What is the cross-reactivity between Penicillin and Ceftriaxone (Rocephin)?

From the Guidelines

Cross-reactivity between penicillin and Rocephin (ceftriaxone) is generally low, estimated at about 0.8% in patients with confirmed penicillin allergy, as reported in the most recent study 1. The chemical structure of cephalosporins, including Rocephin, is distinct from penicillins, with different side chains that reduce the likelihood of cross-reactivity. Key points to consider:

• Patients with mild to moderate penicillin allergies can usually safely receive Rocephin.
• Those with severe penicillin allergies should avoid Rocephin without proper allergy testing or desensitization.
• Characterizing the reaction in detail is crucial before prescribing Rocephin to a patient with a reported penicillin allergy.
• Many patients labeled as "penicillin allergic" can tolerate the medication upon retesting, as penicillin allergies often wane over time.
• For patients with severe penicillin allergies requiring cephalosporin treatment, consultation with an allergist for skin testing or graded challenge may be appropriate, as suggested by recent guidelines 1. Some important considerations:
• The true incidence of cross-reactivity between penicillins and cephalosporins is likely lower than historically reported, with a recent study suggesting a rate of 0.8% 1.
• The degree of cross-reactivity is higher between penicillins and first-generation cephalosporins but is negligible with second- and third-generation cephalosporins, such as Rocephin 1.
• Aztreonam can be used in patients with a suspected immediate-type allergy to cephalosporins other than ceftazidime or cefiderocol, irrespective of severity and time since the index reaction, as recommended by recent guidelines 1.

From the FDA Drug Label

WARNINGS Hypersensitivity Reactions Before therapy with ceftriaxone for injection is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cephalosporins, penicillins and other beta-lactam agents or other drugs. This product should be given cautiously to penicillin and other beta-lactam agent-sensitive patients

• Cross-reactivity between penicillin and ceftriaxone (Rocephin) may occur, as both are beta-lactam agents.
• Patients with a history of hypersensitivity reactions to penicillins should be treated with caution when administering ceftriaxone.
• The drug label recommends careful inquiry into the patient's history of hypersensitivity reactions to penicillins and other beta-lactam agents before instituting therapy with ceftriaxone 2.

From the Research

Cross-Reactivity between Penicillin and Cephalosporins

• The cross-reactivity between penicillin and cephalosporins is lower than previously reported, with an overall cross-reactivity rate of approximately 1% when using first-generation cephalosporins or cephalosporins with similar R1 side chains 3.
• The R1 side chain is responsible for the cross-reactivity between penicillins and cephalosporins, with a strong association between amoxicillin and ampicillin with first- and second-generation cephalosporins that share a similar R1 side chain 3.
• The risk of cross-reactivity varies with the degree of similarity between R1 side chains, with a higher risk associated with aminocephalosporins (16.45%) and a lower risk associated with low-similarity-score cephalosporins (2.11%) 4.

Specific Cephalosporins and Cross-Reactivity

• Cefadroxil, cephalexin, and cefazolin confer an increased risk of allergic reaction among patients with penicillin allergy, while cefprozil, cefuroxime, cefpodoxime, ceftazidime, and ceftriaxone do not increase the risk of an allergic reaction 5.
• Third- or fourth-generation cephalosporins or cephalosporins with dissimilar side chains than the offending penicillin carry a negligible risk of cross-allergy 3.

Evaluation and Management of Penicillin Allergy

• Many patients report allergies to penicillin, but clinically significant IgE-mediated or T lymphocyte-mediated penicillin hypersensitivity is uncommon (<5%) 6.
• The rate of IgE-mediated penicillin allergies is decreasing, and IgE-mediated penicillin allergy wanes over time, with 80% of patients becoming tolerant after a decade 6.
• Direct amoxicillin challenge is appropriate for patients with low-risk allergy histories, while moderate-risk patients can be evaluated with penicillin skin testing 6.