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Background: Skin 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., Methods: We 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., Results: This 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., Conclusions: Examination 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., (Copyright © 2021 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: The challenge of delabeling amoxicillin allergy is an important issue for patients and clinicians, especially when anaphylaxis is reported. A recent study has proposed a clinical decision rule, PEN-FAST, to identify low-risk penicillin allergies., Objective: To validate the PEN-FAST clinical decision rule in a population with high risk of suspected immediate amoxicillin allergy and to identify clinical predictive factors of amoxicillin immediate hypersensitivity., Methods: We retrospectively analyzed medical records of patients with a suspected immediate amoxicillin allergy who carried out an allergologic evaluation by a specialist in the Allergy Unit of Strasbourg University Hospital from 2015 to 2020., Results: A total of 142 adult patients (88 women [62.0%]; median age, 52 [interquartile range, 40.3-62.0] years) were analyzed. Most of them reported anaphylaxis (68.8%). Internal validation of PEN-FAST score revealed a good discrimination with area under the curve of 0.86 (95% confidence interval, 0.79-0.92). A cutoff of less than 3 points for PEN-FAST was used to classify 29 from 142 patients at low risk of allergy, of whom only 2 (6.9%) received positive results of allergy testing. The negative predictive value for successful delabeling was 0.93 (95% confidence interval, 0.77-0.99). Predictive clinical features for immediate amoxicillin hypersensitivity were time since reaction (P < .001), time elapsed between drug intake and first symptom (P < .001), severity grade reaction (P < .001), and treatment or hospitalization required (P < .001)., Conclusion: PEN-FAST has been validated to identify low-risk penicillin allergies in our European cohort of patients mainly reporting anaphylaxis. This is the first reported external validation of a penicillin allergy clinical decision rule internationally., (Copyright © 2021 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Penicillin allergy labels are prevalent, and removal of incorrect labels improves patient outcomes and health economics. Labels may be classified as "low-risk" or "non-low-risk," of which the symptoms of the latter chiefly suggest immunoglobulin E-mediated etiology. Traditionally, "non-low-risk" allergy labels are evaluated by penicillin skin testing followed by graded multistep penicillin drug provocation testing (DPT)., Objective: To evaluate the safety of assessing "non-low-risk" labels with single-step direct DPT., Methods: We consecutively enrolled inpatients and outpatients of a teaching hospital in Sydney, Australia, with penicillin allergy labels requiring penicillin for first-line treatment. Patients were classified as "low-risk" or "non-low-risk" based on the allergy labels. All patients proceeded directly to amoxicillin DPT, unless there was a history of anaphylaxis within 10 years of assessment to a beta-lactam (except for cefazolin) or Gell and Coombs type 2, type 3, or severe type 4 reaction. This was followed by a course of amoxicillin., Results: A total of 149 patients (41 inpatients, 108 outpatients) were enrolled. No patient was excluded from the study. No patient experienced life-threatening reactions to the protocol. There were 85 patients who reported "non-low-risk" allergy labels. One patient developed generalized pruritus and rash that resolved with standard-dose antihistamines, 2 developed delayed benign maculopapular exanthem, and 3 experienced diarrhea during the course of amoxicillin., Conclusion: In our cohort, direct single-step DPT was safe, with only 6 patients with "non-low-risk" allergy experiencing benign reactions. We hope that further studies can be performed into single-step direct DPT to evaluate "non-low-risk" penicillin allergy labels., Trial Registration: ClinicalTrials.gov Identifier: LNR/16/HAWKE/452., (Copyright © 2021 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Penicillin is the most frequently reported drug allergen; however, most of these allergies are not true allergies and do not justify the prescription of alternative, less effective and more expensive antibiotic drugs. We aimed to show that patients at low risk of amoxicillin allergy can safely and efficiently undergo oral provocation challenge (OPC) by their primary care physician., Methods: In this descriptive analysis, we conducted a retrospective chart review of all primary care patients who had undergone OPC from November 2017 to October 2019 in the Amoxicillin Allergy Clinic at the North Perth Family Health Team, Listowel, Ontario. Eligibility for OPC among patients 18 months and older was determined through review of a self-reported patient intake form asking about symptoms, onset, duration, history and family history of allergic reactions, as well as the patient's electronic medical record. Patients were considered to be at low risk of true penicillin allergy if there was no history of anaphylaxis or severe cutaneous reactions. Those with low-risk allergic reactions returned for testing with an OPC to amoxicillin. We collected data on clinical characteristics, antibiotic exposure, parental drug allergy, response to OPC and wait time from referral. We used t tests to describe and compare these variables. Our primary outcome was reaction to OPC by severity as categorized by the World Allergy Organization grading system. Our secondary outcome was the time from referral to completed testing., Results: In total, we included 99 patients (mean age 28.3, standard deviation [SD] 21.2 yr); 72 (73%) were female. Of those tested, 97% ( n = 96) completed the OPC with no reaction, 3% ( n = 3) had mild immediate reactions, and no serious immediate reactions developed. Mean wait time to testing was 59.0 (SD 69.8) days, with a median (interquartile range) of 39.5 (13.5-70.0) days., Interpretation: Oral provocation challenge presents a safe and accessible opportunity for primary care providers to address erroneous allergy labels to penicillin and related drugs within the primary care office setting. There could be positive public health implications if OPC to penicillin drugs is implemented in primary care., Competing Interests: Competing interests: None declared., (© 2021 Joule Inc. or its licensors.)

