Published March 28, 2005Mercedes
E.
|
The penicillin antibiotics are popular and useful antimicrobial drugs because they are very effective and have low toxicity.1 However, they are also one of the most common causes of drug-induced anaphylactic reactions.2 Fatal penicillin-induced anaphylaxis has been reported at a rate of 0.002% among the general population, with 500 to 1,000 deaths per year.3 This chapter will summarize the current understanding of the mechanisms of drug reactions with emphasis on IgE-mediated reactions to penicillins, the risk factor for reactions to penicillins, and the evaluation and management of these patients, including a description of skin testing. |
|
Adverse
|
|
| An
adverse drug reaction is an unintended or undesired effect of a drug therapy.4 Adverse drug reactions can be divided into predictable and unpredictable
categories. Predictable reactions are dose-dependent and related to the
pharmacology of the drug. Common predictable adverse reactions include overdose,
side effect, secondary or indirect effect, secondary effect related to the
underlying disease, and drug-to-drug interaction.4,5 Unpredictable drug reactions are restricted to a small subset of treated
patients and are not related to the pharmacology of the drug. These reactions
include drug intolerance, idiosyncratic reactions, pseudoallergic reactions,
and immunologic reactions. Immunologic reactions can be IgE-mediated or
non-IgE-mediated.4,5
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. |
||||
| Although
the exact prevalence of allergic reactions to penicillin is unknown, allergic
reactions are estimated to occur in approximately 2% of patients treated
with penicillin courses.4 However, a history
of penicillin allergy has been reported in up to 20% of patients admitted
to the hospital.4 Most of these reactions
are skin rashes, such as maculopapular or urticarial. Severe reactions to
penicillin such as anaphylaxis are less common.4 However, penicillin-induced anaphylaxis is potentially life-threatening.
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 risk of penicillin sensitization is increased with multiple short courses of antibiotics and occur with any route of administration.7 Anaphylactic reactions to penicillin occur most commonly in persons between 20 and 49 years old. However, they have been reported in children and in the elderly. Race, sex, personal or family history of atopic disease, and allergy to other drugs do not appear to be predisposing factors. Allergy to the mold Penicillium is not a risk factor for an allergic reaction to penicillin.7 | ||||
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 |
||||
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 |
||||
| If done properly, the skin test is safe, with a rate of systemic reaction of less than 1%.17 Nevertheless, severe reactions such as anaphylaxis and death have occurred. Serious reactions to the penicillin skin test are usually a result of violations of the skin test protocol, such as administering too high a dosage or performing intracutaneous testing without prick/puncture testing beforehand.10 | ||||
| The
exact cross-reactivity between penicillin and others b-lactam antibiotics
is unknown. Clinical cross-reactivity between penicillin and cephalosporin
appears to be low, especially for second- and third-generation cephalosporins.10 However, severe IgE-mediated reactions, including death, have occurred when
a cephalosporin was given to a penicillin-allergic patient. A penicillin
skin test can help to determine those patients who are at increase risk
of severe IgE-mediated reactions when receiving a cephalosporin. A review
of 11 studies concluded that the risk for reaction when receiving cephalosporin
in a patient with a positive skin test to penicillin was approximately 4.4%.18 Reactions to cephalosporin could still occur even with a negative skin test.
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. |
||||
|
