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Date: July 14th, 2021
Reference: Pernica et al. Short-Course Antimicrobial Therapy for Pediatric Community-Acquired Pneumonia: The SAFER Randomized Clinical Trial. JAMA Pediatr. 2021.
Guest Skeptic: Dr. Andrew (Andy) Tagg is an Emergency Physician with a special interest in education and lifelong learning. He is the co-founder of website lead of Don’t Forget the Bubbles (DFTB). When not drinking coffee and reading Batman comics he is playing with his children.
Case: Six-year-old Morten comes into your emergency department (ED) with what looks like pneumonia. He has been febrile with a temp of 39 degrees Celsius, he is mildly tachypneic but shows no real signs of respiratory distress and you can hear some crackles in the right mid-zone. His chest X-ray (CXR) confirms your findings, but he is well enough to be treated as an outpatient.
Background: It is hard to believe we have not covered the common condition of pediatric community acquired pneumonia (CAP) on the SGEM. Perhaps it is because there is limited evidence on this common condition. However, we have covered other pediatric infectious issues like:
- Honey for Cough SGEM#26
- Fever Fear SGEM#95
- Lumbar Punctures SGEM#296
- Bronchiolitis SGEM#228
- Invasive Bacterial Infection SGEM#334
We do have high-quality evidence that a CXR is not necessary to confirm the diagnosis of CAP in patients who are well enough to be managed as outpatients. There is also high-quality evidence that pre-school children do not routinely need antibiotics. This is because most pneumonias in this age-group are caused by viral pathogens (Bradley et al 2011).
Antibiotics are recommended for school age children diagnosed with CAP. However, how long should they be treated is an open question. The IDSA guidelines provide a strong recommendations based on moderate quality of evidence to guide our care. (Bradley et al 2011).
- Treatment courses of 10 days have been best studied, although shorter courses may be just as effective, particularly for more mild disease managed on an outpatient basis. (strong recommendation; moderate-quality evidence)
There is an RCT reporting five days of amoxicillin (80mg/kg divided TID) was non-inferior to ten days for CAP in children six months to 59 months of age (Greenberg et al 2014). This was a relatively small study (n=115) from Israel.
A short course (five days) has also been recommended by the American Thoracic Society and the IDSA for adults with CAP under certain conditions (Metlay et al 2019).
- We recommend that the duration of antibiotic therapy should be guided by a validated measure of clinical stability (resolution of vital sign abnormalities [heart rate, respiratory rate, blood pressure, oxygen saturation, and temperature], ability to eat, and normal mentation), and antibiotic therapy should be continued until the patient achieves stability and for no less than a total of 5 days (strong recommendation, moderate quality of evidence).
Clinical Question: Is a five day course of antibiotic therapy non-inferior to a ten day course to achieve clinical cure for paediatric community-acquired pneumonia?
Reference: Pernica et al. Short-Course Antimicrobial Therapy for Pediatric Community-Acquired Pneumonia: The SAFER Randomized Clinical Trial. JAMA Pediatr. 2021
- Population: Children aged six months to ten years of age diagnosed with community acquired pneumonia (CAP) who are well enough to be treated as an outpatient. CAP was defined as fever (rectal, oral or axillary in 48 hours before presentation), tachypnea (based on age, accessory muscle use or auscultation findings), CXR, or primary diagnosis by the ED physician.
- Exclusions: Empyema or necrotizing pneumonia, preexisting pulmonary disease, congenital heart disease, history of aspiration, malignant neoplasm, immunodeficiency, kidney disfunction, on beta-lactam antibiotics for >24hrs at presentation, 5-days of beta-lactam <72hours before presentation, IV cephalosporin or azithromycin in the ED, suspected mononucleosis, prolonged admission in the previous two months, CAP diagnosed in the previous month, lung abscess in the previous six months or an allergy to penicillin allergy.
- Intervention: Five days of high-dose amoxicillin (90mg/kg/d divided TID) followed by five days of placebo
- Comparison: Ten days of high-dose amoxicillin (90mg/kg/d divided TID)
- Primary Outcome: Clinical cure at 14-21 days
- Secondary Outcomes: Days off school/childcare, missed work days for carers, 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.”
Quality Checklist for Randomized Clinical Trials:
- The study population included or focused on those in the emergency department. Yes
- The patients were adequately randomized. Yes
- The randomization process was concealed. Yes
- The patients were analyzed in in a per-protocol analysis for non-inferiority trials. 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
Results: They recruited a total of 281 children to be included in the trial with a median age of 2.6 years and 57% male.
