Amoxicillin Challenge for Penicillin Allergy

Overseen By Study Coordinator

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: James Tarbox, MD

Must not be taking: Antihistamines, Steroids, Antibiotics

Disqualifiers: High-risk penicillin allergy, Anaphylaxis, Pregnancy, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

The goal of this clinical trial is to learn about dosing when testing to see if a penicillin allergy label can be removed from adults that had been labeled as "penicillin-allergic" previously. The main question it aims to answer is: - In penicillin-allergic patients that are at low risk of having an allergic reaction, is a one-dose oral challenge with amoxicillin (a penicillin-based antibiotic) as safe and effective as a two-dose oral challenge? Participants will, after being identified as having a low-risk penicillin allergy, be administered oral amoxicillin in a controlled setting and then monitored for an allergic reaction. Researchers will compare participants that took one dose of amoxicillin to participants that took two doses of amoxicillin (a small dose and then a larger dose) to see if either group was more likely to develop an allergic reaction.

Will I have to stop taking my current medications?

The trial requires you to stop taking H1- or H2-blockers (like diphenhydramine or famotidine) 72 hours before the test and any antibiotics you are currently taking. If you are on beta blockers or ACE inhibitors, you will discuss with the study team to decide if you should continue them.

What data supports the effectiveness of the drug Amoxicillin for patients with a reported penicillin allergy?

Research shows that many people who think they are allergic to penicillin, including amoxicillin, are not truly allergic. Studies suggest that patients at low risk of amoxicillin allergy can safely take the drug, which helps avoid using less effective and more expensive antibiotics. ^{1 2 3 4 5}

Is amoxicillin generally safe for people with a penicillin allergy?

Studies show that most people who think they are allergic to penicillin can safely take amoxicillin, especially if their past reactions were mild or happened a long time ago. In a study, none of the patients who took an oral amoxicillin challenge had immediate allergic reactions, and only a few had mild symptoms that were not serious. ^{6 7 8 9 10}

How is the drug Amoxicillin unique in treating penicillin allergy?

Amoxicillin is unique in treating penicillin allergy because it can be used in an oral provocation challenge (OPC) to safely test if patients with a reported penicillin allergy truly have an allergy, potentially avoiding the need for less effective and more expensive antibiotics. ^{1 2 6 11 12}

Research Team

James A Tarbox, MD

Principal Investigator

Texas Tech University Health Sciences Center

Eligibility Criteria

This trial is for adults previously labeled as 'penicillin-allergic' but are considered low-risk for an actual allergic reaction. They will be given amoxicillin to see if their allergy label can be safely removed.

Inclusion Criteria

Reports an allergy to one of the following medications: penicillin VK, penicillin G, amoxicillin, ampicillin, dicloxacillin, flucloxacillin, nafcillin, oxacillin, amoxicillin-clavulanate, ampicillin-sulbactam. Subjects with an unspecified penicillin allergy are also eligible to participate.

I have shown interest in the study by contacting or filling out a form.

Exclusion Criteria

I use beta blockers or ACE inhibitors and will discuss penicillin allergy testing with my doctor.

Pregnant (self-reported)

Penicillin allergy deemed to be more than 'low-risk' per PEN-FAST (score ≥ 3 points)

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Direct Oral Challenge

Participants receive either a one-dose or two-dose graded direct oral challenge with amoxicillin to test for penicillin allergy delabeling

1 day

1 visit (in-person)

Immediate Follow-up

Participants are monitored for immediate allergic reactions for at least 1 hour after the final dose of amoxicillin

2 hours

1 visit (in-person)

Short-term Follow-up

Participants are contacted 5 days after the challenge to evaluate for any delayed reactions

5 days

1 phone call

Long-term Follow-up

Participants are contacted 6 months after the challenge to evaluate for any reactions to antibiotics received since successful delabeling

6 months

1 phone call

Treatment Details

Interventions

• Amoxicillin (Anti-bacterial)

Trial Overview The study tests whether a single dose of oral amoxicillin is as safe and effective in delabeling penicillin allergy as a two-dose challenge, with participants monitored for any allergic reactions.

Participant Groups

Group I: One-dose group Experimental Treatment 2 Interventions

Patients assigned to this group will receive a liquid placebo followed by full-dose liquid amoxicillin 250mg PO thirty minutes later.

