Non-immediate Hypersensitivity Research Articles

Simplifying The Drug Provocation Test in Non-Immediate Hypersensitivity Reactions to Amoxicillin in Children: The Experience of a Tertiary Care Allergy Unit.

Simplifying The Drug Provocation Test in Non-Immediate Hypersensitivity Reactions to Amoxicillin in Children: The Experience of a Tertiary Care Allergy Unit.

IFN-γ ELISpot-enabled machine learning for culprit drug identification in nonimmediate drug hypersensitivity

Diagnosing drug-induced allergy, especially nonimmediate phenotypes, is challenging. Incorrect classifications have unwanted consequences. We sought to evaluate the diagnostic utility of IFN-γ ELISpot and clinical parameters in predicting drug-induced nonimmediate hypersensitivity using machine learning. The study recruited 393 patients. Apositive patch test or drug provocation test (DPT) was used to define positive drug hypersensitivity. Various clinical factors were considered in developing random forest (RF) and logistic regression (LR) models. Performances were compared against the IFN-γ ELISpot-only model. Among the 102 patients who had 164 DPTs, most patients had severe cutaneous adverse reactions (35/102, 34.3%) and maculopapular exanthems (33/102, 32.4%). Common suspected drugs were antituberculosis drugs (46/164, 28.1%) and β-lactams (42/164, 25.6%). Mean (SD) age of patients with DPT was 52.7 (20.8) years. IFN-γ ELISpot, fixed drug eruption, Naranjo categories, and nonsteroidal anti-inflammatory drugs were the most important features in all developed models. The RF and LR models had higher discriminating abilities. An IFN-γ ELISpot cutoff value of 16.0 spot-forming cells/106 PBMCs achieved 94.8% specificity and 57.1% sensitivity. Depending on clinical needs, optimal cutoff values for RF and LR models can be chosen to achieve either high specificity (0.41 for 96.1% specificity and 0.52 for 97.4% specificity, respectively) or high sensitivity (0.26 for 78.6% sensitivity and 0.37 for 71.4% sensitivity, respectively). IFN-γ ELISpot assay was valuable in identifying culprit drugs, whether used individually or incorporated in a prediction model. Performances of RF and LR models were comparable. Additional test datasets with DPT would be helpful to validate the model further.

Management of adverse reactions induced by chemotherapy drugs.

There is a broad spectrum of chemotherapy-induced adverse reactions. Hypersensitivity reactions are being extensively studied as they can affect the ideal treatment. The goal of this review is to describe the current management of adverse reactions to chemotherapy, focusing on hypersensitivity events. The range of possible desensitization protocols is increasing, as well as the delabeling algorithms and diagnostic tools. One-bag desensitization protocols, omalizumab use in immediate hypersensitivity reactions, slow desensitization protocols in nonimmediate hypersensitivity reactions and standardization of skin tests for platinum drugs, are some examples. The handling of adverse reactions to chemotherapy is evolving, with the increasing identification of hypersensitivity reactions and the development of strategies for their management, to maintain the culprit drug.

Non-immediate hypersensitivity reactions to iomeprol: Diagnostic value of skin tests and cross-reactivity with other iodinated contrast media.

Iodinated contrast media produce non-immediate hypersensitivity reactions (NIHR). The goal of this prospective study was to determine the utility of skin tests and the subsequent tolerance to negative skin-tested iodinated contrasts in patients with NIHR caused by iomeprol. Prick and intradermal tests with iomeprol, iopamidol, iopromide, and iobitridol were performed in all patients. IV challenge with the causative contrast (iomeprol in 90%) was made if skin tests were negative. In case of a positive skin test with the causal contrast, or a positive challenge test with it, IV challenge test with an alternative, negative skin-tested contrast was performed in all patients. Skin tests were positive in 47.6% (20/42) of patients with NIHR induced by iomeprol. Of the 66 challenge tests performed with negative skin-tested iodinated contrasts, tolerance was confirmed in 35 (53%): 32 iomeron, 2 iobitridol, 1 iopamidol. Cross-reactivity between iomeprol and iopamidol was 22% (4/20 in patients with positive skin tests and 5/21 in patients with negative skin tests). Sensitivity of the skin tests was less than 50% NIHRs due to iomeprol, while the negative predictive value of skin tests in patients who tolerated challenges with alternative contrasts (mainly iopamidol) was 53% (35 tolerated out of 66 performed). The cross-reactivity between iomeprol and iopamidol is high.

