Maintenance of Certification clinical management series Series editor: James T. Li, MD, PhD
Allergy to b-lactam antibiotics Roland Solensky, MD Corvallis, Ore
INSTRUCTIONS Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the instructions listed below: 1. Review the target audience, learning objectives and author disclosures. 2. Complete the pre-test online at www.jacionline.org (click on the Online CME heading). 3. Follow the online instructions to read the full version of the article, including the clinical vignette and review components. 4. Complete the post-test. At this time, you will have earned 1.00 AMA PRA Category 1 CME CreditTM. 5. Approximately 4 weeks later you will receive an online assessment regarding your application of this article to your practice. Once you have completed this assessment, you will be eligible to receive 2 MOC Part II Self-Assessment credits from the American Board of Allergy and Immunology. Date of Original Release: December 2012. Credit may be obtained for these courses until November 30, 2014. Copyright Statement: Copyright Ó 2012-2014. All rights reserved. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is
CLINICAL VIGNETTE In May 2009, a 66-year-old woman with a past medical history of hyperlipidemia and breast cancer is referred for seasonal allergic rhinitis and oral allergy syndrome. She also reports previous allergic reactions to penicillin and trimethoprimsulfamethoxazole. At age 22 years, she received intramuscular penicillin for streptococcal pharyngitis and had immediate symptoms of generalized pruritic urticaria, dyspnea, wheezing, and dizziness. She was treated with injectable epinephrine and rapidly recovered. The trimethoprim-sulfamethoxazole reaction at age 45 years consisted of a maculopapular rash about a week into a treatment course for sinusitis. Penicillin skin testing could not be performed at her initial evaluation because the major penicillin determinant (Pre-Pen; ALK-Abell o, Hørsholm, Denmark) was commercially unavailable, and therefore she was instructed to return in 6 months when Pre-Pen availability was anticipated. During the following 6 months, she received levofloxacin for sinusitis and had bloody diarrhea, and although Clostridium From the Corvallis Clinic. Received for publication June 22, 2012; revised August 13, 2012; accepted for publication August 21, 2012. Corresponding author: Roland Solensky, MD, the Corvallis Clinic, 3680 NW Samaritan Dr, Corvallis, OR 97330. E-mail: [email protected]
0091-6749/$36.00 Ó 2012 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaci.2012.08.021
accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Creditä. Physicians should claim only the credit commensurate with the extent of their participation in the activity. List of Design Committee Members: Roland Solensky, MD (author), and James T. Li, MD, PhD (series editor) Activity Objectives 1. To understand the epidemiology and natural history of penicillin allergy. 2. To recognize the utility of penicillin skin testing. 3. To understand various aspects of penicillin skin testing. 4. To understand the allergic cross-reactivity between penicillins and other b-lactams. Recognition of Commercial Support: This CME activity has not received external commercial support. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: R. Solensky has received grants from Merck and has received payment for lectures from GlaxoSmithKline. J. T. Li has consulted for Abbott.
difficile could not be confirmed, she was treated empirically with metronidazole and gradually recovered. Later, she had foot cellulitis, was treated with oral azithromycin, did not improve, and presented to an emergency department. The treating physician was reluctant to prescribe cephalosporins given her history of penicillin-induced anaphylaxis but, given the limited options, decided to administer the first dose of cephalexin in the emergency department, which she tolerated. She completed the rest of the cephalexin course uneventfully, and the culture grew methicillin-sensitive Staphylococcus aureus. In January 2010, results of penicillin skin testing were negative, and the patient tolerated a single 250-mg dose of penicillin V potassium administered in the office. The primary care physician was instructed to remove the penicillin allergy label from the patient’s record and was advised that she was free to receive all b-lactam antibiotics without increased risk of having allergic reactions. In the 2½ years since evaluation, she tolerated 1 course of amoxicillin and 1 course of amoxicillin/clavulanate. The full version of this article, including a review of relevant issues to be considered, can be found online at www.jacionline. org. If you wish to receive CME or MOC credit for the article, please see the instructions above.
