Should a patient with a history of penicillin allergy undergo skin testing for azithromycin and ceftriaxone (Intravenous) before administration?

Skin Testing for Azithromycin and Ceftriaxone in Penicillin-Allergic Patients

Skin testing is not necessary for either azithromycin or ceftriaxone in patients with a history of penicillin allergy—both drugs can be administered directly without prior testing in most clinical scenarios.

Azithromycin

Azithromycin does not require skin testing and can be safely administered to penicillin-allergic patients without any additional precautions. 1

• Azithromycin is a macrolide antibiotic with no structural relationship to beta-lactam antibiotics (penicillins, cephalosporins) 1
• Clinical studies demonstrate that azithromycin is safe in patients with documented penicillin and cephalosporin allergies, with no cross-reactivity observed 1
• There is no validated skin testing protocol for azithromycin, and none is needed given the absence of cross-reactivity 2

Ceftriaxone

For patients with an unverified history of penicillin allergy (no anaphylaxis), ceftriaxone can be administered directly without skin testing. 2

When Skin Testing is NOT Required:

• Patients with non-anaphylactic penicillin allergy history (e.g., rash, mild urticaria, gastrointestinal symptoms) can receive ceftriaxone without prior testing 2
• The cross-reactivity rate between penicillins and cephalosporins is extremely low—less than 5% in patients with unverified penicillin allergy, and only 3.0% even in confirmed penicillin-allergic patients 2
• Modern cephalosporins like ceftriaxone have unique side chains that minimize cross-reactivity with penicillins 2

When to Consider Penicillin Skin Testing (Not Ceftriaxone Testing):

If the patient has a history of anaphylaxis, angioedema, bronchospasm, or hypotension to penicillin, you have three options 2:

1. Administer ceftriaxone by graded challenge or full dose (preferred approach given low cross-reactivity) 2
2. Perform penicillin skin testing first—if negative, proceed with ceftriaxone; if positive, use graded challenge or desensitization to ceftriaxone 2
3. Use a non-beta-lactam alternative 2

Important Caveats:

• The FDA label for ceftriaxone states that it "should be given cautiously to penicillin-sensitive patients" and warns that "serious and occasionally fatal hypersensitivity reactions have been reported" 3
• However, current evidence-based guidelines indicate that the actual risk is minimal, particularly in patients without a history of severe IgE-mediated reactions 2
• Never perform skin testing for severe non-IgE-mediated reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms) as these are not predicted by skin testing 2
• Patients with multiple drug allergies may warrant skin testing due to possible coexisting sensitivities to the beta-lactam ring itself 2

Clinical Algorithm:

For penicillin-allergic patients needing ceftriaxone:

1. Determine the type of prior reaction:

   • Non-severe (rash, mild urticaria, GI symptoms) → Give ceftriaxone directly 2
   • Severe IgE-mediated (anaphylaxis, angioedema, bronchospasm) → Give ceftriaxone by graded challenge or consider penicillin skin testing first 2
   • Severe non-IgE-mediated (SJS, TEN, DRESS) → Avoid all beta-lactams, do not skin test 2

2. If proceeding with ceftriaxone administration:

   • Ensure emergency equipment is available 3
   • Monitor for 30-60 minutes after administration 3
   • Document the tolerance for future reference 2

The key principle: approximately 90% of patients reporting penicillin allergy are not truly allergic when properly evaluated, and cross-reactivity with modern cephalosporins is rare. 2, 4