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Background: There is a scarcity of prospective studies investigating the relative roles of skin prick and intradermal testing, serum specific IgE, and extended oral challenges in diagnosing children with reported β-lactam allergies., Objective: To determine the sensitivity and specificity of skin testing and serum specific IgE in children with β-lactam allergies, with immediate and nonimmediate historic reactions., Methods: Four hundred children with parent-reported β-lactam allergies were recruited into an open-label prospective study. Detailed allergy histories were collected. Those with medically observed and documented histories of anaphylaxis, requiring epinephrine, or severe cutaneous adverse reactions were excluded. In total, 380 children underwent all testing modalities and a direct provocation test. Each child was followed up for a minimum of 3 years., Results: True allergy in children was uncommon; 8.3% reacted to the direct provocation challenge or the 5-day extended oral provocation challenge. Children reporting cephalosporin allergy or a reaction within 1 year were more likely to react to direct provocation testing. The sensitivity, specificity, and positive predictive value of skin testing were 12.5%, 98.8%, and 20.0% for direct challenge outcomes, 4.76%, 99.0%, and 25.0% for extended challenge outcomes, and 6.9%, 99.0%, and 40.0% for both challenges combined, respectively. Follow-up investigations revealed that 5.7% of children had a mild repeat reaction and 2.7% continued to avoid the culprit despite successful delabeling. The relabeling rate for children readmitted to hospital was 15%, with the relabeing being unfounded., Conclusions: Genuine β-lactam allergies were rare, with over 90% of children effectively delabeled. Skin and serum specific IgE testing did not aid the diagnosis of β-lactam antibiotic allergy in children, regardless of medical history. Extended oral challenges proved valuable in confirming allergies and boosted parental confidence., (Copyright © 2024. Published by Elsevier Inc.)

Background: Maximal skin testing (ST) nonirritant concentrations (NICs) are consistent for penicillin and aminopenicillin among guidelines. However, there is variability among guidelines for maximal ST NICs of cephalosporins., Objective: To determine maximal immediate and delayed ST NICs of 15 β-lactams in β-lactam-tolerant and β-lactam-naïve participants., Methods: We performed a single-center, nonrandomized prospective study between September 2019 and January 2022 in adult participants. Participants received skin prick testing (SPT) and intradermal test (IDT) injections at 6 increasing concentrations of 1 or more β-lactams. A concentration was considered irritant when more than 5% of participants had a positive test. A positive test was defined as a wheal ≥3 mm compared with negative control accompanied by a ≥5 mm flare for SPT/IDT and induration ≥5 mm with associated erythema at 48 hours for delayed readings (dIDT). Sensitivity analyses using 3 alternative IDT positive criteria were conducted., Results: A total of 747 participants with a median age of 64 (interquartile range: 54-72) years (52% male, 85% White, and 92% non-Hispanic) underwent 20,858 skin tests. All undiluted SPT concentrations were nonirritant. We found the following maximal IDT/dIDT NICs (mg/mL): ampicillin (41.6/125), ampicillin-sulbactam (93.8/187.5), aztreonam (6.3/25), cefazolin (55/165), cefepime (35/140), cefoxitin (45/90), ceftaroline (7.5/15), ceftriaxone (58.3/175), cefuroxime (55/110), ertapenem (16.6/50), imipenem-cilastin (6.3/25), meropenem (8.3/25), nafcillin (31.3/62.5), oxacillin (20.9/83.5), and piperacillin-tazobactam (112.5/225). dIDTs were almost all completely nonirritant close to or at undiluted concentrations. There were no differences when we applied 3 IDT positivity criteria to our raw data., Conclusions: Our results suggest that SPTs with undiluted stock β-lactam antibiotic concentrations are nonirritant. Compared with previously published nonirritant concentrations, we propose a 2- to 50-fold increase to the maximal IDT and dIDT NICs of 15 β-lactam antibiotics. When performing dIDTs, a higher concentration should be used rather than the same IDT concentration., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: The prevalence of allergies to beta-lactam antibiotics is significantly overestimated based on anamnestic data - with significant medical and economic consequences. The aim of the study was to determine the frequency of immediate and delayed type reactions to beta-lactam antibiotics in order to optimize diagnostics and therapy. One focus was on the time interval between reaction and testing., Patients and Methodology: Anamnestic and diagnostic data of patients with suspected allergy to beta-lactam antibiotics who were examined in our department between 2020 and 2022 were analyzed., Results: 27/116 (23%) patients reacted in the skin tests. Type I sensitizations were detected in 4/35 patients (11%), type IV sensitizations in 23/83 (28%). In the case of negative in vitro diagnostics and skin testing, inpatient provocation tests were performed in 41/89 (46%). Type I allergies were confirmed in two of the 13 provoked patients (15%) with immediate type reactions, type IV allergies in three of 29 (10%) with delayed type reactions. The results were clearly related to the time interval after reaction. At less than one year, 19% (22/116) reacted, whereas only 4% (5/116) reacted at more than one year (for type I reaction 9% vs. 3%; for type IV reaction 23% vs. 5%).  CONCLUSIONS: The importance of the time interval between clinical event and allergological testing supports the guideline recommendation for skin testing within one year. Guideline recommendations on the diagnostic procedure for unclear reactions that occurred in the more distant past are desirable in order to rule out allergies to beta-lactam antibiotics., (© 2024 The Author(s). Journal der Deutschen Dermatologischen Gesellschaft published by Wiley‐VCH GmbH on behalf of Deutsche Dermatologische Gesellschaft.)

