Classification, Clinical Features, and Management of Classic Hypersensitivity Reactions to Antibiotics

Gell and Coombs ClassificationImmune MechanismClinical FeaturesTiming
Type I: immediate-type hypersensitivityMast cell and/or basophil mediator release directed by drug interaction and/or cross-linking of drug-specific IgE bound to these cellsAnaphylaxis, urticaria, angioedema, gastrointestinal, respiratory, cardiovascular, and neurologic symptomsImmediate: <1 h after drug exposure
Type II: cytotoxic or antibody dependent, hypersensitivityNatural killer cells and macrophages kill IgG- or IgM-coated cells that are directed against the drug or drug metabolite on the patient’s cellsDrug-induced hemolytic anemia, thrombocytopenia1–2 wk after exposurea
Type III: immune complex–mediated hypersensitivityAntibody (IgG>IgM) binds to soluble antigen (often a drug or drug metabolite), forming a circulating immune complexSerum sickness, vasculitis1–2 wk after exposurea
Type IV: delayed-type hypersensitivitiesAn antigen-presenting cell expressing HLA bound to a peptide interacts with a T-cell receptor in the presence of a drug or drug metaboliteb,61Benign, delayed skin rashesNonimmediate: differs according to the specific phenotype (Table 3) but generally 24 h to 1 wk after first exposure and can be quicker (h) on rechallenge exposure
Type IVaAllergic contact dermatitis, maculopapular exanthema, FDE, EM (typically infection, not drug)
Type IVbMore severe cutaneous skin rashes
Type IVcAcute generalized exanthematous pustulosis, DRESS syndrome, SJS and/or TEN, generalized-bullous FDE
Type IVd
  • EM, erythema multiforme; FDE, fixed drug eruption; HLA, human leukocyte antigen; IgG, immunoglobulin G; IgM, immunoglobulin M.

  • a May be sooner if preformed antibodies.

  • b Multiple models have been proposed including hapten/prohapten model, pharmacological interaction (p-i) model and altered peptide repertoire model. In the hapten/prohapten model, a drug/drug metabolite covalently bound to larger protein undergoes intracellular processing to generate modified peptides that are incorporated onto HLA proteins for presentation to T cells.61