Background: Penicillin allergy is frequently reported. In pregnant women, reported penicillin allergy is associated with negative health outcomes and suboptimal group B streptococcal prophylaxis. For individuals having penicillin allergy, skin testing followed by an observed oral challenge is recommended. Previous data indicate a low risk of adverse reaction with skin testing in pregnant women, but the subsequent oral challenge was not routinely pursued., Objective: To determine whether skin testing followed by the outpatient oral challenge is tolerated by pregnant women., Methods: We conducted a retrospective review of all pregnant women who underwent penicillin allergy evaluation at an outpatient allergy and clinical immunology clinic. The patients underwent oral amoxicillin challenges based on the discretion of the allergy provider. We evaluated the index reaction history, skin test results, oral challenge results, and subsequent antibiotic exposure., Results: A total of 46 pregnant women underwent skin testing without adverse reactions, of whom 44 patients (95.6%) received negative results. A total of 18 women (39%) completed an oral challenge without adverse reactions. Patients challenged vs not challenged did not differ in patient age, gestational age, latency since index reaction, or reaction history risk level. Notably, 28 women received intrapartum antibiotics. There was no difference in intrapartum antibiotic administration between those who did or who did not complete an in-office oral challenge (P = .90)., Conclusion: Penicillin skin testing and oral challenge in pregnant women can safely be performed in the outpatient setting. There was no difference in the intrapartum antibiotic use between women who were and those who were not challenged. Further research is needed to determine the utility of oral challenge in pregnant patients., (Copyright © 2020 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

We report the case of a child presenting with an adverse drug reaction highly suggestive of drug-induced enterocolitis syndrome (DIES) to amoxicillin (AMX). A 10-year-old girl developed repetitive vomiting and pallor without cutaneous or respiratory symptoms 2h after AMX intake. DIES is not a well-described entity, and very few data are available in the literature. In the absence of an existing definition, the diagnosis of DIES can only be suspected and is based on its homology with food protein-induced enterocolitis (FPIES). The major criterion is the recurrence of repetitive and often incoercible vomiting occurring within 1-4h of ingestion of the culprit food in the absence of IgE-mediated allergic classic skin and respiratory symptoms. Once the diagnosis of DIES to AMX is suspected, an open challenge with AMX should be undertaken with caution, under medical supervision in a day hospital unit because of the risk of severe recurrence. Once the diagnosis is confirmed, AMX should be contraindicated to avoid severe reactions., (Copyright © 2019 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

Background: Nonprescription of penicillin-containing antibiotics in patients diagnosed with penicillin allergy is associated with morbidity and mortality. Adverse reactions to penicillins comprise type A and B reactions., Objective: To assess the feasibility of penicillin allergy evaluation without penicillin skin testing (PST) for adult patients with type B reactions and the health and economic benefits of this process., Methods: Inpatients at an Australian tertiary hospital between April 1, 2017, and April 30, 2018, with a diagnosis of type B penicillin allergy, requiring a penicillin-containing antibiotic for treatment, were included. All patients underwent clinical history review, PST, and drug provocation testing (DPT)., Results: Seventy-one patients were enrolled. Sixty-three reported a history of type B or unknown adverse reactions. No patients had a history of anaphylaxis requiring intubation or epinephrine within the last 10 years or a history suggesting Gell and Coombs type 2, 3, or 4 (severe) hypersensitivity reaction. Seven did not complete DPT because the treating team used a β-lactam antibiotic other than amoxicillin. Fifty-four of 56 remaining patients (96%) completed 3-day DPT to amoxicillin with no adverse reaction. Two experienced mild cutaneous reactions. Penicillin allergy evaluation was significantly associated with reduced length of stay, reduced hospital expenditure on bed and second-line antibiotics, and reduced readmission rates., Conclusion: Penicillin allergy evaluation with DPT without PST may be feasible for all adult patients with a reported history of type B reactions to penicillins who do not have a history of anaphylaxis within the last 10 years or a type 2, 3, or 4 (severe) hypersensitivity reaction., (Copyright © 2019 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: 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., Objective: To assess the added value of a standardized 7-day pDC in the diagnosis of nonimmediate or unclear penicillin hypersensitivity., Methods: 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., Results: 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., Conclusions: 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., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Direct challenge (DC) may be a safe and effective alternative to penicillin skin testing (PST) in low-risk patients., Objective: To complete a prospective, randomized, controlled trial comparing PST followed by a challenge to amoxicillin versus a 2-step DC to amoxicillin without preceding skin testing in a predefined low-risk patient population., Methods: Penicillin allergy histories were reviewed in patients presenting to an outpatient allergy/immunology practice from April 2018 to August 2018. Patients 5 years or older with a cutaneous-only or unknown reaction (>1 year ago for those aged 5-17 years, >10 years ago for those 18 years or older) were randomized 1:1 to PST or 2-step DC. All children younger than 5 years underwent DC, and patients with extracutaneous reaction histories underwent PST. All groups were monitored 30 minutes after administration of amoxicillin., Results: Penicillin