Background: Drug challenge is the gold standard for identifying causative agents of drug allergies. Although clinical guidelines have recently been published, they do not recommend neuromuscular blocking agent (NMBA) drug challenges. NMBA challenges are rendered difficult by the lack of homogeneity of routine allergy work-ups and the necessity of a specialised setting. Several scenarios support NMBA challenges, such as an ambiguous allergy work-up, a high suspicion of a false-positive skin test or identification of a well tolerated alternative NMBA strategy. Furthermore, routine allergy work-ups may not recognise non-IgE mechanisms, such as IgG or MRGPRX2, whereas drug challenges may reveal them. Finally, if the culprit NMBA is not identified, subsequent anaesthesia regimens will be challenging to implement, resulting in increased risk., Objectives: This literature review discusses the indications, strategies, doses, monitoring methods, limitations, and unresolved issues related to drug challenges for NMBAs., Design: The literature review included randomised controlled trials, observational studies, reviews, case reports, series, and comments on humans., Data Sources: Studies were retrieved from databases (PubMed) and electronic libraries (OVID, EMBASE, Scopus, etc.)., Eligibility Criteria: All studies that referred to the NMBA challenge were included without publication date limitations., Results: NMBA challenge may be considered in NMBA anaphylaxis patients with inconclusive or ambivalent IgE diagnostic work-up under controlled conditions (presence of anaesthetists and allergists with continuous monitoring in a secured environment). To illustrate its utility, a case report of a double NMBA challenge in a patient with NMBA cross-reactivity is presented, along with biological explorations to detect subclinical cellular activation, a novel aspect of this procedure., Conclusion: Drug challenges could be implemented during the NMBA allergy work-up under strict safety conditions at specialised centres with close collaboration between anaesthetists and allergists. This could decrease uncertainty and contribute to defining a safer strategy for subsequent anaesthetic drug regimens., (Copyright © 2024 European Society of Anaesthesiology and Intensive Care. Unauthorized reproduction of this article is prohibited.)

Purpose of Review: Cephalosporins are one of the most prescribed antibiotics worldwide and are implicated in a wide range of hypersensitivity reactions (HSR). This review summarizes recent updates in cephalosporin hypersensitivity with a focus on diagnostic testing., Recent Findings: Reported testing strategies to evaluate different immediate and delayed cephalosporin HSR have included skin testing, in vitro testing, and diagnostic drug challenges. However, the diagnostic performance of in vivo and in vitro tests remains unclear across different hypersensitivity endotypes; adequately powered studies investigating the true positive and negative predictive value of these diagnostic modalities are needed using the reference standard of drug challenges to define cephalosporin hypersensitivity. Refinement of diagnostic testing should be guided by growth in our understanding of cephalosporin antigenic determinants. This growth will be crucial in driving further clarification of cross-reactivity between cephalosporins, and potentially delineating streamlined evaluation processes resulting in reduced unnecessary antibiotic avoidance., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cutaneous adverse drug reactions collectively are delayed drug reactions such as morbilliform drug eruption and severe cutaneous adverse reactions (SCARs). Morbilliform drug eruption may wane over time, be the result of drug viral interactions, and be amenable to slow reintroduction or rechallenge, whereas SCARs are HLA class I restricted, T-cell-mediated reactions that demonstrate durable immunity and warrant lifelong avoidance. SCARs such as drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome and toxic epidermal necrolysis, acute generalized exanthematous pustulosis, and generalized bullous fixed drug eruption often occur in the setting of multiple drugs dosed together. Collectively, they lead to significant morbidity, mortality, and drug safety concerns that could severely limit future treatment options. Currently, no single or combination of diagnostic tests for SCARs such as ex vivo or in vitro testing, in vivo (skin) testing, or other adjunctive tests such as HLA typing have 100% negative predictive value. In this "Controversies in Allergy Review" article, we review the current literature on delayed skin testing (patch and delayed prick/intradermal test) and critically assess the evidence base of its utility across different drugs and clinical phenotypes of delayed hypersensitivity reactions., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Polyethylene glycol (PEG) is a nonprotein polymer that is present in its native (unbound) form as an excipient in a range of products. It is increasingly being utilized clinically in the form of PEGylated liposomal medications and vaccines. PEG is the cause of anaphylaxis in a small percentage of drug reactions; however, diagnosis of PEG allergy is complicated by the variable and poor diagnostic performance of current skin testing protocols., Objective: We assessed the diagnostic performance of PEGylated lipid medications as an alternative to currently described tests that use medications containing PEG excipients., Methods: Nine patients with a strong history of PEG allergy were evaluated by skin testing with a panel of PEG-containing medications and with a PEGylated lipid nanoparticle vaccine (BNT162b2). Reactivity of basophils to unbound and liposomal PEG was assessed ex vivo, and specificity of basophil responses to PEGylated liposomes was investigated with a competitive inhibition assay. More detailed information is provided in this article's Methods section in the Online Repository available at www.jacionline.org., Results: Despite compelling histories of anaphylaxis to PEG-containing medications, only 2 (22%) of 9 patients were skin test positive for purified PEG or their index reaction-indicated PEG-containing compound. Conversely, all 9 patients were skin test positive or basophil activation test positive to PEGylated liposomal BNT162b2 vaccine. Concordantly, PEGylated liposomal drugs (BNT162b2 vaccine and PEGylated liposomal doxorubicin), but not purified PEG2000, consistently induced basophil activation ex vivo in patients with PEG allergy but not in nonallergic controls. Basophil reactivity to PEGylated nanoparticles competitively inhibited by preincubation of basophils with native PEG2000., Conclusion: Presentation of PEG on the surface of a lipid nanoparticle increases its in vivo and ex vivo allergenicity, and improves diagnosis of PEG allergy., Competing Interests: Disclosure statement This work received funding from the Health Services Charitable Gifts Board (HSCGB; project grant 70-05-52-05-20). G.B.P. is supported by the Mary Overton Research Fellowship (HSCGB). Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

