Reducing length of antibiotics for children with ear infections: protocol for a cluster-randomized trial in the USA.

Aim: Preventing unnecessarily long durations of antibiotic therapy is a key opportunity to reduce antibiotic overuse in children 2 years of age and older with acute otitis media (AOM). Pragmatic interventions to reduce durations of therapy that can be effectively scaled and sustained are urgently needed. This study aims to fill this gap by evaluating the effectiveness and implementation outcomes of two low-cost interventions of differing intensities to increase guideline-concordant antibiotic durations in children with AOM. Methods: The higher intensity intervention will consist of clinician education regarding guideline-recommended short durations of antibiotic therapy; electronic health record (EHR) prescription field changes to promote prescribing of recommended short durations; and individualized clinician audit and feedback on adherence to recommended short durations of therapy in comparison to peers, while the lower intensity intervention will consist only of clinician education and EHR changes. We will explore the differences in implementation effectiveness by patient population served, clinician type, clinical setting and organization as well as intervention type. The fidelity, feasibility, acceptability and perceived appropriateness of the interventions among different clinician types, patient populations, clinical settings and intervention type will be compared. We will also conduct formative qualitative interviews with clinicians and administrators and focus groups with parents of patients to further inform the interventions and study. The formative evaluation will take place over 1.5 years, the interventions will be implemented over 2 years and evaluation of the interventions will take place over 1.5 years. Discussion: The results of this study will provide a framework for other healthcare systems to address the widespread problem of excessive durations of therapy for AOM and inform national antibiotic stewardship policy development. Clinical Trial Registration: NCT05608993 (ClinicalTrials.gov).

Transmission risk of COVID-19 in high school and college water polo.

BACKGROUND: Concerns that athletes may be at a higher risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission has led to reduced participation in sports during the COVID-19 pandemic. We aimed to assess COVID-19 incidence and transmission during the spring 2021 high school and college water polo seasons across the United States. METHODS: This prospective observational study enrolled 1825 water polo athletes from 54 high schools and 36 colleges. Surveys were sent to coaches throughout the season, and survey data were collected and analyzed. RESULTS: We identified 17 COVID-19 cases among 1223 high school water polo athletes (1.4%) and 66 cases among 602 college athletes (11.0%). Of these cases, contact tracing suggested that three were water polo-associated in high school, and none were water polo-associated in college. Quarantine data suggest low transmission during water polo play as only three out of 232 (1.3%) high school athletes quarantined for a water polo-related exposure developed COVID-19. In college, none of the 54 athletes quarantined for exposure with an infected opponent contracted COVID-19. However, in both high school and college, despite the physical condition of water polo athletes, both high school (47%) and college athletes (21%) had prolonged return to play after contracting COVID-19, indicating the danger of COVID-19, even to athletes. CONCLUSIONS: While COVID-19 spread can occur during water polo play, few instances of spread occurred during the spring 2021 season, and transmission rates appear similar to those in other settings, such as school environments.

A cluster randomized stepped-wedge trial to de-implement unnecessary post-operative antibiotics in children: the optimizing perioperative antibiotic in children (OPerAtiC) trial.

BACKGROUND: Antibiotic-resistant infections have become a public health crisis that is driven by the inappropriate use of antibiotics. In the USA, antibiotic stewardship programs (ASP) have been established and are required by regulatory agencies to help combat the problem of antibiotic resistance. Post-operative antibiotic use in surgical cases deemed low-risk for infection is an area with significant overuse of antibiotics in children. Consensus among leading public health organizations has led to guidelines eliminating post-operative antibiotics in low-risk surgeries. However, the best strategies to de-implement these inappropriate antibiotics in this setting are unknown. METHODS/DESIGN: A 3-year stepped wedge cluster randomized trial will be conducted at nine US Children's Hospitals to assess the impact of two de-implementation strategies, order set change and facilitation training, on inappropriate post-operative antibiotic prescribing in low risk (i.e., clean and clean-contaminated) surgical cases. The facilitation training will amplify order set changes and will involve a 2-day workshop with antibiotic stewardship teams. This training will be led by an implementation scientist expert (VRM) and a pediatric infectious diseases physician with antibiotic stewardship expertise (JGN). The primary clinical outcome will be the percentage of surgical cases receiving unnecessary post-operative antibiotics. Secondary clinical outcomes will include the rate of surgical site infections and the rate of Clostridioides difficile infections, a common negative consequence of antibiotic use. Monthly semi-structured interviews at each hospital will assess the implementation process of the two strategies. The primary implementation outcome is penetration, which will be defined as the number of order sets changed or developed by each hospital during the study. Additional implementation outcomes will include the ASP team members' assessment of the acceptability, appropriateness, and feasibility of each strategy while they are being implemented. DISCUSSION: This study will provide important information on the impact of two potential strategies to de-implement unnecessary post-operative antibiotic use in children while assessing important clinical outcomes. As more unnecessary medical practices are identified, de-implementation strategies, including facilitation, need to be rigorously evaluated. Along with this study, other rigorously designed studies evaluating additional strategies are needed to further advance the burgeoning field of de-implementation. TRIAL REGISTRATION: NCT04366440. Registered April 28, 2020, https://clinicaltrials.gov/ct2/show/NCT04366440 .

