What is the risk of cross-reactivity with Augmentin (amoxicillin and clavulanic acid) and Ceclor (cefaclor) in patients with a history of allergies to penicillin or other beta-lactam antibiotics?

Cross-Reactivity Between Augmentin (Amoxicillin-Clavulanate) and Ceclor (Cefaclor)

There is significant cross-reactivity between Augmentin and Ceclor, with cefaclor demonstrating a 14.5% cross-reactivity risk in patients with confirmed penicillin allergy, making it unsafe to use cefaclor in patients with a history of amoxicillin or Augmentin allergy. 1

Understanding the Mechanism of Cross-Reactivity

The cross-reactivity between amoxicillin (the penicillin component of Augmentin) and cefaclor is driven by their shared R1 side chain structure, not the beta-lactam ring itself. 1 This side chain similarity is the primary determinant of allergic cross-reactivity between these drugs. 1

• Cefaclor is classified as an amino-cephalosporin that shares an identical R1 side chain with amoxicillin, placing it in the highest risk category for cross-reactivity. 1
• The FDA drug label for amoxicillin explicitly warns that "there have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins." 2, 3

Quantifying the Risk

The evidence demonstrates substantial cross-reactivity rates:

• Cefaclor specifically has a 14.5% cross-reactivity risk in patients with confirmed penicillin allergy. 1
• Amino-cephalosporins as a class (which includes cefaclor, cephalexin, cefadroxil, and cefprozil) demonstrate a 16.45% (95% CI: 11.07-23.75) cross-reactivity rate based on skin testing in patients with proven aminopenicillin allergy. 1
• This elevated risk applies to both immediate-type (IgE-mediated) and delayed-type (T-cell-mediated) allergic reactions. 1

Clinical Decision Algorithm

For patients with any history of Augmentin or amoxicillin allergy:

If the reaction was severe (anaphylaxis, angioedema, hypotension):

• Absolutely avoid cefaclor due to the shared R1 side chain and high cross-reactivity risk. 1
• Choose cephalosporins with dissimilar side chains such as cefazolin (0% cross-reactivity), ceftriaxone, ceftazidime, or cefepime (approximately 2.11% cross-reactivity). 1, 4
• Cefazolin is the safest option as it has a unique R1 side chain with no structural similarity to amoxicillin. 1, 4

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

• Cefaclor may theoretically be administered in a controlled setting prepared to manage allergic reactions, but this is not recommended given safer alternatives exist. 5
• Better practice is to select a cephalosporin with dissimilar side chains (cefazolin, ceftriaxone, cefepime) which carry negligible cross-reactivity risk (<1%). 1

If the reaction was delayed-type (non-severe rash):

• Avoid cephalosporins with similar side chains including cefaclor. 1, 5
• Use cephalosporins with dissimilar side chains regardless of time since the index reaction. 1

Safer Alternative Cephalosporins

When a cephalosporin is needed in a patient with Augmentin/amoxicillin allergy:

• First choice: Cefazolin - unique side chain, negligible cross-reactivity, can be administered directly without testing regardless of severity or timing of previous reaction. 1, 4
• Second choice: Third/fourth-generation cephalosporins with dissimilar side chains (ceftriaxone, ceftazidime, cefepime) - approximately 2.11% cross-reactivity risk. 1
• Avoid: Amino-cephalosporins (cefaclor, cephalexin, cefadroxil, cefprozil) - 14.5-16.45% cross-reactivity risk. 1

Critical Pitfalls to Avoid

• Do not rely on the outdated "10% cross-reactivity" figure that appears on older FDA package inserts - this was based on contaminated cephalosporins before 1980 and is falsely elevated. 1
• Do not assume all cephalosporins are equally safe or equally risky - cross-reactivity is side chain-dependent, not generation-dependent. 4
• The clavulanic acid component of Augmentin does not contribute to cross-reactivity with cefaclor; the issue is entirely related to the amoxicillin component. 2, 3
• These recommendations do not apply to severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome, toxic epidermal necrolysis, or DRESS syndrome - in those cases, all beta-lactams should generally be avoided. 1

Supporting Evidence Quality

The 2022 practice parameter from the Journal of Allergy and Clinical Immunology represents the highest quality and most recent guideline evidence, incorporating a meta-analysis of 21 studies with 1,269 patients with confirmed penicillin allergy. 1 The Dutch SWAB 2023 guideline corroborates these findings with strong recommendations based on moderate quality evidence. 1