Allergy to penicillin can occur via any of the 4 types of Gel-Coombs hypersensitivity reactions, producing distinct clinical histories and physical examination findings. Treatments include penicillin discontinuation, and depending on the type of reaction, epinephrine, antihistamines, and/or glucocorticoids. Most beta-lactams may be safely used in penicillin-allergic patients, with the possible exception of first-generation and second-generation cephalosporins. Penicillin testing includes skin testing, patch testing, and graded challenge. The selection of the type of testing depends on the clinical setting, equipment availability, and type of hypersensitivity reaction. Desensitization may be used in some cases where treatment with penicillins is essential., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: β-Lactams are the most widely used antibiotic family in the world. Nevertheless, they also stand out as the primary culprits for inducing drug hypersensitivity reactions (HSR). Methods: Between May 2018 and March 2023, patients with suspected HSRs to β-lactams, who underwent skin tests (ST), were retrospectively screened. The determinants of allergenic penicillin (DAP) tests, which include penicillin minor and major determinants, clavulanic acid, and amoxicillin, along with ampicillin, sulbactam, the identified culprit drugs, and alternative cephalosporins, which include cefuroxime, ceftriaxone prick and/or intradermal tests, were administered. The analysis focused on identifying positive ST results and determining the true HSRs rates in this patient cohort. Results: Of the 147 patients, 78.9% (n = 116) were women and the median (minimum-maximum) age was 41 years (18-71 years). Mild HSRs (grades 1-2) were observed in 72.78% (n = 107), whereas 24.4% (n = 36) had severe reactions (grades 3-4) and 2.7% (n = 4) had an unknown grade. Of the patients, 64% (n = 94) experienced HSRs within the first hour after the last dose of the identified culprit drug. The overall positivity rate for all STs was 26.5% (n = 39). ST positivity rates were notably higher in individuals who had experienced HSRs within the past 6 months (p = 0.02) and those with severe anaphylaxis (p < 0.001). Conclusion: β-Lactam ST positivity is higher, especially in those with grades 3-4 reactions and consulted a physician within the first 6 months after their HSRs.

Background: Thiocolchicoside is a muscle relaxant, anti-inflammatory, and analgesic. Administered orally, intramuscularly, or topically, this drug is used in the symptomatic treatment of muscular spasms and rheumatologic disorders. Despite its extensive use, thiocolchicoside is a very rare sensitizer., Objective: To evaluate IgE-mediated reaction to thiocolchicoside by basophil activation test., Methods: Allergological work-up with skin prick tests, intradermal tests and basophil activation test with thiocolchicoside., Results: We report the first case of immediate reaction to thiocolchicoside confirmed by basophil activation test in addition to positive skin tests., Conclusions: BAT can be considered a complementary diagnostic tool to demonstrate an IgE-mediated reaction also for muscle relaxant drugs.

Background: Antibiotic treatment is crucial for patients with chronic bacterial infections. Suspected drug allergies often lead to inconsistent therapies and challenging clinical management for patients and caregivers. The objective of this study was to evaluate the value of lymphocyte transformation tests in comparison to skin tests for the prediction of delayed-type allergic reactions., Methods: This prospective, observational study tested the diagnostic value of skin prick tests, intradermal tests (reading: 15 min and 72 h) and lymphocyte transformations tests for the prediction of allergic reactions in CF patients with physician reported allergy to piperacillin/tazobactam, meropenem and ceftazidime. The tests were performed directly before a 14d intravenous drug challenge., Results: We performed 33 drug challenges in 29 subjects. 21 drug challenges were negative (63 %); 12 lead to a reaction (37 %), of those 2 were immediate and 10 were delayed-type. 100 % of the skin prick tests were negative. 97 % (33/34) of the intradermal tests with early reading and 100 % of the intradermal tests with late reading yielded negative results. 5/11 patients who experienced a delayed-type reaction during the drug challenge had a positive lymphocyte transformations test. All 17 patients who did not react had a negative lymphocyte transformations test. For piperacillin/tazobactam, 4/5 patients who experienced a delayed-type reaction during the drug challenge had positive lymphocyte transformations tests. Hence, for piperacillin/tazobactam, the sensitivity of the lymphocyte transformation test for prediction of reactions was 80.0 % and the specificity 100 %., Conclusion: We demonstrate that the lymphocyte transformation test predicts delayed-type allergy to piperacillin/tazobactam in contrast to skin tests., Competing Interests: Declaration of Competing Interest JR has received payments for lectures from Vertex Pharmaceuticals outside of the submitted work. MAM received grants from Vertex Pharmaceuticals; and personal fees for participation in advisory boards, consultancy and lectures from Boehringer Ingelheim, Arrowhead Pharmaceuticals, Vertex Pharmaceuticals, Enterprise Therapeutics, Kither Biotech, and Antabio outside of the submitted work. DJN has received research grants from Merck, AstraZeneca, GSK, and Janssen Pharmaceuticals to study mechanisms of drug hypersensitivity. However, this funding does not directly relate to the research described in this manuscript. Other authors have no conflicts to disclose., (Copyright © 2023. Published by Elsevier B.V.)

