What is the recommended approach to allergy testing for a patient with a suspected antibiotic reaction, including detailed history, skin testing for β‑lactam antibiotics, and graded oral challenge?

Allergy Testing for Antibiotic Allergy

Begin with a detailed allergy history to stratify risk, then proceed directly to label removal without testing for low-risk cases, or advance to formal skin testing and graded oral challenge for higher-risk β-lactam allergies based on reaction severity and timing. 1

Step 1: Obtain a Comprehensive Allergy History

Document the following specific details to risk-stratify the patient 1:

• Patient factors: Exact symptoms of the reaction, date of occurrence, concurrent medications, and comorbidities 1
• Medication factors: Specific drug name, route of administration, timing relative to drug exposure, and dose 1
• Treatment factors: Clinical setting, time to symptom resolution, management provided, and final outcome 1

This detailed history allows you to categorize patients into no/low-risk versus higher-risk groups, which determines whether testing is needed at all 1.

Step 2: Identify Patients Who Can Be Delabeled Without Testing

Remove the antibiotic allergy label immediately without any testing if any of the following criteria apply 1:

• The patient has used the culprit drug since the index reaction without any allergic reaction 1
• The allergy label was based solely on family history or fear of allergy 1
• Reported symptoms are incompatible with true allergy (gastrointestinal complaints only, palpitations, blurred vision, headache) 1
• No temporal association exists between drug exposure and symptom onset 1
• The index reaction was non-severe, confined to skin, and occurred in remote childhood or adolescence 1
• The patient cannot recollect any clinical signs or symptoms of the reaction 1

Over 90% of patients with penicillin allergy labels can be delabeled after proper assessment, with most requiring only history alone 1. This approach is supported by strong evidence showing excellent negative predictive values for low-risk categorization 1.

Step 3: Risk-Stratify Remaining Patients by Reaction Type and Timing

For Non-Severe Immediate-Type Reactions:

• If >5 years since reaction: Administer a therapeutic dose of the culprit β-lactam in a controlled setting without prior testing 1
• If ≤5 years since reaction: Refer for formal allergy work-up with skin testing before re-exposure 1

For Severe Immediate-Type Reactions:

• Refer for formal allergy work-up regardless of time elapsed 1
• If formal testing unavailable and antibiotic indication is vital, consider re-exposure in a controlled setting only 1

For Non-Severe Delayed-Type Reactions:

• If >1 year since reaction: Administer the culprit β-lactam without formal testing 1
• If <1 year since reaction: Avoid exposure 1

For Severe Delayed-Type Reactions:

• Avoid re-exposure to the culprit drug regardless of time elapsed 1
• Only consider use after multidisciplinary team discussion if no acceptable alternatives exist 1

Step 4: Formal Allergy Testing Protocol for β-Lactams

When formal testing is indicated, proceed with the following standardized approach 2:

Skin Testing for Penicillins:

• Perform skin prick testing followed by intradermal testing using penicilloyl-polylysine and native penicillin G 3, 4
• Negative predictive value for penicillin skin tests is 96.3% for immediate-type reactions 2
• Skin testing has excellent safety, with systemic reactions occurring in only 0.7% of tests 2

Skin Testing for Cephalosporins:

• Use the native cephalosporin for skin testing when available 5
• Negative predictive value for cephalosporin skin tests is 100% for immediate-type reactions and 87.5% for delayed reactions 2
• Routine cephalosporin skin testing should be restricted to research settings and is rarely needed clinically 3

Drug Provocation Test (Graded Oral Challenge):

• If skin testing is negative, proceed to graded oral challenge with the culprit antibiotic 1, 2
• Graded challenges are safe, with allergic reactions occurring in only 3.1% of challenges 2
• The pooled prevalence of true penicillin allergy confirmed by challenge is 1.98% in children and 7.78% in adults 1

Step 5: Understanding Cross-Reactivity Patterns

Penicillin-Allergic Patients:

• Cross-reactivity between penicillins and cephalosporins is much lower than historically reported at approximately 0.1% for non-severe reactions 1
• Cross-reactivity is primarily driven by identical or similar side-chain structures, not the β-lactam ring itself 1, 5
• Carbapenems can be administered directly without testing in penicillin-allergic patients, as cross-reactivity is <1% 5, 6
• Aztreonam shows minimal cross-reactivity with penicillins (<1%) except in ceftazidime allergy due to shared side chains 5, 6

Cephalosporin-Allergic Patients:

• Cephalosporins with different side-chain structures can be safely used 1, 3
• Avoid cephalosporins with identical or similar side chains to the culprit drug if the reaction occurred <1 year ago 1
• Carbapenems can be used regardless of time since reaction 1

Critical Pitfalls to Avoid

• Never use cephalosporins in patients with Stevens-Johnson syndrome, toxic epidermal necrolysis, or DRESS syndrome from any β-lactam 1
• Do not assume all β-lactam allergies are cross-reactive; side-chain similarity is the primary determinant, not the β-lactam ring 1, 5
• Avoid unnecessary broad-spectrum antibiotics in unverified allergy, as this increases costs and antimicrobial resistance 2, 4
• Penicillin allergy wanes over time; patients lose skin test sensitivity with longer intervals between reaction and testing 1
• Aminopenicillin-allergic patients may show >30% cross-reactivity with aminocephalosporins due to shared side chains 5

When Formal Testing Is Unavailable

If allergy testing is not accessible and the antibiotic indication is vital 1:

• Administer the antibiotic in a controlled setting with resuscitation equipment available 1
• This applies to non-severe immediate-type reactions ≤5 years old or severe immediate-type reactions when no alternatives exist 1