Optimizing the Diagnostic Approach to Cephalosporin Allergy Testing

Drug Hypersensitivity Clinical Trial

— DACAT  

Official title:

Optimizing the Diagnostic Approach to Cephalosporin Allergy Testing

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06406114
• Other study ID #: 2024p000928
• Secondary ID: U01AI184071
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: August 1, 2024
• Est. completion date: December 31, 2028

Study information

• Verified date: May 2024
• Source: Massachusetts General Hospital
• Contact: Liam R Smith, BS
• Phone: 6177242415
• Email: allergyresearch[@]mgh.harvard.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 300
• Est. completion date: December 31, 2028
• Est. primary completion date: July 1, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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.

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

Related Conditions & MeSH terms

• Anaphylaxis
• Antibiotic Allergy
• Beta Lactam Adverse Reaction
• Cephalosporin Allergy
• Drug Allergy
• Drug Hypersensitivity
• Drug-Induced Anaphylaxis
• Hypersensitivity

Intervention

Drug:
• 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), cefotaxime (100 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), cefotaxime (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), cefotaxime (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.

Locations

Country	Name	City	State
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Rochester General Hospital	Rochester	New York
United States	University of California, San Francisco	San Francisco	California
United States	Mayo Clinic Arizona	Scottsdale	Arizona

Sponsors (2)

Lead Sponsor	Collaborator
Massachusetts General Hospital	National Institute of Allergy and Infectious Diseases (NIAID)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Prevalence of nocebo response	The prevalence of nocebo responses to drug challenges will be measured to understand how often these responses occur during cephalosporin challenges.	Up to 7 weeks
Other	Graded severity of nocebo response reactions	Respiratory, mucocutaneous, and cardiovascular symptoms and clinical presentation of nocebo response reactions will be collected and graded using the United States Drug Allergy Registry (USDAR) grading scale to determine the average severity of nocebo reactions. This scale is scored as either NR (no reaction) or values 0-4 indicating the severity of the reaction, with 0 being the mildest and 4 being the most severe.	Up to 7 weeks
Other	Cephalosporin skin test clinical statistics	The average diameter size of the wheal and flare during cephalosporin skin tests will be determined.	Up to 7 weeks
Other	Tryptase levels in those with confirmed allergy	In participants with confirmed cephalosporin allergy, tryptase levels will be evaluated and compared to determine if tryptase levels are associated with reaction grades.	Up to 7 weeks
Other	Amoxicillin cross-reactivity in those with confirmed cephalosporin allergy	Among those with confirmed cephalosporin allergy, the proportion with cross-reactivity to amoxicillin will be determined.	Up to 7 weeks
Other	Amoxicillin skin test diagnostic characteristics in those with confirmed cephalosporin allergy	Among those with confirmed cephalosporin allergy, the skin test diagnostic characteristics with amoxicillin will be determined, including positive predictive value (PPV), negative predictive value (NPV), and false positive rate.	Up to 7 weeks
Other	Similar cephalosporin skin test diagnostic characteristics in participants with confirmed cephalosporin allergy	Among those with confirmed cephalosporin allergy, the skin test diagnostic characteristics with a similar side-chain cephalosporin will be determined, including positive predictive value (PPV), negative predictive value (NPV), and false positive rate.	Up to 7 weeks
Other	Dissimilar cephalosporin skin test diagnostic characteristics in participants with confirmed cephalosporin allergy	Among those with confirmed cephalosporin allergy, the skin test diagnostic characteristics with a dissimilar side-chain cephalosporin will be determined, including positive predictive value (PPV), negative predictive value (NPV), and false positive rate.	Up to 7 weeks
Other	Graded severity of cephalosporin allergic reactions	Respiratory, mucocutaneous, and cardiovascular symptoms and clinical presentation of cephalosporin allergic reactions will be collected and graded using the United States Drug Allergy Registry (USDAR) grading scale to determine the average severity of cephalosporin reactions. This scale is scored as either NR (no reaction) or values 0-4 indicating the severity of the reaction, with 0 being the mildest and 4 being the most severe.	Up to 7 weeks
Other	Proportion of delayed hypersensitivity reactions to cephalosporins	The proportion of participants with delayed hypersensitivity reactions to cephalosporins will be recorded.	Up to 7 weeks
Other	Incidence of adverse events with cephalosporin diagnostic tests	The incidence rate of allergic and nonallergic adverse events (as graded by the United States Drug Allergy Registry (USDAR) grading scale [grades NR for no reaction and then grades 0-4 with four being the most severe reaction] and National Cancer Institute's Common Terminology Criteria for Adverse Events [grades 1 to 5, with grades 1 being the mildest and grade 5 being death]) in cephalosporin skin tests and drug challenges will be determined.	Up to 7 weeks
Primary	Proportion of participants with confirmed culprit cephalosporin allergy	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.	Up to 7 weeks
Primary	Cephalosporin skin test sensitivity and specificity	Challenge results will be used as a reference standard to determine the sensitivity and specificity of cephalosporin skin testing.	Up to 7 weeks
Primary	Proportion of cross-reactivity to other cephalosporins in confirmed-allergic subjects	The proportion of participants with confirmed cross-reactivity to dissimilar/similar cephalosporins than their culprit will be determined.	Up to 7 weeks
Secondary	Culprit cephalosporin skin test diagnostic characteristics	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.	Up to 7 weeks
Secondary	Cephalosporin skin test diagnostic characteristic performance differences between risk groups	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.	Up to 7 weeks
Secondary	Association between patient demographics and confirmed cephalosporin allergy	Participant demographic traits will be collected and their associations with confirmed cephalosporin allergy will be presented as odds ratios with 95% confidence intervals.	Up to 7 weeks
Secondary	Association between patient allergy history and confirmed cephalosporin allergy	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.	Up to 7 weeks
Secondary	Proportion of nocebo responders	The rate of nocebo response in those undergoing cephalosporin drug challenges will be measured.	Up to 7 weeks
Secondary	Cephalosporin-specific antibody levels	Cephalosporin drug- and hapten-specific antibody levels will be evaluated from serum using ELISA.	Up to 54 months
Secondary	Cephalosporin-specific antibody binding	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.	Up to 54 months