What is the recommended regimen for treating gonorrhea in a patient with a penicillin allergy, including alternatives for severe cephalosporin allergy and inability to use azithromycin?

Gonorrhea Treatment in Penicillin-Allergic Patients

Primary Recommendation

Most patients with reported penicillin allergy can and should receive standard ceftriaxone 500 mg IM plus azithromycin 1 g orally, because true cross-reactivity between penicillins and third-generation cephalosporins is rare (1-3%), and ceftriaxone should not be withheld unless the patient has documented severe cephalosporin allergy or anaphylactic penicillin allergy. 1, 2

Treatment Algorithm Based on Allergy Severity

Step 1: Assess the Type and Severity of Penicillin Allergy

• Non-severe penicillin allergy (rash, mild urticaria without systemic symptoms): Proceed with standard dual therapy—ceftriaxone 500 mg IM plus azithromycin 1 g orally as a single dose. 1, 2

• Anaphylactic penicillin allergy (angioedema, bronchospasm, hypotension) OR documented severe cephalosporin allergy: Use azithromycin 2 g orally as a single dose with mandatory test-of-cure at 1 week. 1, 3

Step 2: Alternative Regimens When Cephalosporins Are Absolutely Contraindicated

If the patient cannot receive any cephalosporin due to confirmed severe allergy:

• First-line alternative: Azithromycin 2 g orally as a single dose 1, 3

  • Cure rate: 98.9% for urogenital infections 4
  • Major limitation: High rate of gastrointestinal adverse events (35.3% of patients, with 2.9% experiencing severe symptoms) 4
  • Critical requirement: Test-of-cure at 1 week using culture (preferred) or NAAT 1, 3

• Second-line alternative: Gentamicin 240 mg IM plus azithromycin 2 g orally as a single dose 1, 2, 3

  • Cure rate: 100% for urogenital, rectal, and pharyngeal infections in clinical trials 5, 6
  • Less painful than ceftriaxone injection 5
  • Important caveat: This regimen is only effective if azithromycin susceptibility is confirmed, as azithromycin resistance ranges from 4-7% in North America to as high as 66% in some regions of East Asia 7

Step 3: Site-Specific Considerations

Pharyngeal gonorrhea requires special attention in penicillin-allergic patients:

• Pharyngeal infections are significantly more difficult to eradicate than urogenital or anorectal infections 1, 2, 3
• Ceftriaxone 500 mg IM is the only reliably effective treatment for pharyngeal gonorrhea (>99% cure rate) 3
• Azithromycin 2 g has limited efficacy data for pharyngeal infections 1
• Gentamicin 240 mg plus azithromycin 2 g achieved 100% cure in pharyngeal infections in one trial 5
• Never use spectinomycin for pharyngeal infections—only 52% effective 1, 2, 3

Step 4: Understanding Cross-Reactivity and Side-Chain Considerations

• Cephalosporins with dissimilar side chains to the culprit penicillin can be used safely in patients with immediate-type or delayed-type penicillin allergy 7
• Avoid cephalosporins with similar side chains to cefalexin, cefaclor, or cefamandole in patients with suspected immediate-type allergy to these specific agents 7
• Carbapenems can be used in a clinical setting for patients with suspected immediate-type cephalosporin allergy 7
• Aztreonam can be used in patients with cephalosporin allergy, except in those with ceftazidime or cefiderocol allergy 7

Regimens That Should NEVER Be Used

• Fluoroquinolones (ciprofloxacin, ofloxacin, levofloxacin): Absolutely contraindicated due to widespread resistance, despite historical cure rates of 99.8% 1, 2, 3
• Azithromycin 1 g as monotherapy: Only 93% effective and risks rapid resistance emergence 1, 2, 3
• Spectinomycin for pharyngeal infections: Only 52% effective at this site 1, 2, 3
• Cefixime 800 mg plus doxycycline: Failed to achieve non-inferiority to ceftriaxone for pharyngeal gonorrhea (all treatment failures were pharyngeal cases) 8

Mandatory Follow-Up Requirements

Test-of-cure is required in the following situations:

• All patients treated with azithromycin 2 g monotherapy: test at 1 week using culture (preferred) or NAAT 1, 3
• All patients treated with cefixime-based regimens: test at 1 week 2, 3
• All patients with pharyngeal infections treated with non-ceftriaxone regimens 1
• If NAAT is positive at follow-up, confirm with culture and perform antimicrobial susceptibility testing 3

Routine test-of-cure is NOT required for patients treated with standard ceftriaxone-based regimens unless symptoms persist. 3

Special Populations

Pregnancy

• Preferred regimen: Ceftriaxone 500 mg IM plus azithromycin 1 g orally—the cross-reactivity risk is acceptable even with reported penicillin allergy 2, 3
• If cephalosporins absolutely contraindicated: Azithromycin 2 g orally as a single dose (limited data in pregnancy) 1
• Never use: Quinolones, tetracyclines, or doxycycline in pregnancy 1, 3

Men Who Have Sex with Men (MSM)

• Only use ceftriaxone 500 mg IM plus azithromycin 1 g orally due to higher prevalence of resistant strains 3
• Do not use quinolones in this population 3

Critical Pitfalls to Avoid

• Do not withhold ceftriaxone based solely on patient-reported penicillin allergy—assess severity first, as most patients can safely receive third-generation cephalosporins 1, 2
• Do not skip test-of-cure when using alternative regimens—treatment failure rates are higher with non-cephalosporin regimens 1
• Do not assume symptom resolution equals cure—microbiological confirmation is essential for alternative regimens 3
• Do not use azithromycin 2 g if azithromycin resistance is suspected or confirmed—consider gentamicin 240 mg IM plus azithromycin 2 g only if susceptibility is documented 7

Partner Management

• Evaluate and treat all sexual partners from the preceding 60 days with the same dual therapy regimen 2, 3
• Patients must avoid sexual intercourse until therapy is completed and both they and their partners are asymptomatic 2, 3
• Always treat presumptively for chlamydia, as coinfection occurs in 20-50% of cases 1, 3