Amoxicillin hypersensitivity: Patient outcomes in a seven-year retrospective study

BackgroundThe beta-lactam antibiotic amoxicillin and the beta-lactamase inhibitor clavulanic acid in combination with amoxicillin are known to cause both immediate- and nonimmediate-type hypersensitivity. ObjectiveTo characterize a large cohort of patients with a history of amoxicillin or amoxicillin-clavulanic acid hypersensitivity. MethodsA retrospective analysis was conducted of the demographics, presentation, investigation, and management of 331 patients presenting to 1 allergy center with a history of hypersensitivity to amoxicillin or amoxicillin-clavulanic acid. ResultsHypersensitivity was confirmed in 37 of 221 patients (17%) who took amoxicillin and 47 of 110 patients (43%) who took amoxicillin-clavulanic acid as the index drug.In immediate hypersensitivity, skin test results confirmed the diagnosis in 66 of 139 patients (47%). Penicillin cross-reactivity was observed in 16 of 36 patients (44%). Of the 16 patients who were cross-reactive, 13 (81%) reacted to amoxicillin-clavulanic acid as the index drug. All patients who had negative skin test results (73/139) underwent drug provocation. The negative predictive value of skin tests was 89%.In nonimmediate hypersensitivity, delayed intradermal tests confirmed diagnosis in 12 of 170 patients (7%). Of the 12 patients whose skin test results were positive, 8 (67%) presented with drug reaction with eosinophilia and systemic symptoms. All patients with a negative skin test result (158/170) underwent drug provocation. The negative predictive value of skin tests was 95%. Penicillin cross-reactivity was observed in 3 of 12 patients (25%).Ten patients were diagnosed with hypersensitivity to clavulanic acid. ConclusionThe negative predictive value of skin tests in both immediate and nonimmediate hypersensitivity reactions is excellent and excludes severe allergy. Nonimmediate hypersensitivity is rare. Confirmed hypersensitivity is more likely if amoxicillin-clavulanic acid is the index drug. Cross-reactivity was more common in patients presenting with immediate hypersensitivity, typically involving benzylpenicillin. A minority of patients were allergic to clavulanic acid.

Machine learning approach for culprit drug identification based on drug-specific interferon-gamma releasing cells and clinical parameters in non-immediate drug hypersensitivity

This study aims to evaluate diagnostic utility for interferon-gamma enzyme-linked immunospot assay (ELISpot) and clinical parameters against drug provocation test (DPT) in predicting drug-induced non-immediate hypersensitivity using a machine learning approach.

Converter Phenotype: A New Profile That Is Not Exclusive to Taxanes.

Introduction: Phenotype I hypersensitivity reactions are the most commonly reported drug reactions; however, precision medicine has made it possible to characterize new phenotypes. A recent communication proposed the existence of a “converter phenotype,” which would affect patients who present non-immediate hypersensitivity reactions and in subsequent exposures develop immediate hypersensitivity reactions. This study aimed to describe the clinical characteristics of converter phenotype reactions and their evolution during desensitization to chemotherapeutic drugs and monoclonal antibodies.Methods: We retrospectively reviewed our database of patients undergoing desensitization to chemotherapy or biological agents and selected those with a converter phenotype. Demographic and clinical characteristics of the patients, the results of skin tests, tryptase and IL-6 levels, and desensitization outcomes were assessed.Results: Of 116 patients evaluated, 12 (10.3%) were identified as having a converter phenotype. The median interval between drug exposure and reaction was 90.6 h (range 8-288 h). After the conversion, phenotype I was the most frequent (58.3%), followed by cytokine release reactions (33.3%). Fifty-one desensitizations were undertaken and all treatments completed, with 10 (19.6%) breakthrough reactions. No new changes in the phenotype were detected.Conclusions: The symptoms of non-immediate drug hypersensitivity reactions may indicate the need for an early allergological evaluation to assess the risk of future immediate drug reactions. Clinical characteristics, skin test results, and biomarkers can help predict responses to rapid drug desensitization, guiding clinicians on how to optimize therapy delivery while maintaining patient safety.

Nonimmediate Hypersensitivity Reaction to Rifaximin Confirmed With a Drug Challenge Test

Nonimmediate Hypersensitivity Reaction to Rifaximin Confirmed With a Drug Challenge Test

Inherent clinical properties of non-immediate hypersensitivity to iodinated contrast media.

