What is the cross-reactivity between Keflex (cephalexin) and amoxicillin in a patient with a known allergy to Keflex?

Cross-Reactivity Between Keflex (Cephalexin) and Amoxicillin in Patients with Keflex Allergy

Patients with a history of cephalexin (Keflex) allergy who are not experiencing anaphylaxis or severe IgE-mediated reactions can safely receive amoxicillin without prior testing, as the cross-reactivity risk is low. 1

Understanding Cross-Reactivity Between Beta-Lactams

The cross-reactivity between cephalosporins and penicillins is primarily determined by the similarity of their R1 side chains:

• Cross-reactivity occurs primarily when antibiotics share identical or similar side chains
• Cephalexin and amoxicillin share similar R1 side chains, which increases potential cross-reactivity 1, 2
• According to the FDA drug label, cross-hypersensitivity among beta-lactam antibiotics has been documented and may occur in up to 10% of patients with a history of penicillin allergy 3

Risk Assessment Based on Reaction Type

For Non-Anaphylactic Keflex Allergy:

• A patient with a history of urticaria or other non-anaphylactic reaction to cephalexin can receive amoxicillin without prior testing 1
• The actual risk of clinically significant cross-reactivity is lower than previously thought, with modern estimates suggesting approximately 1% overall cross-reactivity between penicillins and cephalosporins 4

For Anaphylactic or Severe IgE-Mediated Keflex Allergy:

• Penicillin skin testing and drug challenge should be performed prior to administration of amoxicillin 1
• In patients with documented anaphylaxis to cephalexin, the cross-reactivity risk with amoxicillin is higher (estimated at 12.9-16.45%) due to their similar side chains 2, 5

Clinical Decision Algorithm

1. Assess the severity of the previous cephalexin reaction:

   • Non-anaphylactic reaction (urticaria, mild rash) → Proceed with amoxicillin
   • Anaphylactic or severe IgE-mediated reaction (angioedema, hypotension, respiratory distress) → Perform penicillin skin testing before administering amoxicillin

2. Consider the timing of the reaction:

   • Recent reaction (<5 years) → Higher risk of cross-reactivity
   • Remote reaction (>10 years) → Lower risk as IgE-mediated allergies wane over time, with 80% of patients becoming tolerant after a decade 6

3. Evaluate alternative options if high-risk:

   • Consider antibiotics from different classes if the patient had anaphylaxis to cephalexin and requires immediate treatment
   • For patients requiring beta-lactams, carbapenems may be administered without testing or additional precautions 1

Important Clinical Considerations

• The historical 10% cross-reactivity rate between penicillins and cephalosporins is an overestimate based on older studies when cephalosporins contained penicillin contaminants 6, 4
• Modern studies show much lower rates of cross-reactivity, especially for cephalosporins with dissimilar side chains to the offending penicillin 4
• In extremely rare cases (<1%), patients may have multiple beta-lactam sensitivities not predictable based on side chain structure 2

Monitoring Recommendations

• For patients with non-anaphylactic cephalexin allergy receiving amoxicillin: observe for 30-60 minutes after administration 2
• For patients with any history of severe reactions who receive amoxicillin after negative skin testing: monitor closely and have emergency medications available 1, 3

Remember that while cross-reactivity exists, the risk is much lower than historically believed, and most patients with cephalexin allergy can safely receive amoxicillin, particularly if their original reaction was not severe.