Is it safe to prescribe amoxicillin to a patient with a known allergy to Keflex (cephalexin)?

Amoxicillin Use in Patients with Keflex (Cephalexin) Allergy

Amoxicillin should generally be avoided in patients with a documented cephalexin allergy due to significant cross-reactivity risk (12.9%) between these two antibiotics, which share identical R1 side chain structures. 1, 2

Understanding the Cross-Reactivity Risk

The cross-reactivity between cephalexin and amoxicillin is not due to the shared β-lactam ring, but rather because both drugs have identical R1 side chains at their 6- and 7-positions respectively. 1, 2 This structural similarity creates a meaningful risk of allergic reaction:

• Cephalexin has a 12.9% cross-reactivity rate with penicillin-allergic patients, specifically those with amoxicillin allergy 1, 2
• Amino-cephalosporins (including cephalexin) show 16.45% cross-reactivity (95% CI, 11.07-23.75) with amino-penicillins like amoxicillin due to identical side chains 1, 2
• This elevated risk applies to both immediate-type (IgE-mediated) and delayed-type (T-cell-mediated) allergic reactions 1, 2

Clinical Decision Algorithm Based on Allergy Details

For Immediate-Type Reactions (Anaphylaxis, Urticaria, Angioedema)

If the cephalexin reaction was severe OR occurred within the last 5 years:

• Avoid amoxicillin entirely 1
• Use alternative antibiotics with dissimilar side chains (e.g., azithromycin, fluoroquinolones, or cephalosporins like cefazolin that don't share side chains) 1

If the reaction was non-severe AND occurred >5 years ago:

• Amoxicillin may be administered only in a controlled clinical setting prepared to manage anaphylaxis with epinephrine, IV antihistamines, corticosteroids, and airway management 1, 3

For Delayed-Type Reactions (Rash, Delayed Urticaria)

If the cephalexin reaction occurred within the last year:

• Avoid amoxicillin 1

If the reaction occurred >1 year ago:

• Amoxicillin can be cautiously used, though guidelines still suggest avoidance when possible 1

Critical Caveats and Common Pitfalls

The FDA label for Keflex explicitly warns that cross-hypersensitivity among β-lactam antibiotics "has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy," and that "patients have been reported to have had severe reactions (including anaphylaxis) to both drugs." 3 This warning applies bidirectionally—cephalexin-allergic patients receiving penicillins face similar risks.

Important pitfalls to avoid:

• Do not assume the commonly cited "10% cross-reactivity" applies to all cephalosporins—it specifically applies to those with similar side chains like cephalexin 4, 5
• Do not confuse this situation with cephalosporins that have dissimilar side chains (like cefazolin, ceftriaxone, ceftazidime), which have negligible (<1%) cross-reactivity with penicillins 1, 4
• The reverse scenario (penicillin allergy receiving cephalexin) carries the same 12.9% risk 1, 2

Safer Alternative Approach

Instead of amoxicillin, consider:

• Non-β-lactam antibiotics appropriate for the infection (macrolides, fluoroquinolones, tetracyclines depending on indication) 6
• β-lactams with dissimilar side chains if a β-lactam is essential—though this requires knowing the specific allergy type and timing 1
• Formal allergy testing to confirm the cephalexin allergy before making definitive treatment decisions, as >90% of reported β-lactam allergies are not true IgE-mediated allergies 6

The risk of prescribing amoxicillin to a cephalexin-allergic patient (12.9%) substantially outweighs the benefits in most clinical scenarios, particularly when safer alternatives exist. 1, 2