Group II: Graded, two-dose group Active Control 2 Interventions

Patients assigned to this group will receive liquid amoxicillin (25% of 250mg dose), followed by liquid amoxicillin 187.5mg PO (75% of 250mg dose) thirty minutes later.

Amoxicillin is already approved in Canada for the following indications:

Approved in Canada as Amoxicillin for:

• Bacterial infections
• Respiratory tract infections
• Urinary tract infections
• Skin and soft tissue infections

Who Is Running the Clinical Trial?

James Tarbox, MD

Lead Sponsor

Trials

1

Recruited

380+

Texas Tech University Health Sciences Center

Collaborator

Trials

107

Recruited

11,500+

Findings from Research

In a study of 99 patients at low risk for amoxicillin allergy, 97% successfully underwent an oral provocation challenge (OPC) without any serious reactions, demonstrating the safety of this procedure in primary care settings.

The study suggests that implementing OPC for penicillin allergies in primary care could help correct false allergy labels, potentially improving patient access to effective antibiotics and reducing healthcare costs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amoxicillin oral provocation challenge in a primary care clinic: a descriptive analysis. Gateman, DP., Rumble, JE., Protudjer, JLP., et al.[2021]

Out of 288 subjects with a history of penicillin allergy, 22% were confirmed to be allergic through a combination of skin tests, IgE measurements, and direct challenge tests, highlighting the importance of comprehensive testing for accurate diagnosis.

The study revealed that relying solely on benzyl or phenoxymethyl-penicillin tests would have missed 31% of the confirmed allergic cases, indicating that side chain-specific diagnostic tests are crucial for identifying true penicillin allergies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allergy to penicillin with good tolerance to other penicillins; study of the incidence in subjects allergic to beta-lactams. Blanca, M., Vega, JM., Garcia, J., et al.[2019]

Despite the low likelihood of true penicillin allergy in patients with a documented history, a case study of a 74-year-old woman revealed that rechallenging with amoxicillin/clavulanate led to an allergic reaction, highlighting the potential risks involved in such protocols.

This case underscores the importance of careful assessment and monitoring when considering rechallenge protocols for patients with a long-standing history of penicillin allergy, even when the risk of reactivity is thought to be low.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Penicillin allergy that persisted after 66 years: case report. Anukam, E., Zhu, J.[2023]

Skin tests commonly used to identify penicillin allergies may not effectively detect allergies to specific beta-lactam antibiotics, as shown in six patients who had anaphylactic reactions to amoxicillin but tolerated other beta-lactams.

Four out of the six patients tested positive for amoxicillin skin tests, highlighting the need for more comprehensive allergy testing to ensure patient safety when prescribing beta-lactam antibiotics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allergy to amoxicillin in patients who tolerated benzylpenicillin, aztreonam, and ceftazidime. Martin, JA., Igea, JM., Fraj, J., et al.[2019]

Proper evaluation of penicillin allergy, through skin testing and assessment of previous reactions, is essential for determining whether patients should receive alternative antibiotics or undergo desensitization, especially since penicillin is often the only effective treatment for certain infections.

The review highlights that penicillin allergy can complicate treatment options, particularly with cephalosporins, and emphasizes the need for more research on cross-reactivity and hypersensitivity between these antibiotics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A perspective on penicillin allergy. Lin, RY.[2022]

A study reviewing 325 patient charts found that adjusting electronic medical record alerting rules for β-lactam antibiotics resulted in no cases of anaphylaxis (0%) among patients who received these medications after being documented as allergic to penicillins.

The new alerting rules, which only flagged similar side chain antibiotics, effectively reduced unnecessary alerts for prescribers while maintaining patient safety, although some patients did experience non-anaphylactic delayed reactions like rashes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

β-lactam exposure outcome among patients with a documented allergy to penicillins post-implementation of a new electronic medical record system and alerting rules. Buffone, B., Lin, YC., Grant, J.[2022]

Many patients labeled with a penicillin allergy do not actually have a confirmed allergy, which can lead to unnecessary avoidance of penicillins and other related antibiotics.