Iodinated contrast media (ICM) is a frequently used compound in radiology. Non-immediate hypersensitivity reactions (HSR) appear when a patient leaves the department and usually are undocumented. True hypersensitivity in this group is rarely proved. Single-centre 2014-2018 data were retrospectively analysed. HSR to ICM were classified and investigated according to the time of occurrence (immediate <1hour, non-immediate >1hour). ENDA questionnaire and skin tests (prick or intradermal test) were performed according to ENDA/EAACI recommendations. 69 patients with a clinical history of HSR to ICM were identified, 72.46% were females (n=50). The average age was 56 (SD±13.16) years. Non-immediate HSR occurred in 28.99% (n=20) patients. The suspected culprit drugs were: iodixanol 20% (n=4), iopromide 5% (n=1), diatrizoate 10% (n=2) and iohexol 10% (n=2). Among non-immediate HSR 96.00% (n=19) of patients had skin rashes. A statistically significant correlation was found between the clinical symptoms and the type of reaction (p-value <0.05): isolated skin manifestations mostly occurred in non-immediate HSR 75.00% (n=15). Only 13.04% (n=9) of all the patients were proved to be allergic to a certain ICM after the proposed diagnostic workup. One-third of the hypersensitivity reactions investigated were classified as non-immediate type. Most of them manifested with isolated skin symptoms. The most frequent culprit drug encountered was iodixanol. The overall non-immediate hypersensitivity confirmation rate after diagnostic evaluation was only 15%.

Diagnosis of non-immediate hypersensitivity to amoxicillin in children by skin test and drug provocation tests: A retrospective case-series study

BackgroundSkin rash often occurs upon oral administration of amoxicillin in children, due to non-immediate hypersensitivity. However, information on delayed hypersensitivity to amoxicillin is scarce. Moreover, the appropriate diagnostic method and actual diagnostic rate of delayed hypersensitivity to amoxicillin among Japanese children are unclear. We conducted intradermal tests (IDTs) and drug provocation tests (DPTs) and retrospectively investigated the proportion of children with a definitive diagnosis of non-immediate hypersensitivity to amoxicillin. We then evaluated the characteristics of patients with a positive allergic workup. MethodsWe enrolled children referred for suspected findings of mild or moderate non-immediate hypersensitivity to amoxicillin between August 2018 and March 2020. If the IDT in the delayed phase was negative, DPT with amoxicillin (60–90 mg/kg/day) was performed for 7 days. Non-immediate hypersensitivity to amoxicillin was defined when IDT or DPT was positive. We evaluated the potential of the drug-induced lymphocyte stimulation test (DLST) to reveal hypersensitivity to amoxicillin. ResultsThis study enrolled 27 children. Fourteen children (52%) had hypersensitivity to amoxicillin, of whom 12 had positive IDTs and two had positive DPTs. No differences in age, sex, history of allergic disease, days from oral use to symptom onset, type of rash at symptom onset, generalized rash, and DLST results were observed between the hypersensitivity and non-hypersensitivity groups. ConclusionsExamination should be performed for children with mild or moderate reactions because positive cases have no significant features and half of the suspected cases are negative.

Practice parameters for diagnosing and managing iodinated contrast media hypersensitivity.

Immediate and nonimmediate hypersensitivity reactions to iodinated contrast media (ICM) have been reported to occur in a frequency of about 0.5%-3% of patients receiving nonionic ICM. The diagnosis and management of these patients vary among guidelines published by various national and international scientific societies, with recommendations ranging from avoidance or premedication to drug provocation test. This position paper aims to give recommendations for the management of patients with ICM hypersensitivity reactions and analyze controversies in this area. Skin tests are recommended as the initial step for diagnosing patients with immediate and nonimmediate hypersensitivity reactions; besides, they may also help guide on tolerability of alternatives. Re-exposition or drug provocation test should only be done with skin test-negative ICMs. The decision for performing either re-exposition or drug provocation test needs to be taken based on a risk-benefit analysis. The role of in vitro tests for diagnosis and pretreatment for preventing reactions remains controversial.

