The Case

A 5-year-old girl comes into your emergency department with what seems like community-acquired pneumonia (CAP). She has been febrile with a temp of 102° F and is mildly tachypneic but shows no real signs of respiratory distress. On examination, you can hear some crackles in the right mid-zone. Her chest X-ray (CXR) confirms your findings of CAP, and she is well enough to be treated as an outpatient with oral antibiotics.

Clinical Question

Is five days of oral antibiotic therapy noninferior to 10 days to achieve clinical cure in children with CAP?

Background

Pediatric CAP is a common occurrence.^1,2 The Infectious Diseases Society of America (IDSA) guidelines from 2011 make several recommendations in the management of these children:³

• They do not support routinely obtaining a chest X-ray to confirm the diagnosis in CAP patients who are well enough to be managed as outpatients.
• They do not support preschool children routinely being prescribed antibiotics. This is because most of these CAPs in this age group are caused by viral pathogens.
• They do recommend antibiotics for school-age children diagnosed with CAP.
• How long school-age children should be treated for CAP is an open question. The guidelines provide a strong recommendation based on moderate quality of evidence that a 10-day course has been best studied, but a shorter course may be just as effective.

There is a relatively small (n=115) randomized controlled trial reporting five days of amoxicillin (80 mg/kg divided three times a day [TID]) was noninferior to 10 days for CAP in children 6 months to 59 months of age.⁴ A five-day course has also been recommended by the American Thoracic Society and the IDSA for adults with CAP under certain conditions.⁵

Reference: Pernica JM, Harman S, Kam AJ, et al. Short-course antimicrobial therapy for pediatric community-acquired pneumonia: the SAFER randomized clinical trial. JAMA Pediatr. 2021;175(5):475-482.

• Population: Children age 6 months to 10 years diagnosed with CAP who are well enough to be treated as outpatients
  • Exclusions: See paper for list of exclusions
• Intervention: Five days of high-dose amoxicillin (90 mg/kg/d divided TID) followed by five days of placebo
• Comparison: 10 days of high-dose amoxicillin (90 mg/kg/d divided TID)
• Outcome:
  • Primary Outcome: Clinical cure at 14–21 days defined as meeting all three criteria: significant improvement in dyspnea and increased work of breathing, and no recorded tachypnea, at the day 14–21 follow-up visit; no more than one fever spike as a result of bacterial respiratory illness from day four up to and including the day 14–21 follow-up visit; and lack of a requirement for additional antibacterials or admission to hospital because of persistent/progressive lower respiratory illness during the two weeks after enrollment
  • Secondary Outcomes: Days off school or child care, missed work days for caregivers, adverse reactions, and adherence

Authors’ Conclusions

“Short-course antibiotic therapy appeared to be comparable to standard care for the treatment of previously healthy children with CAP not requiring hospitalization. Clinical practice guidelines should consider recommending 5 days of amoxicillin for pediatric pneumonia management in accordance with antimicrobial stewardship principles.”

Results

A total of 281 children enrolled in the trial, with a median age of 2.6 years. Forty-three percent were female.

Key Result: A five-day course of antibiotics was inferior to a 10-day course of antibiotics in children with CAP.

• Primary Outcome: Clinical cure at 14–21 days after enrollment
  • Per-protocol (PP) analysis: 88.6 percent in the intervention group, 90.8 percent in the control group; risk difference was −0.016 (97.5 percent confidence limit −0.087) and cannot claim noninferiority
  • Intention-to-treat (ITT) analysis: 85.7 percent in the intervention group, 84.1 percent in the control group; risk difference was 0.023 (97.5 percent confidence limit −0.061)
• Secondary Outcomes: Caregivers were off work two days instead of three in the intervention group. All other secondary outcomes were the same.

Evidence-Based Medicine Commentary

1. Representative Cohort: There is a question of whether this cohort represents children with CAP presenting to the emergency department. Only 281 (5 percent) of the 5,406 children diagnosed with CAP were randomized. The study flow diagram shows researchers missed 3,215 possible children to include, suggesting they were not recruited consecutively. This also could have introduced some selection bias.

2. Chest X-Ray: This is not needed to make the diagnosis of CAP in children, and it is actively discouraged by the IDSA guidelines.3

3. Clinical Cure: Their definition of clinical cure included some subjective criteria. Different physicians could have different interpretations on what a “significant improvement” looked like clinically and if the child required additional antibiotics or hospital admission. This could have introduced uncertainty into the data.

4. Statistical Versus Clinical Outcome: This was a noninferiority trial, and they correctly performed a per-protocol analysis. The noninferiority margin was based on several assumptions. Because the one-sided 97.5 percent confidence limit of the point estimate of 7.5 percent was exceeded, a formal conclusion of noninferiority could not be made.

However, this is a statistical outcome and may not be a clinically important difference. Physicians will need to interpret the finding for themselves and think about how to apply the data. Both groups had about a 90 percent clinical cure rate, with only a 1.6 percent absolute risk difference between the five- and 10-day course of antibiotics. Will crossing a one-sided, and seemingly arbitrary, statistical barrier by 1.2 percentage points (7.5 versus 8.7 percent) make a difference in clinically applying this data?

5. External Validity: This trial was conducted at two pediatric emergency departments in Canada. It is unclear if these represent similar patients presenting to community emergency departments, rural emergency departments, or facilities in other countries.

Bottom Line

A five-day course of antibiotics was statistically inferior to the traditional 10-day course for children with CAP treated as outpatients, but it is unclear if this is clinically important.

Case Resolution

You engage in shared decision making with the parents and ask them if they would like a short course of antibiotics (five days) or the traditional course (10 days). Both have about a 90 percent chance of success, but a few more children were not clinically cured after five days of treatment.

Thank you to Dr. Andrew Tagg, who is an emergency physician and co-founder and website lead for Don’t Forget the Bubbles (https://dontforgetthebubbles.com), for his help with this review.

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine. 

References

1. Rudan I, Boschi-Pinto C, Biloglav Z, et al. Epidemiology and etiology of childhood pneumonia. Bull World Health Organ. 2008;86(5):408-416.
2. Pneumonia fact sheet No. 331. World Health Organization website. Accessed July 29, 2021.
3. Bradley JS, Byington CL, Shah SS, et al. The management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. Clin Infect Dis. 2011;53(7):e25-76.
4. Greenberg D, Givon-Lavi N, Sadaka Y, et al. Short-course antibiotic treatment for community-acquired alveolar pneumonia in ambulatory children: a double-blind, randomized, placebo-controlled trial. Pediatr Infect Dis J. 2014;33(2):136-142.
5. Metlay JP, Waterer GW, Long AC, et al. Diagnosis and treatment of adults with community-acquired pneumonia. An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019;200(7):e45-e67.