allergy was reported in 363 of 2465 (14.7%) patients, of which 185 consented to further evaluation. Thirteen patients younger than 5 years underwent DC; all were negative. Thirteen patients with angioedema and/or extracutaneous symptoms underwent PST; 2 of 13 patients had positive PST result. A total of 159 patients were randomized to DC (49.7%) or PST (50.3%). PST result was negative in 70 of 80 (87.5%) patients. All 70 patients had a negative amoxicillin challenge. DC was negative in 76 of 79 (96.2%) patients; positive DC reactions were minor. Average time for patients undergoing PST was 72.7 ± 5.3 minutes and for patients undergoing DC was 66.7 ± 4.8 minutes., Conclusions: In low-risk patients, DC provided a safe and effective alternative to PST in delabeling penicillin allergy. Compared with PST, DC may also take less time, cost less money, and lead to fewer penicillin allergy evaluations with false-positive results., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Amoxicillin is the most common antibiotic prescribed in children with increasing use over time. While up to 10% of children are labelled as amoxicillin allergic, most children can tolerate amoxicillin after allergy evaluation. It is well documented that the label of amoxicillin allergy in children is associated with adverse health outcomes such as antibiotic-resistant infections. However, it remains controversial how best to assess children for amoxicillin allergy. While in general it is recommended that skin testing be done prior to drug provocation test in the evaluation of amoxicillin allergy, there is increasing evidence that drug provocation testing could be done in lower risk children without skin testing prior. The goal of this article as a narrative review is to review the strengths and limitations of skin testing prior to drug provocation test in children who have a history of either immediate or non-immediate, reactions to amoxicillin., (© 2019 John Wiley & Sons Ltd.)

Background: Around 10-15% of the in-patient population carry unsubstantiated 'penicillin allergy' labels, the majority incorrect when tested. These labels are associated with harm from use of broad-spectrum non-penicillin antibiotics. Current testing guidelines incorporate both skin and challenge tests; this is prohibitively expensive and time-consuming to deliver on a large scale. We aimed to establish the feasibility of a rapid access de-labelling pathway for surgical patients, using direct oral challenge., Methods: 'Penicillin allergic' patients, recruited from a surgical pre-assessment clinic, were risk-stratified using a screening questionnaire. Patients at low risk of true, immunoglobulin E (IgE)-mediated allergy were offered direct oral challenge using incremental amoxicillin to a total dose of 500 mg. A 3-day course was completed at home. De-labelled patients were followed up to determine antibiotic use in surgery, and attitudes towards de-labelling were explored., Results: Of 219 patients screened, 74 were eligible for inclusion and offered testing. We subsequently tested 56 patients; 55 were de-labelled. None had a serious reaction to the supervised challenge, or thereafter. On follow-up, 17 of 19 patients received appropriate antimicrobial prophylaxis during surgery. Only three of 33 de-labelled patients would have been happy for the label to be removed without prior specialist testing., Conclusion: Rapid access de-labelling, using direct oral challenge in appropriately risk-stratified patients, can be incorporated into the existing surgical care pathway. This provides immediate and potential long-term benefit for patients. Interest in testing is high among patients, and clinicians appear to follow clinic recommendations. Patients are unlikely to accept removal of their allergy label on the basis of history alone., Clinical Trial Registration: ClinicalTrials.gov: AN17/92982., (Copyright © 2018 British Journal of Anaesthesia. All rights reserved.)

Introduction: Ten percent of hospitalized patients report penicillin allergy; however, recent studies indicate that ∼98% of these patients are not acutely hypersensitive. Unconfirmed penicillin allergy poses public health risks, and an evaluation of penicillin allergy labels is recommended to improve antibiotic stewardship. Although the most widely accepted protocol is penicillin skin testing, followed by oral amoxicillin challenge, time constraints and resources may preclude this. Recent literature supports the safety and efficacy of direct oral amoxicillin challenge in individuals at low risk. Methods: We retrospectively evaluated direct oral challenge acceptance and outcomes in eligible adult outpatients with allergy and with a penicillin allergy label over a 6-month period. Direct oral amoxicillin challenge was recommended in patients with a history of benign rash, benign somatic symptoms, or unknown history associated with the last penicillin exposure >12 months ago. Those with severe reactions or reactions within 12 months of evaluation were not challenged. The patients were monitored for 60 minutes after challenge and were discharged with instructions to call in the event of a delayed reaction. Results: There were 50 of 355 adults (14%) with a penicillin allergy label seen by a single allergist; of these patients, 38 (76%) met our criteria for a direct oral challenge. The index penicillin associated reactions were mostly remote, and 44 subjects (88%) reported reactions >10 years earlier. Four patients (8%) were de-labeled based on history alone. Twenty subjects (40%) consented to challenge in the clinic, and none developed immediate, or to our knowledge, delayed hypersensitivity reactions. Three of 20 patients (15%) developed self-limited subjective symptoms that were not deemed to constitute true immunoglobulin E mediated hypersensitivity. A total of 24 patients (48%) had the penicillin allergy label removed from their medical record. Conclusion: This study added to the accumulating body of evidence that supports the safety and efficacy of direct provocative challenge without preliminary skin testing to exclude penicillin allergy in individuals at low risk. Larger prospective studies are necessary to confirm these observations.