Piperacillin-Tazobactam Hypersensitivity: A Large, Multicenter Analysis

Piperacillin/tazobactam is a broad-spectrum penicillin. Hypersensitivity reactions are less commonly reported than with other penicillins except in patients with cystic fibrosis. Detailed clinical characterization of a patient cohort referred with suspected piperacillin-tazobactam hypersensitivity. Retrospective analysis of the demographic characteristics, clinical presentation, investigation, and management of 87 patients presenting to 5 European allergy centers. Patients underwent skin prick and intradermal testing with piperacillin/tazobactam, major (penicilloyl-polylysine) and minor (sodium penilloate) determinants, amoxicillin, benzylpenicillin, flucloxacillin, co-amoxiclav, clavulanic acid, and meropenem with immediate and, where appropriate, delayed reading of tests. Skin test-negative patients underwent drug provocation to piperacillin/tazobactam and/or other penicillins. A multistep protocol was used, depending on risk assessment. Forty-eight of 87 (55%) patients were diagnosed with hypersensitivity to piperacillin/tazobactam with either positive skin or drug provocation test results, of whom 10 (21%) had a diagnosis of cystic fibrosis. Twenty-six (54%) patients presented with immediate and 22 (45%) with nonimmediate hypersensitivity. Patients with cystic fibrosis predominantly presented with nonimmediate hypersensitivity (70%). Reactions were severe in 52% of immediate reactors (Brown's anaphylaxis grade 3) and moderately severe (systemic involvement) in 75% of nonimmediate reactors. The number of patients with negative skin test results tolerating reintroduction was comparable in immediate (80%) and nonimmediate (88%) hypersensitivity. One-third of patients were cross-sensitized to other penicillins. The cross-sensitization pattern raised the possibility of tazobactam allergy in 3 patients. In 21 patients selectively sensitized to piperacillin/tazobactam (12 immediate, 9 nonimmediate), tolerance to other beta-lactams was demonstrated by drug provocation testing. Piperacillin-tazobactam caused immediate and nonimmediate hypersensitivity with similar frequency. Most patients were selectively sensitized and tolerated other penicillins. Some patients may be allergic to the beta-lactamase inhibitor only.

Assessment of immediate and non-immediate hypersensitivity contrast reactions by skin tests and provocation tests: A review.

Introduction:Allergic and nonallergic hypersensitivity reactions to iodinated contrast media (ICM) and gadolinium-based contrast media are classified as immediate or non-immediate hypersensitivity reactions (IHR and NIHR), respectively. Skin tests and provocation tests are recommended for the evaluation of hypersensitivity reactions to contrast agents; however provocations are not common in clinical practice.Methods:A MEDLINE search was conducted to investigate studies comprising both skin tests and provocation tests that evaluated hypersensitivity reactions to ICM.Results:Nineteen studies were identified that reported on skin tests, followed by provocations. In the case of IHR to ICM, 65/69 (94%) patients with a positive skin test for the culprit media tolerated a challenge with a skin-test-negative alternative ICM. In IHR to ICM with a negative skin test for the culprit media, provocations were positive in 3.2%–9.1% patients. In the case of a NIHR to ICM with a positive skin test, provocation with a skin-test-negative agent was tolerated in 75/105 (71%) of cases. In NIHR with a negative skin test for the culprit agent, re-exposure to the culprit or an alternative was positive in 0%–34.6% patients. Provocations with the same ICM in skin test positive patients with IHR or NIHR were positive for a majority of the patients, although such provocation tests were rarely performed. Data on hypersensitivity reactions, skin tests and provocations with gadolinium-based contrast media were limited; however, they exhibited a pattern similar to that observed in ICM.Conclusion:In both ICM and gadolinium-based contrast media, the risk of an immediate repeat reaction is low when skin tests are negative. In contrast, a provocation with a skin-test-positive contrast medium showed a high risk of an immediate repeat hypersensitivity reaction. Therefore, a thorough medical history is necessary, followed by skin tests. A provocation is recommended, for diagnostic work-up, when the diagnosis is uncertain.

