Clinical Commentary Review Cross-reactivity in b-Lactam Allergy Robert J. Zagursky, PhD, and Michael E. Pichichero, MD Rochester, NY b-Lactam drugs (penicillins, amoxicillin, and cephalosporins) Performance of penicillin allergy testing has shown that account for 42.6% of all severe drug-induced anaphylaxis. In this approximately 90% of patients with a reported history of peni- review, we focus on clinically significant immunologic cross- cillin are not allergic to penicillin. This has important ramifica- reactivity in patients with confirmed penicillin allergy to tions because increased usage of noneb-lactam drugs encourages cephalosporins, and the structural involvement of the R1 and R2 the development of antibiotic-resistant organisms and use of chemical side chains of the cephalosporins causing IgE-mediated alternative antibiotics that have serious side effects.5 The same cross-reactivity with penicillin and other cephalosporins. Skin concern should be applied to patients with a reported history of tests predict IgE-mediated reactions and showed cross-reactivity cephalosporin allergy. between penicillins and early generation cephalosporins that The 2013 American Academy of Pediatrics Sinusitis Guide- shared side chains, but confirmatory challenge data are lacking. line6 endorsed the use of specific cephalosporin antibiotics for the Later-generation cephalosporins, which have distinct side chains, treatment of patients even if there is a report of type I (IgE- do not have any skin test cross-reactivity with penicillin/ mediated) allergy or nonetype I penicillin reactions; however, amoxicillin. There is debate as to the involvement of R2 side for unclear reasons the endorsement in older guidelines excludes chains as the antigenic determinants that cause IgE-mediated penicillin reactions that are type I allergic reactions (2004 hypersensitivity with various cephalosporins. Avoidance of American Academy of Pediatrics and American Academy of cephalosporins, when they are the drug of choice in a penicillin- Family Physicians,7 2013 American Academy of Pediatrics Acute allergic individual, results in significant morbidity that Otitis Media Guidelines, and the 2010 Joint Task Force on outweighs the low risk of anaphylaxis. We conclude that there is Practice Parameters; American Academy of Allergy, Asthma and ample evidence to allow the safe use of cephalosporins in Immunology, the American College of Allergy, Asthma and patients with isolated confirmed penicillin or amoxicillin Immunology, and the Joint Council of Allergy, Asthma and allergy. Ó 2017 American Academy of Allergy, Asthma & Immunology8). Our previous review focused on the immuno- Immunology (J Allergy Clin Immunol Pract 2017;-:---) logic cross-reactivity of patients with a penicillin allergy to certain Key words: b cephalosporins and the structural involvement of the R1 cepha- Anaphylaxis; -Lactam allergy; Penicillin; losporin site for this cross-reactivity.9 Here, we include type I Cephalosporin allergy reactions with penicillins and cephalosporins including the R2 chemical groups as well as cross-reactivity among cephalosporins. INTRODUCTION In 2011, penicillins and cephalosporins were the top 2 classes PENICILLINS, CEPHALOSPORINS, AND OTHER of antibacterial drugs sold in the United States, making up nearly b-LACTAMS: STRUCTURE 60% of all the antibacterial drug market1 and accounted for 55% 2 Early production of natural penicillin resulted in different of global antibiotic drugs consumed in 2010. As of May 2017, structures depending on the liquor used during fermentation. the Food and Drug Administration has approved more than 34 That changed with the production of semisynthetic penicillins b-lactam compounds as active ingredients in drugs for human 3 with different side chains. Today there are a number of different use. In a report by the Allergy Vigilance Network of the penicillins (penams) (see Figure E1 in this article’s Online European registry of recorded drug-induced severe anaphylaxis Repository at www.jaci-inpractice.org). from 2002 to 2010, 42.6% of the cases were caused by b-lactam 4 Shortly after bacterial resistance to penicillin started to drugs: amoxicillin, other penicillins, and cephalosporins. This emerge, a new class of natural penicillin-like antibiotics called provides strong evidence for the need for allergy assessment. cephalosporins was discovered. Both penicillins and cephalo- sporins share a common b-lactam ring that is attached to either a 5-membered thiazolidine ring or a 6-membered dihy- Rochester General Hospital Research Institute, Center for Infectious Diseases and drothiazine (cephem) ring, respectively (Figure 1). These Immunology, Rochester, NY b-lactam antibiotics inhibit the bacterial transpeptidases (also Conflicts