Optimizing the Diagnostic Approach to Cephalosporin Allergy Testing

Phase 2

Not yet recruiting

• Conditions: Drug Allergy; Cephalosporin Allergy; Drug Hypersensitivity; Antibiotic Allergy; Beta Lactam Adverse Reaction; Drug-Induced Anaphylaxis; Cephalosporin Reaction
• Interventions: Drug: Beta-lactam antibiotic (cefazolin, cefuroxime, cefotaxime, ceftazidime, ceftriaxone, cefepime, pre-pen, penicillin G, ampicillin, and histamine) double-blind skin testing; Drug: Culprit cephalosporin (cefazolin, ceftazidime, ceftriaxone, cefepime, cephalexin, cefaclor, cefadroxil, cefuroxime, cefpodoxime, cefdinir, or cefixime) double-blind placebo-controlled drug challenge; Drug: Similar cephalosporin (cefepime, ceftriaxone, cefaclor, cephalexin, cefixime, or cefdinir) antibiotic double-blind placebo-controlled drug challenge; Drug: Dissimilar cephalosporin (ceftriaxone or cefazolin) antibiotic double-blind placebo-controlled drug challenge; Drug: Amoxicillin double-blind placebo-controlled drug challenge

• Registration Number: NCT06406114
• Lead Sponsor: Massachusetts General Hospital

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.

Detailed Description

Background:

In the United States, beta-lactam antibiotics are the leading cause of allergic reactions. Cephalosporin antibiotics, in particular, are the most common cause of drug-induced anaphylaxis and perioperative allergy. For penicillin allergy, the mechanism of allergy and the antigenic determinants are known; validated penicillin skin testing followed by drug challenge has a 100% negative predictive value to exclude an immunoglobulin (Ig)E-mediated reaction. For cephalosporin allergy, the antigenic determinants and mechanism are not known, and skin testing is not validated. The diagnostic test characteristics of skin testing with native cephalosporins remain unclear with no sensitivity nor specificity reported. Although beta-lactam cross-reactivity has been hypothesized to be from the similarity of the R1 side chains, rather than the beta-lactam ring, cross-reactivity estimates among beta-lactams vary. Furthermore, it is not known whether the variance in cross-reactivity is due to true allergy versus sensitization based on positive skin testing, given that drug challenges were not performed on skin-test-positive patients. While an IgE mechanism is assumed for cephalosporin allergy and supported by skin testing that has been positive, the biology has yet to be characterized, and some cephalosporin anaphylaxis can occur on the first exposure, which is inconsistent with an IgE mechanism. Given the complexity of cephalosporin structures and potential epitopes, there may be several distinct biologic pathways involved in cephalosporin allergy. Future diagnostics in cephalosporin allergy are reliant on determination of these biological pathways and finding key haptens.

Aims:

Current national practice guidelines related to cephalosporin allergy assessment are considered conditional and based on low-quality evidence. The overall goal is to identify the optimal diagnostic approach to cephalosporin allergy and determine beta-lactam cross-reactivity, while discovering the mechanism and antigenic determinants of cephalosporin allergy to advance future diagnostics. The investigators will do this through a clinical trial that will generate empirical evidence through novel trial procedures, double-blind skin testing, and double-blind placebo-controlled drug challenges. Specific aims are: 1) To determine the optimal approach to cephalosporin allergy evaluation; 2) To assess beta-lactam cross-reactivity in cephalosporin-allergic individuals; and 3) To investigate the antigenic determinants and mechanism of cephalosporin allergy.

Study Overview:

Enrolled and consented subjects will attend visit 1 for baseline screening, sample collection, double-blind skin testing to a beta-lactam panel, and a double-blind placebo-controlled challenge to their culprit cephalosporin antibiotic. Results of the culprit cephalosporin challenge determine subject's study timeline. Subjects confirmed as non-allergic to their culprit cephalosporin will return for visit 2 for venipuncture and blood collection, ending their participation in the study. Subjects who are confirmed as allergic to their culprit at visit 1 will return for three additional visits; visits 2 and 3 will include double-blind placebo-controlled challenges to a similar side chain and dissimilar side chain cephalosporin (as compared to the side chain of their culprit) to assess cross-reactivity. The order of these two challenges is randomized between visit 2 and 3, and the order of whether a similar or dissimilar side chain cephalosporin is challenged first (in visit 2) differentiates the comparator arms of this study. In visit 4, subjects from both comparator arms will undergo a double-blind placebo-controlled challenge to a penicillin to assess cross-reactivity between cephalosporins and penicillins. Completion of this penicillin challenge marks the end of participation for confirmed-allergic subjects. Venipuncture and sample collection will occur at each visit.

Study Timeline

• Study First Submitted: 2024-04-17
• Study First Submitted QC: 2024-05-07
• Study First Posted: 2024-05-09
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-18
• Last Update Posted: 2024-11-20
• Study Start: 2025-02-01
• Primary Completion: 2028-07-01
• Study Completion: 2028-12-31

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 300

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, and anaphylaxis) to cefazolin, ceftazidime, ceftriaxone, cefepime, cephalexin, cefaclor, cefadroxil, cefuroxime, cefpodoxime, cefdinir, or cefixime.
3. English speaking or non-English speaking with translation services available.

