Recruiting
Phase 2

Cephalosporin Allergy

Sponsor:

Massachusetts General Hospital

Code:

NCT06406114

Conditions

Drug Allergy

Cephalosporin Allergy

Drug Hypersensitivity

Antibiotic Allergy

Beta Lactam Adverse Reaction

Eligibility Criteria

Sex: All

Age: 18 - 70

Healthy Volunteers: Not accepted

Interventions

Beta-lactam antibiotic (cefazolin, cefuroxime, cefotaxime, ceftazidime, ceftriaxone, cefepime, pre-pen, penicillin G, ampicillin, and histamine) double-blind skin testing

Culprit cephalosporin (cefazolin, ceftazidime, ceftriaxone, cefepime, cephalexin, cefaclor, cefadroxil, cefuroxime, cefpodoxime, cefdinir, or cefixime) double-blind placebo-controlled drug challenge

Similar cephalosporin (cefepime, ceftriaxone, cefaclor, cephalexin, cefixime, or cefdinir) antibiotic double-blind placebo-controlled drug challenge

Dissimilar cephalosporin (ceftriaxone or cefazolin) antibiotic double-blind placebo-controlled drug challenge

Amoxicillin double-blind placebo-controlled drug challenge

Study Details

Brief summary:

Cephalosporin antibiotics are commonly used but can result in allergic reactions and anaphylaxis. There is no clear diagnostic approach for cephalosporin-allergic patients, and guidance for the use of other antibiotics in allergic patients is based on side chain chemical similarity and limited skin testing evidence. This project includes a clinical trial and mechanistic studies to optimize the approach to cephalosporin allergy and advance future diagnostics.

Conditions

Drug Allergy

Cephalosporin Allergy

Drug Hypersensitivity

Antibiotic Allergy

Beta Lactam Adverse Reaction

Study ID

NCT06406114

Start date

May 5, 2025

Status verified date

Jan, 2026

Completion date

Dec 31, 2028

Anticipated

Primary completion date

Jul 1, 2028

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: All

Age: 18 - 70

Healthy Volunteers: Not accepted

Inclusion Criteria:

1. Age 18-70 years old.
2. Reaction history consistent with a potential immediate hypersensitivity reaction (pruritus, urticaria, erythema, angioedema, bronchospasm, wheezing, shortness of breath, anaphylaxis, or hypotension) to cefazolin, ceftazidime, ceftriaxone, cefepime, cephalexin, cefaclor, cefadroxil, cefuroxime, cefpodoxime, cefdinir, or cefixime.
3. English speaking or non-English speaking with translation services available.

Exclusion Criteria:

1. Severe concomitant medical condition (e.g., unstable coronary artery disease, congestive heart failure, severe chronic obstructive pulmonary disease, poorly controlled asthma, chronic renal failure, cirrhosis, or end-stage liver disease.)
2. History of Clostridioides difficile infection
3. Chronic spontaneous urticaria or systemic mastocytosis
4. Incident reaction required cardiopulmonary resuscitation
5. Reaction to 2 or more cephalosporin antibiotics
6. Active infection or antibiotic treatment within 7 days
7. Treatment with systemic antihistamines or corticosteroids within 7 days
8. Treatment with omalizumab or dupilumab within 60 days
9. Significant immunosuppression
10. Treatment with a beta-blocker or ACE inhibitor within 7 days
11. Use of investigational drugs within 60 days of participation
12. Anaphylaxis in the last 30 days
13. Penicillin anaphylaxis within the past year confirmed with positive penicillin skin tests
14. Prison or jail inmates, pregnant women, severe cognitive impairment
15. Current, diagnosed, mental illness or current, diagnosed, or self-reported drug or alcohol abuse that, in the opinion of the investigator, would interfere with the participant's ability to comply with study requirements
16. Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study.
17. Inability or unwillingness of a participant to give written informed consent or comply with study protocol

Study Design

Enrollment

300 participants

Anticipated

Allocation

Randomized

Intervention Model

Crossover

Primary purpose

Diagnostic

Interventions and Outcome Measures

Arms

experimental: Similar cephalosporin first

In visit 2, confirmed-allergic subjects will have a double-blind placebo-controlled drug challenge to a similar side chain cephalosporin, followed by a double-blind placebo-controlled challenge to a dissimilar side chain cephalosporin in visit 3. The randomization of which cephalosporin (similar or dissimilar side chain) is challenged in visits 2 and 3 differentiates the two arms.

experimental: Dissimilar cephalosporin first

In visit 2, confirmed-allergic subjects will have a double-blind placebo-controlled drug challenge to a dissimilar side chain cephalosporin, followed by a double-blind placebo-controlled challenge to a similar side chain cephalosporin in visit 3. The randomization of which cephalosporin (similar or dissimilar side chain) is challenged in visits 2 and 3 differentiates the two arms.

