Drug Allergy (IgE-Mediated Immediate Hypersensitivity Reactions

Prick skin testing for most low-molecular-weight drugs is not validated and is interpretable only if the test is positive at a nonirritating concentration.

Testing for IgE-mediated allergy to penicillin (PCN) is validated; skin testing with the metabolic determinants of PCN has a high (more than 98%) negative predictive value. Referral of individuals with a listed PCN allergy to an allergist for evaluation is worthwhile because > 90% have either lost sensitization or do not have a true PCN allergy. Such patients may then safely receive beta-lactam antibiotics, including penicillins and cephalosporins.

Allergy testing to non-PCN drugs is more limited; an allergist may provide guidance about whether re-challenging with the drug would be advisable.

Non-IgE-Mediated Anaphylactic Drug Reactions

Non-IgE–mediated anaphylaxis induced by drugs resembles immediate hypersensitivity reactions but is not mediated by allergen-IgE cross-linking on mast cells or basophils.

Mechanisms include direct mast cell activation (eg, opioids, vancomycin [vancomycin flushing syndrome], neuromuscular blocking agents, fluoroquinolones), complement activation–related pseudoallergy (possible mechanism for heparin or liposomal drug infusions [polyethylene glycol)/COVID mRNA vaccines], or IgG-mediated mechanisms. Contrary to IgE-mediated reactions, these reactions can often be prevented by prophylactic medical regimens.

Radiocontrast Media Reactions

Reactions to radiocontrast media are not usually IgE antibody–mediated, yet they are clinically similar to anaphylaxis and can be life-threatening. If a patient has had an anaphylactoid reaction to conventional radiocontrast media, the risk for a second reaction upon re-exposure may be as high as 30%. Patients with a history of atopy are at increased risk.


Management includes use of low-osmolality contrast preparations and prophylactic administration of prednisone (50 mg orally every 6 hours beginning 13 hours before the procedure) and diphenhydramine (25–50 mg orally, intramuscularly or intravenously 60 minutes before the procedure). Using lower-osmolality radiocontrast media in combination with the pretreatment regimen decreases the incidence of recurrent reactions to < 1%.

Vancomycin Flushing Syndrome

Vancomycin flushing syndrome causes non-IgE–mediated anaphylaxis comprised of flushing, pruritus, and erythema of the upper body.

Initially described as a vancomycin-infusion reaction, it can also occur after intravenous infusion of opioids.

The reaction is related to the rate of drug administration resulting in direct activation of mast cells.


Management includes administration of an antihistamine such as diphenhydramine, 25–50 mg intravenously or intramuscularly, and re-initiation of the vancomycin infusion at no more than half the former rate.

In patients who have previously experienced a vancomycin infusion reaction, premedication with an H1-antagonist (eg, diphenhydramine) and H2-antagonist (eg, cimetidine) is recommended 1 hour before the infusion.

Although rare, anaphylaxis with vancomycin use can occur. Vancomycin skin testing has not been validated as a diagnostic tool. For patients that have experienced anaphylaxis to vancomycin without an acceptable alternative antibiotic, induction of tolerance to vancomycin is possible.

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