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.
Age 18-70 years old.
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.
English speaking or non-English speaking with translation services available.
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.)
History of Clostridioides difficile infection
Chronic spontaneous urticaria or systemic mastocytosis
Incident reaction required cardiopulmonary resuscitation
Crossover
Beta-lactam antibiotic (cefazolin, cefuroxime, cefotaxime, ceftazidime, ceftriaxone, cefepime, pre-pen, penicillin G, ampicillin, and histamine) double-blind skin testing
DrugPercutaneous 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
DrugAfter 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
DrugParticipants 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
DrugParticipants 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
DrugParticipants 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Cephalosporin skin test clinical statistics
The average diameter size of the wheal and flare during cephalosporin skin tests will be determined.
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.
Click on the lead sponsor to view all of their trials.
Massachusetts General Hospital
Lead sponsor
Mayo Clinic
Sponsor institution
National Institute of Allergy and Infectious Diseases (NIAID)
Collaborator