Interventions

Beta-lactam antibiotic (cefazolin, cefuroxime, cefotaxime, ceftazidime, ceftriaxone, cefepime, pre-pen, penicillin G, ampicillin, and histamine) double-blind skin testing

Percutaneous and intradermal skin testing will be performed in all participants. Concentrations for percutaneous testing; cefazolin (330 mg/ml), cefuroxime (90 mg/ml), ceftazidime (100 mg/ml), ceftriaxone (100 mg/ml), cefepime (200 mg/ml), pre-pen (undiluted), penicillin G (10,000 U/ml), ampicillin (20 mg/ml) and histamine (6 mg/ml). Concentrations for the first intradermal testing; cefazolin (3.3mg/ml), cefuroxime (1 mg/ml), ceftazidime (1 mg/ml), ceftriaxone (1 mg/ml), cefepime (2 mg/ml), Pre-PEN (undiluted), penicillin G (1000 U/ml), ampicillin (20 mg/ml), and histamine (0.1 mg/ml). Concentrations for the second intradermal testing; cefazolin (33mg/ml), cefuroxime (10 mg/ml), ceftazidime (10 mg/ml), ceftriaxone (10 mg/ml), cefepime (20 mg/ml), Pre-PEN (undiluted), penicillin G (10,000 U/ml), ampicillin (20 mg/ml) and histamine (0.1 mg/ml). Histamine and saline will be used as positive and negative controls.

Culprit cephalosporin (cefazolin, ceftazidime, ceftriaxone, cefepime, cephalexin, cefaclor, cefadroxil, cefuroxime, cefpodoxime, cefdinir, or cefixime) double-blind placebo-controlled drug challenge

After double-blind skin testing, participants will undergo a 3-step double-blind placebo-controlled drug challenge to their culprit cephalosporin (the cephalosporin they are suspected to be allergic to, either cefazolin, ceftazidime, ceftriaxone, cefepime, cephalexin, cefaclor, cefadroxil, cefuroxime, cefpodoxime, cefdinir, or cefixime). The challenges are 1:1 randomized to the order of active drug versus placebo. In Step 1, participants will receive 1:1000 of a full dose of either the culprit drug or placebo, followed by a 30-minute observation period. In Step 2, participants will receive 1:50 of a full dose of either, followed by another 30-minute observation period. In Step 3, participants are administered the full dose of either agent, followed by a 60-minute observation period. The same testing process is repeated for the second challenge.

Similar cephalosporin (cefepime, ceftriaxone, cefaclor, cephalexin, cefixime, or cefdinir) antibiotic double-blind placebo-controlled drug challenge

Participants will undergo a 3-step double-blind placebo-controlled drug challenge to a cephalosporin antibiotic that shares a similar side chain with their culprit. This will be cefepime for those allergic to ceftriaxone, cefaclor for those allergic to cephalexin, cefixime for those allergic to cefdinir, cefdinir for those allergic to cefixime, cephalexin for those allergic to cefaclor or cephadroxil, and ceftriaxone for those allergic to cefepime, cefuroxime, or cefpodoxime. The challenges are 1:1 randomized to the order of active drug versus placebo. In Step 1, participants will receive 1:1000 of a full dose of either the culprit drug or placebo, followed by a 30-minute observation period. In Step 2, participants will receive 1:50 of a full dose of either, followed by another 30-minute observation period. In Step 3, participants are administered the full dose of either agent, followed by a 60-minute observation period. The same testing process is repeated for the second challenge.