Secondary prevention with penicillin aims to prevent further episodes of acute rheumatic fever and subsequent development of rheumatic heart disease (RHD). Penicillin allergy, self-reported by 10% of the population, can affect secondary prevention programs. We aimed to assess the role for (i) routine penicillin allergy testing and the (ii) safety of penicillin allergy delabeling approaches in this context. We searched MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, WHO ICTRP, ISRCTN, and CPCI-S to identify the relevant reports. We found 2419 records, but no studies addressed our initial question. Following advice from the WHO-Guideline committee and experts, we identified 6 manuscripts on allergy testing focusing on other populations showing that the prevalence of allergy confirmed by testing was low and the incidence of life-threatening reactions to BPG was very low (< 1-3/1000 individuals treated). A subsequent search addressed penicillin allergy delabeling. This found 516 records, and 5 studies addressing the safety of direct oral drug challenge vs. skin testing followed by drug administration in patients with suspected penicillin allergy. Immediate allergic reactions of minor severity were observed for a minority of patients and occurred less frequently in the direct drug challenge group: 2.3% vs. 11.5%; RR = 0.25, 95%CI 0.15-0.45, P < 0.00001, I 2  = 0%. No anaphylaxis or deaths were observed. Severe allergic reactions to penicillin are extremely rare and can be recognized and dealt by trained healthcare workers. Confirmation of penicillin allergy diagnosis or delabeling using direct oral drug challenge or penicillin skin testing seems to be safe and is associated with a low rate of adverse reactions., (© 2024. The Author(s).)

Background: Two-dimensional (2D) classifications of iodinated contrast media (ICM) are insufficient to explain the observed skin test (ST) reactivity patterns in patients with drug hypersensitivity reactions (DHRs) to ICM., Objective: To refine the current view on allergic DHRs to ICM by analyzing ST reactivity patterns in patients with previous reactions to ICM., Methods: Patients with a history of DHR to ICM and positive STs, who presented at the University Hospital of Montpellier between 2004 and 2022, were included in the study. The relative difference between every two ICM products was measured by Manhattan distance and odds ratios were computed for all pairs of products in the immediate reaction (IR) and non-immediate reaction (NIR) ST groups., Results: A total of 181 patients were included in the study. Odds ratio analysis identified significant associations between classical cross-reactive ICM, such as iohexol-ioversol, iohexol-iomeprol, iomeprol-ioversol, and iohexol-iodixanol in the IR ST group and iohexol-ioversol, iopromide-iohexol, and iomeprol-ioversol in the NIR ST group. We also identified uncommon associations, such as ioxitalamate-amidotrizoate in the IR ST group and amidotrizoate-iopamidol and amidotrizoate-ioxitalamate in the NIR ST group. The results were reflected by the Manhattan distance, which suggested the existence of clusters containing the same classically associated ICM as well as uncommon associations, which we hypothesize to be related to similarities in the 3D structure of the respective ICM., Conclusions: Current chemical (2D) classifications cannot explain all observed ST reactivity patterns. Whether the 3D structure can be integrated into the current classifications to interpret the observed ST reactivity patterns and predict tolerance to alternative ICM requires further research., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Intradermal testing with delayed reading (IDTdr), used routinely in many centers, may identify delayed reactions to penicillins. However, few studies have compared the results of IDTdr with drug provocation test (DPT). The aim of this study was to examine the proportion of provocation-positive patients testing positive on IDTdr., Methods: Fifty-seven patients with a positive DPT occurring >2 h after intake of penicillin V, dicloxacillin, pivampicillin, or amoxicillin had an IDTdr with penicillin G, amoxicillin, ampicillin, and dicloxacillin. A control group included 18 patients with negative DPTs with the suspected penicillin., Results: In total 25% (n = 14) of provocation-positive patients tested positive on IDTdr. Among patients with positive IDTdr, 9/14 (64%) versus 11/43 (26%) in the IDTdr negative group (p < 0.05) had required oral steroids to treat skin reactions following DPT. No other differences between IDTdr positive and negative groups were found. No controls had a positive IDTdr., Conclusion: Investigating with IDTdr would have identified 25% of patients with a DPT-verified allergy with delayed reactions. It is difficult to target subgroups who will test positive on IDTdr. There were more patients who tested positive on IDT who had received oral steroids after DPT, and this may be an indication that skin reaction severity plays a role in skin testing diagnostics. Further potential predictors for positivity of IDTdr, such as duration of skin symptoms, should be assessed in large studies in order to optimize the investigations of nonimmediate drug allergic reactions., (© 2021 S. Karger AG, Basel.)

Immediate hypersensitivity to drugs is characterized by symptoms such as hives, swelling, and wheezing. To prevent a negative impact on care, assessment by an allergist is important. Evaluation requires a clear clinical history, but it is often lacking or vague, which makes a diagnosis difficult. Allergists instead can use skin testing and drug challenge to evaluate drug hypersensitivity reactions, which help the patient and provider understand the causative drug(s) and, more importantly, enables the use of the exonerated drug(s). Although penicillin skin testing is standardized, well described, and widely used, skin testing for most other drugs requires the use of a nonirritating skin testing concentration that can have a low negative predictive value. Drug challenges are the criterion standard for confirming tolerance. The allergist must obtain an in-depth clinical history and then follow with skin testing and/or drug challenges when indicated to determine which drugs can be de-labelled and which should be avoided. In this review, we focused on the evaluation of drug hypersensitivity reactions to antibiotics, perioperative agents, biologics, and chemotherapeutics.

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.)

