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- Cross-allergy between penicillins and cephalosporins: a paradigm shiftPublication . Dias, Liliana; Neves, ClaudiaAllergic reactions to beta-lactam antibiotics are the most common cause of allergic drug reactions. The incorrect diagnosis prevents patients from receiving a highly effective therapy. The potential cross-reactivity between penicillin and cephalosporin has very significant therapeutic implications. Penicillins and cephalosporins share a common beta-lactam ring and side chains. A number of studies indicate that the R1 side chain, rather than the ring itself, is the determining factor for cross-reactivity. Herein is presented a review of the immunologic mechanisms implicated in penicillin and cephalosporin cross-reactivity and a practical approach to the use of cephalosporins in patients allergic to penicillin.