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REVIEW Penicillin allergy: Background Penicillin allergy is the most commonly reported medication allergy, with a prevalence rate of 5% to 10%. In older large-scale studies 80% to 90% of patients with a history of penicillin allergy are found not to be allergic, but recent data suggest this has increased to 95%.E1,E2 Potential reasons why most patients with a label of ‘‘penicillin allergy’’ are able to tolerate penicillins include the following: (1) the reaction was mislabeled as allergic, (2) the symptoms were attributable to the underlying illness or an interaction between the illness and the antibiotic, and (3) levels of penicillin-specific IgE wane over time and penicillin allergy is commonly (but not always) outgrown. The medical costs of patients labeled as having penicillin allergy are higher compared with those of patients without a history of penicillin allergy.E3 One reason for this discrepancy is that patients with a history of penicillin allergy are more likely to be treated with more expensive broad-spectrum antibiotics, such as quinolones and vancomycin. In addition to financial costs, clinical care can be compromised because quinolones and vancomycin are risk factors for the development of multiple drug-resistant bacteria, such as vancomycin-resistant Enterococcus species,E4 and quinolones are strongly associated with development of aggressive forms of Clostridium difficile–induced colitis.E5 In several medical centers penicillin skin testing of inpatients with a history of penicillin allergy resulted in large decreases in the use of vancomycin and quinolones (Table E1).E6-E11 This is to be expected because the vast majority of patients with a history of penicillin allergy have negative penicillin skin test results and are able to have antibiotic coverage changed to b-lactams. Penicillin skin testing The immunochemistry of penicillin was characterized in the 1960s, and subsequently, penicillin skin test reagents were developed (Table E2). The major penicillin determinant is commercially available for skin testing as penicilloyl-polylysine (PPL; ie, Pre-Pen), which is penicilloyl conjugated to a polylysine carrier molecule to produce a multivalent antigen. The minor determinants penicilloate and penilloate are not commercially available but are synthesized by various medical centers around the United States for local use. Penicillin G is used for skin testing at a concentration of 10,000 U/mL. Amoxicillin and ampicillin have been used for skin testing at concentrations ranging from 3 to 25 mg/mL, with no consensus regarding the appropriate concentration. The diagnostic utility of skin testing with amoxicillin or ampicillin has not been established. Penicillin skin testing has an excellent record of safety. On the basis of studies conducted in the United States, the negative predictive value (NPV) of penicillin skin testing is greater than 95%, and when challenge reactions occur, they are generally mild.E12,E13 In Europe some investigators reported the NPV to be as low as 70%, and reactions in patients with negative skin test responses were sometimes severe.E14 The reason for these differences is unknown. The importance of minor determinants in penicillin skin testing remains unclear. In large-scale studies about 10% of patients with positive skin test responses have positive results to penicilloate, penilloate, or both (and negative results to PPL and penicillin G).E1,E15 Because of ethical concerns, these patients are not challenged with penicillins, and therefore the positive predictive value
of penicilloate/penilloate skin testing is unknown. When patients with a history of penicillin allergy underwent skin testing with only PPL and penicillin G (without other minor determinants), the NPV in several studies was greater than 95%,E10,E16 which is comparable with that seen when all reagents are used. However, the patient populations might have differed, and it might not be appropriate to compare the results with those of studies that used all penicillin skin test reagents. It is possible that some patients with severe penicillin reaction histories were not challenged in studies using only PPL and penicillin G. Another difference between the United States and Europe is the frequency of selective IgE-mediated allergy to semisynthetic penicillins, such as amoxicillin. These patients react (or elicit positive results on skin testing) to amoxicillin but are able to tolerate penicillin V potassium (and have negative skin test results to PPL, penicillin G, penicilloate, and penilloate). The immune reaction is likely directed at the R-group side chain rather than the core b-lactam portion of the molecule. Selective amoxicillin reactors are rarely found in the United States (3% to 6% of positive penicillin skin test results),E15 whereas in Europe they represent a percentage of positive penicillin skin test results that is an order of magnitude larger.E14 The reason for these differences is unknown.
