The 3 Cs of Antibiotic Allergy-Classification, Cross-Reactivity, and Collaboration

Abstract

Antibiotic allergy labeling is highly prevalent and negatively impacts patient outcomes and antibiotic appropriateness. Reducing the prevalence and burden of antibiotic allergies requires the engagement of key stakeholders such as allergists, immunologists, pharmacists, and infectious diseases physicians. To help address this burden of antibiotic allergy overlabeling, we review 3 key antibiotic allergy domains: (1) antibiotic allergy classification, (2) antibiotic cross-reactivity, and (3) multidisciplinary collaboration. We review the available evidence and research gaps of currently used adverse drug reaction classification systems, antibiotic allergy cross-reactivity, and current and future models of antibiotic allergy care.

Keywords: Antibiotic allergy; Antimicrobial allergy; Cephalosporin allergy; Cross-reactivity; Penicillin allergy; Prevalence.

Figure 1. Re-classification of Adverse Drug Reactions

Adapted from Peter, White et al. 2015 and Phillips et al. 2015

Figure 2. Beta lactam structure and cross reactivity

A. Beta-lactams are classified as ‘penicillin’ if they have a beta-lactam ring fused to a thiazolidine ring. A dihydrothiazine ring in cephalosporins replaces this thiazolidine ring. Monobactams and carbapenems have an alternative adjacent ring structure, a monocyclic ring and five-membered ring respectively. In patients that have a penicillin allergy it is possible to remain sensitised to other ‘penicillins’, including aminopenicillins (amoxicillin, ampicillin) and anti-staphylococcal penicillins (flucloxacillin, oxacillin, dicloxacillin, methicillin, piperacillin-tazobactam, ticarcillin-clavulante), via the thiazolidine ring (‘penicillin ring’), rather than beta-lactam ring. B. Isolated allergy to single penicillin (e.g. amoxicillin) is also possible if a side chain is involved (e.g. “R” side chain). The true rates of overall penicillin-cephalosporin cross-reactivity are dependent on the generation of cephalosporin: <5% with 1^st generation, 2–5% with 2^nd generation and <1% with 3^rd generation^, . If cross-reactivity does persist it is most likely the result of shared “R” side chains (Figure 3)^, . Cross-reactivity between penicillins and cephalosporins with the same R1 side chain such as aminopenicillins and aminocephalsoporins is reported as 14–38%^{, ,} . Some cephalosporins such as cefazolin do not share R1 or R2 groups with any other beta-lactam. Cross-reactivity between cephalosporins is usually based on the shared side chain structures (typically the R1 group) and not the shared cephalosporin dihydrothiazine ring. (36–48%)^, .

Figure 3. Common penicillins, aminopenicillins and cephalosporins that share an identical or similar R₁- and R₂-group side chains

Note: Aminopenicillin/aminocephalosporin cross-reactivity: cefaclor, cefadroxil and cephalexin share an identical R1 group with ampicillin; cefadroxil shares an identical R 1 group with amoxicillin.