Evaluation of antibiotic allergy: the role of skin tests and drug challenges.

Antibiotic allergies are frequently reported in both adult and pediatric populations. While a detailed drug history is essential in the evaluation of antibiotic allergy, the history is typically insufficient to determine the presence of a drug allergy. The most readily available diagnostic testing for evaluating antibiotic allergies are drug skin testing and drug challenges. This review will focus on updates in the evaluation of antibiotic allergy utilizing immediate skin tests, delayed intradermal testing, drug patch tests, and drug challenges for both adults and children with histories of antibiotic allergies.

Drug Allergy Practice Parameter Updates to Incorporate Into Your Clinical Practice.

The drug allergy practice parameter was developed to provide guidance on the diagnosis and management of drug hypersensitivity reactions. It was last updated in 2010. With the growth of research and evidence-based data since then, experts came together to update the practice parameter with a focus on sections that the work group deemed to have significant changes (or were not addressed) in the previous practice parameter. This review is a focused update on aspects of the practice parameter deemed to have the greatest impact on clinical practice and includes significant updates on diagnosis of antibiotic allergy including penicillin, cephalosporin, sulfonamide, fluoroquinolone, and macrolide allergies. Other topics include the evolution in our management approach to patients with aspirin/nonsteroidal anti-inflammatory drug allergy, diagnostic testing for delayed drug hypersensitivity and allergy to chemotherapeutics and biologics, and the key consensus-based statements for clinical practice. Specifically, the updated practice parameter helps allergists understand the place of 1- or 2-step drug challenges that are valuable tools often without the need for skin testing in many clinical situations. A proactive approach to delabeling penicillin allergy as well as unnecessary avoidance of safe antibiotic alternatives for patients with proven penicillin allergy is emphasized. New guidance is provided on management of patients with different phenotypes of aspirin and nonsteroidal anti-inflammatory drug hypersensitivity reactions. Approaches to delayed drug hypersensitivity and use of delayed intradermal and patch testing for specific phenotypes are reviewed. Lastly, practical approaches to management of patients with reactions to chemotherapeutics and biologics are discussed.

Drug allergy.

Drug allergy is one type of adverse reaction to drugs and encompasses a spectrum of hypersensitivity reactions with heterogeneous mechanisms and clinical presentations. A thorough history is essential to the management of drug allergy. Laboratory testing has a very limited role in the management of drug allergy. Graded dose challenges and procedures to induce drug tolerance might be required in patients with drug allergy when there is a definite need for a particular agent. Management of reactions to specific agents, including beta-lactam antibiotics, sulfonamides, local anesthetics, radiocontrast media, angiotensin-converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, and biologic modifiers, will be discussed in further detail.

Penicillin Allergy Evaluation: A Prospective, Multicenter, Open-Label Evaluation of a Comprehensive Penicillin Skin Test Kit.

BACKGROUND: Ten percent of the population claims an allergy to penicillin, but 90% of these individuals are not allergic. Patients labeled as penicillin-allergic have higher medical costs, longer hospital stays, are more likely to be treated with broad-spectrum antibiotics, and develop drug-resistant bacterial infections. Most penicillin skin test reagents are not approved by the Food and drug Administration or readily available to evaluate patients labeled penicillin-allergic. OBJECTIVE: To determine the negative predictive value (NPV) of the Penicillin Skin Test Kit containing the major allergenic determinant (penicilloyl polylysine), a minor determinant mixture (penicillin G, penicilloate, penilloate), and amoxicillin, produced according to Food and Drug Administration standards. METHODS: This was a prospective, multicenter, open-label investigation of penicillin skin testing using the Penicillin Skin Test Kit. Skin test-negative subjects were challenged with 250 mg amoxicillin, whereas skin test-positive patients were not challenged. The primary end point was NPV of the Penicillin Skin Test Kit, defined as the percentage of subjects with negative skin test results who did not experience an IgE-dependent reaction within 72 hours of amoxicillin challenge. RESULTS: In total, 455 patients with a history of penicillin allergy underwent skin testing and 63 (13.8%) had 1 or more positive test results; 65% of the positive test results were to the minor determinant mixture and/or amoxicillin alone. In the per protocol group of 373 skin test-negative subjects, 8 developed potential IgE-dependent reactions following oral amoxicillin challenge, translating to an NPV of 97.9% (95% CI, 95.8-99.1; P < .0001). All but 1 of the reactions was mild or moderate, and most subjects who required treatment received only antihistamines. CONCLUSIONS: The Penicillin Skin Test Kit, containing all relevant penicillin allergenic determinants, demonstrated very high NPV. Removal of a penicillin allergy label in a large majority of currently mislabeled patients has substantial personal and public health implications.

Penicillin and Beta-Lactam Hypersensitivity.

