Penicillin and beta-lactam drug allergies are classified by the Gell-Coombs classification of human hypersensitivity according to mechanisms of tissue injury (14,15):

• Type I – immediate or IgE-mediated
• Type II – cytotoxic or IgG-mediated
• Type III – immune complex mediated
• Type IV – delayed type or T-cell mediated

Type I

Immediate hypersensitivity Type I reactions are IgE- mediated and result in immediate reactions such as anaphylaxis. These are exemplified by symptoms of urticaria, laryngeal edema, wheezing and cardio respiratory collapse, which typically occur within minutes of penicillin or beta-lactam exposure. The most important drug causes of immediate hypersensitivity reactions are antibiotics.

The time of onset for typical reactions is within 1 hour up to 6 hrs.

Type II

When IgG and or IgM antibodies bind to self antigens, they can direct the cytotoxic response against the host itself and cause potentially extensive damage. This is the basis of Type II (cytotoxic) reactions which are characterized by IgG and/or IgM antibodies against cell-surface antigens. These antigens are typically found on circulating blood cells, such as red blood cells, platelets, and neutrophils resulting in hemolytic anemia, thrombocytopenia, and neutropenia respectively.

The time of onset for a typical Type II reaction is >72 hrs to weeks.

Type III

Type III reactions are mediated by immune complexes formed in slight antigen excess. Serum sickness is the prototype for penicillin/beta-lactam Type III reactions. The chief manifestations are fever, rash, urticarial, lymphadenopathy, and arthralgias and typically appear 1-3 weeks after penicillin/beta-lactam exposure.

The time of onset for a typical Type III reaction is > 21 days.

Type IV

Type IV hypersensitivity responses are called delayed reactions and involve T-cells as the major effector cells. The major clinical manifestation of Type IV reactions from beta-lactam antibiotics are cutaneous eruptions such as maculopapular rash.

Other rare manifestations of Type IV reactions are:

• Acute interstitial nephritis
• Severe Cutaneous Allergic Reaction (SCAR)
  • DRESS (Drug reaction with eosinophilia and systemic symptoms)
  • SJS (Stevens Johnson Syndrome)
  • TEN (toxic epidermal necrolysis)
  • AGEP (Acute generalized exanthematous pustulosis)

The time of onset for typical reactions is days to weeks.