Can Keflex (cephalexin) be used in patients allergic to amoxicillin and ampicillin?

Keflex (Cephalexin) Use in Patients Allergic to Amoxicillin and Ampicillin

Keflex (cephalexin) should generally be avoided in patients with amoxicillin and ampicillin allergies due to shared R1 side chains that increase the risk of cross-reactivity. 1

Understanding Cross-Reactivity Risk

Structural Relationship

• Cephalexin shares identical R1 side chains with amoxicillin and ampicillin, which is the primary mechanism for cross-reactivity between these antibiotics 1
• Cross-reactivity between penicillins and cephalosporins is largely based on these R1 side chains, with identical side chains posing the highest risk 1

Risk Assessment Based on Reaction Type

• For immediate-type (IgE-mediated) allergic reactions:

  • Patients with immediate-type allergies to amoxicillin or ampicillin should avoid cephalexin regardless of when the reaction occurred 1
  • The FDA warning states that cross-hypersensitivity among beta-lactam antibiotics has been documented and may occur in up to 10% of patients with penicillin allergy 2

• For delayed-type (non-IgE-mediated) allergic reactions:

  • Patients with delayed-type allergies to amoxicillin or ampicillin that occurred within the past year should avoid cephalexin 1
  • If the delayed-type reaction occurred more than 1 year ago, cephalexin might be considered with caution 1

Alternative Antibiotic Options

For Patients Requiring Cephalosporins

• Cephalosporins with dissimilar R1 side chains to amoxicillin/ampicillin can be used safely 1
• Cefazolin is particularly safe as it does not share side chains with any currently available penicillins 1, 3
• Third- or fourth-generation cephalosporins with dissimilar side chains carry a negligible risk of cross-reactivity 4

Non-Cephalosporin Alternatives

• For conditions like Group A streptococcal pharyngitis, alternatives include:
  • Clindamycin (7 mg/kg three times daily, max 300 mg per dose for 10 days) 1
  • Clarithromycin (7.5 mg/kg twice daily, max 250 mg per dose for 10 days) 1
  • Azithromycin (12 mg/kg once daily, max 500 mg for 5 days) 1

Clinical Considerations

Risk Stratification

• The risk of cross-reactivity is higher for first-generation cephalosporins like cephalexin than for later generations 4
• Studies have found that the overall cross-reactivity between penicillins and cephalosporins is lower than previously reported (approximately 1% rather than 10%), but cephalexin specifically carries higher risk due to shared side chains 4, 5
• Patients with urticaria as their penicillin-allergic manifestation may have higher rates of cross-reactivity with cephalosporins (30.65% vs. 8.11% for other symptoms) 5

Important Caveats

• Most patients with reported penicillin allergies (>90%) do not have true allergies when tested 3
• If cephalexin must be used in a patient with non-severe, immediate-type reactions to amoxicillin/ampicillin that occurred >5 years ago, consider administration in a controlled setting with monitoring 1
• Severe delayed hypersensitivity reactions like Stevens-Johnson Syndrome, hepatitis, or nephritis to penicillins are absolute contraindications to cephalosporin use 3

Conclusion

For patients allergic to amoxicillin and ampicillin, cephalexin (Keflex) should generally be avoided due to shared R1 side chains and documented cross-reactivity. Alternative antibiotics without structural similarity or cephalosporins with dissimilar side chains should be selected instead to minimize risk of allergic reactions and ensure patient safety.