What is the risk of cross-sensitivity between cephalexin and amoxicillin (amoxicillin) in patients with a penicillin allergy?

Cross-Sensitivity Between Cephalexin and Amoxicillin in Patients with Penicillin Allergy

For patients with penicillin allergy, there is a significant risk of cross-sensitivity with cephalexin (12.9%) due to similar side chain structures, particularly in those with confirmed amino-penicillin (amoxicillin) allergy. 1

Risk Factors for Cross-Reactivity

• Cross-reactivity between penicillins and cephalosporins is primarily determined by the similarity of their R1 side chains, rather than the β-lactam ring itself 1
• Cephalexin has been specifically identified as having a significantly increased absolute risk of cross-reactivity (12.9%) in patients with penicillin allergy 1
• The FDA label for cephalexin warns that cross-hypersensitivity among beta-lactam antibiotics may occur in up to 10% of patients with a history of penicillin allergy 2
• Cross-reactivity is higher for amino-cephalosporins (which include cephalexin) that share an identical side chain with a penicillin (16.45%, 95% CI, 11.07-23.75) 1

Type of Allergic Reaction and Cross-Reactivity Risk

Immediate-Type Reactions (IgE-mediated)

• For patients with suspected immediate-type allergy to penicillins, cephalosporins with dissimilar side chains can be used regardless of severity or time since reaction 1
• Patients with a non-severe immediate-type reaction to penicillin >5 years ago may receive cephalosporins with similar side chains (like cephalexin) in a controlled setting 1
• The higher risk of cross-reactivity with amino-cephalosporins is observed in both IgE-mediated (immediate) and T-cell-mediated (delayed) penicillin allergies 1

Delayed-Type Reactions

• For patients with suspected non-severe, delayed-type allergy to penicillins, cephalosporins with dissimilar side chains can be used 1
• Guidelines specifically suggest avoiding cephalosporins with similar side chains (including cephalexin) in patients with suspected non-severe, delayed-type allergy to amoxicillin 1

Specific Relationship Between Amoxicillin and Cephalexin

• There is a strong association between amoxicillin and first-generation cephalosporins (like cephalexin) that share a similar R1 side chain 3
• Patients with positive amoxicillin-IgE show significantly higher rates of specific-cephalexin IgE (14.00% vs. 2.96%) compared to those with negative amoxicillin-IgE 4
• Recent evidence indicates a higher risk of cross-reactivity with cephalexin specifically in patients with confirmed amino-penicillin (amoxicillin, ampicillin) allergy 5

Clinical Approach Based on Allergy History

• For patients with documented penicillin allergy, the risk of cross-reactivity with cephalosporins that have dissimilar side chains is negligible (<1%) 1
• Cefazolin does not share any side chains with currently available penicillins and can be safely used in cases of suspected penicillin allergy 1
• The overall cross-reactivity rate between penicillins and first-generation cephalosporins is approximately 1% (much lower than the previously reported 10%), except when using cephalosporins with similar R1 side chains 3
• Current evidence suggests that the rate of cross-reactivity between penicillin and cephalosporins is about 2%, lower than the 8% previously reported 6

Common Pitfalls and Caveats

• Many patients report penicillin allergies but clinically significant IgE-mediated or T-cell-mediated penicillin hypersensitivity is uncommon (<5%) 6
• Avoiding appropriate cephalosporins in penicillin-allergic patients may lead to the use of broader-spectrum antibiotics, increasing the risk of antimicrobial resistance and adverse events 6
• IgE-mediated penicillin allergy wanes over time, with 80% of patients becoming tolerant after a decade 6
• Both the nuclear structure and R1 side-chain contribute to IgE recognition, meaning cross-reactivity can occur with both first-generation and third-generation cephalosporins 4

Algorithm for Decision Making

1. Determine if the patient has a true penicillin allergy (less than 5% of those with penicillin allergy labels have a true allergy) 5
2. Identify the specific penicillin that caused the reaction (particularly if it was amoxicillin or ampicillin) 1, 5
3. Assess the type of previous reaction:
   • For immediate-type reactions: Avoid cephalexin if the reaction was severe or occurred within the last 5 years 1
   • For delayed-type reactions: Avoid cephalexin if the reaction was to amoxicillin 1
4. Consider alternative cephalosporins with dissimilar side chains (like cefazolin) which have negligible cross-reactivity risk 1
5. If cephalexin must be used in a patient with non-severe penicillin allergy >5 years ago, administer in a controlled setting prepared to manage potential allergic reactions 1