What is the recommended treatment for a patient with strep throat (Group A beta-hemolytic streptococcal pharyngitis) who is resistant to penicillin (PCN)?

Treatment of Strep Throat Resistant to Penicillin

Group A Streptococcus has never developed resistance to penicillin anywhere in the world—if treatment fails, the issue is not true resistance but rather non-compliance, reinfection, or chronic carrier state. 1

Understanding "Penicillin Resistance" in Strep Throat

True penicillin resistance does not exist in Group A Streptococcus (GAS). 1 When patients experience treatment failure with penicillin, the most common causes are:

• Non-compliance with the 10-day regimen (the primary cause of bacteriologic failure) 2
• Chronic pharyngeal carrier state experiencing concurrent viral pharyngitis 1, 3
• Reinfection from close contacts 2
• Co-pathogenicity with beta-lactamase producing organisms 1

Bacteriologic failure rates with penicillin have increased from 2-10% historically to approximately 30% in recent decades, but this reflects compliance issues rather than true resistance. 2

Treatment Algorithm for Penicillin Treatment Failures

First: Determine if This is True Treatment Failure

For symptomatic patients with persistent positive cultures after completing penicillin therapy:

• Retreatment with a different antibiotic is indicated 1
• First-generation cephalosporins demonstrate superior eradication rates compared to penicillin (83% vs 77% long-term eradication) 4

Second: Select the Optimal Alternative Antibiotic

For patients who completed penicillin but remain symptomatic with positive cultures:

Clindamycin is the preferred choice for retreatment, with the following advantages:

• Dosing: 300 mg orally three times daily for 10 days (adults) or 7 mg/kg three times daily for 10 days in children (maximum 300 mg/dose) 1, 3, 5
• Only 1% resistance rate among GAS in the United States 1, 3
• Particularly effective in chronic carriers who have failed penicillin 1, 3
• Strong, moderate-quality evidence supporting efficacy 1, 3

First-generation cephalosporins are an excellent alternative:

• Cephalexin 500 mg orally twice daily for 10 days (adults) or 20 mg/kg twice daily for 10 days in children 1, 3
• Superior bacteriologic eradication compared to penicillin in multiple studies 2, 4
• Strong, high-quality evidence for efficacy 1, 3
• Can be used unless the patient has immediate/anaphylactic penicillin allergy (cross-reactivity risk up to 10% in this population) 1, 3

Third: Consider Macrolides with Caution

Macrolides should be reserved for patients who cannot tolerate beta-lactams:

Clarithromycin 250 mg orally twice daily for 10 days is preferred over azithromycin for retreatment:

• 10 days of clarithromycin achieves 91% eradication vs 82% with 5 days of azithromycin 6
• Macrolide resistance is 5-8% in the United States but varies geographically 1, 3
• In areas with >26% clarithromycin resistance, eradication rates drop dramatically (14-19% for resistant isolates) 4

Azithromycin 500 mg once daily for 5 days is acceptable but less effective:

• Shorter duration correlates with lower eradication rates compared to 10-day regimens 6
• Higher late bacteriologic recurrence rates (OR 1.31) compared to 10-day penicillin 7
• Should not be first-line for retreatment given inferior eradication data 6

Critical Treatment Duration Requirements

All antibiotics except azithromycin require a full 10-day course to achieve maximal pharyngeal eradication and prevent acute rheumatic fever. 1, 3 Shortening the course by even a few days results in appreciable increases in treatment failure rates. 3, 7

For beta-hemolytic streptococcal infections, treatment must continue for at least 10 days to prevent rheumatic fever, which can be prevented even if therapy is initiated up to 9 days after symptom onset. 1, 5

Common Pitfalls to Avoid

Do not assume the patient has "penicillin-resistant strep"—no such organism exists. 1 Instead, investigate compliance, reinfection sources, and consider chronic carrier state. 1, 3

Do not routinely retreat asymptomatic patients with persistent positive cultures—many are chronic carriers who do not require additional antibiotics and are unlikely to spread infection or develop complications. 1, 3

Do not use broad-spectrum cephalosporins (cefdinir, cefpodoxime, cefixime) when narrow-spectrum first-generation agents are appropriate—they are more expensive and more likely to select for antibiotic-resistant flora. 1, 3

Do not prescribe macrolides without checking local resistance patterns—resistance varies geographically and can exceed 25% in some areas, leading to predictable treatment failure. 3, 4

Do not use trimethoprim-sulfamethoxazole, tetracyclines, or older fluoroquinolones—these agents do not eradicate GAS and should never be used for streptococcal pharyngitis. 1

Special Considerations for Chronic Carriers

Chronic carriers are defined as patients with prolonged GAS colonization who experience repeated viral infections. 1, 3 These patients:

• Generally do not require antimicrobial therapy as they are unlikely to spread GAS pharyngitis and are at little risk for complications 3
• Should only be retreated if they have personal or family history of rheumatic fever 1
• May benefit from clindamycin if retreatment is indicated, given its superior eradication in carrier states 1, 3

Post-Treatment Testing

Routine follow-up throat cultures or rapid antigen tests are not recommended for asymptomatic patients who completed therapy. 1, 7 Testing should only be considered in special circumstances such as:

• Patients with personal history of rheumatic fever 1, 7
• Symptomatic patients with recurrent pharyngitis 1
• Patients who remain symptomatic after completing therapy 1

Adjunctive Therapy

Acetaminophen or NSAIDs (ibuprofen) should be offered for moderate to severe symptoms or high fever as adjunctive therapy. 1, 3, 7

Aspirin must be avoided in children due to Reye syndrome risk. 1, 3, 7

Corticosteroids are not recommended as adjunctive therapy. 1, 3