Safely evaluating penicillin allergy with 2-step Graded Oral Challenge


Recent findings revealed the efficacy and safety of the 2-step Graded Oral Challenge method in assessing penicillin allergy risk, offering a promising approach for improved patient care and antibiotic stewardship in low-risk individuals.

Safely evaluating penicillin allergy with 2-step Graded Oral Challenge | Image Credit: © Archivist - © Archivist -

Safely evaluating penicillin allergy with 2-step Graded Oral Challenge | Image Credit: © Archivist - © Archivist -

Penicillin allergy can be safely evaluated using 2-step Graded Oral Challenge (GOC), according to a recent study published in Clinical Infectious Diseases.


  1. Self-reported penicillin or beta-lactam allergy is prevalent, with up to 20% of patients in medical settings and 15% in STI clinics reporting it, yet only a small fraction are confirmed through evaluation.
  2. Overreported beta-lactam allergies lead to broad-spectrum antimicrobial overuse, increased healthcare costs, adverse drug events, longer hospitalizations, and higher mortality rates.
  3. Limited access to allergy evaluations in ambulatory care settings, where STIs are often treated, necessitates rapid and effective evaluation methods due to the complexity and resource requirements of traditional penicillin skin testing (PST).
  4. The Graded Oral Challenge (GOC) method, involving a 2-dose amoxicillin challenge, is recommended by allergy professional organizations for adults with low-risk penicillin allergy histories, showing high efficacy in evaluating penicillin allergy risk.
  5. A randomized clinical trial comparing PST with GOC demonstrated the safety and feasibility of GOC in determining the suitability of penicillin administration in low-risk patients, with a high percentage of participants deemed non-allergic and minimal adverse events reported.

A penicillin or beta-lactam allergy is self-reported in up to 20% of patients in medical settings and 15% in sexually transmitted infection (STI) clinics, but under 5% are confirmed during evaluation. Broad-spectrum antimicrobial overuse, increased health care costs, adverse drug events, surgical site infections, longer hospitalizations, and mortality are associated with overreported beta-lactam allergy.

There is limited access to allergy evaluations in ambulatory care settings where STIs are often treated. Penicillin skin testing (PST) is a common method, but this evaluation requires well-trained personnel, supplies, and time. Therefore, rapid treatment is necessary.

During GOC, penicillin allergy risk is evaluated using a 2-dose amoxicillin challenge. GOC is recommended in adults with low-risk penicillin allergy histories by American allergy professional organizations.

To compare PST with GOC for determining the safety and feasibility of penicillin administration in STI clinic settings, investigators conducted a randomized clinical trial. Participants included individuals aged 18 years or older with a reported history of penicillin or beta-lactam allergy.

Patients positive for HIV with a CD4 count under 200 cells/mm3, past week use of antihistamine, or rashes or extensive tattoos in regions needed for skin testing were excluded from the analysis.

The questionnaire was developed after literature review and expert consultation. High-risk histories excluded from the analysis included potentially IgE-mediated reactions angioedema, throat tightness, shortness of breath, arrhythmia, hypotension, anaphylaxis, hives, and syncope.

Delayed reactions such as severe cutaneous allergic reactions, drug-induced nephritis or hepatitis, serum sickness, blood dyscrasias, and drug feature were also excluded. Low-risk reactions were included, such as unknown remote reaction, rigors, gastrointestinal symptoms, family history of drug allergy, headache, fatigue, hives more than 5 years ago, non-urticarial rash, flushing, and pruritus without rash.

Low-risk patients were randomized to receive PST or GOC. Patients in the PST group received pinprick testing on the volar forearm, followed by internal skin testing using a 27 g needle and syringe.

Benzylpenicillin polylysine was used for testing. Oral amoxicillin 250 mg was given to patients in the PST group with a negative PST test unless they were pregnant, had abnormal vital signs, or had findings that would impede subsequent allergy assessments.

Patients in the GOC group received assessments for peak flow, vital signs, and a physical examination. Eligible patients then received amoxicillin 25 mg oral suspension. After treatment administration, vital signs and peak flow were monitored for 30 minutes. Patients with no reactions during either treatment were told they were not allergic.

There were 206 participants included in the final analysis, 12.7% of whom had HIV. Other than a higher rate of Black patients in the GOC group, demographic characteristics were similar between both groups. Negative prick tests were reported in all participants in the PST group, and 3 participants were excluded from the oral analysis.

A negative challenge was reported in 97% of the remaining participants in the PST group receiving amoxicillin 250 mg, while the remaining 3% presented with potential allergic reactions. Non-specific symptoms were reported in 2% of PST participants, leading to 94% being deemed non-allergic.

Amoxicillin 25 mg challenge to all participants in the GOC group, with a possible allergic reaction reported in 3.8% of patients. During the amoxicillin 250 mg challenge, 4% of the remaining patients experienced an allergic reaction, leading to 91.4% of patients being deemed non-allergic.

In total, 92.7% of low-risk participants were deemed non-allergic. Seventeen adverse events (AEs) were reported in 16 participants, 4 in the PST group and 13 in the GOC group. Of AEs, 88.2% were mild and 11.8% were moderate, with none being severe. In the GOC group, 7 AEs occurred following the first dose vs 5 following the second dose.

These results indicated safety and efficacy of GOC in evaluating the risk of penicillin allergy in low-risk patients. Investigators concluded COG may provide a pathway to improve patient care and antibiotic stewardship.


Rebecca A Lillis, Lindley A Barbee, Candice J McNeil, et al. Randomized multicenter trial for the validation of an easy to administer algorithm to define penicillin allergy status in sexually transmitted infection clinic outpatients. Clinical Infectious Diseases. 2024 doi:10.1093/cid/ciae064

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