Cephalosporin Allergy: Current Understanding and Future Challenges

Abstract

Cephalosporins are commonly used antibiotics both in hospitalized patients and in outpatients. Hypersensitivity reactions to cephalosporins are becoming increasingly common with a wide range of immunopathologic mechanisms. Cephalosporins are one of the leading causes for perioperative anaphylaxis and severe cutaneous adverse reactions. Patients allergic to cephalosporins tend to tolerate cephalosporins with disparate R1 side chains but may react to other beta-lactams with common R1 side chains. Skin testing for cephalosporins has not been well validated but appears to have a good negative predictive value for cephalosporins with disparate R1 side chains. In vitro tests including basophil activation tests have lower sensitivity when compared with skin testing. Rapid drug desensitization procedures are safe and effective and have been used successfully for immediate and some nonimmediate cephalosporin reactions. Many gaps in knowledge still exist regarding cephalosporin hypersensitivity.

Keywords: Allergy; Anaphylaxis; Beta-lactam; Cephalosporin; Cross-reactivity; Penicillin; Skin test.

Figure 1.. Cephalosporin HSRs

This figure demonstrates the proportion of each reported HSR in the electronic health record allergy module attributed to a cephalosporin antibiotic (X-axis), as determined by a large U.S. healthcare system analysis that included 4,017,708 reactions reported by 2,734,506 patients.⁽¹²⁾ The HSRs are on the Y-axis, with the total number of HSRs attributed to cephalosporin antibiotics displayed in parentheses.

Figure 2:. Immunological classification:

Modified Gel Coombs classification of Antibody mediated and delayed T-cell mediated reactions: Cephalosporins are associated with the full spectrum of reactions from Type I - anaphylaxis – IgE mediated; Type II – hemolytic anemia and thrombocytopenia, type III (serum sickness and vasculitis) as well as full spectrum of T-cell mediated reactions (drug reaction with eosinophilia and systemic symptoms, maculopapular eruption, Stevens-Johnson syndrome/toxic epidermal necrolysis, fixed drug eruption, hepatitis and acute generalized exanthematous pustulosis.

Figure 3:. Models of Immune Activation.

The hapten-prohapten model shows the drug covalently binds to a peptide either intracellularly in the endoplasmic reticulum prior to peptide processing and presentation or at the cell surface. The pharmacological interaction model (p-i) shows the drug non-covalently binding to the HLA-molecule and/or T-cell receptor to result in direct T-cell activation. The altered peptide repertoire model shows a drug binding non-covalently in the HLA antigen binding cleft that alters the repertoire of self-peptide ligands leading to presentation of novel peptide ligands that are recognized as foreign and elicit an immune response. TCR – T-cell receptor.

Figure 4:. Sharing of R1 side chains between cephalosporins and other beta-lactams.

Cephalosporin immunogenicity and cross-reactivity appears to be largely dictated by R1 side chains. The group numbers have been labeled for the purpose of illustrating differing R1 side chains. Colored shading represents shared structures with clinical cross-reactivity described. The R1 side chain chemical structure names are: Group 1 (2-amino-N-methoxythiazole-4-carbimidoyl); Group 2 (N-methoxyfuran-2-carbimidoyl); Group 3 ((E)-2-((((2-aminothiazol-4-yl)methylene)amino)oxy)-2-methylpropanoic acid); Group 4A (phenylmethanamine); Group 4B (4-(aminomethyl)phenol); Group 5 (thiophene); Group 6 (tetrazole) *Ceftezole is not available in the U.S.

Figure 4:. Sharing of R1 side chains between cephalosporins and other beta-lactams.

Cephalosporin immunogenicity and cross-reactivity appears to be largely dictated by R1 side chains. The group numbers have been labeled for the purpose of illustrating differing R1 side chains. Colored shading represents shared structures with clinical cross-reactivity described. The R1 side chain chemical structure names are: Group 1 (2-amino-N-methoxythiazole-4-carbimidoyl); Group 2 (N-methoxyfuran-2-carbimidoyl); Group 3 ((E)-2-((((2-aminothiazol-4-yl)methylene)amino)oxy)-2-methylpropanoic acid); Group 4A (phenylmethanamine); Group 4B (4-(aminomethyl)phenol); Group 5 (thiophene); Group 6 (tetrazole) *Ceftezole is not available in the U.S.