What is the cross-reactivity between amoxicillin and Keflex (cephalexin)?

Cross-Reactivity Between Amoxicillin and Cephalexin (Keflex)

Patients with a history of amoxicillin allergy have a significantly higher risk of cross-reactivity with cephalexin (Keflex), with studies showing a cross-reactivity rate of approximately 12.9%. 1

Understanding the Cross-Reactivity Mechanism

The cross-reactivity between penicillins (like amoxicillin) and cephalosporins (like cephalexin) is primarily determined by the similarity of their side chains (R1), rather than the common beta-lactam ring structure:

• Cross-reactivity is highest when the side chains are identical or highly similar
• Amoxicillin and cephalexin have similar R1 side chains, increasing cross-reactivity risk
• The FDA label for cephalexin specifically warns that cross-hypersensitivity among beta-lactam antibiotics may occur in up to 10% of patients with penicillin allergy 2

Risk Stratification by Side Chain Similarity

The risk of cross-reactivity varies based on the similarity of the R1 side chains:

• Amino-cephalosporins with identical side chains to penicillins: 16.45% (95% CI: 11.07-23.75) 1, 3
• Cephalosporins with intermediate similarity: 5.60% (95% CI: 3.46-8.95) 1, 3
• Cephalosporins with low similarity: 2.11% (95% CI: 0.98-4.46) 1, 3

For cephalexin specifically, a meta-analysis showed a significantly increased absolute risk of cross-reactivity of 12.9% in patients with confirmed penicillin allergy 1.

Clinical Recommendations

For Patients with Immediate-Type Penicillin Allergy:

• Avoid cephalexin in patients with confirmed immediate-type allergy to amoxicillin, especially if the reaction occurred within the past 5 years 1
• Consider using cephalosporins with dissimilar side chains instead (e.g., cefazolin) which have negligible cross-reactivity 1, 3
• For patients with non-severe immediate-type allergy to amoxicillin that occurred >5 years ago, cephalexin might be used in a controlled setting with appropriate monitoring 1

For Patients with Delayed-Type Penicillin Allergy:

• Avoid cephalexin if the delayed-type allergic reaction to amoxicillin occurred less than 1 year ago 1
• For reactions that occurred >1 year ago, cephalexin may be considered with caution 1

Practical Approach for Clinicians

1. Determine the type and timing of the previous amoxicillin reaction:

   • Immediate-type (within hours): higher cross-reactivity risk with cephalexin
   • Delayed-type (days later): lower cross-reactivity risk if >1 year ago

2. Assess the severity of the previous reaction:

   • Severe reactions (anaphylaxis, severe skin reactions): avoid cephalexin
   • Non-severe reactions that occurred >5 years ago: may consider cephalexin with monitoring

3. Consider alternatives when appropriate:

   • Use cephalosporins with dissimilar side chains (e.g., cefazolin)
   • Carbapenems and monobactams can be administered without prior testing in patients with penicillin allergy 1, 3

Important Caveats

• The FDA label for cephalexin explicitly warns about cross-hypersensitivity with penicillins 2
• If cephalexin must be used in a patient with amoxicillin allergy, be prepared to treat potential allergic reactions with appropriate emergency measures 2
• The cross-reactivity between amoxicillin and cephalexin is higher than previously thought, particularly for first-generation cephalosporins like cephalexin 4, 5

Remember that while many patients report penicillin allergies, true IgE-mediated or T-cell-mediated hypersensitivity is less common (<5%), but the risk of cross-reactivity with cephalexin remains significant for those with confirmed amoxicillin allergy 6.