Side chain similarities or identities constitute the predominant factor for cross-reactivity between penicillins and cephalosporins, whereas differences in the side-chain structure seem to account for the absence of such cross-reactivity.
We sought to assess the cross-reactivity between penicillins and two cephalosporins (i.e., cefazolin and ceftibuten) that have side chains different from those of penicillins, as well as to evaluate the possibility of using these cephalosporins in penicillin-allergic subjects.
We conducted a prospective study of 131 consecutive subjects who had suffered 170 immediate reactions (mostly anaphylaxis) to penicillins and had positive skin tests to at least one penicillin reagent. All patients underwent skin tests with cefazolin and ceftibuten. Patients with negative results were challenged with them.
One participant had positive skin tests to cefazolin and ceftibuten, as well as to all other reagents tested, including aztreonam and carbapenems. All 129 subjects who underwent challenges with cefazolin and ceftibuten tolerated them. One subject refused cephalosporin challenges.
Subjects with an IgE-mediated hypersensitivity to penicillins could be treated with cephalosporins like cefazolin and ceftibuten, which are among the cephalosporins that have side chain determinants different from those of penicillins. Nevertheless, in patients with such hypersensitivity who need these alternative β-lactams, pretreatment skin tests are advisable because of the possibility of coexisting sensitivities or, much less frequently, of a sensitivity to an antigenic determinant of the common β-lactam ring.

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