyze formation of six TMP primary metabolites: TMP 1-N-oxide (1-NO-TMP) and 3-N-oxide (3-NO-TMP), 3'- and 4'-desmethyl-TMP, a benzylic alcohol (Cα-OH-TMP), and an N-acetyl cysteine (NAC) adduct of TMP (Cα-NAC-TMP). Formation kinetics for each TMP metabolite in human liver microsomes (HLMs) were consistent with single-enzyme Michaelis-Menten kinetics, and Km values were markedly above (≥10-fold) the therapeutic concentrations of TMP (50 µM). The combined results from correlation studies between rates of metabolite formation and marker P450 activities in a panel of HLMs along with inhibition studies utilizing selective P450 inhibitors incubated with pooled HLMs suggested that 1-NO-TMP, Cα-NAC-TMP, and Cα-OH-TMP were predominantly formed by CYP3A4. In contrast, 3-NO-TMP was formed predominantly by CYP1A2 in HLMs and inhibited by α-naphthoflavone. 4'-Desmethyl-TMP, which is believed to be a reactive TMP metabolite precursor, was formed by several P450s, including CYP3A4, correlated with multiple P450 activities, but was inhibited primarily by ketoconazole (up to 50%), suggesting that CYP3A4 makes a major contribution to TMP 4'-demethylation. TMP 3'-demethylation was catalyzed by multiple P450s, including CYP2C9, correlated with CYP2C9 activity, and was inhibited by sulfaphenazole (up to 40%). Overall, CYP2C9 and CYP3A4 appear to be the most significant contributors to TMP primary metabolism.

Urinary biomarkers of trimethoprim bioactivation in vivo following therapeutic dosing in children.

The antimicrobial trimethoprim-sulfamethoxazole (TMP-SMX) is widely used for the treatment of skin and soft-tissue infections in the outpatient setting. Despite its therapeutic benefits, TMP-SMX has been associated with a number of adverse drug reactions, which have been primarily attributed to the formation of reactive metabolites from SMX. Recently, in vitro experiments have demonstrated that TMP may form reactive intermediates as well. However, evidence of TMP bioactivation in patients has not yet been demonstrated. In this study, we performed in vitro trapping experiments with N-acetyl-l-cysteine (NAC) to determine stable markers of reactive TMP intermediates, focusing on eight potential markers (NAC-TMP adducts), some of which were previously identified in vitro. We developed a specific and sensitive assay involving liquid chromatography followed by tandem mass spectrometry for measurement of these adducts in human liver microsomal samples and expanded the methodology toward the detection of these analytes in human urine. Urine samples from four patients receiving TMP-SMX treatment were analyzed, and all samples demonstrated the presence of six NAC-TMP adducts, which were also detected in vitro. These adducts are consistent with the formation of imino-quinone-methide and para-quinone-methide reactive intermediates in vivo. As a result, the TMP component of TMP-SMX should be considered as well when evaluating adverse drug reactions to TMP-SMX.

Clarification of adverse drug reactions by a pharmacovigilance team results in increased antibiotic re-prescribing at a freestanding United States children's hospital.

Documentation of adverse drug reactions (ADRs) is a key factor in guiding future prescribing. However, incomplete documentation is common and often fails to distinguish implicated drugs as true allergies. This in turn leads to unnecessary avoidance of implicated drug classes and may result in sub-optimal prescribing. Pharmacovigilance (PV) programs utilize a systematic approach to clarify ADR documentation and are known to improve patient safety. Yet it remains unclear if PV alters prescribing. Or, if the existence of the ADR documentation itself continues to prompt avoidance of implicated drugs. To address this, our work presents a retrospective cohort study assessing if clarification of antibiotic ADRs by a hospital-wide PV team was associated with future, safe, re-prescribing at a freestanding pediatric hospital in the midwestern United States. First, we compared the likelihood of future prescribing in an antibiotic class with an active ADR, as compared to alternative drug classes, between PV-clarified and non-clarified patients. Second, we assessed differences in adverse event rates 30-days after future prescribing based on PV clarification status. For robustness, analyses were performed on patients with ADRs in four antibiotic classes: penicillin-based beta-lactams (n = 45,642), sulfonamides/trimethoprim (n = 5,329), macrolides (n = 3,959), and glycopeptides (n = 622). Results illustrate that clarification of an ADR by PV was associated with an increased odds of future prescribing in the same drug class (Odds Ratio [95%-CI]): penicillin-based beta-lactams (1.59 [1.36-1.89]), sulfonamides/trimethoprim (2.29 [0.89-4.91]), macrolides (0.77 [0.33-1.61]), and glycopeptide (1.85 [1.12-3.20]). Notably, patients clarified by PV experienced no increase in the rate of adverse events within 30-days following the prescribing of antibiotics in the same class as an active ADR. Overall, this study provides strong evidence that PV reviews safely increase the rate of re-prescribing antibiotics even in the presence of an existing implicated drug ADR.