Background: Unconfirmed penicillin allergy poses substantial public health consequences. The most widely accepted protocol to evaluate penicillin allergy is skin testing followed by an amoxicillin challenge., Objective: To evaluate the safety of direct oral graded challenges to amoxicillin., Methods: A prospective single-blind clinical trial with historical controls of patients ≥7 years old with historical non-life-threatening reactions to penicillin was conducted. Patients received placebo followed by a 2-step graded challenge to amoxicillin. The allergic reaction rate was compared with the rate observed in our previous study that included skin testing and with the currently reported penicillin allergy prevalence in the US population., Results: Of the 155 participants who completed an amoxicillin challenge, 120 patients (77.4%) experienced no reaction whereas 31 patients (20%) experienced nonallergic reactions to either placebo (n = 16) or amoxicillin (n = 15). Four patients (2.6%) developed mild allergic reactions. Significantly (P = .03) fewer patients (4 of 155, 2.6%, 95% confidence interval [CI]: 1.0%, 6.5%) were determined to be allergic compared with 14 of 170 subjects (8.2%, 95% CI: 5.0%, 13.4%) in our previous study where patients were determined to be allergic based on either positive skin tests (n = 11) or allergic challenge reactions after negative skin tests (n = 3). This 2.6% reaction rate was also significantly less than the 10% reported US prevalence of penicillin allergy (P = .003)., Conclusions: Placebo-controlled oral graded challenges to amoxicillin without prior skin testing may be safe for patients ≥7 years old with non-life-threatening historical reactions to penicillin. Amoxicillin can be tolerated by the majority of patients with self-reported penicillin allergy., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Penicillin allergy is the most frequent drug allergy, among which aminopenicillins are reputed for causing delayed rashes in children, particularly in the context of viral infections. Despite a negative allergy evaluation, a significant proportion of individuals continue to avoid penicillin antibiotics for fear of an allergic reaction., Objective: To evaluate the safety and efficacy of a 5-day challenge to amoxicillin and the proportion of subsequent use of amoxicillin., Methods: Pediatric patients with a history of a reaction to amoxicillin were prospectively recruited in the study. All patients were challenged, and those with negative immediate challenges underwent an ambulatory 5-day challenge to amoxicillin to rule out nonimmediate reactions. Patients were called 2 years after their initial allergy evaluation to assess subsequent amoxicillin use and tolerance., Results: One hundred thirty children with a history of amoxicillin allergy underwent a graded drug provocation test (DPT) to amoxicillin. Three patients had a positive immediate challenge, 3 had a positive nonimmediate challenge, and 2 were equivocal. Of the 122 patients with a negative challenge, 114 (93.4%) were reached 2 years after their initial allergy evaluation: 75 had used antibiotics since, of which only 1 (1.3%) had refused to reuse amoxicillin because of fear of an allergic reaction. Finally, the 5-day DPT resulted in a 24.1% decrease in future penicillin avoidance compared with classical single-dose graded DPT performed for 1 day in a historical cohort (P < .0001)., Conclusion: The 5-day challenge is a safe and effective way to rule out nonimmediate amoxicillin allergy, and it ensures better compliance with future penicillin use., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Suspected adverse reactions to amoxicillin are common, but there are no known factors that can predict amoxicillin allergy in children. In addition, methods used for the diagnosis of amoxicillin allergy are not standardized and their role in diagnosis is not clear., Objective: To identify predictive factors and to assess the role of skin test in the diagnosis of amoxicillin allergy in children., Methods: Children with a history of immediate (excluding anaphylaxis) or nonimmediate reactions to amoxicillin were tested by skin prick test, followed by oral graded challenge with amoxicillin. Clinical characteristics of the reaction before and after the challenge were recorded, and data of personal and relatives' drug allergies and atopy were collected for statistical analysis., Results: Skin prick tests followed by an oral graded challenge with amoxicillin were performed on 133 children. The skin test result was not of clinical value because it was negative in all children. Three children (2%) had an immediate reaction and 7 children (5%) had a nonimmediate reaction. Asthma (odds ratio [OR], 0.12; 95% CI, 0.017-0.869; P = .03), family history of drug allergy (OR, 0.12; 95% CI, 0.026-0.613; P = .01), older age at reaction (OR, 0.837; 95% CI, 0.699-1; P = .05), and angioedema (OR, 0.22; 95% CI, 0.043-1.12; marginally significant at P = .069) were associated with reduced chance to pass the oral challenge., Conclusions: Skin prick test did not contribute to the diagnosis of amoxicillin allergy. The presence of asthma, family history of drug allergy, and older age at reaction can be used as predictive factors for true amoxicillin allergy in children., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Adverse drug reactions are common in children, but true drug allergy is rare. It can be difficult to determine whether signs such as skin rashes are caused by the underlying illness or medications prescribed. Accurate diagnosis is important for patient safety and optimal treatment. We review the presentation of drug allergy and discuss current management options for children., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Reports of selective reactions to clavulanic acid (CLV) have increased in recent decades because of its increased prescription in combination with amoxicillin (AX) as AX-CLV. Basophil activation test (BAT) is used for diagnosing beta-lactam immediate hypersensitivity and is the only available in vitro assay for diagnosing patients with immediate hypersensitivity to