DEFINITION

• Immunologic hypersensitivity reaction to beta-lactam antibiotics
  • Beta-lactams include penicillins, cephalosporins, carbapenems, and monobactams. All share the beta-lactam ring. R-group side chains (R, R1, and R2) differentiate compounds.
• Allergy to one penicillin indicates a potential allergy to all penicillins, but cross-reactivity between classes of beta-lactams is variable.[7]
  • 10% of adults in the U.S. self-report penicillin allergy. Clinically significant penicillin hypersensitivity is uncommon < 5%.[1]
  • When tested and challenged, 70-90% of those reporting allergies can tolerate penicillin.[8]
  • This high percentage may be due to the following:
    • The waning of penicillin-specific IgE antibodies over time
    • Mislabeling of drug intolerance or non-immunologically-mediated adverse effects, e.g., headache, diarrhea, allergy.
    • Illness or combination of illness and antibiotic-causing symptoms mislabeled as ’allergy.’
  • Identification of patients with IgE-mediated allergy or a history of severe reactions is paramount.[6]
    • Immediate reactions occur within 1 hour and up to 6 hours after the first dose of the last therapeutic course. Immediate responses are mediated by antigen-specific IgE and subsequent mast cell activation.[2]
      • The presentation can be cutaneous, respiratory, gastrointestinal, and/or cardiovascular, and range from benign urticaria, with or without angioedema, to anaphylaxis.[7]
    • Non-immediate reactions occur more than 6 hours after the first dose of the last therapeutic course. Nonimmediate reactions are mediated by antigen-specific T cells.[2]
      • Clinical presentations range from benign rashes to severe cutaneous adverse reactions.
        • Mucocutaneous eruption with epidermal detachment: Stevens-Johnson syndrome (< 10% body surface area) and toxic epidermal necrolysis (>30% body surface area).[12]
          • 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 is based on immunopathology.[13]
  • Type I, anaphylactic
    • The drug cross-links IgE ab bound to basophils and mast cells with subsequent release of mediators: histamine, prostaglandins, proteases, and leukotrienes.
    • Produces urticaria, angioedema, laryngeal edema, bronchospasm, hypotension, and 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 the 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 are derived from the core ring structure. The bicyclic structure consists of a 4-member beta-lactam ring and a 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), a synthetic analog of a major antigenic determinant: comprises 95% of tissue-bound penicillin. [accessed 11/7/2022 at https://www.penallergytest.com/]
    • Benzylpenicillin + its alkaline product (penicilloate) and acid product (penilloate) (optimal reagents for skin testing) are minor determinants: formed less often than penicilloyl but clinically significant.
  • 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.
      • Cystic fibrosis patients treated repeatedly with anti-pseudomonal antibiotics may develop a side-chain-specific allergy.