Background: The first-line method in the diagnosis of patients who describe an immediate reaction after penicillin intake is a skin test (ST) with penicillin reagents. Objectives: We aimed to determine the safety and diagnostic value of penicillin STs in the diagnosis of immediate reactions to penicillins in pediatric patients. Methods: The study included pediatric patients with suspected immediate reaction to penicillin who were subjected to STs by using a standard penicillin test kit as well as suspected penicillin and the drug provocation tests (DPT) with the suspected penicillin at our clinic. Results: A total of 191 patients (53.9% boys) with a median age of 6.83 years (interquartile range, 4.2-12 years) were included in the study. The time from drug intake to the onset of reaction was ≤1 hour in 138 patients (72.3%) and 1 to 6 hours in 53 patients (27.7%). Penicillin allergy (PA) was confirmed by diagnostic tests in 36 of the 191 patients (18.8%). In multivariate logistic regression analysis, the history of both urticaria and angioedema (odds ratio [OR] 27.683 [95% confidence interval {CI}, 3.143-243.837]; p = 0.003) and anaphylaxis (OR 56.246 [95% CI, 6.598-479.489]; p < 0.001) were the main predictors of a PA diagnosis. Although ST results were positive in 23 patients (63.8%), 13 patients (26.2%) had positive DPT results despite negative ST results. The negative predictive value (NPV) of STs was calculated 92.2% (155/168). None of our patients experienced immediate or delayed systemic and/or local reactions in relation to the STs. Conclusion: A history of urticaria with angioedema and anaphylaxis were the main predictors of true PA in children with suspected immediate reactions. STs with penicillin reagents are safe for use in children. Although STs have a high NPV, DPT is the gold standard for diagnosis. DPTs should be performed as the final step of the diagnostic evaluation of PA in patients with negative ST results.

Competing Interests: The author has disclosed no conflicts of interest.

Objective: This study sought to evaluate available evidence of the safety of penicillin skin testing (PST), challenge, and desensitization in pregnancy, with efforts to improve perinatal care for patients with a penicillin allergy history and mitigate the negative sequelae of unverified penicillin allergy labels., Methods: A systematic review of studies was conducted using Cochrane Library, Medline, EMBASE, and International Pharmaceutical Abstracts. Included were peer-reviewed studies without date restrictions, published in English or French, relating to PST, challenge, or desensitization in pregnancy. Editorials, opinion pieces, and letters were excluded. Review authors independently screened citations and full-text articles, extracted data, and conducted quality assessment. Given the heterogeneity of study designs, a narrative synthesis was conducted., Results: The search identified 1195 references, of which 18 studies met inclusion criteria. In total there were 231 patients with varying histories of penicillin allergy, the majority requiring treatment for syphilis or group B streptococcal (GBS) disease during pregnancy. Of the 203 participants who underwent PST, 83.7% had negative test results. Allergy-related reactions were rare in PST (1.5%) and challenge (0%), and although these reactions were more common in desensitization (19.7%), most were benign. Among the 231 cases, only one adverse pregnancy outcome was reported (0.4%)., Conclusion: This review demonstrates that the known prevalence of true penicillin allergy extends to pregnant women. PST and desensitization can be safely applied during pregnancy and are tools that should be used more frequently. Further data on the safety of challenge during pregnancy are recommended., (Copyright © 2019 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Background: Suspected antibiotic hypersensitivity in children is a frequent reason for consultation. Skin test performance and drug provocation test (DPT) duration are controversial issues. The objective of this study was to assess the effectiveness of diagnostic tests used in the study of antibiotic hypersensitivity and to estimate an optimal duration for DPT., Methods: Sixty-two children with a suspected hypersensitivity reaction to antibiotics were studied. Skin tests were performed on all patients. In the case of negative results, DPTs were performed for a duration similar to the time elapsed from the start of treatment until the onset of the reaction., Results: The frequency of antibiotic hypersensitivity in the study population was 8.1% (5 of 62). Only 1 patient showed positive skin tests. The other allergic patients were diagnosed by DPT, which reproduced the reaction within the first 6 hours in all but one of them., Conclusions: Shortening DPT duration may decrease the sensitivity of the test for the diagnosis of non-IgE-mediated hypersensitivity; however, it should be considered as an opportunity to reduce the resulting microbial resistances.

Summary: Objectives. To describe clinical manifestations and performed diagnostic workup, focusing drug challenge tests (DCT), in patients with drug allergy. Methods. Retrospective study including all patients with skin tests (STs) or DCT-based drug allergy diagnosis, between 01/2014 - 06/2018 in a Portuguese allergy unit. Data were collected from electronic and paper-based clinical records. Results. We had 75 drug allergy diagnoses. Most index reactions were mild and major or equal 1 hour after drug intake. 59 (78%) diagnoses were based on DCTs, all based on multistep protocols with major or equal 3 predicted steps. Only 10% of the DCT were positive during up-dosing; timing and severity of the index reaction predicted DCT interruption during up-dosing. Conclusions. Most drug allergy diagnoses were based on multistep DCT. The identified predictors of DCT interruption during up-dosing can support the development of more personalized DCTs protocols.

Summary: Clindamycin is widely used in the prophylaxis and treatment of infections due to its broad spectrum of antimicrobial activity. Hypersensitivity to clindamycin seems to be not very common (less than 1% of drug-allergic reactions) and it mostly appears as delayed T-cell mediated. For the diagnosis, skin testing is considered to be highly sensitive and rather safe, but cutaneous and systemic reactions have been described. Provocation test is considered the gold standard. However, it includes the possibility of severe reactions. We reported two cases of delayed allergic reaction to clindamycin, confirmed with a positive lymphocyte transformation test, showing this in vitro test like a promising diagnostic method because of its usefulness and safety.