CLV. However, few studies, and with limited numbers of patients have been published., Objective: The aim of this study was to establish the sensitivity, specificity, and negativization rates of BAT to AX and CLV., Methods: We studied 115 patients with immediate allergic reactions after AX-CLV treatment, 57 with selective reactions to AX (group A), 58 with selective reactions to CLV (group B), and 28 tolerant subjects. BAT was performed with AX in group A and with CLV in group B. A 4-year follow-up study was performed in patients with an initial positive BAT result., Results: The overall sensitivity of BAT was 55%, specificity 89%, and positive predictive value (PPV) 96%. For group A, sensitivity was 47%, specificity 93%, and PPV 93%; for group B, sensitivity was 62%, specificity 89%, and PPV 92%. Follow-up study showed a faster negativization rate of BAT for group A, with around 40% of patients becoming negative at 12 months in both groups., Conclusions: The high PPV of BAT to CLV shows its potential value as a complementary tool to the allergological workup of patients with immediate allergic reactions after AX-CLV treatment. Importantly, the assay should be done within the first 12 months after the reaction to reduce false-negative results., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The current diagnostic algorithm for beta-lactam allergy is based on skin and provocation tests, both of which carry a certain risk of inducing hypersensitivity reactions. Thus, non-invasive in vitro tests reliable enough to replace skin and provocation tests at least in a portion of patients are desirable. We aimed to verify the utility of IFN-γ ELISPOT as a first-line test in patients with suspected non-immediate hypersensitivity reaction to amoxicillin (AMX) and penicillin (PNC). The prospective observational study included 24 patients with recent, suspected non-immediate hypersensitivity reaction to AMX or PNC and 6 recently-exposed healthy subjects. In vitro tests were performed in all patients and healthy subjects: a) IFN-γ ELISPOT with PNC, AMX and amoxicillin plus clavulanic acid (AMX-CL); b) penicillin specific IgE; c) basophil activation test (BAT). Skin and provocation tests followed only in certain patients. IFN-γ ELISPOT results with PNC and AMX stimulation did not differ from the unstimulated condition. The highest IFN-γ responses to AMX-CL were close to previously published criteria in three patients; one of which had true hypersensitivity according to drug provocation tests. Five patients with confirmed hypersensitivity by skin tests showed no response to the culprit antibiotic on IFN-γ ELISPOT assay. Our results did not support the utility of IFN-γ ELISPOT in the diagnosis of mild, non-immediate hypersensitivity to amoxicillin and penicillin.

Background: Patients can react to amoxicillin (AX) and clavulanic acid (CLV) taken in combination because of selective reactions to either drug. However, scant information exists concerning patients who react simultaneously to both compounds., Objective: To analyze the mechanisms involved in 4 patients who developed allergic reactions to AX-CLV administration (3 with immediate IgE-mediated reaction and 1 with nonimmediate T-cell-mediated reaction) and who responded specifically to both AX and CLV., Methods: Skin tests with benzylpenicillin (BP), AX, and CLV were done and, if necessary, drug provocation tests with BP/penicillin V, AX, and AX-CLV were carried out. In immediate reactors, serum specific IgE to benzylpenicilloyl and amoxicilloyl was determined by using the CAP-FEIA system (Pharmacia Diagnostics, Uppsala, Sweden), and basophil activation test to BP, AX, CLV, and AX-CLV was done. In nonimmediate reactors, immunohistochemistry of skin biopsy and analysis of dendritic cell maturation and T-cell-specific response to BP, AX, CLV, and AX-CLV at both acute and resolution phases of the reaction were conducted., Results: All patients with immediate reactions (N = 3) had good tolerance to BP and penicillin V. Two cases also had specific IgE to AX and all had a basophil activation test positive to AX, CLV, and AX-CLV. The patient with a nonimmediate reaction exhibited dendritic cell and T-lymphocyte responses specific to both AX and CLV. Finally, the analysis of the cells infiltrating the skin and peripheral blood during the acute phase indicated a T H 1 pattern response., Conclusions: Our study provides evidence that reactions to both AX and CLV can appear in the same patient., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Amoxicillin (AX) is the ß-lactam most often involved in IgE-mediated reactions. Diagnosis is based mainly on skin testing, although sensitivity is not optimal. We produced a new AX derivative, amoxicilloyl-poly-L-lysine (APL), and analyzed its recognition of IgE using the passive histamine release test (pHRT)., Methods: The study population comprised patients (n=19) with confirmed AX allergy and specific IgE to AX and controls (n=10) with good tolerance to AX. pHRT was performed using "IgE-stripped" blood from a single donor that was sensitized in vitro by patient sera and incubated with AX or APL. Histamine release was determined and expressed as nanograms of histamine released per milliliter of blood., Results: The clinical symptoms were anaphylaxis (n=9), urticaria (n=7), erythema (n=2), and nondefined immediate reactions (n=1). The median (IQR) time interval between reaction and study was 90 (60-240) days and between drug intake and development of symptoms 24 (10-60) minutes. The median sIgE level was 3.37 (0.95-5.89) kUA/L. The sensitivity of pHRT to APL was 79% and the specificity 100%, which were higher than data obtained with pHRT to AX (63% sensitivity and 90% specificity). There was a positive correlation between maximal histamine release levels obtained with AX and APL (r=0.63)., Conclusions: In patients with immediate hypersensitivity reactions to AX, APL showed higher sensitivity and specificity than the culprit drug, AX, when tested in vitro by pHRT. This indicates that APL can improve the in vitro diagnostic accuracy of allergic reactions to AX. Further assessment of skin testing is necessary.