of interest: The authors declare that they have no relevant conflicts of called penicillin-binding proteins) that catalyze the peptido- interest. glycan cross-linking reaction involved in bacterial cell wall Received for publication June 12, 2017; revised August 18, 2017; accepted for publication August 24, 2017. biosynthesis. Another difference between penicillins and ceph- Available online -- alosporins is that cephalosporins contain additional modifica- fi Corresponding author: Michael E. Pichichero, MD, Research Institute, Rochester tions at the R2 chemical group. These modi cations have General Hospital, 1425 Portland Ave, Rochester, NY 14621. E-mail: Michael. resulted in antibiotic therapy with broader spectrum of activity [email protected]. targeting gram-positive and gram-negative bacteria and better 2213-2198 10 Ó 2017 American Academy of Allergy, Asthma & Immunology pharmacokinetic properties. Cephalosporins can be roughly http://dx.doi.org/10.1016/j.jaip.2017.08.027 classified into various generations on the basis of their 1 2 ZAGURSKY AND PICHICHERO J ALLERGY CLIN IMMUNOL PRACT MONTH 2017 H H Allergy, Asthma and Immunology, and the Joint Council of R N R1 N 1 S S 8 1 CH 1 Allergy, Asthma and Immunology) and the European 6 5 3 7 6 2 2 O Network for Drug Allergy and the European Academy of O 7 N4 8 5 3 19,20 3 CH3 N Allergy and Clinical Immunology guidelines for skin 4 R O O 2 testing (prick or intradermal) for penicillin reactivity include a β-lactam ring β-lactam ring OH minor determinant mixture of the natural metabolized peni- O O OH Penicillin Cephalosporin cillin G products along with penicilloyl polylysine (also known by its trade name Pre-Pen)21 and other possible b-lactam drugs OH for initial skin testing. However, the recommendation is R H complicated by the fact that the minor determinant mixture is R1 1 N CH3 H3C not commercially available in the United States. As an alter- R2 S O native, skin testing using penicilloyl polylysine, penicillin, and N N O amoxicillin without using minor determinant mixture, and if O O S negative, followed by oral amoxicillin challenge has been pro- 22 OH O OH posed. A penicillin skin test result is considered positive if a O Monobactam greater than or equal to 5 mm wheal surrounded by erythema is Carbapenem observed.23 Cephalosporyl is a natural metabolized determinant product FIGURE 1. Chemical core structures of b-lactam and mono- of a cephalosporin but is unstable and undergoes multiple frag- bactam antibiotics. The b-lactam ring shown and present in all mentations of the dihydrothiazine ring and the haptenic de- structures. “R” represents side chains that differ among the terminants are unknown.24,25 Thus, a “minor determinant antibiotics. mixture” consisting of a partially fragmented b-lactam ring does not exist for cephalosporins. However, unlike the R2 side chain which may be eliminated, the R side-chain structure of cepha- appearance in time (see Table I). The earliest generation focused 1 losporins usually remains intact and is the major factor for cross- mainly on the R chemical group, whereas the later generations 1 reactivity between cephalosporins and penicillins.19,24,26-29 Skin focused on modifications at both the R and R groups. Today, 1 2 testing for cephalosporins has been undertaken in more than 20 there are more than 50 cephalosporin antibiotics, 18 licensed in studies but the positive and negative predictive values of the the United States (see Figure E1). results are less well established.30 Currently, cephalosporin skin Additional modifications to the basic core structures of both tests are done with the native molecule (intravenous preparations penicillins and cephalosporins have been made. Examples of or crushed tablets solubilized in buffer) and can predict hyper- these are the prodrugs of penicillin that contain changes at the C 3 sensitivity only to the specific cephalosporin skin test reagent or carboxy position and in cephalosporins that contain a 7-a- cephalosporins with similar side chains. The European Network methoxy group at C (cephamycins) or where the sulfur atom at 7 on Drug Allergy recommends using a nonirritating skin test position 1 is replaced with an oxygen atom (oxacephems). Other concentration of 2 mg/mL for all cephalosporins, but increasing types of b-lactamecontaining antibiotics are carbapenems such the concentration may identify additional skin test positive pa- as meropenem, imipenem, and ertapenem and monobactams tients as reported using a nonirritating concentration of 20 mg/ such as aztreonam. mL cefazolin.31 We and others have used 1 to 20 mg/mL for Carbapenems are similar to penicillins but the b-lactam ring is scratch and intradermal testing, whereas others have used a 10- attached to a 5-member carbon-only