Understanding the characteristics that differentiate low-risk from high-risk patients for true penicillin allergy is crucial for proper assessment and management of antibiotic treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Penicillin allergy-getting the label right. [2017]

In a study of 50 adults with a penicillin allergy label, 76% were eligible for a direct oral amoxicillin challenge, and none experienced immediate or delayed hypersensitivity reactions, indicating the safety of this approach.

The study found that 48% of participants had their penicillin allergy label removed after the challenge, supporting the efficacy of direct oral challenges in de-labeling patients who are not truly allergic.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Direct oral amoxicillin challenge without preliminary skin testing in adult patients with allergy and at low risk with reported penicillin allergy. Kuruvilla, M., Shih, J., Patel, K., et al.[2019]

Most reported penicillin allergies are not clinically significant, and skin testing can safely confirm or refute true IgE-mediated allergies, allowing for the safe use of penicillin in many patients.

There is minimal cross-reactivity between penicillins and other beta-lactam antibiotics, meaning that cephalosporins and other alternatives can be safely used even in patients with a confirmed penicillin allergy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Penicillin and beta-lactam allergy: epidemiology and diagnosis. Macy, E.[2022]

Penicillin, particularly amoxicillin, is a common cause of allergic reactions and anaphylaxis, with adverse events occurring in 1% to 10% of cases, and up to 10% of these can be life-threatening, especially in patients without prior allergy history.

The case of a 5-year-old girl who experienced a severe allergic reaction to amoxicillin highlights the importance of recognizing and managing penicillin hypersensitivity, especially in pediatric dental settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse reaction to amoxicillin: a case report. da Fonseca, MA.[2013]

A case study of a woman who developed allergic reactions to amoxicillin-clavulanic acid after previously tolerating it well suggests that sensitization can occur even after prior exposure without issues.

Testing revealed that while she had undetectable IgE levels to several beta-lactam antibiotics, she developed specific IgE to penicillin V later, indicating a unique sensitization to the combination of amoxicillin and clavulanic acid rather than cross-reactivity with other beta-lactams.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selective sensitization to clavulanic acid and penicillin V. González de Olano, D., Losada, PA., Caballer, Bde L., et al.[2013]

In a study of 247 children and adolescents with suspected allergies to penicillin, amoxicillin, and cephalosporins, only 34% were confirmed to have IgE-mediated reactions through skin testing and oral challenges, indicating that many diagnosed allergies may not be true allergies.

The study found that after negative skin tests, 163 patients safely received beta-lactam antibiotics, with only 1.8% experiencing mild adverse reactions, highlighting the importance of skin testing to accurately identify patients who can tolerate these medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diagnosis of penicillin, amoxicillin, and cephalosporin allergy: reliability of examination assessed by skin testing and oral challenge. Pichichero, ME., Pichichero, DM.[2019]

References

1. Canada pubmed.ncbi.nlm.nih.gov

Amoxicillin oral provocation challenge in a primary care clinic: a descriptive analysis. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Allergy to penicillin with good tolerance to other penicillins; study of the incidence in subjects allergic to beta-lactams. [2019]

3. England pubmed.ncbi.nlm.nih.gov

Penicillin allergy that persisted after 66 years: case report. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Allergy to amoxicillin in patients who tolerated benzylpenicillin, aztreonam, and ceftazidime. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

A perspective on penicillin allergy. [2022]

6. Canada pubmed.ncbi.nlm.nih.gov

β-lactam exposure outcome among patients with a documented allergy to penicillins post-implementation of a new electronic medical record system and alerting rules. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Penicillin allergy-getting the label right. [2017]

8. United States pubmed.ncbi.nlm.nih.gov

Direct oral amoxicillin challenge without preliminary skin testing in adult patients with allergy and at low risk with reported penicillin allergy. [2019]

9. United States pubmed.ncbi.nlm.nih.gov

Penicillin and beta-lactam allergy: epidemiology and diagnosis. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Adverse reaction to amoxicillin: a case report. [2013]

11. Spain pubmed.ncbi.nlm.nih.gov

Selective sensitization to clavulanic acid and penicillin V. [2013]

12. United States pubmed.ncbi.nlm.nih.gov

Diagnosis of penicillin, amoxicillin, and cephalosporin allergy: reliability of examination assessed by skin testing and oral challenge. [2019]