Background: Allergic reactions to amoxicillin are very common occurrences in the pediatric age group; however, onset of symptoms can present a diagnostic dilemma., Case Presentation: We present a case series that describes three children (8-year-old white girl, 2-year-old white boy and 14-month-old Chinese boy) who presented with varied onset of allergic reactions to amoxicillin, specifically immediate (within the first hour after exposure) and non-immediate onset. One child developed immediate onset allergy to oral challenge with amoxicillin although his clinical history was evident for non-immediate onset allergy to amoxicillin. He was the only case that had a positive skin test to penicillin. Two other children presented with reactions toward the end of their treatment course of amoxicillin, yet one patient developed immediate onset allergy while the other patient developed non-immediate onset allergy after challenge., Conclusions: This case series demonstrates diagnostic challenges facing physicians assessing allergic reactions to amoxicillin. As onset of reactions can dictate severity and pathogenic type of allergy, a thorough clinical history and subsequent appropriate diagnostic testing including medication challenge can help establish the diagnosis.

Introduction: A history of an adverse reaction to amoxicillin, irrespective of the mechanism involved, significantly elevates patients' anxiety and affects therapeutic decisions in the future, leading to unnecessary avoidance of antibiotics. As a consequence, it would be useful to find a safe and reliable protocol for typing safe alternative antibiotics. The aim of the study was to determine negative predictive value of typing safe antibiotic in patients with a history of hypersensitivity reaction to amoxicillin., Material and Methods: 71 patients, aged 20-83, with a history of an adverse reaction to amoxicillin were retrospectively analysed. On the basis of the reaction type they were divided into three groups: A - symptoms not typical for hypersensitivity reactions, B - allergy manifested by urticaria and/or angioedema, C - anaphylaxis. In group A amoxicillin was tested, in group B - cefuroxime, and in group C - macrolide: azithromycin or clarithromycin. Telephone follow-up visits were performed twice: 6-12 months and 3-5 years after the clinical assessment to evaluate tolerance of antibiotics. On the basis of the follow-up results, the negative predictive value (NPV) of the protocol was calculated., Results: The full diagnostic protocol was applied in 62 participants. Amoxicillin was found safe in 22, cefuroxime - in 21 and macrolide - in 19 patients. No anaphylactic reactions were observed during the tests. On the basis of the telephone follow-up, the NPV of the protocol was 96% in the first follow-up and 97% in the second one., Conclusion: A stepwise approach including SPTs, ICTs and provocations with amoxicillin / cefuroxime/macrolide - depending on a patient's history - is safe and allows typing an antibiotic in the vast majority of patients.

Background: Immediate allergic reactions to β-lactam antibiotics are considered to be one of the most important drug hypersensitivities. A positive skin test (ST) with a combination of major and minor penicillin determinants is usually sufficient to recommend avoidance of the culprit drug, whereas a negative ST is usually followed by an oral challenge test (OCT). Recently, concern has been raised regarding the role of amoxicillin (AMX) ST in the diagnosis of AMX allergy., Objective: The aim of this study was to examine the additive value of AMX determinants in STs of patients with immediate hypersensitivity reactions to AMX or AMX-clavulanate (AMX-C)., Methods: Patients with a history of immediate AMX or AMX-C allergy underwent an ST using a combination of penicilloyl-polylysine (PPL) and minor determinants as well as AMX. An ST with AMX-C was added when appropriate., Results: Thirty-one patients were evaluated. Eight patients, all of them with a history of AMX allergy, had positive reactions only to the AMX component. Two patients with AMX-C allergy had a positive ST reaction only to the AMX-C component. Moreover, only 14 patients (13 with AMX and 1 with AMX-C allergy) had a positive reaction to PPL, whereas most patients (54.8%) had positive reactions to other determinants. One patient, who was positive for AMX, developed several urticarial lesions after the test., Conclusions: Skin testing with AMX and AMX-C is mandatory in patients with immediate allergy to these drugs. Failure to perform it may result in a false-negative ST jeopardizing these patients with anaphylactic reactions during a hazardous OCT., (© 2016 S. Karger AG, Basel.)

