Optimizing the Diagnostic Approach to Cephalosporin Allergy Testing
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 300
- 试验地点
- 9
- 主要终点
- Proportion of participants with confirmed culprit cephalosporin allergy
研究概览
简要总结
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.
详细描述
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 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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Diagnostic
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Skin test reagents will be labeled blinded and prepared by a trained clinical trials pharmacy to maintain blinding. Drug challenges will be performed double-blind in a similar manner. The administrator, reader, and participant will all be blinded for each of these procedure types.
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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
- •Reaction to 2 or more cephalosporin antibiotics
- •Active infection or antibiotic treatment within 7 days
- •Treatment with systemic antihistamines or corticosteroids within 7 days
- •Treatment with omalizumab or dupilumab within 60 days
- •Significant immunosuppression
- •Treatment with a beta-blocker or ACE inhibitor within 7 days
- •Use of investigational drugs within 60 days of participation
- •Anaphylaxis in the last 30 days
- •Penicillin anaphylaxis within the past year confirmed with positive penicillin skin tests
- •Prison or jail inmates, pregnant women, severe cognitive impairment
- •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
- •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.
- •Inability or unwillingness of a participant to give written informed consent or comply with study protocol
研究组 & 干预措施
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.
干预措施: Beta-lactam antibiotic (cefazolin, cefuroxime, cefotaxime, ceftazidime, ceftriaxone, cefepime, pre-pen, penicillin G, ampicillin, and histamine) double-blind skin testing (Drug)
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.
干预措施: Culprit cephalosporin (cefazolin, ceftazidime, ceftriaxone, cefepime, cephalexin, cefaclor, cefadroxil, cefuroxime, cefpodoxime, cefdinir, or cefixime) double-blind placebo-controlled drug challenge (Drug)
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.
干预措施: Similar cephalosporin (cefepime, ceftriaxone, cefaclor, cephalexin, cefixime, or cefdinir) antibiotic double-blind placebo-controlled drug challenge (Drug)
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.
干预措施: Amoxicillin double-blind placebo-controlled drug challenge (Drug)
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.
干预措施: Culprit cephalosporin (cefazolin, ceftazidime, ceftriaxone, cefepime, cephalexin, cefaclor, cefadroxil, cefuroxime, cefpodoxime, cefdinir, or cefixime) double-blind placebo-controlled drug challenge (Drug)
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.
干预措施: Similar cephalosporin (cefepime, ceftriaxone, cefaclor, cephalexin, cefixime, or cefdinir) antibiotic double-blind placebo-controlled drug challenge (Drug)
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.
干预措施: Dissimilar cephalosporin (ceftriaxone or cefazolin) antibiotic double-blind placebo-controlled drug challenge (Drug)
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.
干预措施: Amoxicillin double-blind placebo-controlled drug challenge (Drug)
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.
干预措施: Dissimilar cephalosporin (ceftriaxone or cefazolin) antibiotic double-blind placebo-controlled drug challenge (Drug)
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.
干预措施: Beta-lactam antibiotic (cefazolin, cefuroxime, cefotaxime, ceftazidime, ceftriaxone, cefepime, pre-pen, penicillin G, ampicillin, and histamine) double-blind skin testing (Drug)
结局指标
主要结局
Proportion of participants with confirmed culprit cephalosporin allergy
时间窗: 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
时间窗: 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
时间窗: Up to 7 weeks
The proportion of participants with confirmed cross-reactivity to dissimilar/similar cephalosporins than their culprit will be determined.
次要结局
- Culprit cephalosporin skin test diagnostic characteristics(Up to 7 weeks)
- Cephalosporin skin test diagnostic characteristic performance differences between risk groups(Up to 7 weeks)
- Association between patient demographics and confirmed cephalosporin allergy(Up to 7 weeks)
- Association between patient allergy history and confirmed cephalosporin allergy(Up to 7 weeks)
- Proportion of nocebo responders(Up to 7 weeks)
- Cephalosporin-specific antibody levels(Up to 54 months)
- Cephalosporin-specific antibody binding(Up to 54 months)
研究者
Kimberly Blumenthal, MD, MSc
Principal Investigator
Mayo Clinic