Utilization of the Sharing Antimicrobial Reports for Pediatric Stewardship (SHARPS) Collaborative electronic mailing list (listserv) by healthcare professionals.

Optimizing pediatric antimicrobial stewardship is challenging. In this retrospective study, we evaluated 515 original e-mails to 482 members of the Sharing Antimicrobial Reports for Pediatric Stewardship (SHARPS) Collaborative electronic mailing list (idlistserv@kids.wustl.edu). The plurality of threads discussed clinical practice guidelines, and pharmacists were most likely to initiate and respond. Representation was geographically diverse within and outside the United States.

Use of Antimicrobial Agents in Hospitalized Children for Noninfectious Indications.

In this point-prevalence study of 32 US children's hospitals, we determined that 1.7% of hospitalized children received at least 1 antimicrobial agent for a non-infection-related reason; macrolides were used most commonly. Antimicrobial stewardship efforts to understand and affect use for these reasons is an unmet need; additional research considering the individual and societal effects of these antimicrobial-prescribing practices should be undertaken.

Appropriateness of Antibiotic Prescribing in United States Children's Hospitals: A National Point Prevalence Survey.

BACKGROUND: Studies estimate that 30%-50% of antibiotics prescribed for hospitalized patients are inappropriate, but pediatric data are limited. Characterization of inappropriate prescribing practices for children is needed to guide pediatric antimicrobial stewardship. METHODS: Cross-sectional analysis of antibiotic prescribing at 32 children's hospitals in the United States. Subjects included hospitalized children with ≥ 1 antibiotic order at 8:00 am on 1 day per calendar quarter, over 6 quarters (quarter 3 2016-quarter 4 2017). Antimicrobial stewardship program (ASP) physicians and/or pharmacists used a standardized survey to collect data on antibiotic orders and evaluate appropriateness. The primary outcome was the percentage of antibiotics prescribed for infectious use that were classified as suboptimal, defined as inappropriate or needing modification. RESULTS: Of 34 927 children hospitalized on survey days, 12 213 (35.0%) had ≥ 1 active antibiotic order. Among 11 784 patients receiving antibiotics for infectious use, 25.9% were prescribed ≥ 1 suboptimal antibiotic. Of the 17 110 antibiotic orders prescribed for infectious use, 21.0% were considered suboptimal. Most common reasons for inappropriate use were bug-drug mismatch (27.7%), surgical prophylaxis > 24 hours (17.7%), overly broad empiric therapy (11.2%), and unnecessary treatment (11.0%). The majority of recommended modifications were to stop (44.7%) or narrow (19.7%) the drug. ASPs would not have routinely reviewed 46.1% of suboptimal orders. CONCLUSIONS: Across 32 children's hospitals, approximately 1 in 3 hospitalized children are receiving 1 or more antibiotics at any given time. One-quarter of these children are receiving suboptimal therapy, and nearly half of suboptimal use is not captured by current ASP practices.

Mass spectrometric measurement of urinary kynurenine-to-tryptophan ratio in children with and without urinary tract infection.

BACKGROUND: Indoleamine-2,3-dioxygenase (IDO) catalyzes the first step of tryptophan (Trp) catabolism, yielding kynurenine (Kyn) metabolites. The kynurenine-to-tryptophan (K/T) ratio is used as a surrogate for biological IDO enzyme activity. IDO expression is increased during Escherichia coli urinary tract infection (UTI). Thus, our objective was to develop a method for measurement of Kyn/Trp ratio in human blood and urine and evaluate its use as a biomarker of UTI. METHODS: A mass spectrometric method was developed to measure Trp and Kyn in serum and urine specimens. The method was applied to clinical urine specimens from symptomatic pediatric patients with laboratory-confirmed UTI or other acute conditions and from healthy controls. RESULTS: The liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was linear to 500 µmol/L for both Trp and Kyn. Imprecision ranged from 5 to 15% for Trp and 6-20% for Kyn. Analytical recoveries of Trp and Kyn ranged from 96 to 119% in serum and 90-97% in urine. No correlation was found between the K/T ratio and circulating IDO mass (r = 0.110) in serum. Urinary Kyn and Trp in the pediatric test cohort demonstrated elevations in the K/T ratio in symptomatic patients with UTI (median 13.08) and without UTI (median 14.38) compared to healthy controls (median 4.93; p < 0.001 for both comparisons). No significant difference in K/T ratio was noted between symptomatic patients with and without UTI (p = 0.84). CONCLUSIONS: Measurement of Trp and Kyn by LC-MS/MS is accurate and precise in serum and urine specimens. While urinary K/T ratio is not a specific biomarker for UTI, it may represent a general indicator of a systemic inflammatory process.

