According to the elapsed time between drug administration and development of the adverse reactions can be classified as immediate, accelerated, or late reactions. Immediate reactions usually occur within 1 hour of administration of the drug. These reactions include but are not limited to anaphylaxis, urticaria, asthma, and angioedema. Accelerated reactions occur between 1 and 72 hours after drug administration and consist mostly of urticaria and maculopapular rashes. Late reactions occur after 72 hours of drug administration. Common late reactions are skin rashes, erythema multiforme, serum sickness, hemolytic anemia, Stevens-Johnson syndrome, and toxic epidermal necrolysis.

According to the type of immunologic mechanism involved, allergic reactions can be classified as IgE-mediated (type 1) and non-IgE-mediated. Non-IgE-mediated reactions include antibody-mediated (type 2); immune complex-mediated (type 3); and T-lymphocyte-mediated (type 4).⁶ Adverse reactions mediated by IgE antibodies will be the focus of our discussion; non-IgE-mediated reactions will not be further addressed in this chapter.

Penicillin is a chemical hapten with a low molecular weight of 300 d that needs to bind to a tissue macromolecule, usually a protein, to become immunogenic.⁷ The breakdown products of penicillin include the penicilloyl group, known as the major determinant because it is the major penicillin metabolic product (approximately 85% to 90% of the penicillin breakdown products).⁷ The minor haptenic determinants or minor determinant mixture, so called because they are formed in smaller quantities,⁷ are composed of the parent penicillin molecules, penicilloate, penicilloylamine, penilloate, and other simple chemical products of penicillin.⁷ Immediate reactions following penicillin administration are mediated through IgE antibodies against either the major or minor determinants, or both.

The presence of IgE antibodies to penicillin can be detected through a skin test to penicillin or a radioallergosorbent test (RAST) to penicillin.

The skin test for penicillin demonstrates the presence or absence of specific IgE antibodies to major and minor penicillin determinants. IgE antibodies to major determinants can be detected by using benzylpenicilloyl polylysine (Pre-Pen). Minor determinant reagents are not commercially available, although penicillin G at concentration of 10,000 U/mL has been used as a partial source of minor determinant.⁷ Methods of preparation of the minor determinants have been published elsewhere.^8,9 Histamine and saline skin tests are used as a positive and negative control, respectively.

Prick testing is done first, and the results are read 15 to 20 minutes later. If the prick test findings are negative, intradermal testing is performed.

The skin test is positive if the major or minor determinant tests have a wheal that is larger than 3 mm that the wheal produced by the negative saline control. Both prick and intradermal tests are done using diluted penicillin G at a concentration of 10,000 u/ml, Pre-pen at full strenght and minor determinant mixture if available. If skin test for penicillin using major determinants (benzylpenicilloyl), a mixture of minor determinants and pencillin G is negative, up to 99% of patients will tolerate penicillin. If skin testing using benzylpenicilloyl and penicillin G (as the sole source of minor determinants) is negative, approximately 97% of patients with a negative skin test will tolerate penicillin.¹⁰ However, a few patients who are at risk for anaphylactic reaction will be missed with this testing method because penicillin G does not contain all the minor determinants.¹⁰

Up to 4% of patients with a negative skin test to both the major and minor determinants will develop non-life-threatening allergic reactions if they receive penicillin again.¹¹ Anaphylaxis to penicillin in patients with a history of penicillin allergy and a negative penicillin skin test has not been reported.⁴ On the other hand, if a patient has a positive history and a positive skin test to penicillin, there is a 50% or greater chance of an immediate IgE-mediated reaction if penicillin is received again. These patients should receive an equally efficacious alternative antibiotic or be desensitized.¹⁰

A penicillin skin test predicts only the presence of IgE antibodies for the major or minor penicillin determinants at the time of application and does not predict the future development of IgE-mediated reactions during subsequent courses of penicillin. A penicillin skin test does not predict non-IgE-mediated reactions caused by other immune mechanisms, such as cytotoxic antibody-mediated reactions, antibody-antigen immune complex-mediated reactions, and delayed-type cell-mediated reactions.¹²