Drug hypersensitivity reactions (DHRs) may be classified based on timing (immediate vs delayed), mechanisms, and pattern of clinical manifestations. Management may include selection of alternative, non-cross reactive agents, drug allergy testing, graded challenge and/or desensitization. Immediate skin testing only identifies risk for immediate-type allergic DHR and has a negative predictive value for only a limited number of drugs (eg, penicillin). Desensitization induces a temporary state of tolerance that is maintained only so long as the drug is continued. This article discusses special considerations about antibiotics, angiotensin-converting enzyme inhibitors, anesthetic agents, aspirin and nonsteroidal antiinflammatory drugs, radiocontrast media, and chemotherapeutic agents., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The relationship between cephalosporin hypersensitivity and a history of β-lactam hypersensitivity is unclear. We evaluated the usefulness of routine intradermal cefazolin skin testing and its relationship with the history of β-lactam hypersensitivity., Methods: The electronic medical records of patients who underwent intradermal cefazolin (0.3 mg/mL) skin testing without negative controls from January 2010 to January 2011 at Seoul National University Bundang Hospital were evaluated. The history of β-lactam hypersensitivity of the patients was taken. Immediate adverse reactions after cefazolin injection were evaluated by searching the electronic medical records for key words and reviewing consultation documents of allergy specialists or dermatologists. The medical records of the patients were reviewed by an allergist., Results: There were 13,153 cases of cefazolin skin testing over the 13-month study period. Among the 12,969 cases with negative skin test results, 8 had immediate hypersensitivity related to cefazolin (0.06%). The negative predictive value of cefazolin skin testing alone was 99.94%. The overall positivity rate of cefazolin skin tests was 1.4% (184/13,153). Of the cases with a history of allergy to β-lactams, 15% (6/40) showed a positive cefazolin skin test result compared to only 1.36% (178/13,113) of cases with no such history ( P < 0.001) including some false-positive tests., Conclusion: The results suggest that routine screening involving cefazolin skin testing without negative controls is not useful for all patients, but could be helpful for those with a history of β-lactam hypersensitivity, although a large prospective study is needed to confirm this., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2019 The Korean Academy of Medical Sciences.)

Background: Recent research has shown that a large majority of patients with a history of penicillin allergy are acutely tolerant of penicillins and that there is no clinically significant immunologic cross-reactivity between penicillins and cephalosporins or other β-lactams. The standard test to confirm acute tolerance is challenge with a therapeutic dose. Skin testing is useful only when the culprit antibiotic can haptenate serum proteins and induce an immunoglobulin E-mediated reaction and the clinical history demonstrates such high risk that a direct oral challenge may result in anaphylaxis., Objective: To review and evaluate the current practice of skin testing for antibiotics (other than penicillin) in critically ill patients by means of a systematic literature review., Methods: This systematic review was performed using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines. Several electronic databases were searched using the following terms: antibiotics, skin test (tests, testing), intensive care, intensive care unit, ICU, critical care, critical care unit., Results: Twenty-three articles were identified for inclusion in this review. The results indicate a lack of standardized skin testing for all antibiotics in critical care settings. Oral challenge with nonirritating concentrations of antibiotics can be helpful in determining allergy to these drugs., Conclusions: Critical care providers should evaluate antibiotic allergy using nonirritating concentrations before administering antibiotics to patients. Introduction of a standardized skin test for all antibiotics in intensive care unit patients to help select the most appropriate antibiotic treatment regimen might help save lives and reduce costs., (©2019 American Association of Critical-Care Nurses.)

OBJECTIVE. Adverse drug reactions (ADRs) to radiocontrast media are a significant social and economic burden and are difficult to predict. Because some ADRs to radiocontrast media may be immunologically induced, a skin test with diluted 1:10 radiocontrast media has been used to predict ADRs. However, using this test in clinical practice is difficult because of its low sensitivity. SUBJECTS AND METHODS. This study enrolled 36 patients with a history of immediate ADR to radiocontrast media who visited the Allergy and Asthma Clinic of Severance Hospital from 2017 to 2018. Patients underwent intradermal testing (IDT) with five types of diluted (1:10) and undiluted radiocontrast media (iohexol, iobitridol, iopamidol, iopromide, and iodixanol). The IDT result was regarded as positive if at least one radiocontrast medium elicited a positive reaction. Positivity of IDT and sensitivity to the culprit radiocontrast medium were calculated and compared. For subsequent CT examinations with a radiocontrast medium, the contrast agent eliciting a negative skin reaction in IDT was selected, excluding the previous culprit radiocontrast medium. RESULTS. IDT positivity and sensitivity for the culprit radiocontrast medium at 1:10 dilution were 47.2% and 47.2%, respectively, whereas the positivity and sensitivity for the undiluted radiocontrast medium were 86.1% and 75.0%, respectively. The positivity and sensitivity were higher with frequent radiocontrast medium use or with severe reaction. Of 22 patients who underwent another CT examination with the contrast medium selected on the basis of IDT results, 21 (95.5%) did not experience an ADR. CONCLUSION. IDT to prevent ADR should be performed with undiluted radiocontrast medium. Selecting an alternative radiocontrast agent on the basis of IDT results can be clinically useful to prevent recurrent ADRs to radiocontrast media.

