Prior to 1980, penicillins and cephaloporins were often produced using the same fungus and the chance for contamination during the manufacturing process was high. The belief was that the beta-lactam ring similarities must be the cause. How wrong we were.
More recent studies have determined that the actual risk of cross-reactivity relates more to a side chain similarity and probably not the beta-lactam ring at all. Therefore it makes sense that if a penicillin and a cephalosporin share that particular (R-1) side-chain similarity, the risk of cross-reactivity is increased. Such is the case with amoxicillin or ampicillin with:
- 1st generation cephalosporins: cefadroxil, cefatrizine, cephalexin, cephradine
- 2nd generation cephalosporins: cefaclor, cefprozil
Campagna Review Article
- Overall cross-reactivity rate between cephalosporins and penicillins in patients reporting a penicillin allergy = 1%. 
- Overall cross-reactivity rate in patients with a confirmed penicillin allergy = 2.5%.
- Cross-reactivity between penicillins and MOST 1st and 2nd generation cephalosporins is negligible.
- Cross-reactivity between penicillins and ALL 3rd and 4th generation cephalosporins is negligible.
- If a patient has an allergy to amoxicillin or ampicillin, avoid cefadroxil, cefaclor, cefatrizine, cefprozil, cephalexin, and cephradine.
- Campagna JD, Bond MC, Schabelman E, Hayes BD. The use of cephalosporins in penicillin-allergic patients: A literature review. J Emerg Med. 2012;42(5):612-20