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Management of Persons Who Have a History of Penicillin Allergy

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Sexually Transmitted Diseases Treatment Guidelines, 2010

No proven alternatives to penicillin are available for treating neurosyphilis, congenital syphilis, or syphilis in pregnant women. Penicillin also is recommended for use, whenever possible, in HIV-infected patients. Of the adult U.S. population, 3%–10% have experienced an immunoglobulin E (IgE)-mediated allergic response to penicillin (238,239), such as urticaria, angioedema, or anaphylaxis (i.e., upper airway obstruction, bronchospasm, or hypotension). Readministration of penicillin to these patients can cause severe, immediate reactions. Because anaphylactic reactions to penicillin can be fatal, every effort should be made to avoid administering penicillin to penicillin-allergic patients, unless they undergo acute desensitization to eliminate anaphylactic sensitivity.

Although an estimated 10% of persons who report a history of severe allergic reactions to penicillin continue to remain allergic their entire lives, with the passage of time, most persons who have had a severe reaction to penicillin stop expressing penicillin- specific IgE (238,239). These persons can then be treated safely with penicillin. Penicillin skin testing with the major and minor determinants of penicillin can reliably identify persons at high risk for penicillin reactions (238,239). Although these reagents are easily generated and have been available for more than 30 years, only benzylpenicilloyl poly-L-lysine (Pre-Pen [i.e., the major determinant]) and penicillin G have been available commercially. These two tests identify an estimated 90%–97% of the currently allergic patients. However, because skin testing without the minor determinants would still miss 3%–10% of allergic patients and because serious or fatal reactions can occur among these minor-determinant–positive patients, caution should be exercised when the full battery of skin-test reagents is not available (Box 2). Manufacturers are working to ensure better availability of the Pre-Pen skin test reagent as well as an accompanying minor determinant mixture.


If the full battery of skin-test reagents is available, including both major and minor determinants (see Penicillin Allergy Skin Testing ), patients who report a history of penicillin reaction and who are skin-test negative can receive conventional penicillin therapy. Skin-test–positive patients should be desensitized before initiating treatment.

If the full battery of skin-test reagents, including the minor determinants, is not available, the patient should be skin tested using benzylpenicilloyl poly-L-lysine (i.e., the major determinant) and penicillin G. Patients who have positive test results should be desensitized. One approach suggests that persons with a history of allergy who have negative test results should be regarded as possibly allergic and desensitized. Another approach in those with negative skin-test results involves test-dosing gradually with oral penicillin in a monitored setting in which treatment for anaphylactic reaction can be provided.

If the major determinant (Pre-Pen) is not available for skin testing, all patients with a history suggesting IgE-mediated reactions to penicillin (e.g., anaphylaxis, angioedema, bronchospasm, or urticaria) should be desensitized in a hospital setting. In patients with reactions not likely to be IgE-mediated, outpatient-monitored test doses can be considered.

Penicillin Allergy Skin Testing

Box 2. Skin-test reagents for identifying persons at risk for adverse reactions to penicillin*

Major Determinant

    • Benzylpenicilloyl poly-L-lysine (PrePen) (AllerQuest, Plainville Connecticut) (6 x 10-5M).

Minor Determinant Precursors†

    • Benzylpenicillin G (10-2M, 3.3 mg/mL, 10,000 units/mL)
    • Benzylpenicilloate (10-2M, 3.3 mg/mL)
    • Benzylpenicilloate (or penicilloyl propylamine) (10-2M, 3.3 mg/mL)

Positive Control

    • Commercial histamine for intradermal skin testing (1.0 mg/mL)

Negative Control

    • Diluent (usually saline) or allergen diluent

* Adapted from Saxon A, Beall GN, Rohr AS, Adelman DC. Immediate hypersensitivity reactions to beta-lactam antibiotics. Ann Intern Med 1987;107:204–15. Reprinted with permission from G.N. Beall and Annals of Internal Medicine.
† Aged penicillin is not an adequate source of minor determinants. Penicillin G should be freshly prepared or should come from a fresh-frozen source.

Patients at high risk for anaphylaxis, including those who 1) have a history of penicillin-related anaphylaxis, asthma, or other diseases that would make anaphylaxis more dangerous or 2) are being treated with beta-adrenergic blocking agents, should be tested with 100-fold dilutions of the full-strength skin-test reagents before being tested with full-strength reagents. In these situations, patients should be tested in a monitored setting in which treatment for an anaphylactic reaction is available. If possible, the patient should not have taken antihistamines recently (e.g., chlorpheniramine maleate or fexafenadine during the preceding 24 hours, diphenhydramine HCl during the preceding 4 days, or hydroxyzine or phenathiazines during the preceding 3 weeks).


Dilute the antigens either 100-fold for preliminary testing (if the patient has had a life-threatening reaction to penicillin) or 10-fold (if the patient has had another type of immediate, generalized reaction to penicillin within the preceding year).

Epicutaneous (Prick) Tests

Duplicate drops of skin-test reagent are placed on the volar surface of the forearm. The underlying epidermis is pierced with a 26-gauge needle without drawing blood. An epicutaneous test is positive if the average wheal diameter after 15 minutes is ≥4 mm larger than that of negative controls; otherwise, the test is negative. The histamine controls should be positive to ensure that results are not falsely negative because of the effect of antihistaminic drugs.

Intradermal Test

If epicutaneous tests are negative, duplicate 0.02-mL intradermal injections of negative control and antigen solutions are made into the volar surface of the forearm by using a 26- or 27-gauge needle on a syringe. The margins of the wheals induced by the injections should be marked with a ball point pen. An intradermal test is positive if the average wheal diameter 15 minutes after injection is >2 mm larger than the initial wheal size and also is >2 mm larger than the negative controls. Otherwise, the tests are negative.


Patients who have a positive skin test to one of the penicillin determinants can be desensitized (Table 1). This is a straightforward, relatively safe procedure that can be performed orally or IV. Although the two approaches have not been compared, oral desensitization is regarded as safer and easier to perform. Patients should be desensitized in a hospital setting because serious IgE-mediated allergic reactions can occur. Desensitization usually can be completed in approximately 4–12 hours, after which time the first dose of penicillin is administered. After desensitization, patients must be maintained on penicillin continuously for the duration of the course of therapy.