Key Result: A 5-day course of antibiotics was not non-inferior to a 10-day course of antibiotics in children with CAP.
- Primary Outcome: Clinical cure at 14-21 days after enrollment
- Per-Protocol Analysis: 88.6% in the intervention group 90.8% in the control group. Risk difference −0.016 (97.5% Confidence Limit −0.087) and cannot claim non-inferiority
- Intention-to-Treat Analysis: 85.7% in the intervention group and 84.1% in the control group. Risk difference 0.023 (97.5% 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.
1. Included Children: Of the 5,406 children diagnosed with pneumonia over the duration of the trial only 281 were randomized. There were 3,215 possible patients missed suggesting they were not recruited consecutively. Only 5% of all possible patients made it into the trial. Are these 281 children typical of the cohort of all cases of pneumonia or different?
2. Chest X-Ray (CXR): Do you really need a CXR to diagnose mild pneumonia? It is actively discouraged in our Australian guidelines and PIDS and the IDSA also recommend not doing it. Certainly, if you are worried about an alternative diagnosis such as inhaled foreign body but in mild pneumonia that you are going to send home?
Around one-quarter did not have a formal radiologist report of pneumonia. They state in the publication: “It is suboptimal that some study participants were not believed to have radiographic findings consistent with pneumonia by the attending radiologist”
We have talked about CXR before for diagnosing pneumonia in adults (SGEM#287 and SGEM#298). It is an imperfect gold standard (Copper Standard Bias). Even if the CXR is “positive” it does not mean a child has a bacterial pneumonia. Prescribing antibiotics to patient with a viral pneumonia is unlikely to have a patient-oriented outcome (POO).
They did do nasopharageal swabs on some of the children and found no significant differences in clinical cure rates among those with respiratory viruses or M pneumoniae detected compared with those without.
3. Clinical Cure: Their definition of clinical cure included subjective criteria. This could have introduced uncertainty into the data. They did use a definition that was similar to that used in other studies of 5-day CAP therapy in children (Harris et al 1998) and adults (Dunbar et al 2003)
Their specific definition was children meeting all three of the following criteria:
- significant improvement in dyspnoea and increased work of breathing, and no recorded tachypnoea, at the day 14-21 follow-up visit;
- no more than 1 fever spike (as defined above) as a result of bacterial respiratory illness from day 4 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 2 weeks after enrollment.
You can see that different physicians could have different interpretations on what a “significant improvement” looked like clinically and if the child required additional antibiotics or hospital admission.
4. Non-Inferiority: This was non-inferiority trial and they correctly performed a per-protocol analysis. The non-inferiority margin was based on several assumptions. Because the 1-sided 97.5% confidence limit of the point estimate of 7.5% was exceeded, a formal conclusion of non-inferiority 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% clinical cure rate with only a 1.6% absolute risk difference. Will crossing the one-sided statistical barrier by 1.2% (7.5% vs 8.7%) make a difference in clinically apply this data?
5. External Validity: This trial was conducted at two pediatric emergency departments in Canada. It is unclear if these represent the same patients presenting to Canadian community EDs, rural EDs or in other countries like Australia.
Comment on Authors’ Conclusion Compared to SGEM Conclusion: We generally agree with their conclusions.
SGEM Bottom Line: A five-day course of antibiotics was not non-inferior to the traditional ten-day course of antibiotics for children with CAP treated as outpatients.
Case Resolution: We would give a five day course of antibiotics with a good safety net in place. We would ensure the parents arranged follow-up with their primary care physician and knew when it was important to come back to the emergency department.
Clinical Application: If you are giving out antibiotics to children with suspected CAP then it is reasonable to consider a five-day course rather than a ten-day course of amoxicillin. However, it could result in more children not achieving a clinical cure. This should be discussed with parents/care-givers.
What Do I Tell My Patient? I would tell the parents/care-givers that your child has pneumonia. It is safe to treat him with antibiotics at home. We have some evidence that five days is almost as good as ten days of treatment. Would you like the short course or long course of antibiotics?
Keener Kontest: Last weeks’ winner was Bill Stoltzfuz from Jackson, Mississippi. He knew “Amazing Grace” is a Christian hymn published in 1779, with words written in 1772 by the English poet and Anglican clergyman John Newton (1725–1807).
Listen to the podcast this week to hear the trivia question. Email your answer to TheSGEM@gmail.com with “keener” in the subject line. The first correct answer will receive a cool skeptical prize.
- REBEL EM: The SAFER Trial – Pediatric CAP
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