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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 systemic 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. Abnormal vital signs or unstable physical exam at Visit 1
13. Prison or jail inmates, pregnant women, severe cognitive impairment
14. 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
15. 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.
16. Inability or unwillingness of a participant to give written informed consent or comply with study protocol

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Similar cephalosporin first	Culprit cephalosporin (cefazolin, ceftazidime, ceftriaxone, cefepime, cephalexin, cefaclor, cefadroxil, cefuroxime, cefpodoxime, cefdinir, or cefixime) double-blind placebo-controlled drug challenge	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.
Similar cephalosporin first	Similar cephalosporin (cefepime, ceftriaxone, cefaclor, cephalexin, cefixime, or cefdinir) antibiotic double-blind placebo-controlled drug challenge	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.
Similar cephalosporin first	Dissimilar cephalosporin (ceftriaxone or cefazolin) antibiotic double-blind placebo-controlled drug challenge	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.
Dissimilar cephalosporin first	Beta-lactam antibiotic (cefazolin, cefuroxime, cefotaxime, ceftazidime, ceftriaxone, cefepime, pre-pen, penicillin G, ampicillin, and histamine) double-blind skin testing	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.
Dissimilar cephalosporin first	Culprit cephalosporin (cefazolin, ceftazidime, ceftriaxone, cefepime, cephalexin, cefaclor, cefadroxil, cefuroxime, cefpodoxime, cefdinir, or cefixime) double-blind placebo-controlled drug challenge	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.
Dissimilar cephalosporin first	Similar cephalosporin (cefepime, ceftriaxone, cefaclor, cephalexin, cefixime, or cefdinir) antibiotic double-blind placebo-controlled drug challenge	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.
Dissimilar cephalosporin first	Dissimilar cephalosporin (ceftriaxone or cefazolin) antibiotic double-blind placebo-controlled drug challenge	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.
Similar cephalosporin first	Beta-lactam antibiotic (cefazolin, cefuroxime, cefotaxime, ceftazidime, ceftriaxone, cefepime, pre-pen, penicillin G, ampicillin, and histamine) double-blind skin testing	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.
Similar cephalosporin first	Amoxicillin double-blind placebo-controlled drug challenge	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.
Dissimilar cephalosporin first	Amoxicillin double-blind placebo-controlled drug challenge	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.

Primary Outcome Measures

Name	Time	Method
Proportion of participants with confirmed culprit cephalosporin allergy	Up to 7 weeks	Placebo-controlled drug challenges will be used to confirm or disprove participant's cephalosporin allergies, and the proportion of included participants with confirmed allergies will be measured.
Cephalosporin skin test sensitivity and specificity	Up to 7 weeks	Challenge results will be used as a reference standard to determine the sensitivity and specificity of cephalosporin skin testing.
Proportion of cross-reactivity to other cephalosporins in confirmed-allergic subjects	Up to 7 weeks	The proportion of participants with confirmed cross-reactivity to dissimilar/similar cephalosporins than their culprit will be determined.

Secondary Outcome Measures

Name	Time	Method
Culprit cephalosporin skin test diagnostic characteristics	Up to 7 weeks	The diagnostic testing characteristics of culprit cephalosporin skin tests will be evaluated, including positive predictive value (PPV), negative predictive value (NPV), and false positive rate.
Cephalosporin skin test diagnostic characteristic performance differences between risk groups	Up to 7 weeks	Allergy history risk will be measured using a validated Drug Allergy History Tool. The PPV, NPV, and false positive rate of skin testing will then be compared through regression modeling to show differences in diagnostic characteristic performance between high-risk and low-risk groups.
Association between patient demographics and confirmed cephalosporin allergy	Up to 7 weeks	Participant demographic traits will be collected and their associations with confirmed cephalosporin allergy will be presented as odds ratios with 95% confidence intervals.
Association between patient allergy history and confirmed cephalosporin allergy	Up to 7 weeks	A validated Drug Allergy History Tool will be used to collect participant's allergy history, and associations of allergy history with confirmed cephalosporin allergy will be presented as odds ratios with 95% confidence intervals.
Proportion of nocebo responders	Up to 7 weeks	The rate of nocebo response in those undergoing cephalosporin drug challenges will be measured.
Cephalosporin-specific antibody levels	Up to 54 months	Cephalosporin drug- and hapten-specific antibody levels will be evaluated from serum using ELISA.
Cephalosporin-specific antibody binding	Up to 54 months	Cephalosporin drug antibody binding epitopes will be presented using nanoallergens to evaluate rates of antibody binding and cell degranulation to gain a mechanistic understanding of cephalosporin allergy.

Trial Locations

Locations (5)

University of California, San Francisco; 🇺🇸 San Francisco, California, United States

Mayo Clinic Arizona; 🇺🇸 Scottsdale, Arizona, United States

Rochester General Hospital; 🇺🇸 Rochester, New York, United States

Vanderbilt University Medical Center; 🇺🇸 Nashville, Tennessee, United States

University of Texas Southwestern Medical Center; 🇺🇸 Dallas, Texas, United States