Correspondence
Cephalosporin Allergy
N Engl J Med 2002; 346:380-381January 31, 2002
- Article
To the Editor:
We make the following observations about the review of cephalosporin allergy by Kelkar and Li (Sept. 13 issue).1 First, anti-cephalosporin IgE antibody assays are available and are used by clinicians in Australasia. Second, specific haptenic determinants involved in hypersensitivity to cephalosporins have been identified.2,3 Some of the cross-reactivity between cephalosporins and penicillin G results from the presence of IgE directed against a group as small as the methylene substituent linking the side chain to the rest of the penicillin molecule.2 Cephalosporins exhibit greater heterogeneity of allergenic determinants than penicillin because of their extra side chain (R2) on the dihydrothiazine ring, and different fine structural recognition sites have been identified in patients who are allergic to cefaclor.3,4 Our immunochemical studies have revealed a spectrum of allergenic determinants ranging in specificity from side-chain (R1 or R2) groups to compound determinants embracing one or both ring structures.2-5
Third, our extensive experience in clinical and laboratory testing suggests that cephalosporin allergy is much more common than penicillin allergy (Table 1Table 1
Results of Radioimmunoassays for the Detection of IgE against “-Oyl” and “-Anyl” Conjugates of 12 Different Cephalosporins and Penicillins in 1682 Patients with Possible β-Lactam Allergy.).5 We use radioimmunoassays to measure major determinants (penicilloyl and cephalosporoyl) and minor determinants (penicillanyl and cephalosporanyl) for up to six different penicillins and six different cephalosporins. The higher incidence of IgE antibodies against cephalosporins was not anticipated and most likely reflects both increased use of cephalosporins and greater parenteral exposure to these drugs.5 5 ReferencesKarl W. Baumgart, M.B., Ph.D.
Douglass Hanly Moir Pathology, Ryde, NSW 2113, Australia
kbaumgart@dhm.com. au Brian A. Baldo, Ph.D.
NSL Health, Melbourne, VIC 3000, Australia1
Kelkar PS ,Li JT-C . Cephalosporin allergy. N Engl J Med 2001;345:804-809
Full Text | Web of Science | Medline2
Harle DG ,Baldo BA . Drugs as allergens: an immunoassay for detecting IgE antibodies to cephalosporins. Int Arch Allergy Appl Immunol 1990;92:439-444
CrossRef | Medline3
Pham NH ,Baldo BA . Beta-lactam drug allergens: fine structural recognition patterns of cephalosporin-reactive IgE antibodies. J Mol Recognit 1996;9:287-296
CrossRef | Web of Science | Medline4
Baldo BA . Diagnosis of allergy to penicillins and cephalosporins: structural and immunochemical considerations. Allergy Clin Immunol Int 2000;12:206-212
CrossRef5
Baldo BA ,Pham NH ,Zhao A . Chemistry of drug allergenicity. Curr Opin Allergy Clin Immunol 2001;1:327-335
CrossRef | Medline
To the Editor:
Kelkar and Li recommend avoiding cephalosporin use in patients with a history of penicillin allergy and more specifically in patients who have a positive skin test for allergy to penicillin. This strategy is not supported by the data from the studies they cite. On the basis of their Table 3, the authors could also have argued, inappropriately, that the skin test itself reduces the risk of a reaction to cephalosporin by 86 percent, from 4 in 34 (11.8 percent) to 8 in 486 (1.6 percent, P<0.001). They have partially misrepresented the data from Shepherd and Burton,1 who really reported four adverse reactions, not zero, in the 159 patients with a negative skin test. If one uses these data to recalculate the reported rates of adverse reactions to cephalosporins in the groups with positive and negative skin tests (6 of 135 and 6 of 351, respectively) one finds no significant difference (P=0.08). However, the disparate qualities of the data cited in Table 3 make combining these data and their combined analysis invalid.
The authors' statement that “these prospective studies are too small to evaluate accurately the value of skin testing in patients with a history of allergy to penicillin” is also not supported by the data they present. In the single largest study that has been conducted to explore this question,2 one reaction occurred in a group of 62 patients with positive skin tests for penicillin allergy who were exposed to parenteral cephalosporins. The 95 percent confidence interval for this proportion, 0.016, was 0.004 to 0.085. Finally, there are no data to support the authors' recommendation that penicillin skin tests be performed in persons with a history of adverse reaction only to cephalosporins.3,4
4 ReferencesEric Macy, M.D.
Kaiser Permanente, San Diego, CA 92111
eric.m. macy@kp. org 1
Shepherd GM ,Burton DA . Administration of cephalosporin antibiotics to patients with a history of penicillin allergy. J Allergy Clin Immunol 1993;91:262-262 abstract.
Web of Science2
Saxon A ,Beall GN ,Rohr AS ,Adelman DC . Immediate hypersensitivity reactions to beta-lactam antibiotics. Ann Intern Med 1987;107:204-215
Web of Science | Medline3
Anne S ,Reisman RE . Risk of administering cephalosporin antibiotics to patients with histories of penicillin allergy. Ann Allergy Asthma Immunol 1995;74:167-170
Web of Science | Medline4
Pre-Pen. Spokane, Wash.: Hollister-Stier Laboratories LLC, 1999 (package insert).