The detection of IgE antibodies to penicillin by a skin test is affected by the amount of time between the original allergic drug reaction and the skin test. Many patients with documented IgE antibodies to penicillin by skin test lose the sensitivity with time. It is estimated that up to 80% of patients with a history of immediate reactions to penicillin will have a negative skin test at 10 years.¹² However, these patients may be at increased risk of sensitization to penicillin on subsequent administration compared with the rest of the population.¹³

The RAST and the enzyme-linked immunosorbent assay (ELISA) are also used to detect IgE antibodies, but only to the major penicillin determinant. Therefore, these tests are less sensitive than the skin test.¹⁰ On the other hand, a positive RAST result indicates the presence of IgE antibodies to penicillin, and patients with a positive test should be considered at increased risk for reaction.¹¹

EVALUATION AND MANAGEMENT OF PATIENTS
WITH A HISTORY OF PENICILLIN ALLERGY

Although most patients with a history of penicillin allergy do not have penicillin-specific IgE antibodies as detected by skin test and can safely take penicillin, patients with a history of penicillin allergy are more likely to experience a reaction on subsequent courses than those without a history.¹⁰ It is recommended that any patient with either a vague or convincing history of penicillin allergy who requires penicillin needs a skin test to determine the presence of penicillin-specific IgE antibodies before it is assumed that the patient will tolerate penicillin.¹⁰ Up to 33% of patients with a vague history of penicillin allergy will have a positive penicillin skin test.¹⁴ Some authors suggest that the penicillin skin test needs to be repeated before each course of penicillin, especially for patients with history of IgE-mediated reaction who received intravenous penicillin, because of the risk of resensitization.⁴ However, Solensky et al have reported that none of 46 patients with history of penicillin allergy and a negative penicillin skin test resensitized after receiving three courses of oral penicillin V.¹⁵

Because of the lack of commercially available penicillin minor determinants for skin testing, some authorities recommend a test-dose challenge in patients with a history of penicillin allergy and negative skin tests to major determinants and penicillin G.⁶ A test-dose challenge might be done using 1/100 of the therapeutic dose (1/1,000 of the therapeutic dose if the previous reaction was severe), followed by 1/10 of the dose, and then the full therapeutic dose if there is no reaction.⁶ If a reaction occurs during the test-dose challenge and the drug is essential for treatment of the patient, penicillin desensitization is recommended.⁶ Adverse reactions reported with reintroduction of penicillin in patients with positive history and a negative skin test have all been mild and self-limited; no life-threatening false-negative reactions have been documented.¹⁶

If the penicillin skin test is positive and the treatment with a penicillin antibiotic is essential, desensitization is needed. Oral and intravenous protocols for penicillin desensitization have been published.^2,5,6,16 Oral desensitization is apparently safer than parenteral desensitization.¹⁶ The basic principle for oral or parenteral (intravenous) desensitization is similar. The initial dose is very small, usually 1/10,000 of the recommended dose. The dose is usually doubled every 15 minutes until the full therapeutic dose is achieved. Adverse reactions are expected to occur during and after the desensitization procedure.¹⁶ Most of these reactions are mild, such as pruritus, rhinitis, wheezing, and urticaria.¹⁶ These reactions require symptomatic treatment, and the dose of penicillin should be repeated until tolerated. Severe reactions, such as laryngeal edema, require rapid treatment until the patient is stable and a reduction of the next penicillin dose by one third or more of the previous provoking dose.⁶ When desensitization is achieved, continuous treatment with penicillin is required to avoid the return of the IgE-sensitive state. A time lapse greater than 12 hours may allow such sensitivity to return.⁶

Patients who react to β-lactam antibiotics other than penicillin may have antibodies directed to side-chain structures rather than to the β-lactam ring. Such antibodies have the potential to cause anaphylaxis.¹⁰ Carbapenems (eg, imipenem) should be considered cross-reactive to penicillin.^10,12 On the other hand, aztreonam (a monobactam) rarely cross-reacts with penicillin, possibly because of the lack of a second nuclear ring structure.^10,12

Penicillin skin testing may also serve as a method for decreasing the amount used of broad-spectrum antibiotics such as vancomycin and fluoroquinolones.^19,20 These antibiotics, when used extensively, are associated with the emergence of multidrug-resistant pathogens and increased morbidity and mortality.

Regardless of the importance of penicillin skin testing, manufacturing problems in the commercial production of the testing preparation may restrict its availability. Without this preparation, skin testing will become difficult, and a good and reliable diagnostic test will be lost.