Non-Immediate Hypersensitivity Reaction to Rifaximin Confirmed With a Drug Challenge Test

Non-Immediate Hypersensitivity Reaction to Rifaximin Confirmed With a Drug Challenge Test

Features of non-immediate hypersensitivity to iodinated contrast media according to Vilnius university hospital Santaros Klinikos data

Features of non-immediate hypersensitivity to iodinated contrast media according to Vilnius university hospital Santaros Klinikos data

Altered levels of complement components associated with non-immediate drug hypersensitivity reactions

Nonimmediate drug hypersensitivity reactions (niDHRs) range from mild-type maculopapular exanthema (MPE) to severe type Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) with unentirely clarified pathogenesis. This study sought to explore whether complement components participated in niDHRs. The participants comprised of three groups as follows: MPE (n = 65), SJS/TEN (n = 13, contains 7 SJS, 2 SJS-TEN overlap and 4 TEN), and equal healthy controls (n = 78). Skin pathological changes were confirmed by hematoxylin and eosin staining. The mRNA and protein levels of complement components were assessed. In the MPE group, there were no alterations in complement components at the protein and mRNA levels found except for a decrease in factor H mRNA. In the SJS/TEN group, up-regulated levels of C3aR and C5aR mRNA and down-regulated factor H mRNA levels in blood were noted. A lower plasma protein level of C3, Factor H and a higher level of C3a, C5, C5a, C5b-9, Factor B (p < 0.05) were found in the SJS/TEN group compared with in the control (p < 0.05). In SJS/TEN skin lesions, indirect immunofluorescence assays showed positive specific staining for C5b-9, but not C3. Both C3aR and C5aR were positive staining in the SJS/TEN samples, while staining for C1q, mannose-binding lectin (MBL), Factor B, and Factor H were only weak or negative. The findings reported here are the first to define the expression profiles/extent of the presence of various complement components at the mRNA and protein levels in niDHRs, especially in SJS/TEN. These altered complement components might, at least in part, be integral to the mechanisms underlying the pathogeneses of SJS and TEN.

Provocation Tests in Nonimmediate Hypersensitivity Reactions to β-Lactam Antibiotics in Children: Are Extended Challenges Needed?

To determine if repeated doses of a β-lactam antibiotic are required to reproduce a nonimmediate hypersensitivity reaction in children.This retrospective observational study included 97 patients younger than 14 years of age with history of at least 1 reaction to a β-lactam antibiotic and with symptoms that began at least 6 hours after the first dose of the implicated medication.All patients underwent a 1-day in-hospital graded provocation test, with a cumulative dose of 65% of the daily dose of the β-lactam antibiotic under study, followed by hospital observation for 2 hours. If no reaction appeared over the same amount of time between dosing and symptoms during the index reaction, the patient was instructed to continue 2 daily antibiotic doses at home over the same number of days it took for the index reaction to appear. The total duration of study was variable for each patient.A positive reaction was recorded in 14 patients (14.4%). The hospital provocation triggered 3 immediate reactions and 8 delayed reactions. The home provocation triggered 1 immediate reaction and 2 delayed reactions. The most frequent manifestation of an adverse reaction was a maculopapular exanthem. Previous symptoms, implicated medication, and demographic characteristics of patients (with exception of sex) were not predictors for the appearance of delayed reactions. Male sex and a history of more than 1 previous reaction with any β-lactam antibiotic were associated with immediate or late reactions during hospital provocation.Nonimmediate reactions to β-lactam antibiotics in children may be triggered with a 1-day provocation test. The authors suggest a 1-day provocation test followed by an observational period of at least the time interval observed in the index reaction. If this provocation is negative, an extended home provocation could be pursued.The results of the current study are encouraging, with the minority of studied patients exhibiting adverse symptoms, most of which were triggered during the hospital rather than the home provocation. Data from the current study do not exclude the possibility that reactions may occur hours to days after a single-day provocation attempt. The authors pose the question of whether all patients who will react are able to be provoked with a single-day attempt with prolonged subsequent observation. Additional study is needed to assess larger numbers of children with nonimmediate adverse reactions to β-lactam antibiotics. Additional data on risk assessment and pretest predictive measures will lead to benefits both for individual patients and community antibiotic stewardship.

A practical 16-day desensitization protocol in lenalidomide-induced non-immediate hypersensitivity reactions

