What investigations should be sent for a suspected amoxicillin-clavulanic acid allergy?

Investigations for Suspected Amoxicillin-Clavulanic Acid Allergy

For suspected amoxicillin-clavulanic acid allergy, no immediate laboratory investigations are required during the acute reaction; instead, obtain a detailed clinical history documenting the exact reaction type, timing, and severity, then refer to an allergy specialist for formal skin testing and potentially basophil activation testing 4-6 weeks after resolution. 1

Immediate Clinical Documentation (No Lab Tests Needed Acutely)

The most critical "investigation" is obtaining a comprehensive allergy history that determines whether formal allergy testing is even necessary. 1 Document the following specific details:

• Exact timing: Record when symptoms began relative to the last dose (minutes to hours suggests immediate Type I hypersensitivity; days suggests delayed Type IV hypersensitivity) 1
• Specific symptoms: Note whether the reaction involved single organ system (non-severe) versus multi-system involvement with respiratory compromise, hypotension, or severe GI symptoms (severe) 1
• Severity classification: Determine if the reaction meets criteria for severe (anaphylaxis, Stevens-Johnson syndrome, DRESS, AGEP) versus non-severe (isolated urticaria, maculopapular rash without organ involvement) 1
• Prior tolerance: Document whether the patient had previously tolerated amoxicillin-clavulanic acid or other beta-lactams 1

Serum Tryptase (Only for Suspected Anaphylaxis)

If anaphylaxis occurred (Grade II-IV reaction with multi-system involvement), obtain serum tryptase levels during the acute reaction and at baseline. 1

• Draw tryptase during the acute reaction (ideally within 1-4 hours of symptom onset) and again at baseline (24 hours or more after complete resolution) 1
• An increase above 1.2 × baseline + 2 μg/L confirms mast cell degranulation and supports IgE-mediated anaphylaxis 1
• This test is not useful for delayed-type reactions (maculopapular rash appearing days later) 1

Referral for Formal Allergy Testing (4-6 Weeks Post-Reaction)

All patients with Grade II-IV reactions and Grade I reactions with generalized urticaria should be referred to an allergy specialist for skin testing. 1, 2, 3

Skin Testing Protocol

The allergy specialist will perform:

• Skin prick tests followed by intradermal tests to amoxicillin, clavulanic acid separately, and the combination 1, 4, 5
• Testing should occur at least 4-6 weeks after resolution to avoid false negatives 1
• For immediate reactions: Skin tests have 47% sensitivity and 89% negative predictive value 6
• For delayed reactions: Delayed intradermal reading at 24-48 hours has only 7% sensitivity but 95% negative predictive value 7, 6

Basophil Activation Test (BAT)

• BAT measuring CD63 expression can identify specific IgE-mediated allergy to clavulanic acid when skin tests are negative 5, 8
• This is particularly useful because patients can be sensitized to amoxicillin alone, clavulanic acid alone, or both simultaneously 4, 5, 8
• BAT is not widely available but should be considered at specialized centers 5

Drug Provocation Testing

• If skin tests and BAT are negative, supervised drug provocation with amoxicillin alone, then clavulanic acid (if available), then the combination confirms tolerance 5, 7, 6
• This should only occur in a controlled setting with emergency resources available 1, 9

Common Pitfalls to Avoid

• Do not assume all rashes represent true IgE-mediated allergy: Most childhood rashes during antibiotic use are viral exanthems, not true allergies 2, 3
• Do not avoid all beta-lactams unnecessarily: Cross-reactivity between amoxicillin-clavulanic acid and other beta-lactams depends on R1 side-chain similarity; cephalosporins with dissimilar side chains are generally safe 2, 3, 9
• Do not rechallenge within 1 year for delayed-type reactions: Allow adequate time for immune tolerance to potentially develop 3, 9
• Do not forget to test clavulanic acid separately: Up to 43% of reactions to amoxicillin-clavulanic acid are due to clavulanic acid alone, and these patients can safely receive amoxicillin 4, 5, 6

Alternative Antibiotics While Awaiting Testing

• For non-severe reactions, consider trimethoprim-sulfamethoxazole, azithromycin, clarithromycin, or cephalosporins with dissimilar R1 side chains 2, 3
• Document the allergy label as "amoxicillin-clavulanic acid allergy - delayed, non-severe" to prevent unnecessary broad-spectrum antibiotic use 3, 9