Background: Use of penicillin skin testing (PST) to rule out penicillin (PCN) allergies is safe and effective in immunocompetent patients; however, data on immunocompromised patients are limited., Objective: We aimed to determine safety, efficacy, and clinical impact of PST in immunocompromised patients with cancer., Methods: A quality improvement process establishing a PST service was implemented at MD Anderson Cancer Center. Adult patients admitted to leukemia and genitourinary medical oncology (GUMO) services with history of possible type I reactions to PCN were eligible for testing., Results: Between April and October 2017, 218 patients with reported PCN allergies were screened; 100 met inclusion criteria and underwent PST (67 leukemia, 33 GUMO). The most common reported allergy was to PCN (64%), with 61% reporting cutaneous reactions and 79% reporting reactions more than 20 years ago. PST with oral challenge results were overwhelmingly negative (95%); only 4% tested positive, and 1 test result was indeterminate (negative histamine control). After negative PST and oral challenge results, 51% patients were transitioned to PCN-based antibiotics during the same hospitalization. During the follow-up period (median 177 days), 65 of 95 patients were readmitted (185 total readmissions), and 51 patients required antibiotic therapy, with 37 receiving a PCN-based antibiotic (accounting for 336 days of therapy). No patient who received PCN-based antibiotics experienced an immediate-type allergic reaction., Conclusions: Our findings support PST use in immunocompromised hosts. The widespread use of PST in patients with cancer will allow for optimal use of antimicrobial therapy and stewardship, which are vital in a population at increased risk for infections., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The practice of skin testing prior to administration of antibiotics in the absence of a history of allergy is non-existent in the western world. Reports on skin testing in the absence of known allergy are unheard of in the medical literature. The practice of giving a test dose prior to administration of the antibiotic is also practiced very sporadically and has no scientific basis. Despite this In India in most major institutions both in government and private hospitals , general practice set up and small and medium nursing homes, skin testing prior to administration of antibiotics remain extremely common and is even considered to be negligent if not practiced. In this review the evidence for skin testing and test dose before antibiotic administration has been examined. Based on the evidence available skin testing should be restricted to patients with a history of prior penicillin allergy for whom penicillin or other B-lactam antibiotic is the drug of choice and there is no suitable alternative.1 There is no need to do skin testing without a history of penicillin allergy even if the drug is to be administered parenterally. Test dose administration does not protect patients from anaphylactic reactions and hence the practice has no scientific basis., (© Journal of the Association of Physicians of India 2011.)

The diagnosis of drug allergy is essentially based on a detailed anamnesis, involving the doctors who first treated the patient, and skin testing (prick, intradermal and epicutaneous / patch tests). In the allergological practice / clinic, provocation tests with the presumed trigger are only carried out if the indication is very clear (see articles in this issue on drug allergy children, allergies to betalactam and other antibiotics as well as analgesic intolerance). The provocation with a probably tolerable alternative is in the foreground. Unfortunately, the skin tests of certain drug groups have a low sensitivity even under optimal conditions, but very good specificity. Accordingly, positive skin tests are mostly relevant, but negative skin tests cannot rule out an allergy. In recent years, it has therefore proved successful to carry out supplementary laboratory tests in the clarification of drug allergies. The serological tests (IgE) are of little help. In contrast, the test forms based on the analysis of leukocytes (basophil activation test, BAT, and lymphocyte transformation test, LTT) have gained in importance and complement the diagnostic repertoire. In the combination of all test methods (skin test, LTT, BAT, sometimes provocation test) the trigger of a drug allergy can be defined in a good 70 % of cases and in most cases a safe therapeutic alternative can be found. In the following, we will discuss the importance of laboratory diagnostics in drug allergy.

Suspected perioperative allergic reactions are often severe. To avoid potentially life-threatening re-exposure to the culprit drug, establishing a firm diagnosis and identifying the culprit is crucial. Drug provocation tests are considered the gold standard in drug allergy investigation but have not been recommended in the investigation of perioperative allergy, mainly because of the pharmacological effects of drugs such as induction agents and neuromuscular blocking agents. Some specialised centres have reported benefits of provocation testing in perioperative allergy investigation, but the literature on the subject is limited. Here we provide a status update on the use of drug provocation testing in perioperative allergy, including its use in specific drug groups. This review is based on a literature search and experiences of the authors comprising anaesthesiologists and allergists with experience in perioperative allergy investigation. In addition, 19 participating centres in the International Suspected Perioperative Allergic Reaction Group were surveyed on the use of provocation testing in perioperative allergy investigation. A response was received from 13 centres in eight European countries, New Zealand, and the USA. Also, 21 centres from the Australian and New Zealand Anaesthetic Allergy Group were surveyed. Two centres performed provocation routinely and seven centres performed no provocations at all. Nearly half of the centres reported performing provocations with induction agents and neuromuscular blocking agents. Drug provocation testing is being used in perioperative allergy investigation in specialised centres, but collaborations between relevant specialties and multicentre studies are necessary to determine indications and establish common testing protocols., (Copyright © 2019 British Journal of Anaesthesia. All rights reserved.)

Background: There is no perfect agreement on how to perform an allergy workup in suspected beta-lactam (BL)-allergic children, since skin test (ST)-induced pain is often a limitation. The aim of the study was to assess the possibility of reducing the number of ST in children when performing a complete allergy workup for BL hypersensitivity reactions., Methods: A retrospective analysis of all patients referring to the Allergy Unit of the University Hospital of Montpellier (France) with positive responses in immediateand non-immediate-reading ST to a BL over a 16-year period was performed, to determine the positive predictive value (PPV) of ST. All pediatric patients with a suspected BL hypersensitivity were skin-tested with the suspected drug only, during the following 54 months., Results: A total of 319 patients reporting 328 BL reactions were included in the retrospective study. The PPV of ST for the reported drug was of 99.4%. Based on the results, the number of patients to include in the prospective study was estimated to be 101. In the prospective study, 229 children were included. We diagnosed a BL hypersensitivity in 12 children (5.2%): Diagnosis was reached in 6 (50.0%) through ST (delayed reading for all) and in 6 through drug provocation test (DPT)., Conclusion: ST with BL should therefore be performed as a screening test, before DPT, and testing only the suspected drug may be sufficient when dealing with children., (© 2019 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Purpose of Review: Pediatric drug hypersensitivity is a rapidly evolving field. The purpose of this paper is to review the current state of pediatric drug hypersensitivity and highlight new developments in diagnosis and management., Recent Findings: This paper will discuss the safety and use of risk stratification to proceed directly to oral challenge without prior skin testing for β-lactam reactions. We review unique aspects of pediatric drug challenges and desensitizations. It is important to accurately diagnose pediatric drug hypersensitivity reactions through a detailed history, physical examination, and available diagnostic testing. Understanding of the underlying mechanism leads to appropriate classification which is necessary to direct management. The decision to perform drug challenge, desensitization, or recommend avoidance of a medication can have a significant impact on a patient's treatment. Utilization of weight-based dose and infusion rate adjustments for current drug challenge and desensitization protocols optimize success.

