Penicillin Allergy

Background

• Penicillin allergy is an immune-mediated reaction to penicillin or its metabolic products and is classified into 4 types based on the reaction mechanism, presenting symptoms, and time of symptom onset.
  • Type I allergy is immunoglobulin E (IgE)-mediated, has an onset within 1 hour of exposure, and presents with symptoms such as urticaria, wheezing, and anaphylaxis.
  • Type II allergy is characterized by immunoglobulin M (IgM) and immunoglobulin G (IgG) immune complex cytotoxic destruction of renal interstitial cells or red blood cells caused by complement fixation which typically presents > 72 hours after exposure with hemolytic anemia, thrombocytopenia, granulocytopenia (rare), proteinuria, and/or hematuria.
  • Type III allergy is characterized by circulating immune complexes (IgG- or IgM-hapten complex) which fix complements and form aggregates which deposit in the renal vasculature, joints, or skin. Clinical findings present 10-21 days after exposure and may include fever, vasculitis, serum sickness, interstitial nephritis, arthralgia, lymphadenopathy, splenomegaly, and/or erythema multiforme.
  • Type IV allergy is characterized by a T-cell-mediated proinflammatory cytokine release in response to penicillin antigen which presents > 48 hours after exposure with a morbilliform rash or contact dermatitis. Stevens-Johnson syndrome, acute generalized exanthematous pustulosis (AGEP), drug rash with eosinophilia and systemic symptoms (DRESS), and drug-induced hypersensitivity syndrome (DIHS) are additional but rare Type IV reactions.
• More than 90% of patients reporting a penicillin allergy are found not to be allergic based on skin testing.

Evaluation

• Thorough evaluation of patients with a reported penicillin allergy is essential prior to prescribing.
  • Patients with a suspected Type I allergy should undergo skin prick testing followed by intradermal skin testing if negative.
  • Patients presenting with a nonpruritic morbilliform eruption can be safely tested using a graded drug challenge but other Type II-IV allergies are diagnosed by clinical presentation as there are no specific tests to otherwise make the diagnosis.
  • A graded drug challenge involves introducing 3-6 gradually increasing doses until a therapeutic dose is achieved in patients who are unlikely to be allergic and in patients who have ambiguous skin testing results.
• If Stevens-Johnson syndrome/Toxic epidermal necrolysis is suspected, avoid penicillin and do not perform penicillin skin testing or graded drug challenges

Management

• Anaphylaxis requires prompt emergency treatment (Strong recommendation) with airway assessment and management, intramuscular epinephrine 0.2-0.5 mg (0.01 mg/kg in children up to 0.3 mg), antihistamines including diphenhydramine and ranitidine, and parenteral IV fluid support for blood pressure, if necessary. Corticosteroids are also usually provided although evidence for their efficacy in anaphylaxis is limited.
• Patients with a negative penicillin skin test:
  • can take penicillin with minimal risk (Weak recommendation)
  • should consider having their first dose of penicillin administered using a graded drug challenge (Weak recommendation)
  • have a very low rate of resensitization to penicillin, cephalosporins, and other beta-lactam antibiotics
• Patients with a positive penicillin skin test should:
  • receive alternatives to beta-lactam antibiotics
  • avoid first-generation cephalosporins
  • consider receiving cephalosporins using a graded drug challenge or through desensitization
• If a patient has a positive penicillin skin test and no alternative antibiotic is available, desensitization using a protocol of incrementally increasing doses of the drug can be used to induce temporary tolerance in patients with a Type I allergy but carries a risk of anaphylaxis and death (Strong recommendation).
• Absolute contraindications to desensitization include:
  • Stevens-Johnson syndrome/ toxic epidermal necrolysis
  • drug-induced hypersensitivity syndromes
  • drug reaction with eosinophilia and systemic symptoms
  • drug-induced lupus erythematosus
• Relative contraindications to desensitization include:
  • history of anaphylaxis
  • uncontrolled asthma
  • concurrent illness
  • hemodynamic instability
  • certain medications, including beta blockers and angiotensin-converting enzyme (ACE) inhibitors