Critically Appraised Topic: Is a 5-day course of high-dose amoxicillin adequate for treatment of pediatric CAP:
Summary Of Methods/Findings
Study 1: This was a 2-center, parallel-group, non-inferiority RCT of children aged 6 months to 10 years with clinical diagnosis of community-acquired pneumonia (CAP) that was deemed safe to be treated outpatient.
Inclusion Criteria: children aged 6 months to 10 years with CAP that can be treated outpatient and all of the following: 1) fever within 48 hours before presentation 2) tachypnea, increased work of breathing on exam or auscultatory findings of CAP, CXR findings, primary diagnosis of CAP by ED physician.
Exclusion Criteria: predisposing condition; if they received >24 hours beta-lactam at presentation, >5 day course of beta lactam <72 hours before presentation, or if they received IV cephalosporin or azithromycin. Also excluded were patients with infectious mononucleosis due to concern for rash, CAP in last month, lung abscess in last 6 months, >48 hour admission to hospital in last 2 months, and penicillin allergies.
Objective was to determine if 5 days of high-dose amoxicillin for CAP was associated with noninferior rates of clinical cure compared with 10 days of high-dose amoxicillin.
Methods: A 1:1 randomization scheme was developed and only study pharmacists who did not recruit or follow-up patients had access to lists. Subsequently, 5 days of high-dose amoxicillin therapy followed by 5 days of placebo (intervention group) vs 5 days of high-dose amoxicillin followed by a different formulation of 5 days of high-dose amoxicillin (control group) was studied. Follow-ups were completed at 3-5, 5-7, and 14-21 days and caregiver diaries were queried.
Primary outcomes included clinical cure: initial improvement in first 4 days, significant improvement in dyspnea/WOB with no tachypnea at 14-21 day visit, no more than 1 fever spike after day 4, lack of additional /hospital admission.
Secondary outcomes included clinical cure not requiring additional intervention, absence days from school/daycare, caregiver work disruption, adverse drug reaction, serious drug reaction, patient adherence, recurrence of presumed respiratory illness.
Results: The primary outcome, overall clinical cure at 14-21 days via ITT analysis, was similar between the 2 groups; cure in 108/126 participants (85.7%) in the intervention group and 106/126 (84.1%) in the control group (RD, 0.023; 97.5% CL, −0.061). The PP analysis results were similar, with cure in 101/114 patients (88.6%) in the intervention group and 99/109 (90.8%) in the control group (RD, −0.016; 97.5% CL, −0.087). In the strict PP analysis, clinical cure was documented in 73/82 patients (89.0%) of the intervention group and in 74/83 (89.1%) of the control group (RD, −0.011; 97.5% CL, −0.096).
Study 2: This was a double-blind, randomized, placebo-controlled trial of children aged 6-59 months with a radiographic and clinical diagnosis of community-acquired pneumonia (CAP).
required all of the following: 1) age 6–59 months 2) pneumonia on CXR 3) temp ≥ 38.5°C 4) WBC ≥ 15,000/mm3 5) CAP treated as outpatient.
Exclusion Criteria: were any of the following: within ≤14 days 2) need of parenteral treatment 3) oxygen saturation <94% 4) known impaired immunity 5) ≥2 pneumonia episodes in the last year 6) chronic illness influencing current illness (NOT asthma) 7) presence of an infection requiring a longer/different 8) unavailability for follow up 9) known β-lactam hypersensitivity 10) known allergy to soy milk.
Objective was to determine if there was a difference in absence of treatment failure between a 3 vs 5 vs 10 day course of high-dose amoxicillin for pediatric CAP.
Methods: The patients were randomized and an unblinded study coordinator who did not participate in other portions set up the kits. In Stage 1 (3 vs 5 vs 10day), all participants received amoxicillin for 3 days in their 1st package. On the 4th day, all participants opened their 2nd package which either contained placebo or amoxicillin for 7 days to complete a 10-day course. In stage 2, the same occurred, but the 2nd package was opened on day 6.
Primary outcome was absence of treatment failure within 30 days (defined as: non-responsive or deteriorating so that the study drug needed to be replaced, or if the patient was hospitalized, or no response to the current treatment).
Secondary outcomes included the following: temperature, difficult breathing, restlessness, coughing, loss of appetite and sleep disturbances assessed daily by the parents.
Results: All 4 failures occurred in the 3-day arm (4/10; 40%) versus 0/56 and 0/42 in the 5-day and 10-day arms, respectively (P < 0.001, 3-day versus 5-day or 10-day arm.
Study 1: Strengths include RCT, blinded. Statistical analysis was strong. Weaknesses include many CXR were deemed to be PNA by EM physicians were negative by radiologists but still included. Another limitation was that though the study presented NPS results, much of it was viral or missing. In addition, primary outcome was too stringent and unrealistic as it only allowed for one fever spike so they had to create a secondary outcome to account for clinically cured without intervention. Other limitations: no formal power analysis or sample size calculation noted
Study 2: Strengths include RCT, blinded, and radiographs confirmed by multiple providers for presence of PNA. In addition, sample size was calculated with 95%/97%/98%/99% probability of cure in 5 day and 10 day arm, and met goal enrollment with each probability. Limitations include treatment failure was poorly defined and appeared to be more clinical/subjective. In addition, this study only looked at patients from 6 months to 59 months of age with no explanation, while Study 1 looked at children until 10 years. This may leave this study less applicable to children of all ages. Lastly, this study initially had 3 arms (3 day, 5 day and 10 day), but ultimately created another stage (due to failure in 3 day) to compare 5 day vs 10 day. Other limitations: fever poorly defined (route?), inclusion criteria somewhat random, no data on microbiology found in patients, chronic illness in exclusion criteria poorly defined
Conclusions: Based on my review of the literature, I believe there needs to be more RCTs with adequate sample sizes and more generalizable data for me to change my clinical practice from 10 days to 5 days. However, this is great data that sets the foundation for future studies.
Study 1: Study 1: J, Harman S, Kam A et al. Short-Course Antimicrobial Therapy for Pediatric Community-Acquired Pneumonia. JAMA . 2021;175(5):475. doi:10.1001/jamapediatrics.2020.6735
Study 2: Greenberg D, Givon-Lavi N, Sadaka Y, Ben-Shimol S, Bar-Ziv J, Dagan R. Short-course Antibiotic Treatment for Community-acquired Alveolar Pneumonia in Ambulatory Children. Pediatric Infectious Disease Journal. 2014;33(2):136-142. doi:10.1097/inf.0000000000000023