What are alternative antibiotics to penicillin (Penicillin) for treating adults with streptococcal (Strep) infections who are allergic to penicillin?

Alternative Antibiotics to Penicillin for Adult Strep Throat

For adults with streptococcal pharyngitis who are allergic to penicillin, first-generation cephalosporins (cephalexin or cefadroxil) are the preferred first-line alternatives if the allergy is non-immediate, while clindamycin or azithromycin should be used for patients with immediate/anaphylactic penicillin reactions. 1, 2

Treatment Algorithm Based on Type of Penicillin Allergy

Non-Immediate (Non-Anaphylactic) Penicillin Allergy

First-generation cephalosporins are the preferred choice with strong, high-quality evidence:

• Cephalexin 500 mg twice daily for 10 days 1, 2
• Cefadroxil 1 gram once daily for 10 days 1, 2

These agents have demonstrated high efficacy in eradicating Group A Streptococcus and are supported by the strongest evidence base. 1 The once-daily dosing of cefadroxil may improve adherence compared to twice-daily cephalexin. 1

Critical caveat: Up to 10% of patients with immediate hypersensitivity to penicillin may have cross-reactivity with first-generation cephalosporins, so these should be avoided in patients with a history of anaphylaxis, angioedema, or urticaria to penicillin. 1, 2

Immediate/Anaphylactic Penicillin Allergy

All beta-lactams must be avoided in these patients. 1, 2 The following alternatives are recommended:

Clindamycin (preferred for severe allergy):

• 300 mg three times daily for 10 days 1, 2
• Strong, moderate-quality evidence supports its use 1
• Particularly effective in chronic streptococcal carriers 2, 3
• Clindamycin resistance among Group A Streptococcus in the United States is approximately 1% 2
• FDA-approved for serious streptococcal infections in penicillin-allergic patients 4

Azithromycin:

• 500 mg once daily for 5 days (or 12 mg/kg once daily, maximum 500 mg) 1, 2
• Strong, moderate-quality evidence 1
• Only requires 5 days of treatment due to prolonged tissue half-life 1, 2
• FDA-approved as an alternative to first-line therapy for streptococcal pharyngitis 5
• Important limitation: Macrolide resistance among Group A Streptococcus varies geographically, with approximately 5-8% resistance in the United States 2

Clarithromycin:

• 250 mg twice daily for 10 days 1, 2
• Strong, moderate-quality evidence 1
• Requires full 10-day course unlike azithromycin 1, 2

Critical Treatment Duration Requirements

All antibiotics except azithromycin require a full 10-day course to achieve maximal pharyngeal eradication of Group A Streptococcus and prevent acute rheumatic fever. 1, 2 Azithromycin is the only exception, requiring only 5 days due to its unique pharmacokinetics. 1, 2, 5

Shorter courses with other antibiotics have been studied but are not endorsed due to lack of comprehensive data demonstrating equivalent efficacy in preventing rheumatic fever. 1

Relative Strengths of Evidence

The evidence hierarchy for penicillin alternatives is:

1. First-generation cephalosporins (non-immediate allergy): Strong, high-quality evidence from multiple guidelines 1, 2
2. Clindamycin: Strong, moderate-quality evidence; particularly effective in treatment failures and carriers 1, 2, 4
3. Macrolides (azithromycin/clarithromycin): Strong, moderate-quality evidence but with resistance concerns 1, 2

Common Pitfalls to Avoid

Do not prescribe shorter courses than recommended (except for azithromycin's 5-day regimen), as this can lead to treatment failure, continued transmission, and increased risk of acute rheumatic fever. 1, 2

Do not assume all penicillin-allergic patients cannot receive cephalosporins. Only those with immediate/anaphylactic reactions (urticaria, angioedema, anaphylaxis) should avoid cephalosporins due to the 10% cross-reactivity risk. 1, 2 Patients with non-immediate reactions (e.g., delayed rash) can safely receive cephalosporins. 1

Be aware of local macrolide resistance patterns before prescribing azithromycin or clarithromycin, as resistance varies geographically and temporally. 1, 2, 3 In areas with high macrolide resistance (>10%), consider clindamycin as the preferred non-beta-lactam option. 2

Do not use trimethoprim-sulfamethoxazole, tetracyclines, or fluoroquinolones for streptococcal pharyngitis, as these are not effective or recommended. 1, 2

Special Considerations

Chronic carriers (asymptomatic patients with persistently positive cultures) generally do not require antimicrobial therapy, as they are unlikely to spread infection or develop complications. 1, 2 However, if treatment is indicated for chronic carriage, clindamycin is particularly effective due to its ability to eradicate the organism. 2, 3

Post-treatment cultures are not routinely recommended for asymptomatic patients who have completed therapy. 2 Follow-up testing should only be considered in special circumstances, such as patients with a history of rheumatic fever. 2