Background: An increasing number of patients show immediate selective hypersensitivity reactions to clavulanic acid (CLV) and amoxicillin (AX), probably due to their increased prescription. The maintenance of this response should be established., Objective: To assess that the immediate hypersensitivity selective response to AX or to CLV is maintained after repeated administration of penicillin G (PG)/penicillin V (PV) and AX., Methods: Patients with proven immediate hypersensitivity to AX (Group A) or CLV (Group B) were included. Diagnosis was performed using skin tests with major and minor determinants of PG (PPL/MDM), AX and CLV and by drug provocation test (DPT) if required. Selectivity was established by confirming tolerance to PG/PV (Group A) and to PG/PV and AX (Group B). The maintenance of the selective response was verified by repeating DPT, 15 days after the initial investigation, with the same procedure., Results: Of 51 patients, 78% belonged to Group A and 22% to Group B. Most had anaphylaxis. In Group A, 72% were skin test positive; 28% required DPT. In Group B, 63% were skin test positive; 37% required DPT. Only two AX-selective cases developed positive responses after re-provocation with PG/PV. No cases selective for CLV developed a positive response to PG, PV or AX., Discussion: The selective response to AX appears consistent, and a response to penicillin determinants only develops in a minority of cases. For the case of CLV, the selective response appears not to be modified by exposure to penicillin determinants, meaning that patients with CLV allergy can take penicillin derivatives safely., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A label-free biosensing strategy for amoxicillin (AX) allergy diagnosis based on the combination of novel dendrimer-based conjugates and a recently developed nanoplasmonic sensor technology is reported. Gold nanodisks were functionalized with a custom-designed thiol-ending-polyamido-based dendron (d-BAPAD) peripherally decorated with amoxicilloyl (AXO) groups (d-BAPAD-AXO) in order to detect specific IgE generated in patient's serum against this antibiotic during an allergy outbreak. This innovative strategy, which follows a simple one-step immobilization procedure, shows exceptional results in terms of sensitivity and robustness, leading to a highly-reproducible and long-term stable surface which allows achieving extremely low limits of detection. Moreover, the viability of this biosensor approach to analyze human biological samples has been demonstrated by directly analyzing and quantifying specific anti-AX antibodies in patient's serum without any sample pretreatment. An excellent limit of detection (LoD) of 0.6ng/mL (i.e. 0.25kU/L) has been achieved in the evaluation of clinical samples evidencing the potential of our nanoplasmonic biosensor as an advanced diagnostic tool to quickly identify allergic patients. The results have been compared and validated with a conventional clinical immunofluorescence assay (ImmunoCAP test), confirming an excellent correlation between both techniques. The combination of a novel compact nanoplasmonic platform and a dendrimer-based strategy provides a highly sensitive label free biosensor approach with over two times better detectability than conventional SPR. Both the biosensor device and the carrier structure hold great potential in clinical diagnosis for biomarker analysis in whole serum samples and other human biological samples., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Quantitation of specific IgE by immunoassay is a recommended in vitro test for the diagnosis of immediate hypersensitivity reactions to betalactams (BLs), particularly when skin test results are negative. IgE antibodies that recognize the common nuclear structure of all BLs or the specific side chain structure can be mainly distinguished by immunoassays. The aim of this study was to develop an immunoassay system to detect IgE antibodies with different specificities. Cellulose discs conjugated with benzylpenicillin (BP), amoxicillin (AX) or both drugs, with poly-l-lysine (PLL) as carrier molecule, were used as solid phases in the radioallergosorbent test (RAST). Direct and inhibition radioimmunoassay studies were made to verify the structures recognized by serum IgE antibodies from penicillin-allergic patients. Our results indicated that the addition of both haptens did not decrease the capacity to capture IgE when serum specific to either BP or AX was used, at least in terms of sensitivity. In addition, the inclusion of two haptens improved significantly the levels of IgE detection in patients who recognized both BP and AX. Therefore, the use of a solid phase with a carrier molecule conjugated with two determinants (AX and BP) is helpful to recognize IgE antibodies against either of these determinants and is useful for screening sera with different specificities., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Myocarditis often occurs due to viral infections and postviral immune-mediated responses. Hypersensitivity myocarditis is a rare form of myocarditis. Numerous drugs can induce myocarditis, which is typically reversible after withdrawal of the causative agent. Here, we report a case of hypersensitivity myocarditis that was probably triggered by amoxicillin and that resolved completely with heart failure management as well as discontinuation of the drug. A 68-year-old woman presented with acute chest pain mimicking acute coronary syndromes, but the coronary angiography was normal. A recent history of taking medications, skin rash, and peripheral eosinophilia suggested a diagnosis of hypersensitivity myocarditis, which was confirmed by cardiac magnetic resonance imaging and endomyocardial biopsy.