To the Editor:
Penicillin G has progressively been replaced by other β-lactam antibiotics, in terms of both prescribing habits and the induction of allergic reactions1,2; as a result, skin testing with antigenic determinants of penicillin G is no longer sufficient for evaluating patients for allergy to β-lactams, and other determinants, such as those of amoxicillin or cephalosporins, must be used instead.1-3 The assumption that anaphylaxis from cephalosporins is rare is based on insufficient evidence from individual case studies. Anaphylaxis from β-lactams has become more common2 and is accompanied by a reduced rate of positive skin tests for major determinants of penicillin G and an increased rate of positive tests for minor determinants of other β-lactams, including cephalosporins.2,3 The degree of cross-reactivity among cephalosporins is not necessarily greater than that between penicillins and cephalosporins. It depends on the similarities in the chemical structures (nuclear or side-chain) that are recognized by specific IgE antibodies or sensitized T cells. For example, the cross-reactivity between cephadroxil and amoxicillin is greater than that between cephadroxil and another unrelated side-chain cephalosporin.4
4 ReferencesCristobalina Mayorga, Ph.D.
Maria J. Torres, M.D., Ph.D.
Hospital Carlos Haya, 29009 Malaga, Spain
labinves@hch.sas. cica. es Miguel Blanca, M.D., Ph.D.
Hospital Universitario La Paz, 28046 Madrid, Spain1
Blanca M ,Vega JM ,Garcia J , et al. Allergy to penicillin with good tolerance to other penicillins: study of the incidence in subjects allergic tobetalactams. Clin Exp Allergy 1990;20:475-481
CrossRef | Web of Science | Medline2
Torres MJ ,Romano A ,Mayorga C , et al. Diagnostic evaluation of a large group of patients with immediate allergy to penicillins: the role of skin testing. Allergy 2001;56:850-856
CrossRef | Web of Science | Medline3
Romano A ,Mayorga C ,Torres MJ , et al. Immediate allergic reactions to cephalosporins: cross-reactivity and selective responses. J Allergy Clin Immunol 2000;106:1177-1183
CrossRef | Web of Science | Medline4
Miranda A ,Blanca M ,Vega JM , et al. Cross-reactivity between a penicillin and a cephalosporin with the same side chain. J Allergy Clin Immunol 1996;98:671-677
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Dr. Macy points out that the risk of a systemic reaction to cephalosporin is low (1 in 62 in one study), even among patients with a positive skin test for allergy to penicillin.1 However, deaths caused by anaphylaxis from cephalosporins do occur, and they seem to occur more frequently among patients with a history of penicillin allergy.2 Dr. Macy cites a potential rate of systemic reactions of up to 8.5 percent. We suggest the clinical circumstances of each case should determine whether or not this level of risk can be accepted. A careful review of the medical literature indicates that there is insufficient evidence on which to base a recommendation for a universally applicable strategy. We offer skin testing for penicillin allergy as one strategy, particularly for patients who have a high likelihood of cephalosporin allergy and a history of a serious reaction to penicillin.
Dr. Macy implies that we recommend penicillin skin tests for patients with a history of cephalosporin allergy. The cross-reactivity of penicillin and cephalosporins suggests that penicillin should be administered with caution in patients with a history of a systemic reaction to cephalosporins. Penicillin skin tests can be helpful in this clinical situation.
Drs. Baumgart and Baldo and Dr. Mayorga and colleagues state that cephalosporin allergy is common and provide data or references on tests for IgE antibodies or skin tests for allergy to cephalosporins. Sensitization to cephalosporins and drug reactions caused by hypersensitivity to cephalosporins may be increasing. There is a distinction between sensitization, as revealed by IgE antibody tests or skin tests, and clinical drug allergy.
Baumgart and Baldo and Mayorga et al. offer helpful details of the immunochemistry of β-lactam antibiotics. Study of haptenic determinants of β-lactam antibiotics may lead to the development of anti-cephalosporin IgE antibody assays and reagents for skin tests for immediate-hypersensitivity reactions that can find a place in routine clinical practice. However, the sensitivity and specificity of such tests do not provide sufficient support for clinical decisions. Anaphylaxis from β-lactam antibiotics is a life-threatening event.
2 ReferencesJames T. Li, M.D., Ph.D.
Mayo Clinic and Foundation, Rochester, MN 55905
li.james@mayo. edu Pramod Kelkar, M.D.
Indianapolis Allergy and Asthma Physicians, Indianapolis, IN 46202-12871
Saxon A ,Beall GN ,Rohr AS ,Adelman DC . Immediate hypersensitivity reactions to beta-lactam antibiotics. Ann Intern Med 1987;107:204-215
Web of Science | Medline2
Pumphrey RS ,Davis S . Under-reporting of antibiotic anaphylaxis may put patients at risk. Lancet 1999;353:1157-1158
CrossRef | Web of Science | Medline
- Citing Articles (5)
Citing Articles
1
Philippe Lagacé-Wiens, Ethan Rubinstein. (2012) Adverse reactions to β-lactam antimicrobials. Expert Opinion on Drug Safety1-19
CrossRef2
Michael E. Pichichero. (2007) Use of selected cephalosporins in penicillin-allergic patients: a paradigm shift. Diagnostic Microbiology and Infectious Disease 57:3, S13-S18
CrossRef3
Michael E. Pichichero. (2005) Evidence Supporting the Use of Cephalosporin Antibiotics in Penicillin-Allergic Patients. Pediatric Asthma, Allergy & Immunology 18:4, 230-246
CrossRef4
Brian A. Baldo, Nghia H. Pham. (2002) Immunoglobulin E binding determinants on ??-lactam drugs. Current Opinion in Allergy and Clinical Immunology 2:4, 297-300
CrossRef5
(2002) Current Awareness. Pharmacoepidemiology and Drug Safety 11:5, 421-436
CrossRef