Characteristics of Pediatric Antimicrobial Stewardship Programs: Current Status of the Sharing Antimicrobial Reports for Pediatric Stewardship (SHARPS) Collaborative.

In response to the growing epidemic of antibiotic-resistant bacterial infections, antimicrobial stewardship programs (ASP) have been rapidly implemented in the United States (US). This study examines the prevalence of the Centers for Disease Control and Prevention's (CDC) seven core elements of a successful ASP within a large subset of US Children's Hospitals. In 2016, a survey was conducted of 52 pediatric hospitals assessing the presence of the seven core elements: leadership commitment, accountability, drug expertise, action, tracking, reporting, and education. Forty-nine hospitals (94%) had established ASPs and 41 hospitals (79%) included all seven core elements. Physician accountability (87%) and a dedicated ASP pharmacist or drug expert (88%) were present in the vast majority of hospitals. However, substantial variability existed in the financial support allotted to these positions. This variability did not predict program actions, tracking, reporting, and education. When compared with previous surveys, these results document a dramatic increase in the prevalence and resources of pediatric stewardship programs, although continued expansion is warranted. Further research is required to understand the feasibility of various core stewardship activities and the impact on patient outcomes in the setting of finite resources.

Design of the silent cerebral infarct transfusion (SIT) trial.

BACKGROUND: Silent cerebral infarct (SCI) is the most common cause of serious neurological disease in sickle cell anemia (SCA), affecting approximately 22% of children. The goal of this trial is to determine whether blood transfusion therapy will reduce further neurological morbidity in children with SCI, and if so, the magnitude of this benefit. PROCEDURE: The Silent Cerebral Infarct Transfusion (SIT) Trial includes 29 clinical sites and 3 subsites, a Clinical Coordinating Center, and a Statistical and Data Coordinating Center, to test the following hypothesis: prophylactic blood transfusion therapy in children with SCI will result in at least an 86% reduction in the rate of subsequent overt strokes or new or progressive cerebral infarcts as defined by magnetic resonance imaging (MRI) of the brain. The intervention is blood transfusion versus observation. Two hundred and four participants (102 in each treatment assignment) will ensure 85% power to detect the effect necessary to recommend transfusion therapy (86% reduction), after accounting for 10% drop out and 19% crossover rates. MRI examination of the brain is done at screening, immediately before randomization and study exit. Each randomly assigned participant receives a cognitive test battery at study entry, 12-18 months later, and study exit and an annual neurological examination. Blood is obtained from all screened participants for a biologic repository containing serum and a renewable source of DNA. CONCLUSION: The SIT Trial could lead to a change in standard care practices for children affected with SCA and SCI, with a consequent reduction in neurological morbidity.

Clinical trials in children--How are they implemented?

Drug metabolism in children may differ from adults and adverse events may occur that are not predictable from the adult experience. Clinical trials of safety and efficacy are needed both for new treatments and those that may already be in use but have not been tested in infants and children. The role and responsibilities of different participants in a trial are discussed, including the steering committee, the clinical and statistical co-ordinating centers, and the data and safety monitoring board. Advantages of external vs internal pilot studies are reviewed. Information that is available on the websites of the Food and Drug Administration and the National Institute of Neurological Disorders and Stroke may be helpful to those planning clinical trials of interventions in children.

Risk of recurrent stroke in children with sickle cell disease receiving blood transfusion therapy for at least five years after initial stroke.

OBJECTIVE: To test the hypothesis that children with sickle cell disease (SCD) who have an initial stroke temporally unrelated to another medical event are at higher risk for recurrent stroke than are children who had strokes temporally related to medical events. METHODS: A retrospective cohort study of children with SCD and stroke who received regularly scheduled blood transfusions for a minimum of 5 years was conducted. Medical records were examined for the documentation of antecedent or concurrent medical events (hypertension, acute chest syndrome, aplastic crisis, fever associated with infection, exchange transfusion) associated with physician contact within 14 days before the initial stroke. RESULTS: A total of 137 pediatric patients from 14 centers were studied. Mean age at first stroke was 6.3 years (1.4 to 14.0 years) with mean follow-up of 10.1 years (5 to 24 years). Thirty-one (22%) patients had a second stroke (2.2 per 100 patient years); 26 patients had an identified medical or concurrent event associated with their initial stroke. None of these patients had recurrent stroke 2 or more years after the initial event. The remaining 111 patients had an ongoing risk of recurrent stroke (1.9 per 100 patient-years) despite long-term transfusions (P =.038). CONCLUSIONS: The absence of an antecedent or concurrent medical event associated with an initial stroke is a major risk factor for subsequent stroke while receiving regular transfusions.