Background: Although allergic drug reactions have been considered to be immediate (IgE mediated) or delayed (T-cell effector mechanisms), accelerated reactions have also been defined; however, they have not been sufficiently studied., Objective: To study the mechanisms involved in accelerated reactions to amoxicillin., Methods: We monitored the response in 3 patients who had an accelerated reaction to amoxicillin. A T-cell effector response was searched after a Drug Provocation Test. Symptoms were recorded after initiation of the reaction, and sequential samples were taken at different intervals after challenge. Skin biopsy specimens were also taken, and a lymphocyte transformation test (LTT) was performed., Results: After the drug provocation test, all 3 patients had a positive response within 2 to 6 hours of drug administration, with full expression at 6 hours, requiring corticoids and antihistamine treatment. They had generalized erythema with facial angioedema but no cardiovascular or respiratory symptoms. Monitoring of the response revealed the presence in the skin of CD4 and CD8 lymphocytes with increased expression of homing and cell activation markers. Immunohistochemistry revealed a perivascular mononuclear cell infiltrate with activated CD4 and CD8 cells expressing perforin and granzyme B. No tryptase release was detected in either the affected tissue or the peripheral blood. The LTT result was positive in all 3 patients., Conclusion: We found that accelerated reactions to β-lactams are mediated by effector T cells. The increase in different T-cell markers and a positive LTT result to amoxicillin, in parallel with the occurrence of symptoms after challenge, support this mechanism., (Copyright © 2013 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Skin testing with amoxicillin (AX) is necessary to diagnose immediate hypersensitivity reactions to this β-lactam. A commercial AX (DIA-AX) has recently become available for skin testing., Objective: The aim of this study was to compare DIA-AX with the injectable form (INJ-AX) in patients who have well-demonstrated IgE-mediated hypersensitivity to AX., Methods: Chemical characterization using high-performance liquid chromatography of both DIA-AX and INJ-AX reagents was performed. Patients diagnosed with an immediate allergic reaction to AX and a positive skin test to INJ-AX (N=55) were re-evaluated within 6 months by performing skin testing with INJ-AX and DIA-AX. Basophil activation test (BAT) and Radioallergosorbent test (RAST) inhibition assay using both reagents were performed in a selected group of patients., Results: The chemical analysis indicated that both DIA-AX and INJ-AX contained an AX compound with a purity above 95%. In the re-evaluation, 53 (96.4%) cases maintained skin test positivity to INJ-AX and were also positive to DIA-AX. Comparison of the papule area between the two reagents showed no significant differences between both reagents. BAT was performed in 30 samples and was positive to both compounds in 15 cases; no patient had a positive result to just one reagent. RAST inhibition studies using three individual cases and a pool of positive sera showed that the percentage inhibition detected with DIA-AX and INJ-AX was parallel and almost exactly the same., Conclusions: This study shows that DIA-AX is equivalent to INJ-AX in terms of skin test response, as well as with in vitro immunochemical and biological tests. DIA-AX can therefore be used in the diagnosis of immediate hypersensitivity reactions., (© 2011 Blackwell Publishing Ltd.)

Background: Skin testing of subjects with immediate hypersensitivity to amoxicillin is performed using major and minor determinants of benzylpenicillin plus amoxicillin. However, sensitivity is not optimal, and other determinants need to be considered. We assessed the sensitivity of stable, well-characterized minor determinants of amoxicillin in subjects with immediate allergic reactions to amoxicillin to improve skin test sensitivity., Methods: Amoxicillin, amoxicilloic acid, and diketopiperazine were prepared and characterized by reverse-phase HPLC, tested in vivo by skin testing and in vitro by basophil activation test and RAST inhibition assay., Results: Patients with immediate hypersensitivity to amoxicillin were selected: Group A (n = 32), skin test positive just to amoxicillin; Group B (n = 19), skin test positive to benzylpenicillin determinants; Group C (n = 10), skin test negative and amoxicillin drug provocation test positive. In Group A, 27 subjects (81.8%) were skin test positive to amoxicillin, ten (30.3%) to amoxicilloic acid, two (6.1%) to diketopiperacine, and six (18.2%) negative. In Group B, nine (50%) were positive to amoxicillin, eight (42.1%) to amoxicilloic acid, none to diketopiperacine, and nine (50%) negative. In Group C, skin tests were negative. BAT was positive to amoxicillin in 26 patients (50.9%), to amoxicilloic acid in 15 (29.1%), and diketopiperazine in four (7.8%). RAST inhibition studies showed > 50% inhibition in all sera, with the highest concentration of amoxicillin and amoxicilloic acid., Conclusions: The combination of minor determinants of amoxicillin, amoxicilloic acid, and diketopiperazine seems to be of no greater value than the use of amoxicillin alone. Further efforts are needed to find new structures to improve sensitivity in the diagnosis of immediate hypersensitivity to betalactams.