Time to challenge penicillin allergy labels

Clinical question

Can low-risk patients with β-lactam allergy receive an oral β-lactam challenge safely?

Bottom line

In adults with a history of nonsevere cutaneous reaction to a β-lactam more than 5 to 10 years ago, the penicillin allergy label can be removed 87% to 98% of the time. Direct oral challenge with a β-lactam is likely as safe and effective as doing a skin test first. The risk of severe adverse reaction is less than 1%.

Evidence

• Oral challenge alone versus skin test followed by oral challenge (if skin test is negative):

  • - Two RCTs in patients recruited from outpatient allergy clinics with nonsevere cutaneous reaction to β-lactam more than 1 year ago (children)¹ or more than 10 years ago (adults)^1,2:

    • — In 1 RCT (382 adults) of 250 to 500 mg of amoxicillin,² there were no serious adverse effects, hospitalizations, or emergency department visits. The allergy label was removed for more than 98% (both groups). There was 1 immune-mediated reaction in each group (cutaneous, mild) less than 1 hour after the test. There was delayed rash or urticaria in 3.2% versus 1.6% for skin test (no statistical difference).

    • — In 1 RCT (159 adults and children) of 20 to 40 mg of amoxicillin, then 200 to 400 mg 30 minutes later,¹ reaction occurred less than 30 minutes after testing in 4% (cutaneous, mild) versus 0% for skin test (no statistical difference; PEER team calculation). The allergy label was removed in 96% versus 87% (no statistical difference).

• Oral challenge with no prior skin testing:

  • - Six systematic reviews of cohort studies in children and adults (mostly outpatients, 2 to 31 cohorts, 595 to 6980 oral challenges)^3-8:

  • - Immediate or delayed hypersensitivity reactions in 2.7% to 8.8%.^3-7

  • - Severe reactions (eg, anaphylaxis needing epinephrine, serum-like illness, interstitial nephritis) occurred in 0% to 0.04%.^6-8 An additional systematic review had inconsistent reporting.³

• Limitations included variation in definitions of low-risk patients and harms (eg, anaphylaxis); and limited primary care data.

Context

• About 10% of people report a penicillin allergy.⁹ The use of broad-spectrum antibiotics in patients with erroneous allergy labels has been associated with longer hospitalizations, increased risk of Clostridium difficile infections, and increased medical costs.¹⁰

• Amoxicillin is associated with non–immunoglobulin E (delayed onset) rash in 7% or fewer children, usually with concurrent viral infection.¹⁰

Implementation

Guidelines recommend a direct amoxicillin challenge (with no preceding skin test) for adults with remote history (>5 years) of benign cutaneous reactions to β-lactams.¹⁰ An option would be 250 to 500 mg of amoxicillin with a 1-hour observation period (with antihistamine and epinephrine available). As RCTs come from specialty clinics, not primary care, referral to a specialist clinic would also be reasonable. For adults with a history of anaphylaxis or recent immunoglobulin E–mediated reaction, a skin test should be done before an oral challenge.¹⁰ Patients with a history of severe cutaneous reactions to β-lactams (eg, drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome) should not be tested and should not take β-lactams.¹⁰