Short- vs Standard-Course Outpatient Antibiotic Therapy for Community-Acquired Pneumonia in Children: The SCOUT-CAP Randomized Clinical Trial

Abstract

Importance: Childhood community-acquired pneumonia (CAP) is usually treated with 10 days of antibiotics. Shorter courses may be effective with fewer adverse effects and decreased potential for antibiotic resistance.

Objective: To compare a short (5-day) vs standard (10-day) antibiotic treatment strategy for CAP in young children.

Design, setting, and participants: Randomized double-blind placebo-controlled clinical trial in outpatient clinic, urgent care, or emergency settings in 8 US cities. A total of 380 healthy children aged 6 to 71 months with nonsevere CAP demonstrating early clinical improvement were enrolled from December 2, 2016, to December 16, 2019. Data were analyzed from January to September 2020.

Intervention: On day 6 of their originally prescribed therapy, participants were randomized 1:1 to receive 5 days of matching placebo or 5 additional days of the same antibiotic.

Main outcomes and measures: The primary end point was the end-of-treatment response adjusted for duration of antibiotic risk (RADAR), a composite end point that ranks each child's clinical response, resolution of symptoms, and antibiotic-associated adverse effects in an ordinal desirability of outcome ranking (DOOR). Within each DOOR rank, participants were further ranked by the number of antibiotic days, assuming that shorter antibiotic durations were more desirable. Using RADAR, the probability of a more desirable outcome was estimated for the short- vs standard-course strategy. In a subset of children, throat swabs were collected between study days 19 and 25 to quantify antibiotic resistance genes in oropharyngeal flora.

Results: A total of 380 children (189 randomized to short course and 191 randomized to standard course) made up the study population. The mean (SD) age was 35.7 (17.2) months, and 194 participants (51%) were male. Of the included children, 8 were Asian, 99 were Black or African American, 234 were White, 32 were multiracial, and 7 were of unknown or unreported race; 33 were Hispanic or Latino, 344 were not Hispanic or Latino, and 3 were of unknown or unreported ethnicity. There were no differences between strategies in the DOOR or its individual components. Fewer than 10% of children in either strategy had an inadequate clinical response. The short-course strategy had a 69% (95% CI, 63-75) probability of a more desirable RADAR outcome compared with the standard-course strategy. A total of 171 children were included in the resistome analysis. The median (range) number of antibiotic resistance genes per prokaryotic cell (RGPC) was significantly lower in the short-course strategy compared with the standard-course strategy for total RGPC (1.17 [0.35-2.43] vs 1.33 [0.46-11.08]; P = .01) and β-lactamase RGPC (0.55 [0.18-1.24] vs 0.60 [0.21-2.45]; P = .03).

Conclusions and relevance: In this study, among children responding to initial treatment for outpatient CAP, a 5-day antibiotic strategy was superior to a 10-day strategy. The shortened approach resulted in similar clinical response and antibiotic-associated adverse effects, while reducing antibiotic exposure and resistance.

Trial registration: ClinicalTrials.gov Identifier: NCT02891915.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Williams reported grants from National Institutes of Health and the US Centers for Disease Control and Prevention during the conduct of the study. Dr Creech reported grants from National Institutes of Health during the conduct of the study. Dr Walter reported a contract from National Institute of Allergy and Infectious Diseases during the conduct of the study and grants from Pfizer and Moderna; and serving on the Vaxcyte advisory board outside the submitted work. Dr Martin reported personal fees from Merck outside the submitted work. Dr Newland reported grants from National Institutes of Health during the conduct of the study and grants from Agency for Healthcare Research and Quality outside the submitted work. Dr Howard reported grants from Arkansas Children’s Hospital during the conduct of the study. Dr Staat reported grants from National Institutes of Health during the conduct of the study. Dr Oler reported support from National Institutes of Health during the conduct of the study. Dr Tuyishimire reported support from National Institutes of Health during the conduct of the study. Dr Conrad reported support from National Institutes of Health during the conduct of the study. Dr Pettigrew reported grants from National Institutes of Health during the conduct of the study. Dr Fowler reports personal consultancy fees from Novartis, Novadigm, Durata, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co, Cerexa, Tetraphase, Trius, MedImmune, Bayer, Theravance, Basilea, Affinergy, Janssen, xBiotech, Contrafect, Regeneron, Basilea, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, C3J, Armata, Valanbio, Akagera, Aridis; grants from National Institutes of Health, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck, Medical Biosurfaces, Locus, Affinergy, Contrafect, Karius, Genentech, Regeneron, Basilea, and Janssen; royalties from UpToDate; stock options Valanbio; a patent pending in sepsis diagnostics; educational fees from Green Cross, Cubist, Cerexa, Durata, Theravance, and Debiopharm; and an editor’s stipend from Infectious Diseases Society of America. Dr Creech reports personal consultancy fees from Astellas, Vir Biotechnology, Horizon Therapeutics, Altimmune, Premier Healthcare; grants from Merck and GSK; and royalties from UpToDate. Dr Evans reported grants from National Institute of Allergy and Infectious Diseases during the conduct of the study. Dr Huskins reported grants from National Institute of Allergy and Infectious Diseases during the conduct of the study; serving on the Pfizer end point adjudication committee and the ADMA Biologics advisory board outside the submitted work; and that he owns shares of stock in Pfizer, Bristol Meyers Squibb, and Zimmer Biomet. No other disclosures were reported.

Figures

Figure 1.. Short-Course Outpatient Therapy of Community Acquired Pneumonia (SCOUT-CAP) Clinical Trial Schema

SCOUT-CAP was a multicenter randomized double-blind placebo-controlled superiority clinical trial evaluating a short-course (5 days) vs standard-course (10 days) strategy of oral β-lactam therapy for outpatient treatment of pediatric CAP. Participants were enrolled on days 3 to 6 of their initially prescribed (prestudy) oral β-lactam therapy and randomized 1:1 to a strategy of 5 days of matching placebo (short course) or an additional 5 days of their initially prescribed prestudy antibiotic (standard course). Outcome assessment visits (OAV) occurred on study days 6 to 10 (OAV1) and 19 to 25 (OAV2). At these time points, each participant’s clinical outcome was categorized according to a desirability of outcome ranking (DOOR), an 8-level ordinal outcome created from 3 components: adequate clinical response (absence of a medically attended visit, surgical procedure, or receipt of nonstudy antibiotics for persistent or worsening pneumonia after randomization), resolution of symptoms (absence of fever, elevated respiratory rate, and moderate or severe cough), and the presence and severity of antibiotic-associated adverse effects (irritability, vomiting, diarrhea, allergic reaction, stomatitis, or candidiasis).

Figure 2.. Short-Course Outpatient Therapy of Community Acquired Pneumonia (SCOUT-CAP) CONSORT Diagram

Outcome assessment visits (OAV) occurred on study days 6 to 10 (OAV1) and 19 to 25 (OAV2). For the intention to treat analysis, 1 or more desirability of outcome ranking components were imputed for 36 participants at OAV1 and 50 participants at OAV2.

Figure 3.. Inadequate Clinical Response, Persistent Symptoms, and Antibiotic-Associated Adverse Effects, Intention-to-Treat Population at Outcome Assessment Visit 1

Frequencies (%) by treatment strategy and risk differences (95% CIs) for each component of the desirability of outcome ranking. Risk differences were compared using Fisher exact tests. The Newcombe method with continuity correction was used to compute 95% CIs for risk differences.