What treatment options are available for strep infections resistant to penicillin (antibiotic) or amoxicillin (antibiotic)?

Treatment Options for Penicillin/Amoxicillin-Resistant Streptococcal Infections

For streptococcal infections when penicillin or amoxicillin cannot be used, clindamycin is the preferred alternative for patients with immediate/anaphylactic penicillin allergy, while first-generation cephalosporins (cephalexin or cefadroxil) are preferred for non-immediate allergies. 1, 2

Treatment Algorithm Based on Type of Penicillin Resistance/Allergy

For Non-Immediate (Non-Anaphylactic) Penicillin Allergy

• First-generation cephalosporins are the preferred first-line alternatives 3, 1, 2
• Cephalexin: 500 mg twice daily for adults; 20 mg/kg per dose twice daily for children (maximum 500 mg/dose) for 10 days 1, 2, 4
• Cefadroxil: 1 gram once daily for adults; 30 mg/kg once daily for children (maximum 1 gram) for 10 days 1, 2, 4
• These options have strong, high-quality evidence supporting their efficacy 1, 2

For Immediate/Anaphylactic Penicillin Allergy

All beta-lactams must be avoided due to up to 10% cross-reactivity risk 1, 2, 4

Preferred option: Clindamycin

• Dosing: 300 mg three times daily for adults; 7 mg/kg per dose three times daily for children (maximum 300 mg/dose) for 10 days 3, 1, 2, 4
• Clindamycin has strong, moderate-quality evidence and demonstrates high efficacy even in chronic carriers 1, 2, 4
• Resistance rate is approximately 1% among Group A Streptococcus isolates in the United States 2, 4
• Clindamycin should be used for eradication of throat carriage when first-line penicillin therapy has been unsuccessful 3

Alternative option: Azithromycin

• Dosing: 500 mg once daily for adults; 12 mg/kg once daily for children (maximum 500 mg) for 5 days 1, 2, 4, 5
• Azithromycin requires only 5 days due to its prolonged tissue half-life 3, 1, 2, 4
• Important caveat: Macrolide resistance among Group A Streptococcus is approximately 5-8% in the United States but varies geographically 3, 1, 2, 4
• Because some strains are resistant to azithromycin, susceptibility tests should be performed when patients are treated with this agent 5

Other macrolide options:

• Clarithromycin: 7.5 mg/kg per dose twice daily (maximum 250 mg/dose) for 10 days 1, 2
• Erythromycin: 20-40 mg/kg/day divided 2-3 times daily for 10 days 3, 2
• Erythromycin is less preferred due to gastrointestinal side effects 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 3, 1, 2, 4

• Shortening the course by even a few days results in appreciable increases in treatment failure rates 2
• The primary goal is not only symptomatic improvement but also prevention of acute rheumatic fever, which requires adequate bacterial eradication 2
• Therapy can be safely postponed up to 9 days after symptom onset and still prevent acute rheumatic fever 2

Special Clinical Situations

For Necrotizing Fasciitis or Streptococcal Toxic Shock Syndrome

Combination therapy with clindamycin PLUS penicillin is essential 3

• Clindamycin suppresses streptococcal toxin and cytokine production and was found superior to penicillin in animal models 3
• Penicillin should be added because of potential resistance of Group A streptococci to clindamycin 3
• Macrolide resistance in the United States is <5.0% among Group A streptococci, but clindamycin resistance exists in some strains 3

For Healthcare Worker Carriage Requiring Eradication

Pharyngeal carriage treatment options: 3

• Oral penicillin V (500 mg four times daily for 10 days)
• Amoxicillin (500 mg three times daily for 10 days)
• Clindamycin (300 mg four times daily for 10 days) should be used when first-line penicillin therapy has been unsuccessful 3
• Azithromycin (maximum 500 mg once daily for 3 days) 3

Non-pharyngeal carriage (vaginal, anal, skin): 3

• Penicillin treatment alone may not be sufficient 3
• Clindamycin 300 mg four times daily for 10 days 3
• Azithromycin 500 mg once daily for 5 days, with some limited reports of combining with oral rifampicin or oral vancomycin 3

For Penicillin-Resistant Streptococcal Endocarditis

Treatment is qualitatively similar to penicillin-susceptible cases, but with important modifications: 3

• Aminoglycoside treatment must be given for at least 2 weeks (not shortened) 3
• Short-term therapy regimens are not recommended 3
• For highly resistant isolates (MIC ≥4 mg/L), vancomycin might be preferred combined with aminoglycosides 3

Common Pitfalls to Avoid

1. Do not use cephalosporins in patients with immediate/anaphylactic penicillin reactions due to the 10% cross-reactivity risk 1, 2, 4

2. Do not prescribe shorter courses than recommended (except for azithromycin's 5-day regimen) as this leads to treatment failure and complications 1, 2

3. Check local macrolide resistance patterns before prescribing azithromycin, clarithromycin, or erythromycin as resistance varies geographically and can lead to treatment failure 1, 2, 4

4. Do not use trimethoprim-sulfamethoxazole (Bactrim) for strep throat due to high resistance rates (50%) and lack of efficacy against Group A Streptococcus 2

5. Do not assume all penicillin-allergic patients cannot receive cephalosporins - only those with immediate/anaphylactic reactions should avoid them 2

6. Penicillin failure rates have increased from 2-10% in the early 1970s to approximately 30% currently, primarily due to lack of compliance with the 10-day regimen, reexposure to infected contacts, copathogenicity, and antibiotic-associated eradication of protective pharyngeal flora 6

Post-Treatment Follow-Up

• Routine post-treatment throat cultures or rapid antigen detection tests are not recommended for asymptomatic patients who have completed therapy 1, 2, 4
• Testing should only be considered in special circumstances, such as patients with a history of rheumatic fever 1, 2, 4
• For healthcare workers requiring eradication, clearance screens should be taken 24 hours after completing treatment, and again at 1,3,6, and 12 weeks following the end of treatment 3

Resistance Considerations

• No clinical isolate of Group A Streptococcus has ever been documented to be resistant to penicillin anywhere in the world 3
• Clindamycin resistance remains very low at approximately 1% in the United States 2, 4
• Macrolide resistance is approximately 5-8% among pharyngeal isolates in the United States but varies significantly by geography 3, 1, 2, 4
• In areas with high macrolide resistance (>10%), cephalexin or clindamycin are preferred over macrolides 2