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Sexually Transmitted Diseases
Sexually Transmitted Diseases  >  Treatment Guidelines  >  Sexually Transmitted Diseases Treatment Guidelines 2006
Sexually Transmitted Diseases Treatment Guidelines 2006

Management of Patients 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 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 such as urticaria, angioedema, or anaphylaxis (i.e., upper airway obstruction, bronchospasm, or hypotension). Re-administration 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.

An estimated 10% of persons who report a history of severe allergic reactions to penicillin remain allergic. With the passage of time, the majority of persons who have had a severe reaction to penicillin stop expressing penicillin-specific IgE. These persons can be treated safely with penicillin. The results of many investigations indicate that skin testing with the major and minor determinants of penicillin can reliably identify persons at high risk for penicillin reactions. Although these reagents are easily generated and have been available for >30 years, only benzylpenicilloyl poly-L-lysine (Pre-Pen® [i.e., the major determinant]) and penicillin G have been available commercially. Testing with only the major determinant and penicillin G identifies 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 minordeterminant–positive patients, specialists suggest exercising caution when the full battery of skin-test reagents is not available (Box 1). An additional challenge has occurred with the recent unavailability of Pre-Pen®; however, plans for future availability of this product have been made, as well as a companion minor determinant mixture.

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If the full battery of skin-test reagents is available, including the 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.

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. Some specialists suggest that persons who have negative test results should be regarded as probably allergic and should be desensitized. Others suggest that those with negative skin-test results can be test-dosed 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 (anaphylaxis, angioedema, bronchospasm, or urticaria) to penicillin should be desensitized in a hospital setting. In patients with reactions not likely to be IgE mediated, outpatient oral desensitization or monitored test doses may be considered.

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Penicillin Allergy Skin Testing

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 terfenadine during the preceding 24 hours, diphenhydramine HCl or hydroxyzine during the preceding 4 days, or astemizole during the preceding 3 weeks).


Dilute the antigens either 1) 100-fold for preliminary testing if the patient has had a life-threatening reaction to penicillin or 2) 10-fold if the patient has had another type of immediate, generalized reaction to penicillin within the preceding year.

BOX 1. Skin-test for identifying persons at risk for adverse reactions to penicillin*

Major Determinant
  • Benzylpenicilloyl poly-L-lysine (Pre-Pen® [Taylor Pharmacal Company, Decatur, Illinois]) (6 x 10-5M).
Minor Determinant Precusors
  • Benzylpenicillin G (10-2M, 3.3 mg/mL, 6,000 units/ mL),
  • Benzylpenicilloate (10-2M, 3.3 mg/mL), and
  • Benzylpenicilloate (or penicilloyl propylamine) (10-2M, 3.3 mg/mL).
Positive Control
  • Commercial histamine for epicutaneous skin testing (1 mg/mL).
Negative Control
  • Diluent used to dissolve other reagents, usually phenol saline.

* 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.

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 intra-dermal 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 diameters of the wheals induced by the injections should be recorded.

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 hours, after which the first dose of penicillin is administered. After desensitization, patients must be maintained on penicillin continuously for the duration of the course of therapy.

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

Penicillin V
suspension dose
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  

Observation period: 30 minutes before parenteral administration of penicillin.

* Reprinted with permission from the New England Journal of Medicine. 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.
Interval between doses: 15 minutes; elapsed time: 3 hours and 45 minutes; and cumulative dose: 1.3 million units.
§ The specific amount of drug was diluted in approximately 30 mL of water and then administered orally.

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