There are several theories discussed regarding which molecular component of the cephalosporins is actually responsible for the alleged cross-reactivity. Here is the excerpt from the article cited:
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ACEP Now: Vol 33 – No 02 – February 2014“Penicillins have a cross allergy with first-generation cephalosporins (odds ratio 4.8; confidence interval 3.7–6.2) and a negligible cross allergy with second-generation cephalosporins (odds ratio 1.1; confidence interval 0.6–2.1). Laboratory and cohort studies confirm that the R1 side chain is responsible for this cross reactivity. Overall cross reactivity between penicillins and cephalosporins is lower than previously reported, though there is a strong association between amoxicillin and ampicillin with first- and second-generation cephalosporins that share a similar R1 side chain” (Campagna, JD, et al. The use of cephalosporins in penicillin-allergic patients:A literature review, J Emerg Med. 2012;42(5):612.)
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