Evaluation of patients with a history of penicillin allergy The evaluation of patients with a history of penicillin allergy with penicillin skin testing is ideally performed electively before the need for antibiotic therapy. Patients with histories of severe non–IgE-mediated reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, interstitial nephritis, and hemolytic anemia, are not candidates for skin testing or challenge and should avoid penicillins indefinitely. Patients with reaction histories compatible with a potential IgE-mediated mechanism (eg, pruritic rashes, urticaria, angioedema, and anaphylaxis) might undergo penicillin skin testing with PPL, penicillin G, amoxicillin, or ampicillin and, if available, penicilloate or penilloate. Reaction history is known to be a poor predictor of skin test results, and therefore penicillin allergy cannot be diagnosed accurately solely based on the history. Prick puncture skin testing should be performed first, and if results are negative, they should be followed by intradermal skin testing. Negative penicillin skin test results are ideally followed by oral challenge to unequivocally prove lack of allergy; otherwise, there is a reluctance by future treating physicians to prescribe b-lactams. The challenge can be administered stepwise (graded challenge) or as a single dose, depending on the reaction history and the skin test reagents used. Penicillin resensitization is a theoretic concern in patients with a history of penicillin allergy who have negative skin test results and tolerate a course of penicillin. However, on the basis of numerous studies, the resensitization rate in both pediatric and adult patients treated with oral penicillins is consistently low and comparable with the rate of sensitization.E17,E18 Therefore penicillin skin testing does not need to be routinely repeated in patients with a history of penicillin allergy who have tolerated 1 or more courses of penicillins.E19 There are fewer data on resensitization after parenteral penicillin, and therefore repeat penicillin skin testing might be considered in patients with a history of penicillin allergy who have tolerated a course of parenteral penicillin.E19
Penicillin/cephalosporin allergic cross-reactivity Penicillins and cephalosporins share a common b-lactam ring, and hence there is the potential for IgE-mediated allergic crossreactivity. Retrospective studies of cephalosporin treatment of patients with a history of penicillin allergy (without prior confirmation of penicillin allergy) are problematic because most patients were likely not allergic to penicillin at the time of treatment, and there was probable selection bias in excluding patients with a history of severe penicillin reactions.E20 Studies in which patients with positive penicillin skin test results were challenged with cephalosporins, as summarized in a recent American Academy of Allergy, Asthma & Immunology work group report, show an overall reaction rate of approximately 3% (2% since 1980).E21 These findings are confounded by the lack of control groups (eg, patients challenged with non–b-lactam antibiotics or placebo) and the fact that the challenges were not blinded. It is known that patients allergic to one drug are more likely to react to a second non–cross-reacting drug,E22 and therefore some of the cephalosporin-induced reactions might have been the result of an independent immunologic event, reflecting the immune response of a subject prone to independent IgE-mediated sensitization rather than structural cross-reactivity. The American Academy of Allergy, Asthma & Immunology workgroup report (‘‘Cephalosporin administration to patients with a history of penicillin allergy’’) and drug allergy practice parameter reached similar conclusions regarding cephalosporin treatment of patients with a history of penicillin allergy.E19,E21 If possible, penicillin skin testing should be used to help guide management because most patients have negative test results and can receive all b-lactams safely. Without prior penicillin skin testing, depending on the penicillin reaction history and method of cephalosporin administration (oral vs parenteral), cephalosporins can be administered under observation through either single-dose or graded challenges. In patients with positive penicillin skin test results, the options are a cephalosporin graded challenge or rapid desensitization. Amoxicillin and ampicillin contain R-group side chains identical to the R1-group side chains of cephadroxil and cephalexin, respectively. On the basis of very limited data, 10% to 38% of patients selectively allergic to amoxicillin or ampicillin (tolerant of penicillin) react on open challenge with the corresponding cephalosporin.E23,E24 Therefore amoxicillin- and ampicillinselective reactors should avoid cephalosporins with identical R1-group side chains (for a list of b-lactams that share identical side chains, see Solensky et alE19). Penicillin/carbapenem allergic cross-reactivity Studies over the last decade have demonstrated very little allergic cross-reactivity between penicillins and carbapenems. Although the body of evidence is not as large, the findings on penicillin/carbapenem cross-reactivity very closely parallel the data on penicillins/cephalosporins.E25 Therefore the recommendations regarding administration of carbapenems to patients with a history of penicillin allergy with or without prior penicillin skin testing are identical to what were presented above for cephalosporins.E19 Cephalosporin allergy The overall allergic reaction rate to cephalosporins is approximately 10-fold lower than that to penicillins. Anecdotal evidence
