Short-course antimicrobial therapy for paediatric respiratory infections (SAFER): study protocol for a randomized controlled trial

Abstract

BackgroundCommunity-acquired pneumonia (CAP) is commonly diagnosed in children. The Infectious Disease Society of America guidelines recommend 10 days of high-dose amoxicillin for the treatment of non-severe CAP but 5-day “short course” therapy may be just as effective. Randomized trials in adults have already demonstrated non-inferiority of 5-day short-course treatment for adults hospitalized with severe CAP and for adults with mild CAP treated as outpatients. Minimizing exposure to antimicrobials is desirable to avoid harms including diarrhoea, rashes, severe allergic reactions, increased circulating antimicrobial resistance, and microbiome disruption.MethodsThe objective of this multicentre, randomized, non-inferiority, controlled trial is to investigate whether 5 days of high-dose amoxicillin is associated with lower rates of clinical cure 14–21 days later as compared to 10 days of high-dose amoxicillin, the reference standard. Recruitment and enrolment will occur in the emergency departments of McMaster Children’s Hospital and the Children’s Hospital of Eastern Ontario. All children in the study will receive 5 days of amoxicillin after which point they will receive either 5 days of a different formulation of amoxicillin or a placebo. Assuming a clinical failure rate of 5% in the reference arm, a non-inferiority margin of 7.5%, one-sided alpha set at 0.025 and power of 0.80, 270 participants will be required. Participants from a previous feasibility study (n = 60) will be rolled over into the current study. We will be performing multiplex respiratory virus molecular testing, quantification of nasopharyngeal pneumococcal genomic loads, salivary inflammatory marker testing, and faecal microbiome profiling on participants.DiscussionThis is a pragmatic study seeking to provide high-quality evidence for front-line physicians evaluating children presenting with mild CAP in North American emergency departments in the post-13-valent pneumococcal, conjugate vaccine era. High-quality evidence supporting the non-inferiority of short-course therapy for non-severe paediatric CAP should be generated prior to making changes to established guidelines. Trial registrationClinicalTrials.gov, NCT02380352. Registered on 2 March 2015.Electronic supplementary materialThe online version of this article (10.1186/s13063-018-2457-2) contains supplementary material, which is available to authorized users.

Short-Course Antimicrobial Therapy for Pediatric Community-Acquired Pneumonia

“…The primary outcome was assessed using intention-to-treat (ITT) analysis, per-protocol (PP) analysis including those participants adherent to medications (ie, >80% of antimicrobial doses taken and no additional antibiotics taken for nonpneumonia infections), and strict PP analysis including only those in the PP group whose radiographs had radiologist-confirmed pneumonia. To be conservative, we specified a priori that the PP analysis would be primary . Secondary outcomes were analyzed using PP and ITT approaches.…”

Efficacy, safety and impact on antimicrobial resistance of duration and dose of amoxicillin treatment for young children with Community-Acquired Pneumonia: a protocol for a randomIsed controlled Trial (CAP-IT)

“…Its factorial nature will inform amoxicillin dose and duration, and the optimal regimen for minimal AMR selection. Combined with the results of ongoing trials (including SAFER 43 and SCOUT-CAP [accessible at https://clinicaltrials.gov/ct2/show/NCT02891915 ]) in similar healthcare systems, findings from the CAP-IT trial will improve and streamline cost-effective care on a global scale. 24 …”