Background: Beta-lactams are the mainstay for treating methicillin-susceptible Staphylococcus aureus (MSSA) infections complicated by bacteremia due to superior outcomes compared with vancomycin. With approximately 11% of inpatients reporting a penicillin (PCN) allergy, many patients receive suboptimal treatment for MSSA bacteremia., Objective: Evaluate the cost-effectiveness of penicillin skin testing (PST) in adult patients with self-reported PCN allergy in an inpatient setting undergoing treatment for MSSA bacteremia., Methods: A decision analytic model was developed comparing an acute care PST intervention to a scenario with no confirmatory allergy testing. The primary outcome was the incremental cost-effectiveness ratio (ICER) from the health-sector perspective over a 1-year time horizon using quality-adjusted life years (QALYs) as the measure for effectiveness. One-way and probabilistic sensitivity analyses were conducted to assess the uncertainty of the ICER estimation., Results: Over a 1-year time horizon, PST services applied to all MSSA bacteremia patients reporting a PCN-allergy would result in a cost per patient of $12,559 and 0.73 QALYs while no PST services would have a higher cost per patient of $13,219 and 0.66 QALYs per patient. This resulted in a cost-effectiveness estimate of -$9,429 per QALY gained. Varying the cost of implementing PST services determined a break-even point of $959.98 where any PST cost less than this amount would actually be cost saving., Conclusions: Patients reporting a PCN allergy on admission may receive sub-optimal alternative therapies to beta-lactams, such as vancomycin, for MSSA bacteremia. This economic analysis demonstrates that inpatient PST services confirming PCN allergy are cost-effective for patients with MSSA bacteremia., Competing Interests: TJM reports personal fees from Summit Therapeutics, G&W Laboratories, and Paratek Pharmaceuticals outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: The hypersensitivity reaction to penicillin is a public health problem. Immunological responses to penicillin and other beta-lactam antibiotics can be classified into immediate and non-immediate responses. The immediate hypersensitivity is mediated by IgE; however, the non-immediate sensitivity is facilitated by other isotypes of antibody or T lymphocytes., Objective: This research detected the non-IgE antibody value against penicillin in allergic and normal people., Methods: Thirty-eight samples from patients with positive or negative intradermal skin testing results of penicillin allergy were included in this study. The total antibody and IgM levels against penicillin G were defined by in-house ELISA test., Results: The results showed a significant (P< 0.05) elevation in total immunoglobulin and non-IgM anti-penicillin antibody of sensitive groups; however, the anti-penicillin IgM was significantly greater in non-sensitive peoples., Conclusions: Although the sensitized people to penicillin cannot be certainly detected with the total antibody, specific IgG and IgM value against penicillin, these values are good indicators for prediction of immediate and late response of the immune system to penicillin.

Within the broad category of adverse drug reactions in children, there has been a recent focus specifically on the evaluation of children with antibiotic allergy, in particular, beta-lactam allergy. The potential consequences of being labeled beta-lactam allergy are increasingly recognized. Appropriate evaluation of children with suspected reactions to antibiotics is essential as it is increasingly being recognized that the label of "penicillin allergy" is associated with adverse health and economic outcomes. This review will focus on the 3 main classes of antibiotics reported to cause allergic reactions in children: beta lactams (penicillin derivatives and cephalosporins), macrolides, and sulfonamides. This article is a narrative review of the prevalence, diagnosis, and management of different types of antibiotic allergies in children. Our review reveals that antibiotic allergy is often overreported and not appropriately diagnosed in the pediatric age groups. There is a recent shift in the diagnostic paradigm from the use of skin tests and if negative challenges to the use of challenge only in the pediatric age group. Larger studies to establish the usefulness and safety of this new approach as well as updated guidelines are needed., (© 2019 S. Karger AG, Basel.)

Background: The majority of patients for elective surgery and with a history of penicillin allergy are placed on alternative prophylactic antibiotic therapies, which have been associated with the emergence of multidrug-resistant pathogens and increased morbidity and mortality rates. However, self-reporting of penicillin allergy alone may overestimate the prevalence of penicillin allergy in the population. Objective: To assess the effects of preoperative antibiotic allergy testing protocols in reducing the use of non-beta-lactam antibiotics. Methods: We searched medical literature data bases through July of 2018. Two reviewers independently extracted data from published studies and assessed the risk of bias in cohort studies by using the Newcastle-Ottawa Scale. We collected information related to study design, methodology, demographics, interventions, and outcomes. We pooled odds ratios for the rate of prescribing non-beta-lactam antibiotics by using a fixed-effects model. Results: Of 905 citations screened for eligibility, nine studies met inclusion criteria for qualitative analysis. Studies reported that the rates of non-beta-lactam use after preoperative skin testing ranged from 6 to 30%. In addition, four of the nine studies had sufficient control data to be included in a meta-analysis. These four studies found that preoperative testing protocols significantly decreased the rates of prescribing non-beta-lactam antibiotics compared with usual care (odds ratio 3.64 [95% confidence interval, 2.67-4.98]; p < 0.0001). Seven studies reported on adverse drug reactions after preoperative skin testing and found that the rate of such reactions was rare. Conclusion: Preoperative antibiotic allergy testing protocols seemed to be a safe and effective tool in reducing the use of non-beta-lactam antibiotics during surgery.