What is the protocol for penicillin (antibiotic) testing in patients with suspected allergy?

Penicillin Allergy Testing Protocol

For patients with suspected penicillin allergy, routine pre-treatment skin testing is NOT recommended in individuals without a reported allergy history, but for those with a reported allergy, a risk-stratified approach using detailed history-taking followed by direct oral challenge (without prior skin testing) is the preferred protocol for most low-risk patients. 1

Key Epidemiologic Context

• Approximately 8-12% of patients carry a penicillin allergy label, but less than 5% of labeled patients have true confirmed allergy when appropriately tested 1, 2
• In adults with reported penicillin allergy, only about 5-8% are truly allergic; in children, this drops to approximately 2% 1
• Over 90% of penicillin allergy labels can be removed after proper assessment 1

Protocol for Patients WITHOUT Prior Allergy History

Routine penicillin skin testing before first-time penicillin administration is NOT recommended due to the extremely low rate of anaphylaxis (approximately 1.5 per million in skin test-negative patients) 1, 3

• Administer penicillin in a healthcare facility equipped to manage anaphylaxis 1
• Observe patient for immediate reactions (minimum 30-60 minutes post-administration) 1

Protocol for Patients WITH Reported Penicillin Allergy

Step 1: Detailed History Assessment (Risk Stratification)

Immediate delabeling WITHOUT any testing is appropriate when: 1

• The culprit drug was used successfully since the index reaction without allergic symptoms
• The allergy label is based solely on family history or fear of allergy
• Reported symptoms are clearly non-immunologic (gastrointestinal complaints only, headache, palpitations, blurred vision, nausea, diarrhea)
• No temporal association exists between drug exposure and symptom onset
• Patient has no recollection of the incident

Step 2: Risk Classification for Remaining Patients

Low-Risk Features (proceed to direct oral challenge): 1

• Cutaneous-only reactions (non-severe rash, mild urticaria)
• Remote history (>1 year ago, preferably >10 years for adults)
• Vague or poorly documented reaction
• Pediatric age at time of reaction
• No history of anaphylaxis, angioedema, or severe cutaneous adverse reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis)

High-Risk Features (consider specialist referral or skin testing first): 1

• Recent reaction (<1 year ago)
• History of anaphylaxis, angioedema, or severe cutaneous adverse reactions
• Mucosal or systemic involvement
• Reaction observed and documented by healthcare personnel
• Age 18-60 years at time of reaction (higher risk than children or elderly >60)
• Multiple short courses of parenteral or topical penicillin exposure 1

Step 3: Direct Oral Challenge Protocol (Preferred for Low-Risk Patients)

Direct oral challenge WITHOUT prior skin testing is safe and effective in low-risk patients, with 94-96% tolerating the challenge successfully 1

Challenge Protocol: 1

• Use amoxicillin (most commonly) or the specific implicated penicillin if known
• Administer in 1-2 steps:
  • Two-step approach: Give 10% of therapeutic dose, observe 30-60 minutes, then give remaining 90%, observe minimum 60 minutes
  • One-step approach: Give full therapeutic dose in select very low-risk patients
• Minimum observation period: 60-90 minutes after final dose 1
• Have emergency equipment available (epinephrine, antihistamines, corticosteroids)

Expected reaction rates with direct oral challenge: 1

• Low-risk patients: 3.6-6.6% develop mild reactions (typically rash)
• Most reactions are mild and respond to antihistamines
• No deaths or anaphylaxis reported in recent systematic reviews 1

Step 4: Skin Testing Protocol (Alternative for High-Risk or When Preferred)

When skin testing is performed: 1

• Use benzylpenicillin (penicillin G) 6 mg/mL and/or amoxicillin 20 mg/mL
• Include penicilloyl-polylysine (major determinant) and minor determinant mixture when available
• Perform skin prick test first; if negative, proceed to intradermal testing (0.02 mL)
• Read results after 15 minutes
• If skin test is negative, proceed to oral challenge (as above) to confirm tolerance
• If skin test is positive, avoid penicillin or consider desensitization if penicillin is essential 4

Important caveat: Skin test sensitivity is only 30.7% with specificity of 96.8%, meaning negative skin tests do NOT rule out allergy—oral challenge is still required 1

Step 5: Extended Challenge and Follow-Up

• After successful in-office challenge, prescribe a 5-day course of penicillin (extended challenge) to assess for delayed reactions 1
• Contact patient at 5 days to assess for delayed hypersensitivity reactions 1
• Document successful challenge and remove allergy label from medical record

Critical Pitfalls to Avoid

• Do not rely on vague history alone to avoid penicillin: 33% of skin test-positive patients had vague allergy histories 5
• Do not assume skin testing alone is sufficient: Negative skin tests require oral challenge confirmation 1, 6
• Do not use serum-specific IgE testing: Commercial fluorometric enzyme immunoassays have poor sensitivity (19.3%) and are not useful for evaluation 1
• Do not forget time factor: Penicillin-specific IgE wanes over time; reactions >1 year ago have significantly lower risk of recurrence 1
• Do not perform routine skin testing in patients without allergy history: This is not cost-effective and unnecessary given extremely low anaphylaxis rates 1

Special Consideration: Cross-Reactivity

• Cross-reactivity between penicillins and second/third-generation cephalosporins is likely no higher than with other antibiotic classes 4
• Carbapenems and monobactams are safely used in confirmed penicillin allergy 2
• Cephalosporins with different side chains can be used even in specific cephalosporin allergy 2