U01AI184071

Optimizing the diagnostic approach to cephalosporin allergy testing (DACAT trial) - Project summary

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.

Current national practice guidelines related to cephalosporin allergy assessment are considered conditional and based on low-quality evidence.

Our 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.

We 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.

Our 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.

We will achieve these aims through collaboration with an established network of drug allergy specialists.

Our study is the first clinical trial in drug allergy that investigates diagnostic strategies and mechanisms for a common and important antibiotic class.

This project aligns with NIH/NIAID goals to advance drug allergy research and PAR-21-083 to support high-risk clinical trials with mechanistic studies.

Mayo Clinic Jacksonville (A Nonprofit Corporation)

NOT APPLICABLE

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Jacksonville, Florida 322241865 United States

Single Zip Code

NIAID Clinical Trial Implementation Cooperative Agreement (U01 Clinical Trial Required) (PAR-21-083)

Amendment Since initial award the total obligations have increased 220% from $2,921,132 to $9,351,163.