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suggests that most reactions to cephalosporins are directed at the R-group side chains rather than the core b-lactam portion of the molecule. Therefore the allergic cross-reactivity among cephalosporins is probably not extensive, but data on cephalosporin challenges of patients proved to be allergic to another cephalosporin are lacking. Skin testing with nonirritating concentrations of cephalosporins (2-20 mg/mL) has been used to identify IgEmediated allergy, but its sensitivity and specificity are uncertain. Cephalosporin administration to patients with a history of allergy to another cephalosporin should be carried out cautiously, either through graded challenge or rapid desensitization, depending on the severity of the previous reaction.E19
THE CASE REVISITED This case highlights several aspects of b-lactam allergy. Although the allergic cross-reactivity between penicillins and cephalosporins is low, it is common practice to avoid cephalosporins in patients labeled as allergic to penicillin. By virtue of ruling out penicillin allergy in most subjects, penicillin skin testing allows patients to avoid treatment with alternate antibiotics, which might not be as effective (azithromycin in this example) or have a less favorable side effect profile (levofloxacin). When penicillin skin testing first came into use in the early 1970s, its use was limited to situations in which there was no alternative to treatment with penicillin or a first-generation cephalosporin. Today, with the expansion of antibiotic options, such a clinical scenario is rare. Additionally, in the 1970s, the natural history of penicillin allergy and potential for resensitization were unknown. Research since then has shown that most (but not all) patients lose penicillin-specific IgE antibodies, and therefore evaluation with penicillin skin testing opens up treatment with b-lactams in approximately 90% of patients with a history of penicillin allergy. Lack of significant penicillin resensitization after repeated oral therapy means that skin testing need not be repeated before each penicillin course. This increases the usefulness of a single negative penicillin skin test result. Evidence has shown that use of penicillin skin testing reduces the use of vancomycin and quinolones (Table E1). Penicillin skin testing might be cost-effective, but more research is needed, and further data are important to attain given that reimbursement and ability to pursue evaluations and treatments in medicine might soon be tied to cost-effectiveness. Lastly, although this patient, like most, was not referred specifically for penicillin allergy, such an evaluation benefits the patient and in turn educates primary care physicians about the availability of penicillin skin testing.
REFERENCES E1. Jost BC, Wedner HJ, Bloomberg GR. Elective penicillin skin testing in a pediatric outpatient setting. Ann Allergy Asthma Immunol 2006;97:807-12. E2. Macy E, Schatz M, Lin CK, Poon K- Y. The falling rate of positive penicillin skin tests from 1995 to 2007. Perm J 2009;13:12-8. E3. Sade K, Holtzer I, Levo Y, Kivity S. The economic burden of antibiotic treatment of penicillin-allergic patients in internal medicine wards of a general tertiary care hospital. Clin Exp Allergy 2003;33:501-6. E4. Martinez JA, Ruthazer R, Hansjosten K, Barefot L, Snydman DR. Role of environmental contamination as a risk factor for acquisition of vancomycin-resistant enterococci in patients treated in a medical intensive care unit. Arch Intern Med 2003;163:1905-12. E5. Loo VG, Poirier L, Miller MA, Oughton M, Libman MD, Michaud S, et al. A predominantly clonal multi-institutional outbreak of Clostridium difficileassociated diarrhea with high morbidity and mortality. N Engl J Med 2005; 353:2442-9.
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E6. Harris AD, Sauberman L, Kabbash L, Greineder DK, Samore MH. Penicillin skin testing: a way to optimize antibiotic utilization. Am J Med 1999;107:166-8. E7. Arroliga ME, Radojicic C, Gordon SM, Popovich MJ, Bashour A, Melton AL, et al. A prospective observational study of the effect of penicillin skin testing on antibiotic use in the intensive care unit. Infect Control Hosp Epidemiol 2003;24:347-50. E8. Nadarajah K, Green GR, Naglak M. Clinical outcomes of penicillin skin testing. Ann Allergy Asthma Immunol 2005;95:541-5. E9. Park MA, Markus PJ, Matesic D, Li JTC. Safety and effectiveness of a preoperative allergy clinic in decreasing vancomycin use in patients with a history of penicillin allergy. Ann Allergy Asthma Immunol 2006;97:681-7. E10. del Real GA, Rose ME, Ramirez-Atamoros MT, Hammel J, Gordon SM, Arroliga AC, et al. Penicillin skin testing in patients with a history of beta-lactam allergy. Ann Allergy Asthma Immunol 2007;98:355-9. E11. Frigas E, Park MA, Narr BJ, Volcheck GW, Danielson DR, Markus PJ, et al. Preoperative evaluation of patients with history of allergy to penicillin: comparison of 2 models of practice. Mayo Clin Proc 2008;83:651-7. E12. Macy E, Mangat R, Burchette RJ. Penicillin skin testing in advance of need: multiyear follow-up in 568 test result-negative subjects exposed to oral penicillins. J Allergy Clin Immunol 2003;111:1111-5. E13. Gadde J, Spence M, Wheeler B, Adkinson NF. Clinical experience with penicillin skin testing in a large inner-city STD Clinic. JAMA 1993;270:2456-63. E14. Torres MJ, Romano A, Mayorga C, Moya MC, Guzman AE, Reche R, et al. Diagnostic evaluation of a large group of patients with immediate allergy to penicillins: the role of skin testing. Allergy 2001;56:850-6. E15. Macy E, Burchette R. Oral antibiotic adverse reactions after penicillin skin testing: multi-year follow-up. Allergy 2002;57:1151-8. E16. Green GR, Rosenblum AH, Sweet LC. Evaluation of penicillin hypersensitivity: value of clinical history and skin testing with penicilloyl-polylysine and penicillin G. J Allergy Clin Immunol 1977;60:339-45.
