PROJECT SUMMARY/ABSTRACT Although viruses are the leading cause of community-acquired pneumonia (CAP) in young children, antibiotics are prescribed for most children with CAP. Antibiotic overuse has substantial societal and individual consequences, including promotion of antimicrobial resistance, antibiotic-associated side effects and severe complications. Procalcitonin (PCT) is a biomarker that is increased in patients with bacterial infections but is not typically elevated in viral infections. A low PCT level has been shown to have a high negative predictive value for detection of typical bacteria in children with CAP. Similarly, PCT algorithms have decreased antibiotic use without increasing adverse events in adults and children; however, clinicians may be hesitant to use PCT, as the clinical efficacy of avoiding antibiotics in outpatient children with low-risk clinical characteristics and low PCT levels has not been evaluated. The overall objective of this work is to test the hypothesis that low-risk children managed as outpatients with CAP and PCT levels <0.25 ng/mL treated with placebo have similar clinical response to those treated with antibiotics, with fewer adverse effects, through a large-scale, multi- institutional randomized trial (RCT). Given the complexities of conducting an RCT of this nature, the overall objective of this R34 is to evaluate and finalize the study population, trial procedures and study outcomes necessary for the development of this future RCT, while assessing study feasibility through a pilot trial. Specific Aim 1 is to refine and finalize the study population, outcomes, procedures, instruments and training materials for a trial examining the need for antibiotics in low-risk children with CAP. As parent and clinician input is critical to the success of a “no antibiotics” strategy, we will perform qualitative semi-structured interviews with key stakeholders and use Delphi methodology with a panel of pediatric CAP experts to refine and finalize the study population, procedures and outcomes. We will also evaluate the reliability and feasibility of using mobile video chat technology to evaluate the clinical response of children with CAP, which we will leverage in the future RCT. Specific Aim 2 is to implement and establish feasibility of all study procedures by conducting a 3-site pilot trial of amoxicillin vs placebo in low-risk children with CAP and PCT levels <0.25 ng/mL. We will enroll and randomize 36 children at 3 participating sites. This pilot trial will provide necessary data to plan the large-scale definitive trial, including assessment of facilitators and barriers of study participation, estimating enrollment and attrition rates, evaluating study procedures and interventions in a real- world setting, and determining adherence rates. In addition, we will demonstrate the ability to collect outcomes important to the future RCT, including clinical response, symptom resolution, adverse events and quality of life. The subsequent large RCT will be significant, as it will definitively address whether antibiotics are beneficial in low-risk children with CAP, representing an innovative departure from the status quo by shifting from empirical antibiotic use for all children with CAP to a targeted approach.

PROJECT NARRATIVE The long-term goal of this project is to evaluate the benefits and harms of antibiotics compared with placebo in low-risk young children with community-acquired pneumonia and a low procalcitonin, a biomarker that is typically low in viral infections where antibiotics are not required. This Clinical Trials Pilot Studies proposal will conduct preliminary studies, including a 36-patient pilot study at 3 sites, to finalize study procedures and evaluate the feasibility of a future large-scale clinical trial. These results will have a positive impact by providing a safe, objective, and timely strategy to avoid unnecessary antibiotic use in pneumonia, one of the most common infections in children and a leading cause of pediatric antibiotic use, thus improving individual and societal health by decreasing the development of antibiotic resistance and unnecessary adverse drug effects.