Cross-Reactivity Between Cephalosporins and Penicillins: A Story of Side-Chains

The cross-reactivity between cephalosporins and penicillins is an important topic in medicine. In this article an experienced infectious diseases pharmacist discusses the importance of chemical structure side chains in considering when an allergy to a penicillin may translate into an allergy for a cephalosporin and vice versa.

Authored By: Meghan Jeffres, Pharm.D.

(@PharmerMeg on Twitter)

[Last updated 30 June 2017]

Origins for cross-reactivity

Cephalothin was the first cephalosporin marketed in 1964. Cross-reactivity between penicillin and cephalothin was first reported in 1966. Four of 51 patients (8%) with a penicillin allergy also had a reaction to cephalothin [1]. Additional studies reported similar frequencies of cross-reactivity [2, 3]. These inaugural studies led to the teaching that cross-reactivity between penicillins and cephalosporins ranges from 5-10%.

This over-generalization of cross-reactivity has resulted in the avoidance of all cephalosporins, not just cephalothin, in patients labeled as penicillin allergic. Beta-lactam avoidance has resulted in an increase in the use of secondary antibiotics (namely vancomycin and fluoroquinolones), and thus an increase in resistant infections, treatment failures, and cost [4-6].

More recent data

More recent studies challenge the idea of broad cross-reactivity between penicillin and cephalosporins. Romano et al. performed cephalosporin skin tests on 128 patients with immediate hypersensitivity to a penicillin derivative [7]. The cephalosporins tested were cephalothin, cefamandole, cefuroxime, ceftriaxone, cefotaxime, and ceftazidime. Based on the theory of side chains being the culprit of cross-reactivity, only exposure to cephalothin should result in a positive skin test, as it is the only cephalosporin tested with a similar side chain to penicillin. While cephalothin was the most common cephalosporin to cause a reaction (9 of 128, 7%), five other patients reacted to a cephalosporin. Unfortunately authors did not include details of which cephalosporin caused the reaction as well as what penicillin derivative was the parent reaction.

Romano et al. more recently performed beta-lactam skin tests on 214 patients with delayed hypersensitivity to penicillin [8]. Six beta-lactams were tested, three with similar side chains to penicillins, and three with dissimilar side chains. Cross-reactivity was found in 40 (19%) of patients. All reactions were from the three cephalosporins with side chains similar to penicillin derivatives. Cefaclor and cephalexin have similar side chains to ampicillin and resulted in positive skin tests in 39 and 31 patients, respectively. Cefadroxil has a similar side chain to amoxicillin and resulted in positive skin tests in 17 patients.

Focusing on side-chains

In an effort to organize side chain details, the table presented here lists penicillins and cephalosporins with similar side chains. An “X” in a square indicates when two beta-lactams share a similar side chain structure.

The exact risk of cross-reactivity between each pair in this table is largely unknown and likely varies amongst pairs. Until more data is available, avoiding beta-lactams with similar side chains is an appropriately cautious approach. For example, it would be appropriate to avoid using cephalexin in patients with an amoxicillin allergy, but that same patient could safely receive cefazolin.

It is also important to remember that a patient could have an allergic reaction to a dissimilar beta-lactam, however this likely represents a second allergic reaction, not cross-reactivity of the parent allergen.

For more information on the cross-reactivity between cephalosporins and penicillins, readers are referred to the references noted here as well as these two excellent reviews: