Penicillin Allergy

PATHCHAT Edition No. 51
October 2018
Please contact your local Ampath pathologist for more information.

Authors:

• Dr. Louise Murray (Chemical Pathologist, Immunology Department)
• Dr. Cathy van Rooyen (Clinical Virologist, Immunology Department)

Introduction

✅ Penicillin Allergy Overview:

• Most commonly reported antibiotic allergy.
• Less than 20% of patients with a reported penicillin allergy are truly allergic.
• Many individuals avoid penicillin unnecessarily, leading to alternative antibiotic use with higher costs and side effects.

📌 Penicillin metabolism produces benzyl penicilloyl (major determinant) and multiple minor determinants (e.g., penilloate, penicilloate, benzyl-n-propylamine). Both major and minor determinants contribute to allergic reactions.

Approach to Diagnosing Drug Allergy

✅ Key Steps:

1. Obtain a detailed history to determine if the reaction was an immunologically mediated allergy.
2. Classify the reaction as immediate or delayed.
3. Identify the underlying immunological mechanism:
   • IgE-mediated reactions (immediate onset).
   • Basophil-mediated reactions (immediate or delayed).
   • Complement-mediated immune complex reactions (delayed).
   • T-cell mediated reactions (delayed).

🔹 Risk Factors for True Penicillin Allergy:

• History of hypersensitivity to other drugs.
• Frequent penicillin administration.
• Intravenous administration route.
• History of atopy.

📌 Most patients labeled as penicillin-allergic can safely tolerate the drug upon formal testing.

Available In Vitro Tests for Penicillin Allergy

🔹 Tests for Immediate Reactions:

• ImmunoCap IgE (Penicilloyl G, Penicilloyl V, Amoxycilloyl, Ampicilloyl).
• CAST (Cellular Antigen Stimulation Test) for:
  • PPL (Major determinant).
  • MDM (Minor determinants).
  • Penicillin V, Penicillin G, Amoxicillin, Ampicillin, Clavulanic Acid.
• Minimum diagnostic panel:
  • PPL, MDM, Amoxicillin + Clavulanic Acid.

🔹 Tests for Delayed Reactions:

• CAST:
  • PPL, MDM, Clavulanic Acid + Amoxicillin.
• Lymphocyte Transformation Tests (LTTs) or MELISA:
  • Pen V, Pen G, PPL, MDM, Ampicillin, Clavulanic Acid, Amoxicillin.
• Minimum diagnostic panel:
  • PPL, MDM, Amoxicillin + Clavulanic Acid.

📌 Endorsed by the Immunology Peer Group.

Skin Prick Testing (SPT) & Drug Challenge

✅ Indications for SPT:

• For patients with a suspected penicillin allergy who test negative on in vitro assays.
• Performed using:
  • Penicillin major determinant (PPL).
  • Minor determinant mixture (MDM) (if available).

✅ Limitations of SPT:

• PPL and MDM reagents are expensive and unstable, limiting availability in South Africa.
• Alternative approach:
  • SPT using commercially available penicillin drugs (tablets or vials).
  • Can be performed at Ampath Allergy Clinic (Pretoria) and by other allergy specialists.

✅ Negative Predictive Value of SPT:

• 99% when both major and minor determinants test negative.

✅ Drug Challenge Test (If SPT & In Vitro Tests Are Negative):

• Protocols available at www.aaaai.org/penicillinallergy.
• Not indicated for Stevens-Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN) cases.

📌 SPT and drug challenge help confirm tolerance in patients with reported penicillin allergy.

Management of Confirmed Penicillin Allergy

✅ Key Recommendations:

• Avoid all penicillins if allergy is confirmed.
• Educate the patient on alternative antibiotics.
• Document allergy status in medical records.
• Desensitization can be done in cases where no alternative exists.

📌 Protocols for drug desensitization are available (Chang et al., 2012).

Cross-Reactivity Between Beta-Lactam Antibiotics

✅ Cephalosporins:

• Cross-reactivity with penicillins is estimated at ~10%.
• Lower risk with third-generation cephalosporins (2–5% cross-reactivity).

✅ Carbapenems (Imipenem, Meropenem, Doripenem, Ertapenem):

• Share a beta-lactam ring with penicillins.
• However, 99% of penicillin-allergic patients tolerate carbapenems.

📌 Cross-reactivity varies between beta-lactam antibiotics, with newer cephalosporins and carbapenems generally safe for most penicillin-allergic patients.

American Academy of Allergy, Asthma & Immunology (AAAAI) Guidelines

✅ Approach to Penicillin Allergy Testing:

• For low-risk patients (unlikely IgE-mediated allergy):
  • Perform direct oral amoxicillin challenge to confirm tolerance.
• For high-risk patients (likely IgE-mediated allergy):
  • Perform IgE testing or skin prick testing before re-exposure.

✅ European Approach (Common in South Africa):

• Basophil activation tests are increasingly used for beta-lactam allergy testing.

📌 Penicillin allergy testing is a critical component of antibiotic stewardship, improving patient outcomes by enabling penicillin use when safe.

Key Takeaways for Clinicians

✅ Most reported penicillin allergies are unconfirmed, leading to unnecessary antibiotic avoidance.
✅ Skin prick testing (SPT) and drug challenge can safely rule out penicillin allergy in most cases.
✅ Cross-reactivity between penicillins and third-generation cephalosporins is low (~2–5%).
✅ Carbapenems (e.g., meropenem) are tolerated by 99% of penicillin-allergic patients.
✅ Penicillin allergy testing should be considered part of antibiotic stewardship efforts.

📌 Accurate penicillin allergy testing can expand treatment options, reduce antibiotic resistance, and improve patient care.

References

1. Chang C et al. (2012). Overview of penicillin allergy. Clinical Reviews in Allergy and Immunology, 43: 84–97.
2. American Academy of Allergy, Asthma and Immunology (AAAAI). Penicillin allergy guidelines. Available at: www.aaaai.org/penicillinallergy.
3. Macy E (2015). Penicillin allergy: optimizing diagnostic protocols. Current Opinion in Allergy and Clinical Immunology, 15: 308–313.
4. Gonzalez-Estrada A & Radojicic C (2015). Penicillin allergy: A practical guide for clinicians. Cleveland Clinic Journal of Medicine, 82: 295–300.