Beta-lactam allergy

Lisa A. Spacek, M.D., Ph.D., N. Franklin Adkinson, Jr., M.D.
Beta-lactam allergy is a topic covered in the Johns Hopkins ABX Guide.

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  • 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.

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Last updated: January 29, 2017