BackgroundDesensitization in immediate-type hypersensitivity reactions (HRs) caused by chemotherapeutics is well described and standardized for many drugs. However, there are no standardized protocols in non-immediate HRs. ObjectiveTo evaluate the effectiveness of a 16-day desensitization protocol in the non-immediate HRs induced by lenalidomide. MethodsAccording to our previously published slow desensitization protocol, we desensitized patients who had experienced non-immediate HRs attributable to lenalidomide. The protocol was started with the 1/100 of the daily-prescribed dose in milligrams of the culprit drug; then the doses were slowly increased to complete the procedure in 16 days. Demographic and clinical features of the patients were further appraised. ResultsTen patients (mean age was 64.7 ± 10.8 years; 7 male) were successfully desensitized to lenalidomide. The mean reaction time was 7.3 ± 3.9 days in the history, and the reaction types were delayed urticaria (n = 4), eczematous rash (n = 3), and maculopapular eruptions (n = 3). The desensitization was successfully completed in 16 days in 9 patients. In 1 patient, maculopapular eruptions developed on the 11th day, and the patient was treated with corticosteroids. We repeated the previous tolerated dose longer and completed with a slower dose increasement, and the targeted dose was achieved in 35 days. ConclusionThe 16-day desensitization protocol seemed to be safe and effective in the non-immediate type drug HRs caused by lenalidomide.

The Limited Value of Prolonged Drug Challenges in Nonimmediate Amoxicillin (Clavulanic Acid) Hypersensitivity

Misdiagnosis of amoxicillin (clavulanic acid) (AX(/CL)) hypersensitivity has serious consequences. A drug challenge (DC) is the final diagnostic to affirm or infirm AX(/CL) hypersensitivity. However, uncertainties remain whether a prolonged drug challenge (pDC) should benefit the diagnosis of a nonimmediate AX(/CL) hypersensitivity. To assess the added value of a standardized 7-day pDC in the diagnosis of nonimmediate or unclear penicillin hypersensitivity. A total of 132 patients with a history of a nonimmediate hypersensitivity reaction or an unclear reaction to AX(/CL) or an undefined penicillin with a negative diagnostic workup including a single-day DC (DC) with AX(/CL) were selected. In all these patients, an additional pDC with AX(/CL) was planned. Thirteen patients started the pDC immediately after the DC. To ensure that hypersensitivity symptoms manifesting during the pDC course do not result from the DC, in the remaining 119 patients, the pDC was scheduled after a washout of 1 week. A total of 128 patients (12 without washout, 116 with washout) completed the pDC. Three patients reacted with a mild maculopapular exanthema. However, the value of a pDC was evidenced in only 1 patient who reacted during her pDC after an uneventful washout. In 2 patients pDC was cancelled because they reacted during the washout. A pDC is of limited added value to the diagnostic algorithms of nonimmediate hypersensitivity reaction or unclear hypersensitivity reactions to AX(/CL). In our hands, the traditionally recommended diagnostic algorithm that offers a 1-day DC as a final diagnostic in patients with negative workup for AX(/CL) is appropriate.

Flucloxacillin Hypersensitivity: Patient Outcomes in a Multicenter Retrospective Study

Flucloxacillin is a narrow-spectrum, beta-lactamase-resistant penicillin. Type I (IgE-mediated) and type IV (T-cell-mediated) reactions are less frequently reported than with other penicillins. To undertake a detailed clinical characterization of a cohort of patients referred with suspected flucloxacillin hypersensitivity. We retrospectively analyzed demographic characteristics, presentation, investigation, and management of 108 patients presenting to 4 UK centers. Patients underwent skin prick and intradermal testing with flucloxacillin, major (benzylpenicilloyl poly-l-lysine) and minor determinants, amoxicillin, and benzylpenicillin with immediate and, where appropriate, delayed reading of the test. In the immediate group, a further 14 patients were tested to ampicillin and 16 to Augmentin (co-amoxiclav-combination of clavulanic acid and amoxicillin). Skin test-negative patients underwent oral drug provocation. A multistep protocol was used, depending on risk assessment. Forty of 108 (37%) patients were diagnosed with hypersensitivity to flucloxacillin, of whom 33 (82.5%) showed immediate and 7 (17.5%) nonimmediate hypersensitivity, respectively. In the immediate group, most reactions were severe: 19 of 33 (58%). Intradermal testing had a higher negative predictive value (86%) in the immediate group than in the nonimmediate group (67%). Only a minority of patients (6 of 17 [35%]) with IgE-mediated allergy were cross-sensitized on intradermal testing with other penicillins, compared with 3 of 4 (75%) in the delayed group. Immediate hypersensitivity reactions to flucloxacillin are more common than delayed. Cross-sensitization to other penicillins appears higher in delayed reactions than in immediate. The negative predictive value of intradermal testing is higher in the immediate group than in the nonimmediate group. Drug provocation testing remains the diagnostic criterion standard.