E17. Hershkovich J, Broides A, Kirjner L, Smith H, Gorodischer R. Beta lactam allergy and resensitization in children with suspected beta lactam allergy. Clin Exp Allergy 2009;39:726-30. E18. 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;162:822-6. E19. Solensky R, Khan DA, Bernstein IL, Bloomberg GR, Castells MC, Mendelson LM, et al. Drug allergy: An updated practice parameter. Ann Allergy Asthma Immunol 2010;105:259-73, e78. E20. Daulat SB, Solensky R, Earl HS, Casey W, Gruchalla RS. Safety of cephalosporin administration to patients with histories of penicillin allergy. J Allergy Clin Immunol 2004;113:1220-2. E21. Cephalosporin administration to patients with a history of penicillin allergy. Available at: http://www.aaaai.org/Aaaai/media/MediaLibrary/PDF%20Documents/Practice %20and%20Parameters/Cephalosporin-administration-2009.pdf. Accessed September 4, 2012. E22. Apter AJ, Kinman JL, Bilker WB, Herlim M, Margolis DJ, Lautenbach E, et al. Is there cross-reactivity between penicillins and cephalosporins? Am J Med 2006; 119(354):e11-20. E23. Audicana M, Bernaola G, Urrutia I, Echechipia S, Gastaminza G, Munoz D, et al. Allergic reactions to betalactams: studies in a group of patients allergic to penicillin and evaluation of cross-reactivity with cephalosporin. Allergy 1994;49: 108-13. E24. Miranda A, Blanca M, Vega JM, Moreno F, Carmona MJ, Garcia JJ, et al. Crossreactivity between a penicillin and a cephalosporin with the same side chain. J Allergy Clin Immunol 1996;98:671-7. E25. Atanaskovic-Markovic M, Gaeta F, Gavrovic-Jankulovic M, Velickovic TC, Valluzzi RL, Romano A. Tolerability of imipenem in children with IgEmediated hypersensitivity to penicillins. J Allergy Clin Immunol 2009;124: 167-9.
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TABLE E1. Effect of penicillin allergy evaluation on use of broad-spectrum antibiotics Study
Percentage of patients with negative penicillin skin test responses
Effect on broad-spectrum antibiotic use (% of patients)
Harris et alE6
Vancomycin: 25% / 0% Quinolones: 27% / 14%
Arroliga et alE7 Nadarajah et alE8
Vancomycin/quinolones: 100% / 58% Vancomycin: 77% / 8% Quinolones: 26% / 3%
Park et alE9 del Real et alE10
Vancomycin: 30% / 16% Vancomycin: 37% / 16% Quinolones: 36% / 13%
Vancomycin: 28% / 10%
Frigas et alE11
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TABLE E2. Commonly used penicillin skin test reagents Reagent
PPL Penicillin G Penicilloate/penilloate Ampicillin (intravenous) Amoxicillin (intravenous)
6 3 10 mol/L 10,000 U/mL 0.01 mol/L 3-25 mg/mL 3-25 mg/mL
Commercially available as Pre-Pen Commercially available, requires dilution Not commercially available in United States Commercially available, requires dilution Not commercially available in United States