In conclusion, the presence of IgE antibodies to penicillin can be determined by the use of the penicillin skin test. With this test, we can identify those patients who have a low risk for immediate hypersensitivity reactions to penicillin or penicillin derivatives and can receive these compounds, and those patients who should avoid using them.

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2. Solensky R, Mendelson LM. Systemic reactions to antibiotics. Immunol Allergy Clin North Am. 2001;21:679-697.
   
   
3. Neugut AI, Ghatak AT, Miller RL. Anaphylaxis in the United States: an investigation into its epidemiology. Arch Intern Med. 2001;161:15-21.
   
   
4. Mendelson LM. Adverse reactions to b-lactam antibiotics. Immunol Allergy Clin North Am. 1998;18:745-757.
   
   
5. Patterson R, DeSwarte RD, Greenberger PA, Grammer LC, Brown JE, Choy AC. Drug allergy and protocols for management of drug allergies. Allergy Proc. 1994;15:239-264; erratum 1995;16:53.
   
   
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7. Erffmeyer JE, Blaiss MS. Proving penicillin allergy. Postgrad Med. 1990;87:33-35,39,41.
   
   
8. Ressler C, Neag PM, Mendelson LM. A liquid chromatographic study of stability of the minor determinants of penicillin allergy: a stable minor determinant mixture skin test preparation. J Pharm Sci. 1985;74:448-454.
   
   
9. Levine BB, Redmond AP. Minor haptenic determinant-specific reagins of penicillin hypersensitivity in man. Int Arch Allergy Appl Immunol. 1969;35:445-455.
   
   
10. The diagnosis and management of anaphylaxis. Joint Task Force on Practice Parameters, American Academy of Allergy, Asthma and Immunology, American College of Allergy, Asthma and Immunology, and the Joint Council of Allergy, Asthma and Immunology. J Allergy Clin Immunol. 1998;101 (pt 2):S465-S528.
    
    
11. Miles AM, Bain B. Penicillin anaphylaxis: a review of sensitization, treatment, and prevention. J Assoc Acad Minor Phys. 1992;3:50-56.
    
    
12. Executive summary of disease management of drug hypersensitivity: a practice parameter. Joint Task Force on Practice Parameters, American Academy of Allergy, Asthma and Immunology, the American College of Allergy, Asthma and Immunology, and the Joint Council of Allergy, Asthma and Immunology. Ann Allergy Asthma Immunol. 1999;83:665-700.
    
    
13. Sogn DD, Evans R III, Shepherd GM, et al. Results of the National Institute of Allergy and Infectious Diseases Collaborative Clinical Trial to test the predictive value of skin testing with major and minor penicillin derivatives in hospitalized adults. Arch Intern Med. 1992;152:1025-1032.
    
    
14. Solensky R, Earl HS, Gruchalla RS. Penicillin allergy: prevalence of vague history in skin test-positive patients. Ann Allergy Asthma Immunol. 2000;85:195-199.
    
    
15. Solensky R, Earl HS, Gruchalla RS. Lack of penicillin resensitization in patients with a history of penicillin allergy after receiving repeated penicillin courses. Arch Intern Med. 2002;162:822-826.
    
    
16. Adkinson NF Jr. Drug allergy. In: Middleton E Jr, Reed CE, Ellis EF, et al, eds. Allergy Principles and Practice. St. Louis, MO: Mosby-Year Book, 1998:1212-1224.
    
    
17. Valyasevi MA, Van Dellen RG. Frequency of systemic reactions to penicillin skin tests. Ann Allergy Asthma Immunol. 2000;85:363-365.
    
    
18. Kelkar PS, Li JT. Cephalosporin allergy. N Engl J Med. 2001;345:804-809.
    
    
19. Arroliga ME, Wagner W, Bobek MB, Hoffman-Hogg L, Gordon SM, Arroliga AC. A pilot study of penicillin skin testing in patients with history of penicillin allergy admitted to a medical ICU. Chest. 2000;118:1106-1108.
    
    
20. Li JT, Markus PJ, Osmon DR, Estes L, Gosselin VA, Hanssen AD. Reduction of vancomycin use in orthopedic patients with a history of antibiotic allergy. Mayo Clin Proc. 2000;75:902-906.

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