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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 more than 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 because it is either not standardized in practice or in reagent preparation, or the reaction may not be IgE-mediated; an allergist may provide guidance about the likelihood and severity of future exposures to determine whether re-challenging with the drug would be advisable.

Shenoy  ES  et al. Evaluation and management of penicillin allergy: a review. JAMA. 2019;321:188.
[PubMed: 30644987]  


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) via the Mas-related G protein coupled receptor-X2 receptors, 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. Some diseases that produce allergic or pseudoallergic conditions are listed in eTable 20–4.

eTable 20–4.Uncommon allergic and pseudoallergic conditions.

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