Penicillin allergy: A practical guide for clinicians

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Diagnostic tests

Skin testing. The only validated test for diagnosing IgE-mediated reactions caused by penicillin is the immediate hypersensitivity skin test,9 which should be performed by a board-certified allergist. The test consists of skin-prick and intradermal testing with the major determinant (penicilloyl-polylysine), the minor determinant (penicillin G), a negative control (normal saline), and a positive control (histamine). Minor-determinant mix is not commercially available in the United States.

Results of skin-prick testing are read 15 minutes after application. A positive response is a wheal at least 3 mm larger in diameter (with equivalent erythema) than the negative control done simultaneously. Intradermal testing is only done after a negative skin-prick test. If the allergic reaction was severe (ie, anaphylaxis), skin testing should be done at least 4 to 6 weeks after the reaction.

A history of severe non–IgE-mediated reaction to penicillin is a contraindication to skin-prick testing for penicillin allergy. The positive predictive value of penicillin skin testing is 50%, and the negative predictive value is 97%.3,7,9,13

Commercial in vitro testing (serum-specific IgE assays) for IgE-mediated hypersensitivity to penicillin is inferior to skin testing in terms of the negative predictive value and is not a suitable substitute for penicillin skin testing.


If skin testing is positive, use another antibiotic, or refer for desensitization

If penicillin skin testing is positive (Figure 2), use another antibiotic that is equally efficacious. Patients who absolutely need a beta-lactam may undergo drug desensitization, performed by a board-certified allergist.

The skin-prick test is the only validated test for IgE-mediated reactions to penicillin

During desensitization, patients receive progressively higher doses of the drug every 15 to 20 minutes subcutaneously or intravenously, or every 20 to 30 minutes orally, until a full therapeutic dose is tolerated. Most protocols begin with a dose ranging from 1/10,000 to 1/1,000 of the final dose, depending on the severity of the allergic reaction.9,17

Using modern protocols, the success rate for tolerance induction is extremely high (75% to 100% in patients with cystic fibrosis, a group with a high rate of drug allergy18–20).

Drug desensitization is contraindicated in patients with non–IgE-mediated reactions.

If skin testing is negative, refer for graded-dose challenge

If skin testing is negative (Figure 2), graded-dose challenge is recommended. This procedure must be done by a board-certified allergist. If the original reaction was life-threatening, graded-dose challenge may entail giving 1/100 of the therapeutic dose. Then, if no reaction occurs during a brief observation period (usually 30 minutes), a full dose is given. However, many patients can start with 1/10 or even a full dose of the drug, especially if the original reaction was limited to the skin and the penicillin skin test is negative.

Graded-dose challenge is contraindicated if the original reaction was a severe non–IgE-mediated reaction.


Penicillin is the only antibiotic for which skin testing is reliable and validated. If a drug that cross-reacts with penicillin is needed, it is important to know the rate of cross-reactivity (Table 3). The rate of cross-reactivity between penicillin and aminopenicillins (amoxicillin and ampicillin) is less than 1.3% in the United States.10,21 However, the cross-reactivity rate among aminopenicillins and cephalosporins is between 10% to 40%. For that reason, patients with prior reactions to aminopenicillins should avoid cephalosporins that share identical R-chain side groups with aminopenicillins.9,22

The rate of cross-reactivity between penicillin and cephalosporins was reported as 10% 40 years ago.23,24 But this was with early, first-generation cephalosporins that may have been contaminated with penicillin. The cross-reactivity rate with cephalosporins today is 3%.25 In general, first- and second-generation cephalosporins cause more allergic reactions than third- and fourth-generation cephalosporins.26

Patients with a history of penicillin allergy who require a cephalosporin should still undergo penicillin skin testing. Skin testing with cephalosporins has not been validated. However, skin testing with nonirritating concentrations of cephalosporins9 may be done to elucidate IgE reactions.

In a study by Romano et al,27 110 patients who had positive results on penicillin skin testing completed graded-dose challenge with the carbapenem antibiotic imipenem. The rate of cross-reactivity between penicillin and imipenem was less than 1%.

Monobactam antibiotics do not cross-react with other beta-lactams, except ceftazidime with aztreonam. This is probably because of similarities in their chemical structure.

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