Dissimilar cephalosporin (ceftriaxone or cefazolin) antibiotic double-blind placebo-controlled drug challenge

Participants will undergo a 3-step double-blind placebo-controlled drug challenge to a cephalosporin antibiotic that has a dissimilar side chain to their culprit. This will be ceftriaxone for those allergic to cefazolin, and cefazolin for those allergic to any other cephalosporin. The challenges are 1:1 randomized to the order of active drug versus placebo. In Step 1, participants will receive 1:1000 of a full dose of either the culprit drug or placebo, followed by a 30-minute observation period. In Step 2, participants will receive 1:50 of a full dose of either, followed by another 30-minute observation period. In Step 3, participants are administered the full dose of either agent, followed by a 60-minute observation period. The same testing process is repeated for the second challenge.

Amoxicillin double-blind placebo-controlled drug challenge

Participants will optionally undergo a 3-step double-blind placebo-controlled drug challenge to Amoxicillin. The challenges are 1:1 randomized to the order of active drug versus placebo. In Step 1, participants will receive 1:1000 of a full dose of either the culprit drug or placebo, followed by a 30-minute observation period. In Step 2, participants will receive 1:50 of a full dose of either, followed by another 30-minute observation period. In Step 3, participants are administered the full dose of either agent, followed by a 60-minute observation period. The same testing process is repeated for the second challenge. The order of challenge to similar vs. dissimilar cephalosporin will be randomized as well.

Primary outcome measure

  • Proportion of participants with confirmed culprit cephalosporin allergy [ Time Frame: Up to 7 weeks ]
  • Cephalosporin skin test sensitivity and specificity [ Time Frame: Up to 7 weeks ]
  • Proportion of cross-reactivity to other cephalosporins in confirmed-allergic subjects [ Time Frame: Up to 7 weeks ]

Central Contacts and Locations

Central contacts

Cara Yelverton, BSc, PhD

6177242415cyelverton@mgh.harvard.edu

Kell Lopez, BS

6177320589klopez5@bwh.harvard.edu

Locations

Mayo Clinic Arizona

Recruiting

Scottsdale, Arizona, United States, 14607

Contacts

Alexei Gonzalez-Estrada, MD

904-953-2451gonzalez.alexei@mayo.edu

Renee Nunez, BS

480-574-1826Nunez.Renee@mayo.edu

Principal Investigator:

Alexei Gonzalez-Estrada, MD

University of California, San Francisco

Recruiting

San Francisco, California, United States, 94143

Contacts

Monica Tang, MD

415-514-8044dacat@ucsf.edu

Lina Kamil

916-743-8466Lina.Kamil@ucsf.edu

Massachusetts General Hospital

Recruiting

Boston, Massachusetts, United States, 02114

Contacts

Aleena Banerji, MD

6177263850ABANERJI@mgh.harvard.edu

Noah Im, BS

617-726-2974noim@mgh.harvard.edu

Principal Investigator:

Aleena Banerji, MD

Rochester General Hospital

Recruiting

Rochester, New York, United States, 14621

Contacts

Allison C Ramsey, MD

585-922-8350allison.ramsey@rochesterregional.org

Dawn Shefflin, RN

585-922-8314dawn.sheflin@rochesterregional.org

Principal Investigator:

Allison C Ramsay, MD

Vanderbilt University Medical Center

Recruiting

Nashville, Tennessee, United States, 37232

Contacts

Elizabeth Phillips, MD

6153100339elizabeth.j.phillips@vumc.org

April O'Connor, RN

615-957-6057april.oconnor@vumc.org

Principal Investigator:

Elizabeth Phillips, MD

University of Texas Southwestern Medical Center

Recruiting

Dallas, Texas, United States, 75390

Contacts

David A Khan, MD

214-406-5119Dave.Khan@UTSouthwestern.edu

Sophia Lopez, BS

469-444-0531Sophia.Lopez@UTSouthwestern.edu

Principal Investigator:

Dave Khan, MD

More Information

Sponsor

Massachusetts General Hospital

Last update posted

Sep 4, 2026

Last verified

Jan, 2026

Keywords

  • Allergy
  • Antibiotic
  • Cephalosporin
  • Penicillin
  • Beta-lactam
  • Drug challenge
  • Skin testing
  • Adverse reaction
  • Anaphylaxis
  • Perioperative anaphylaxis

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-09. This information was provided to ClinicalTrials.gov by Massachusetts General Hospital on 2026-09-04.