Question

• In otherwise healthy children under 5, is high-dose amoxicillin as compared to regular (or low-dose) amoxicillin more effective in the outpatient management of community acquired pneumonia?

Clinical Bottom Lines

1. Randomized, clinical trials looking at clinical outcomes of high-dose vs. regular dose amoxicillin for the treatment of CAP in children in the United States are lacking. ⁵, ⁶

2. In one double blind, randomized controlled trial in Pakistan, children aged 2-59 months with non-severe pneumonia (per WHO guidelines) and treated with high-dose amoxicillin did not show improved clinical outcomes compared to those treated with standard dose amoxicillin. ¹

3. In the United States, however, consensus opinion favors treatment of CAP in children 4mos to 4years with high-dose amoxicillin (80-90mg/kg/day). ³,⁴

Summary of Key Evidence

1. Study rationale: Increasing treatment failure rates for CAP have been noted in Pakistan. If this is secondary to an increase in resistant Streptococcus Pneumoniae, then high-dose amoxicillin should result in fewer treatment failures.
2. Multi-center, double blind, randomized trial, conducted in outpatient departments of 4 hospitals in Pakistan.
3. Included: Children aged 2-59 months with cough and DIB, classified as “non-severe pneumonia” according to WHO guidelines. Must live within municipal limits of urban region or within walking distance in rural regions.  Exclusions: underlying chronic illness, history of 3 or more episodes of wheeze or acute asthma, antibiotic use in the previous 48 hrs.
4. 900 children enrolled. 876 children completed treatment and follow-up through Day 14.
5. Children were randomized to receive either standard dose (45mg/kg/day) or double dose (90mg/kg/day) amoxicillin divided into three equal doses for 3 days.
6. Primary outcome: treatment failure (as defined by clinically “worse”) on day 5.  There was no statistically significant difference in the treatment failure rate between the two groups.
7. Secondary outcome: relapse by day 14.  There was no statistically significant difference in the relapse rates between the two groups. ¹

Additional Comments

• Limitations in applicability of this article to the patient population in question: Pakistan vs. US, pneumonia defined as cough & RR >40, duration of treatment only 3 days, heptavalent pneumococcal vaccine is not standard of care, therapy success was defined as “clinical resolution,” “improved,” or “same.”
• When no or few clinical guidelines exist, we must look to consensus opinion and professional organizations (e.g. AAP) for treatment recommendations.
• Current recommendations for the treatment of S. pneumo and CAP are heavily based on AOM research and currently published guidelines for treatment of AOM. ²,³
• Is it reasonable to treat these two infections the same? Are they caused by the same strains of S. pneumo? Is the concentration of amoxicillin achieved in the lung comparable to (or higher) than that achieved in middle ear fluid?
• Other factors complicating treatment decisions: 1) antibiotic MIC’s are a gradually but constantly moving target 2) children will often have co-infections 3) does in vitro resistance translate to in vivo resistance?
• Bottom line: Consensus opinion favors treatment of CAP in children 4mos to 4yrs with high-dose amoxicillin secondary to increasing S. pneumo resistance rates, as well as amoxicillin’s favorable side effect, cost, and bioavailability profile. ³, ⁴

Citation

1. Hazir T, Qazi SA, Bin Nisar Y, Maqbool S, Asghar R, Iqbal I, Khalid S, Randhawa S, Aslam S, Riaz S, Abbasi S. Comparison of standard versus double dose of amoxicillin in the treatment of non-severe pneumonia in children aged 2-59 months: a multi-centre, double blind, randomised controlled trial in Pakistan. Arch Dis Child, 2007 April; 92(4): 291-7.
2. American Academy of Pediatrics and American Academy of Family Physicians, Subcommittee on Management of Acute Otits Media. Diagnosis and Management of Acute Otitis Media. Pediatrics. 2004; 113 (5): 1451-1465.
3. American Academy of Pediatrics, Committee on Infectious Diseases. Therapy for Children with Invasive Pneumococcal Infections. Pediatrics. 1997; 99 (2): 289-299.
4. McIntosh K. Community Acquired Pneumonia in Children. N Engl J Med. 2002; 346 (6): 429-437.
5. Low DE, Pichichero ME, Schaad UB. Optimizing Antibacterial Therapy for Community Acquired Respiratory Tract Infections in Children in an Era of Bacterial Resistance. Clinical Pediatrics. 2004; 43 (2): 135-151.
6. Pelton SI, Hammerschlag MR. Overcoming Current Obstacles in the Management of Bacterial Community-Acquired Pneumonia in Ambulatory Children. Clinical Pediatrics. 2005; 44 (1): 1 - 17.

CAT Author: Alicia Prisco, MD

CAT Appraisers: Robert Schumacher, MD

Date appraised: November 21, 2007