SGEM#359: Meet Me Halfway on the Duration of Antibiotics for Non-Severe Pediatric Community-Acquired Pneumonia

Date: February 7th, 2022 Reference: Williams et al. Short- vs standard-course outpatient antibiotic therapy for community-acquired pneumonia in children: the scout-cap randomized clinical trial. JAMA Pediatrics 2022 Guest Skeptic: Dr. Dennis Ren is a pediatric emergency medicine fellow at Children’s National Hospital in Washington, DC. Case: A three-year-old boy presents to the emergency department (ED) with fever and cough. On exam, he is breathing a little fast and his oxygen saturation is 94% on room air but otherwise appears comfortable. You appreciate some decreased breath sounds and crackles on your lung exam. You make a clinical diagnosis of community-acquired pneumonia (CAP) and plan to send him home with a 10-day course of amoxicillin. His mother asks you, “Last time he took antibiotics for that long, he had terrible diarrhea. Do you think we can do fewer days of antibiotics and still treat the pneumonia?” Background: We have covered the topic of pediatric community-acquired pneumonia before on the SGEM #338 (Are Children with CAP Safe and Sound if Treated for 5 days rather than 10 days of antibiotics?) with Dr. Andrew Tagg on the Canadian SAFER Trial [1]. This trial suggested that a 5-day course of antibiotics was not non-inferior to the traditional 10-day course of antibiotics for children with CAP treated as outpatients. Things were much simpler when I started my pediatric training. I learned that a well-appearing child presenting to clinic with fever, slight tachypnea, and focal lung exam findings could be diagnosed with pneumonia by history and physical exam alone and go home with 10 days of amoxicillin BID. But now for some reason, this topic feels more complicated…maybe because there are so many different ways people go about diagnosing pneumonia and such variability in the reliability of physical exam findings [2,3]. Since we covered the SAFER trial, we have also had the CAP-IT [4] trial from the United Kingdom and Ireland which evaluated both high and low-dose amoxicillin for the treatment of CAP over three or seven days. They found that both a lower dose and a shorter duration of antibiotic therapy was non-inferior to higher dose, longer duration antibiotic therapy. They did find that cough persisted longer with the group that received a shorter duration of antibiotic therapy but overall adherence to medication was better in the group receiving a shorter duration of antibiotics. Why so many pneumonia studies? Ultimately, we want to find that balance of treating an infection but avoiding antibiotic-associated adverse effects and antibiotic resistance. So where is that sweet spot?  Clinical Question: Is a 5-day course of antibiotics superior to a 10-day course for the treatment of non-severe community-acquired pneumonia in children with respect to clinical outcomes, adverse effects, and antimicrobial resistance? Reference: Williams et al. Short- vs standard-course outpatient antibiotic therapy for community-acquired pneumonia in children: the scout-cap randomized clinical trial. JAMA Pediatrics 2022 Population: Children 6 to 71 months of age from 8 US cities diagnosed with uncomplicated CAP demonstrating early clinical improvement (no fever, tachypnea, severe cough) on day 3 to 6 of their initially prescribed oral beta-lactam therapy. Excluded: Severe pneumonia (Hospitalization, radiographic evidence of parapneumonic effusion, empyema, lung abscess, pneumatocele or Microbiologically confirmed Staph aureus or Strep pyogenes pneumonia. Parenteral or combination antibiotic therapy. Undergoing surgery or invasive airway procedures 7 days prior to diagnosis of CAP. Beta-lactam allergy. Concurrent bacterial infection necessitating >5 days of antibiotics. Aspiration pneumonia, bronchiolitis, bronchitis, acute asthma exacerbation. Chronic medical conditions. History of pneumonia within prior 6 months Intervention: Short 5 days course of previously prescribed antibiotic therapy (amoxicillin, amoxicillin with clavulanate, cefdinir) with 5 days of placebo Comparison: Standard course of 10 days of previously prescribed antibiotic therapy Outcomes: Primary Outcome: End of treatment response adjusted for duration of antibiotic risk (RADAR) at the first outcome assessment visit (OAV1) which occurred on study days 6 to 10. This was a 2-step process: Desirability of outcome ranking (DOOR) based on adequate clinical response, resolution of symptoms, presence, and severity of antibiotic-associated adverse effects. Ranked overall experience based on actual reported treatment duration Secondary Outcomes: RADAR at the second outcome assessment visit (OAV2) on study days 19 to 25. A portion of participants