Penicillin causes non-allergic anaphylaxis by activating the contact system

Area of Science:

• Immunology
• Pharmacology
• Biochemistry

Background:

• Immediate hypersensitivity reactions (IHR) include allergic and non-allergic types; anaphylaxis is severe IHR.
• True penicillin allergy is rare, with many reported cases being spurious.
• Penicillin can trigger anaphylaxis even in patients negative for skin tests and specific IgE.

Purpose of the Study:

• To investigate the non-allergic mechanisms underlying penicillin-induced anaphylaxis.
• To explore the role of the contact system and bradykinin in penicillin reactions.
• To identify potential diagnostic markers for penicillin-induced risks.

Main Methods:

• Assessed penicillin's effect on body temperature and blood pressure in animal models (mice, rats).
• Utilized bradykinin-B2 receptor antagonist (icatibant) to counter penicillin's effects.
• Investigated penicillin's direct activation of the contact system (factor XII) in vitro using plasma and endothelial cells.
• Measured bradykinin levels in rat plasma and cell cultures.

Main Results:

• Penicillin induced hypothermia in mice and hypotension in rats, independent of IgE.
• These effects were reversed by icatibant, and penicillin increased plasma bradykinin.
• Penicillin directly activated the contact system FXII-dependently and promoted bradykinin release.
• Other beta-lactams also activated the contact system in vitro.
• Individual plasma showed variable FXII activation by penicillin, indicating personalized responses.

Conclusions:

• Penicillin-initiated non-allergic anaphylaxis is mediated by contact system activation and subsequent bradykinin release.
• This finding may lead to improved diagnostics for predicting penicillin-induced risks.
• Understanding this mechanism could help avoid inappropriate clinical treatments.