Management of Persons Who Have a History of Penicillin Allergy

No proven alternatives to penicillin are available for treating neurosyphilis, congenital syphilis, or syphilis in pregnant women. Penicillin also is recommended, whenever possible, for persons with HIV infection. The prevalence of reported penicillin allergy in the United States is about 8%–10% (451-453) and might be higher in hospitalized persons (454). The prevalence of reported penicillin allergy in developing countries is unknown; however, limited data suggest that penicillin is one of the most frequently reported allergies in some developing countries (455,456). Of persons reporting penicillin allergy, 10%–15% have a positive skin test suggestive of a penicillin allergy; these persons are at risk for an immunoglobulin E (IgE)-mediated allergic response to penicillin such as urticaria, angioedema, or anaphylaxis (i.e., upper airway obstruction, bronchospasm, or hypotension) (428-430,457,458). Re-administration of penicillin to patients with a history of IgE-mediated hypersensitivity reactions 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 persons, unless they undergo induction of drug tolerance (also referred to as “desensitization”) to temporarily eliminate IgE-mediated hypersensitivity. However, many persons with a reported history of penicillin allergy likely have had other types of adverse drug reactions or have lost their sensitivity to penicillin over time and can safely be treated with penicillin.

Penicillin skin testing with the major and minor determinants of penicillin can reliably identify persons at high risk for IgE-mediated reactions to penicillin (458,459). Although the testing reagents are easily generated, only the major determinant (benzylpenicilloyl poly-L-lysine [Pre-Pen]) and penicillin G have been available commercially. These two tests identify an estimated 90%–99% of the allergic patients. However, because skin testing without the minor determinants would still fail to identify 1%–10% of allergic persons and because serious or fatal reactions can occur among these minor-determinant–positive persons, caution should be exercised when the full battery of skin-test reagents is not available (Box 2) (457-460). Manufacturers are working on a minor determinant mixture, but at the time of publication, no such product has been cleared by FDA for use in the United States. Penicillin skin testing has been used in a variety of settings to improve antibiotic use (453,461-463).

Some studies have reported cross-reactivity rates as high as 10% among persons with a history of penicillin allergy who take cephalosporins. However, more recent studies indicate a lower rate (<2.5%) of cross reactivity between these drugs (428-431,464). Risk is highest with first-generation cephalosporins and cephalosporins that have similar R-group side chains to specific penicillins (465,466). The risk for penicillin cross-reactivity between most second-generation (cefoxitin) and all third generation cephalosporins (cefixime and ceftriaxone) is negligible (428-431); cefoxitin, cefixime, and ceftriaxone do not have an R group side chain similar to penicillin G.


Persons with a history of severe non-IgE-mediated reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, interstitial nephritis, and hemolytic anemia) are not candidates for skin testing or challenge and should avoid penicillins indefinitely. If the full battery of skin-test reagents is available, including both major and minor determinants (see Penicillin Allergy Skin Testing), persons who report a history of penicillin reaction and who are skin-test negative can receive conventional penicillin therapy. Persons with positive skin test results should be desensitized before initiating treatment.

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 scratch testing (1.0 mg/mL)
Negative Control
  • Diluent (usually saline) or allergen diluent


Source: Adapted from Saxon A, Beall GN, Rohr AS, Adelman DC. Immediate hypersensitivity reactions to beta-lactam antibiotics. Ann Intern Med 1987;107:204–15.

* Aged penicillin is not an adequate source of minor determinants. Penicillin G should either be freshly prepared or come from a fresh-frozen source.

If the full battery of skin-test reagents, including the minor determinants, is not available, skin testing should be conducted using the major determinant (Pre-Pen) and penicillin G. Those persons who have positive test results should be desensitized. For persons with negative skin tests, a subsequent observed challenge to the penicillin of choice is recommended. In addition, for persons with a history of severe or recent suspected IgE-mediated reactions to penicillin with negative skin testing, the penicillin of choice should be given by graded challenge. If the major determinant is not available for skin testing, all persons with a history suggesting IgE-mediated reactions to penicillin (e.g., anaphylaxis, angioedema, bronchospasm, or urticaria) should be desensitized in a hospital setting. In persons with reactions not likely to be IgE-mediated, outpatient-monitored graded challenges can be considered.

Penicillin Allergy Skin Testing

Persons at high risk for anaphylaxis, including those who 1) have a history of penicillin-related anaphylaxis or other IgE-mediated reactions, 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, testing should be performed in a monitored setting in which treatment for an anaphylactic reaction is available. If possible, antihistamines (e.g., chlorpheniramine maleate, fexofenadine, diphenhydramine HCL, and hydroxyzine) should not have been taken within the 5 days before skin testing.


Dilute the antigens in saline either 100-fold for preliminary testing (if the patient has had a IgE- mediated reaction to penicillin) or 10-fold (if the patient has had another type of immediate, generalized reaction to penicillin within the preceding year). Pre-Pen is provided full-strength (6 x 10–5 meq penicilloyl) in a single dose ampoule. Penicillin G is diluted to 10,000 IU/ml in saline and aliquoted in sterile vials that remain stable for at least 6 months if frozen.

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 histamine controls. Otherwise, the tests are negative. If the duplicates are discordant, a second set of duplicate tests can be used to resolve the ambiguity.


Persons 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 intravenously. Modified protocols might be considered based on an individual’s symptoms, drug of choice, and route of administration (467-469). Although the two approaches have not been compared, oral desensitization is regarded as safer and easier to perform. Desensitization should occur in a hospital setting because serious IgE-mediated allergic reactions can occur; the procedure can usually be completed in approximately 4–12 hours, after which time the first dose of penicillin is administered. After desensitization, penicillin should be maintained continuously for the duration of the course of therapy. Once the course is completed, if penicillin is required in the future, the desensitization procedure should be repeated.

TABLE 1. Oral desensitization protocol for persons with a positive skin test*

Penicillin V suspension dose Amount§ (units/mL) mL Units Cumulative dose (units)
 1 1,000 0.1 100 100
 2 1,000 0.2 200 300
 3 1,000 0.4 400 700
 4 1,000 0.8 800 1,500
 5 1,000 1.6 1,600 3,100
 6 1,000 3.2 3,200 6,300
 7 1,000 6.4 6,400 12,700
 8 10,000 1.2 12,000 24,700
 9 10,000 2.4 24,000 48,700
10 10,000 4.8 48,000 96,700
11 80,000 1.0 80,000 176,700
12 80,000 2.0 160,000 336,700
13 80,000 4.0 320,000 656,700
14 80,000 8.0 640,000 1,296,700

Source:  Wendel GO, Jr, Stark BJ, Jamison RB, Melina RD, Sullivan TJ. Penicillin allergy and desensitization in serious infections during pregnancy. N Engl J Med 1985;312:1229–32.

*Note: Observation period was 30 minutes before parenteral administration of penicillin.

Interval between doses, 15–30 minutes; elapsed time, 4–8 hours; cumulative dose, 1.3 million units.

§ The specific amount of drug was diluted in approximately 30 mL of water and then administered orally.