Beta-lactam allergy

Beta-lactam allergy is a topic covered in the Johns Hopkins ABX Guide.

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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.

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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.

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Last updated: December 11, 2022