Variation in antibiotic resistance patterns for children and adults treated at 166 non-affiliated US facilities using EHR data.

Background: Antibiotic resistance (AR) is a global public health threat. Surveillance of baseline AR and trends and emerging resistance among priority bacterial isolates with respect to the age of the patients and the type of healthcare setting are required due to differences in antimicrobial need and use in these populations. Methods: We performed a retrospective study using deidentified electronic health record (EHR) data in the Cerner Health Facts™ data warehouse. Antibiotic susceptibility data were extracted for all bacterial isolates of interest at 166 non-affiliated healthcare facilities reporting microbiology susceptibility results of the FDA recommended antibiotics between the years 2012 to 2017. We assessed and visualized the slope coefficient from linear regression to compare changes in resistance over time for the four patient care groups. Results: The trends in resistance rates to clinically relevant antibiotics were influenced by age and care setting. For example, ertapenem-resistant Enterobacter cloacae isolates from children overall increased significantly compared with adults (0.7% to 9.8%, 2.1% to 2.8%, P = 0.00013) and isolates from children in paediatric facilities increased significantly compared with facilities treating adults and children (0.1% to 27.1%, 0.9% to 3.8%, P = 0.0002). Conclusions: Large-scale analysis of EHR data from 166 facilities shows that AR patterns for some bug-drug combinations vary by care setting and patient age. We describe novel data visualizations to interpret large-scale EHR data on the prevalence and trends of AR that should influence antimicrobial prescribing and antimicrobial stewardship programme interventions.

Adherence to antimicrobial agent recommendations and utilization during drug shortages.

PURPOSE: Antimicrobial shortages occur frequently, but the impact on antimicrobial use is not well defined. The study objectives were to characterize utilization of antimicrobial agents with established restrictions during a medication shortage, assess utilization of shortage antimicrobials following shortage resolution, and examine use of recommended alternative antimicrobials during the shortage period. METHODS: Five antimicrobials were restricted due to shortages from 2015 through 2020. Chart review of inpatients receiving a shortage medication during each restriction period was performed to determine factors influencing adherence to established restriction criteria. To assess antimicrobial utilization during shortages and following shortage resolution, days of therapy per 1,000 patient days were analyzed for each shortage and alternative antimicrobial. RESULTS: Across 266 patients receiving shortage antimicrobials, antimicrobial use was adherent to restriction criteria for 151 patients (57%). Meropenem, ampicillin/sulbactam, and piperacillin/tazobactam had the greatest adherence. Median duration of therapy was shorter in the nonadherent group than in the adherent group (4 vs 2 days, P < 0.0001). Shortage antimicrobial use was more likely to be nonadherent for indications such as sepsis rule out, surgical prophylaxis, and urinary tract infection. Adherence increased with use of visual cues in the chart (99% vs 94%, P = 0.03). Utilization of shortage agents decreased during shortage and restriction periods. After shortage resolution, utilization exceeded baseline usage for all agents except meropenem and metronidazole, for which usage returned to baseline. Utilization of 1 to 2 recommended alternative agents for each shortage agent significantly increased during the shortage and restriction periods. CONCLUSION: Current strategies for restriction significantly decreased utilization of shortage antimicrobials, but additional opportunities exist. Identifying alternative agents and providing visual cues increased adherence.

A COVID-19 Testing Preference Study in Schools.

OBJECTIVES: The Centers for Disease Control and Prevention identifies in-school COVID-19 testing as a key mitigation strategy to protect students and staff during the COVID-19 pandemic. Both nasal and saliva samples are acceptable, but existing school guidance does not state a preferred test method. METHODS: From May 2021 through July 2021, we performed a randomized, crossover study in kindergarten through 12th grade (K-12) schools to evaluate student and staff preference for self-collected nasal or saliva testing. Participants performed both collection types and participated in a standardized questionnaire assessing the preferred method. RESULTS: A total of 135 students and staff participated. Staff, middle school, and high school students preferred the nasal swab (80/96, 83%), whereas elementary students were mixed (20/39, 51% preferred saliva). Reasons reported for preferring the nasal swab included being faster and easier. Reasons reported for preferring saliva included being easier and more fun. Despite their preference, 126 (93%) and 109 (81%) participants would take the nasal swab or saliva test again, respectively. CONCLUSIONS: The anterior nasal test was the preferred testing method by students and staff, although preference varied by age group. Willingness to perform both tests again in the future was high. Identifying the preferred testing modality is important to increase acceptance and participation in COVID-19 in-school testing programs.