also consented to throat swab collection at the second outcome assessment visit to evaluate antibiotic resistance genes in oropharyngeal flora. Trial: Prospective, multicenter randomized double-blind placebo-controlled superiority clinical trial. Authors’ Conclusions: “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.” Quality Checklist for Randomized Clinical Trials: The study population included or focused on those in the emergency department. No The patients were adequately randomized. Yes The randomization process was concealed. Yes The patients were analyzed in the groups to which they were randomized. Yes The study patients were recruited consecutively (i.e. No selection bias). Unsure The patients in both groups were similar with respect to prognostic factors. Yes All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes All groups were treated equally except for the intervention. Yes Follow-up was complete (i.e. at least 80% for both groups). Yes All patient-important outcomes were considered. Yes The treatment effect was large enough and precise enough to be clinically significant. Unsure Lack of conflicts of interest. No Results: They included 380 children (189 randomized to short course and 191 randomized to standard course). Mean age was 36 months, 51% male and 91% were treated with amoxicillin. Key Result: 5-day course of antibiotics for the treatment of outpatient CAP was superior to a 10-day course (similar efficacy, similar adverse events, while reducing antibiotic exposure and resistance). Primary Outcome: No significant difference in proportions of inadequate clinical response, persistent symptoms, or antibiotic-associated adverse effects between short-course vs standard-course groups. Short course therapy had 69% (95% CI, 63% to 75%) probability of more desirable RADAR outcome compared to standard course. This reflects the probability of a better DOOR (clinical response, resolution of symptoms, and antibiotic-associated adverse effects) for a randomly selected participant from the short course vs the standard course strategy. Secondary Outcomes: 1. Potential Selection Bias: They included 380 patients over a three-year study period. They do not remark on whether patients were enrolled consecutively, but I would assume there were probably quite a few more cases of pneumonia diagnosed across multiple institutions in that study period than were included in the final analysis. There was also some subjectivity in the enrollment. Patients could not have been included if they had a severe cough. Who decided whether the cough was severe and did they have some objective measure? They also used tachypnea to exclude patients. Measuring tachypnea is well known to be inaccurate and lack inter-rater reliability [5-7]. These factors may lead to some selection bias. 2. Included Patients: Patients included in this study were relatively healthy from 6 months to 71 months of age. We need to be cautious when extrapolating the results to children with underlying conditions or outside those age ranges. 3. Outcomes: We need to say a few things about the outcomes in this trial Complicated: Their primary outcome was a composite outcome which can make a fuzzier target. It was also a little hard to interpret. ClinicalTrials.gov Data - We should applaud the authors of this study for reporting the primary and secondary outcomes that they originally proposed. It is still surprising the number of published research trials in which the reported outcomes differ from the proposed outcomes. DOOR Score: The DOOR score evaluated patient-oriented outcomes, specifically clinical response, persistence of symptoms, and adverse effects from antibiotic therapy. We acknowledge that these have a degree of subjectivity including grading of cough severity and adverse effects of antibiotic therapy. Resistomes: A subgroup of the patients had throat swabs to assess for antibiotic resistance genes (ARGs) expressed as resistance genes per prokaryotic cell (RGPC). The authors reported that there were significantly lower RGPCs in the group that had short-course therapy in comparison to standard therapy. This is a lab-oriented outcome that brings up a few questions: Does this assessment of respiratory flora from a throat swab really correlate with what is happening in the lungs? What does a difference of 1.17 vs 1.33 mean clinically if anything? Is this going to be a persistent change? 4. Diagnosis of Pneumonia: All the patients included in this study were previously diagnosed with CAP in an outpatient clinic, urgent care centre, or emergency department. Unfortunately, we do not know how the diagnosis of pneumonia was made. Was it by clinical exam findings? Chest radiograph? Respiratory cultures? How accurate were these diagnoses? However,