What are the indications, contraindications, and recommended procedure for skin testing before administering a beta‑lactam antibiotic to a patient with a reported immunoglobulin E‑mediated allergy?

Skin Testing for Beta-Lactam Antibiotics in Patients with Reported IgE-Mediated Allergy

For patients with a history of severe IgE-mediated reactions (anaphylaxis, angioedema, hypotension) to beta-lactams who require a parenteral cephalosporin, perform skin testing with the specific cephalosporin needed at nonirritating concentrations, followed by a drug challenge if negative. 1

Indications for Skin Testing

Skin testing is indicated specifically for:

• Patients with anaphylactic or convincing histories of IgE-mediated reactions (anaphylaxis, angioedema, hypotension, urticaria within 1 hour of first dose) who require parenteral beta-lactam therapy 1
• Patients with severe immediate-type reactions occurring within the past 5 years, regardless of the specific beta-lactam needed 1
• Patients requiring parenteral cephalosporins with a history of cephalosporin anaphylaxis, even when the R1 side chains differ from the culprit drug 1

Skin testing is NOT indicated for:

• Patients without a history of beta-lactam allergy—this practice has no scientific basis and is not performed in evidence-based medicine 2
• Patients with non-severe reactions that occurred more than 5 years ago—these patients can receive a therapeutic dose in a controlled setting without prior testing 1
• Patients with delayed-type reactions (rashes appearing after 1 hour)—skin testing does not predict these reactions 1

Absolute Contraindications to Skin Testing

Never perform skin testing or re-challenge in patients with:

• Stevens-Johnson syndrome or toxic epidermal necrolysis 3
• Drug reaction with eosinophilia and systemic symptoms (DRESS) 3
• Severe cutaneous adverse reactions (SCARs) 1
• Hemolytic anemia 3
• Drug-induced liver injury 1
• Acute interstitial nephritis 1, 3
• Severe hepatitis 3

These patients should avoid the culprit drug permanently and require multidisciplinary consultation if no alternative exists 1, 3

Recommended Skin Testing Procedure

Pre-Testing Considerations

• Discontinue antihistamines until their effects have dissipated, as they attenuate skin test responses 4
• Perform testing in an appropriate healthcare setting under direct medical supervision with immediate access to anaphylaxis treatment 4, 3
• Test sensitivity decreases over time—testing is most reliable when performed soon after the reaction, ideally within 6 months 1, 5

Step-by-Step Testing Protocol

For Penicillin Allergy Evaluation:

1. Begin with puncture (prick) testing on the inner volar forearm using penicilloyl-polylysine (PRE-PEN) and native penicillin 4, 3
2. Apply a small drop and make a single shallow puncture through the drop 4
3. Read at 10-15 minutes: positive = wheal ≥5 mm with erythema and itching 4
4. If puncture test is negative, proceed to intradermal testing with 0.01-0.02 mL to raise a 3 mm bleb 4
5. Read intradermal test at 20 minutes: positive = wheal ≥5 mm larger than initial bleb with itching 4
6. If skin tests are negative, perform an oral amoxicillin challenge to confirm tolerance 3

For Cephalosporin Skin Testing (Parenteral Agents Only):

• Epicutaneous (prick) concentrations 1:

  • Cefazolin: 200 mg/mL
  • Cefuroxime: 90 mg/mL
  • Cefotaxime, ceftazidime, ceftriaxone: 100 mg/mL
  • Cefepime: 2 mg/mL

• Intradermal concentrations (if prick negative) 1:

  • Cefazolin: 2.0 mg/mL then 20 mg/mL
  • Cefuroxime: 1 mg/mL
  • Cefotaxime, ceftazidime, ceftriaxone: 1 mg/mL
  • Cefepime: 2 mg/mL

• A negative cephalosporin skin test must be followed by a drug challenge to confirm tolerance, as the validity of cephalosporin skin testing remains uncertain 1

Interpretation and Clinical Action

If Skin Test is Positive:

• The patient has drug-specific IgE antibodies 1
• Either administer a skin test-negative alternative beta-lactam with dissimilar R1 side chains 1
• Or proceed with desensitization if the specific drug is essential 1

If Skin Test is Negative:

• Always perform a graded drug challenge (1-2 steps) to confirm tolerance before prescribing the antibiotic 1
• The negative predictive value of penicillin skin testing is 100% when followed by challenge 6
• Challenge steps should be determined by allergy history severity, clinical stability, and R1 side chain similarity 1

Critical Pitfalls to Avoid

• Do not rely on skin testing alone—negative tests require confirmation with drug challenge, as sensitivity is imperfect 1
• Do not perform skin testing for oral cephalosporins—it has no clear clinical utility 1
• Do not assume cross-reactivity is high—actual penicillin-cephalosporin cross-reactivity is only 2-4.8%, not the 10% listed on package inserts 1
• Do not skin test patients with non-IgE-mediated reactions—testing only predicts immediate hypersensitivity 1
• Recognize that most "allergies" are not real—over 90% of reported beta-lactam allergies are not confirmed upon formal evaluation 1, 7

Understanding Cross-Reactivity by Side Chains

Cross-reactivity is primarily determined by R1 side chain similarity, not the beta-lactam ring 1:

• Aminocephalosporins (cephalexin, cefadroxil, cefprozil, cefaclor) share R1 side chains with amoxicillin/ampicillin and have 16.45% cross-reactivity 1
• Low-similarity cephalosporins (cefazolin, cefpodoxime, ceftriaxone, ceftazidime) have only 2.11% cross-reactivity 1
• Cefazolin has a unique side chain and demonstrates very low cross-reactivity with penicillins despite being first-generation 1