DEFINITION

• Immunologic hypersensitivity reaction to beta-lactam antibiotics. Allergy to one penicillin indicates potential allergy to all penicillins, but cross-reactivity between classes of beta-lactams is variable.
  • 10% of adults in U.S. self-report penicillin allergy. But as many as 90% of these can tolerate penicillin.[3]
    • This high percentage may be due to:
      • Waning of penicillin-specific IgE antibodies over time
      • Mislabeling of a reaction (e.g., diarrhea) as allergic
      • Illness or combination of illness and antibiotic causing symptoms attributed to allergy
  • Identification of patients with IgE-mediated allergy or history of severe reaction is paramount.
    • Severe reactions include:
      • Anaphylaxis
      • Mucocutaneous eruption with epidermal detachment: Stevens-Johnson syndrome (< 10% body surface area) and toxic epidermal necrolysis (>30% body surface area).[5]
        • Presents as painful new skin eruption, sore throat, and fever or malaise
        • Associated with specific human leukocyte antigen allotypes
      • Drug-induced hypersensitivity syndrome (DiHS) with multiorgan involvement; Drug Reaction/Rash with Eosinophilia and Systemic Symptoms (DRESS)
• Gell and Coombs classification based on immunopathology[7]
  • Type I, anaphylactic
    • IgE ab bound to basophils and mast cells is cross-linked by drug with subsequent release of mediators: histamine, prostaglandins, proteases, and leukotrienes
    • Produces urticaria, angioedema, laryngeal edema, bronchospasm, hypotension, abdominal distress (per oral)
  • Type II, cytotoxic
    • IgG ab binds to drug-haptenated host cells such as renal cells or red blood cells
    • Causes interstitial nephritis, thrombocytopenia, or hemolytic anemia
  • Type III, immune complex formation
    • IgG- and IgM-mediated, soluble antigen-antibody complexes
    • Leads to serum sickness syndromes
  • Type IV, cell-mediated hypersensitivity
    • Sensitized T lymphocytes
    • Produces contact dermatitis, maculopapular eruptions, eosinophilia, Stevens-Johnson syndrome, exfoliative dermatitis
• Levine classification based on timing of symptom appearance
  • Immediate (< 1hr) and accelerated (1-72hrs) reaction, IgE-mediated, includes:
    • Skin: pruritus, flushing, urticaria, angioedema
    • Respiratory: wheezing, laryngeal edema, dyspnea, bronchospasm
    • Gastrointestinal: abdominal distress with emesis or diarrhea
    • Cardiovascular: hypotension
  • Late (>72hrs) reaction, non-IgE-mediated, multiple underlying immunologic mechanisms.
• Pathogenesis:
  • Penicillin allergens derived from core ring structure, bicyclic structure consists of 4-member beta-lactam ring and 5-member thiazolidine ring.
  • Penicillin covalently binds proteins spontaneously under physiologic conditions, enzymatic metabolism is not required.
    • BenzylPenicilloyl poly-L-lysine (PrePen, ALK-Abello, Round Rock, TX), synthetic analog of major antigenic determinant: comprises 95% of tissue-bound penicillin.
    • Benzylpenicillin + its alkaline product (penicilloate) and acid product (penilloate) (optimal reagents for skin testing) are minor determinants: formed less often than penicilloyl, but clinically important.
  • R-group side chain, less commonly the epitope for allergic reactions
    • Some immediate-type reactions to amoxicillin and ampicillin are due to IgE-ab directed at R-group side chains.
    • Selective allergy to aminopenicillins is less common in the US than allergy to beta-lactam core ring structure.
    • CF patients treated repeatedly with anti-pseudomonal antibiotics may develop side-chain specific allergy.