Penicillin vs Amoxicillin for Strep Throat
Penicillin V remains the drug of choice for strep throat in adults and older children, while amoxicillin is preferred for younger children due to better taste and suspension availability. 1, 2
First-Line Treatment Selection
For adults and older children:
- Penicillin V 250 mg three to four times daily OR 500 mg twice daily for 10 days is the recommended first-line treatment 1, 2
- Penicillin is preferred because of proven efficacy, narrow spectrum, safety, and low cost 1, 2
- No documented penicillin resistance in Group A Streptococcus exists anywhere in the world 3
For younger children:
- Amoxicillin 50 mg/kg once daily (maximum 1000 mg) for 10 days is preferred over penicillin 2
- The preference is based on better taste acceptance and availability as suspension, not superior efficacy 2
- Research shows amoxicillin at 40 mg/kg/day achieves 87.9% clinical cure versus 70.9% with conventional penicillin dosing, though this may reflect inadequate penicillin dosing rather than true superiority 4
Critical Dosing Considerations
Penicillin V dosing frequency matters:
- Twice-daily dosing is as efficacious as three to four times daily dosing 5
- Once-daily penicillin is associated with 12 percentage points lower cure rate and should NOT be used 5
- Once-daily amoxicillin does not show this decreased efficacy 5
Treatment duration is non-negotiable:
- A full 10-day course is essential to achieve maximal pharyngeal eradication and prevent acute rheumatic fever 1, 2
- Shortening the course by even a few days results in appreciable increases in treatment failure rates 3
When to Consider Alternatives
Intramuscular benzathine penicillin G:
- 1.2 million units as a single injection is preferred when compliance with 10-day oral therapy is unlikely 2
For penicillin-allergic patients:
- First-generation cephalosporins (cephalexin 20 mg/kg twice daily for 10 days) for non-immediate allergy 2
- Clindamycin (7 mg/kg three times daily, maximum 300 mg per dose, for 10 days) for immediate/anaphylactic allergy 2
- Macrolides are third-line due to 5-8% resistance rates in the United States 3, 6
Common Pitfalls to Avoid
Do NOT use once-daily penicillin:
- Meta-analysis demonstrates significantly lower cure rates compared to twice-daily or more frequent dosing 5
Do NOT assume amoxicillin is superior to penicillin:
- The perception that penicillin is declining in effectiveness may be due to inadequate dosing, not true resistance 4
- Cochrane review found uncertain evidence of clinically relevant differences between penicillin and other antibiotics 7
Do NOT prescribe amoxicillin to adolescents without considering mononucleosis:
- Risk of rash if Epstein-Barr virus is present 2
Do NOT use amoxicillin or ampicillin for penicillin-failure cases:
- They are penicillin congeners and will fail for the same reasons 3
Evidence Quality and Nuances
The 2012 European guideline recommends penicillin V twice or three times daily for 10 days when antibiotics are indicated 1. The most recent 2025 guidelines from multiple societies (American Academy of Pediatrics, Infectious Diseases Society of America) consistently endorse penicillin as first-line, with amoxicillin reserved for younger children primarily for palatability 2.
Research from 2000 showed higher bacteriologic cure rates with amoxicillin (79.3%) versus penicillin (54.5%), but this likely reflects inadequate penicillin dosing rather than true superiority 4. A 2021 Cochrane review found low-certainty evidence showing no clinically relevant differences between penicillin and other antibiotics for symptom resolution 7.
The key distinction is practical, not pharmacological: both drugs are equally effective when dosed appropriately, but amoxicillin's once-daily dosing and better taste make it preferable for young children, while penicillin's narrow spectrum and lower cost make it preferable for adults and older children who can tolerate it 2, 5.