From the Guidelines
A third-generation cephalosporin is less likely to cause a reaction in patients with penicillin allergy compared to first-generation cephalosporins due to structural differences in their side chains. The most recent and highest quality study, published in 2022 1, suggests that the cross-reactivity between penicillins and cephalosporins is lower than previously thought, with a cross-reactivity rate of approximately 2% for third-generation cephalosporins. This is because third-generation agents like ceftriaxone, cefotaxime, and cefixime have side chains that differ significantly from penicillins, reducing the likelihood of an allergic reaction. In contrast, first-generation cephalosporins such as cefazolin and cephalexin have side chains more similar to penicillins, resulting in higher cross-reactivity rates.
The key factors to consider when evaluating the risk of cross-reactivity between penicillins and cephalosporins include:
- The structural similarity between the side chains of the two antibiotics
- The presence of identical or similar side chains, which can increase the risk of cross-reactivity
- The use of skin testing and drug challenges to confirm tolerance to a particular cephalosporin
According to the study published in 2019 1, the risk of a reaction to a cephalosporin is higher in those with true penicillin allergy, and is estimated to be 2-5%. However, the study also notes that the significance of positive skin testing in this context remains poorly understood, and that sensitivity to a cephalosporin with dissimilar R1 and R2 side chains should be explored with skin tests and a graded drug challenge if this is negative.
In general, third-generation cephalosporins are generally safer choices when antibiotics from completely different classes cannot be used, due to their lower cross-reactivity rates and reduced risk of allergic reactions. However, patients with severe penicillin allergies should still exercise caution with any cephalosporin, and skin testing and drug challenges should be used to confirm tolerance to a particular antibiotic.
From the Research
Cephalosporin Allergy in Penicillin-Allergic Patients
- A 3rd generation cephalosporin is less likely to cause a reaction than a 1st generation cephalosporin in patients with a possible penicillin allergy due to the differences in their chemical structure 2, 3, 4.
- The cross-reactivity between penicillins and cephalosporins is lower than previously reported, with an overall cross-reactivity rate of approximately 1% when using 1st generation cephalosporins or cephalosporins with similar R1 side chains 2.
- The use of 3rd or 4th generation cephalosporins or cephalosporins with dissimilar side chains than the offending penicillin carries a negligible risk of cross-allergy 2, 3, 4.
- Studies have shown that 1st generation cephalosporins have a modest cross-allergy with penicillins, but cross-allergy is negligible with 2nd and 3rd generation cephalosporins 3, 4.
- The role of chemical structure in determining the risk of cross-reactivity between specific agents is paramount, with similarities in side chain structure predicting cross-allergy between cephalosporins and penicillins 3, 4.
Risk of Allergic Reaction
- The risk of an allergic reaction to a cephalosporin in penicillin-allergic patients is smaller than previously postulated, with a significant increase in allergic reactions to 1st generation cephalosporins, but no increase with 2nd and 3rd generation cephalosporins 3, 4.
- The odds ratio for cross-reactivity between penicillins and 1st generation cephalosporins is 4.8, while the odds ratio for 2nd and 3rd generation cephalosporins is 1.1 and 0.5, respectively 2, 3.
- Certain cephalosporins, such as cefprozil, cefuroxime, ceftazidime, and ceftriaxone, do not increase the risk of an allergic reaction in penicillin-allergic patients 4, 5.