What is the protocol for a penicillin challenge in patients with a history of allergy to penicillin?

Penicillin Challenge Protocol for Patients with History of Penicillin Allergy

For patients with a history of penicillin allergy, the recommended protocol includes penicillin skin testing followed by an oral challenge if skin testing is negative, with specific modifications based on reaction history.

Risk Stratification

The approach to penicillin challenge should be stratified based on the patient's reaction history:

Low-Risk Patients

• Benign cutaneous reactions (maculopapular exanthems, urticaria without systemic symptoms)
• Remote reactions (>1 year ago)
• Reactions in childhood without systemic involvement
• Unknown reactions without documentation of anaphylaxis

High-Risk Patients

• History of anaphylaxis
• Angioedema
• Hypotension
• Respiratory symptoms
• Recent severe reactions
• Blistering or exfoliative skin reactions

Testing Protocol

Standard Protocol (High-Risk Patients)

1. Skin Testing Components:

   • Major determinant: Penicilloyl-poly-lysine (Pre-Pen) at 6 × 10^-5 mol/L
   • Minor determinant: Penicillin G at 10,000 units/mL
   • Positive control: Histamine
   • Negative control: Saline

2. Skin Testing Procedure:

   • Begin with epicutaneous (prick) testing
   • If negative, proceed to intradermal testing
   • Positive test: wheal ≥3 mm larger than negative control with ≥5 mm flare

3. Oral Challenge (if skin testing negative):

   • Single therapeutic dose of amoxicillin (typically 250-500 mg)
   • Observe for 60 minutes
   • For patients with history of severe reactions, consider 2-step challenge (small dose followed by full dose)

Modified Protocol (Low-Risk Patients)

• Direct oral amoxicillin challenge without prior skin testing is recommended for pediatric patients with history of benign cutaneous reactions 1
• Direct oral challenge may also be considered for adults with low-risk reaction histories 1, 2

Special Considerations

Cross-Reactivity

• For patients with cephalosporin allergy history requiring penicillin:
  • If history of anaphylaxis to cephalosporins: penicillin skin testing and drug challenge should be performed 1
  • If history of non-anaphylactic reaction to cephalosporins with dissimilar R1 side chains: direct challenge to penicillin may be considered 1

Follow-Up and Documentation

• After negative testing and challenge, provide patients with written documentation (wallet card) indicating they are no longer penicillin allergic 1
• Update all medical records to remove penicillin allergy label 1
• Routine repeat testing is not necessary, even with repeated courses of penicillin (oral or IV) 1, 3

Safety and Efficacy

• Less than 2% of patients who are skin test-positive experience systemic reactions during testing 4
• The negative predictive value of penicillin skin testing is >95% 4
• Direct oral challenges in low-risk individuals have shown very low rates of severe reactions 1, 2
• Single-day challenges are generally sufficient to detect clinically significant delayed reactions 1

Common Pitfalls and Caveats

• False positives: Penicillin skin testing has a relatively high rate of false positive results 2
• Resensitization: Resensitization after oral treatment with penicillins is rare in both pediatric and adult patients 1
• Electronic health records: Penicillin allergy labels are frequently not universally removed or sometimes reappear after being removed 1
• Delayed reactions: Standard testing focuses primarily on immediate IgE-mediated reactions and may not detect delayed hypersensitivity reactions 4

The evidence strongly supports that properly performed penicillin allergy evaluation is safe and effective at identifying patients who can safely receive penicillin antibiotics, thereby reducing unnecessary use of alternative antibiotics and improving patient outcomes.