Ten percent of patients report penicillin allergy, but more than 90% of these individuals can tolerate penicillins. Skin testing remains the optimal method for evaluation of possible IgE-mediated penicillin allergy and is recommended by professional societies, as the harms for alternative antibiotics include antimicrobial resistance, prolonged hospitalizations, readmissions, and increased costs. Removal of penicillin allergy leads to decreased utilization of broad-spectrum antibiotics, such as fluoroquinolones and vancomycin. There is minimal allergic cross-reactivity between penicillins and cephalosporins. IgE-mediated allergy to cephalosporins is usually side-chain specific and may warrant graded challenge with cephalosporins containing dissimilar R1 or R2 group side chains.

Drug hypersensitivity.

Allergic drug reactions compose a small percentage of ADRs, yet they are commonly encountered in clinical practice, and physicians are taught routinely to question patients about these reactions during history taking. Among antibiotics, the immunochemistry of penicillins has been elucidated,leading to the development of validated skin test reagents to diagnose type 1 allergy. Currently, the temporary commercial unavailability of Pre-Pen makes accurate penicillin skin testing impossible; however, this important skin test reagent is expected to become available sometime in 2006. Type 1 allergies to most other drugs lack comparable diagnostic tests, and their diagnosis is therefore driven by the patient's history. When readministration of medications to which patients report previous reactions is indicated, it may be almost always successfully accomplished by means of either graded challenge or desensitization.

Lack of penicillin resensitization in patients with a history of penicillin allergy after receiving repeated penicillin courses.

BACKGROUND: Up to 10% of the population reports an allergy to penicillin, yet more than 80% of these individuals lack penicillin-specific IgE antibodies. A negative result on a penicillin skin test is highly accurate in identifying who can safely receive the antibiotic at the time of testing. However, its negative predictive value for future courses is unknown because it is uncertain whether patients with a history of penicillin allergy are at risk of becoming resensitized. OBJECTIVE: To determine the rate of penicillin resensitization in adult patients with a history of penicillin allergy after they are challenged with repeated courses of oral penicillin. METHODS: Adult patients with a history of penicillin allergy consistent with an IgE-mediated mechanism were recruited and underwent penicillin skin testing. Those with negative skin test results were challenged with 3 successive 10-day courses of penicillin V potassium (250 mg by mouth 3 times a day), providing their penicillin skin test results remained negative prior to each course. Patients with positive skin test results were not challenged. RESULTS: Of 53 patients with initially negative skin test results, 46 completed the protocol, and each tolerated all 3 courses of penicillin with negative skin test results throughout. No patients had a converted skin test result from negative to a positive, yielding a resensitization rate of 0% (upper 95% confidence interval, 2.1%). CONCLUSIONS: Adult patients with a history of penicillin allergy are not at increased risk of resensitization after receiving 3 courses of oral penicillin. Because a negative penicillin skin test result is predictive for subsequent oral administrations beyond the time of testing, adult patients with a history of penicillin allergy can be skin tested electively, which may avoid unnecessary treatment with alternate broad-spectrum antibiotics.

Drug desensitization.

Although most patients who report a history of drug allergy are not truly allergic, this article focuses on those individuals with confirmed drug hypersensitivity. Desensitization is an immunologic method that allows allergic patients to receive the sensitizing drug safely. Classically, the procedure is applied in IgE-mediated reactions, but its use has been extended to other drug reactions. The most common clinical scenarios wherein desensitization may be needed are reviewed. The discussion includes rapid desensitization of patients with IgE-mediated allergies to penicillin and other classes of antibiotics, and sulfonamide desensitization of HIV-positive patients.

Hypersensitivity reactions to beta-lactam antibiotics.

Clinicians commonly encounter patients with a history of allergy to penicillin and other beta-lactam antibiotics, since about 10% of the population reports such an allergy. At the same time, it is known that about 90% of these patients are not truly allergic and could safely receive beta-lactam antibiotics. Instead, these patients are treated unnecessarily with alternate broad-spectrum antibiotics, which increases costs and contributes to the development and spread of multiple drug-resistant bacteria. In the case of penicillin, relevant allergenic determinants that elicit immune responses are known. Hence, validated diagnostic skin testing to detect the presence of drug-specific IgE antibodies is available. For non-penicillin beta-lactams, the immunogenic determinants that are produced by degradation are unknown, and diagnostic skin testing is of more limited value. Ideally, patients with a history of penicillin allergy should be evaluated when they are well and not in immediate need of antibiotic therapy. Patients who are found to be penicillin skin test-negative may be safely treated with all beta-lactam antibiotics. Penicillin skin test-positive patients should only receive a penicillin-class antibiotic via rapid desensitization, and only in cases when an alternative agent cannot be substituted. Penicillin skin test-positive patients may be safely treated with monobactams. The extent of allergic cross-reactivity between penicillin arid cephalosporins/carbapenems is uncertain; therefore penicillin skin test-positive patients should only receive these antibiotics via cautious graded challenge or desensitization. Identification of patients who erroneously carry a label of beta-lactam allergy leads to improved utilization of antibiotics and slows the spread of multiple drug-resistant bacteria.