For an adult with a sore throat suspected to be caused by group A streptococcus, should I use azithromycin or amoxicillin?

Amoxicillin is Superior to Azithromycin for Group A Streptococcal Pharyngitis

Amoxicillin (or penicillin) is the drug of choice for confirmed Group A streptococcal pharyngitis in adults, with azithromycin reserved only for patients with immediate/anaphylactic penicillin allergy who cannot tolerate clindamycin. 1, 2

Why Amoxicillin is First-Line

• Zero documented penicillin resistance exists worldwide among Group A Streptococcus, guaranteeing reliable bacterial eradication, whereas macrolide resistance (including azithromycin) ranges from 5-8% in the United States and varies geographically 1, 3, 4

• Amoxicillin has proven efficacy in preventing acute rheumatic fever, the primary goal of treating streptococcal pharyngitis, with strong evidence from controlled studies 1

• Narrow antimicrobial spectrum minimizes selection pressure for resistant flora compared to broader-spectrum agents like azithromycin 1, 2

• Lower cost and excellent safety profile make amoxicillin the most cost-effective option 1, 2

Recommended Dosing

• Amoxicillin: 500 mg orally twice daily for 10 days in adults; 50 mg/kg once daily (maximum 1000 mg) or 25 mg/kg twice daily (maximum 500 mg per dose) for 10 days in children 1, 2

• Penicillin V: 500 mg orally 2-3 times daily for 10 days in adults; 250 mg 2-3 times daily for 10 days in children 1, 2

When Azithromycin May Be Used

Azithromycin should only be prescribed when penicillin/amoxicillin AND first-generation cephalosporins AND clindamycin cannot be used 3, 4

• For immediate/anaphylactic penicillin allergy (anaphylaxis, angioedema, urticaria within 1 hour), all beta-lactams including cephalosporins carry up to 10% cross-reactivity risk and must be avoided 3, 2

• Clindamycin is preferred over azithromycin for immediate penicillin allergy, with only ~1% resistance in the United States versus 5-8% macrolide resistance 3, 2, 4

• Azithromycin dosing: 500 mg once daily for 5 days in adults; 12 mg/kg once daily (maximum 500 mg) for 5 days in children 3, 2, 4

Critical Treatment Duration

• A full 10-day course is mandatory for amoxicillin/penicillin to achieve maximal pharyngeal eradication and prevent acute rheumatic fever, even if symptoms resolve within 3-4 days 1, 2

• Azithromycin requires only 5 days due to its prolonged tissue half-life, making it the sole exception to the 10-day rule 3, 2, 4

• Shortening the course by even a few days markedly increases treatment failure rates and rheumatic fever risk 1, 2

Evidence Comparing Azithromycin to Penicillin

• In three U.S. controlled trials, azithromycin (12 mg/kg daily for 5 days) was clinically and microbiologically superior to penicillin V at Days 14 and 30, with bacteriologic eradication rates of 95% versus 73% at Day 14 and 77% versus 63% at Day 30 5

• However, approximately 1% of azithromycin-susceptible isolates became resistant following therapy, highlighting the risk of promoting resistance 5

• Despite these trial results, major guidelines do not recommend azithromycin as first-line because penicillin's zero resistance rate, proven rheumatic fever prevention, narrow spectrum, and lower cost outweigh azithromycin's marginally better short-term eradication in research settings 1, 3, 4

Treatment Algorithm for Penicillin-Allergic Patients

1. Non-immediate (delayed) penicillin allergy (mild rash >1 hour after exposure): Use first-generation cephalosporins (cephalexin 500 mg twice daily for 10 days), with only 0.1% cross-reactivity risk 3, 2

2. Immediate/anaphylactic penicillin allergy: Use clindamycin 300 mg three times daily for 10 days as first choice, with ~1% resistance 3, 2

3. If clindamycin cannot be used: Azithromycin 500 mg once daily for 5 days is acceptable, but be aware of 5-8% macrolide resistance 3, 2, 4

Common Pitfalls to Avoid

• Do not prescribe azithromycin as first-line therapy when penicillin or amoxicillin can be used—this unnecessarily broadens antibiotic spectrum and promotes resistance 3, 4

• Do not ignore local resistance patterns—macrolide resistance varies geographically and can exceed 10% in some areas 3, 4

• Do not use cephalosporins in patients with immediate/anaphylactic penicillin reactions due to 10% cross-reactivity risk 3, 2

• Do not shorten the amoxicillin course below 10 days based on clinical improvement—this increases treatment failure and rheumatic fever risk 1, 2

Adjunctive Symptomatic Treatment

• Acetaminophen or NSAIDs (ibuprofen) should be offered for moderate to severe sore throat or fever 1, 2, 4

• Avoid aspirin in children due to Reye syndrome risk 1, 2, 4

• Corticosteroids are not recommended as adjunctive therapy 1, 2, 4