Randomized Multicenter Trial for the Validation of an Easy-to-Administer Algorithm to Define Penicillin Allergy Status in Sexually Transmitted Infection Clinic Outpatients.

BACKGROUND: Approximately 15% of patients in sexually transmitted infection (STI) clinics report penicillin allergies, complicating treatment for syphilis and gonorrhea. Nonetheless, >90% do not have a penicillin allergy when evaluated. We developed and validated an algorithm to define which patients reporting penicillin allergy can be safely treated at STI clinics with these drugs. METHODS: Randomized controlled trial to assess feasibility and safety of penicillin allergy evaluations in STI clinics. Participants with reported penicillin allergy answered an expert-developed questionnaire to stratify risk. Low-risk participants underwent penicillin skin testing (PST) followed by amoxicillin 250 mg challenge or a graded oral challenge (GOC)-amoxicillin 25 mg followed by 250 mg. Reactions were recorded, and participant/provider surveys were conducted. RESULTS: Of 284 participants, 72 (25.3%) were deemed high risk and were excluded. Of 206 low-risk participants, 102 (49.5%) underwent PST without reactions and 3 (3%) had mild reactions during the oral challenge. Of 104 (50.5%) participants in the GOC, 95 (91.3%) completed challenges without reaction, 4 (4.2%) had mild symptoms after 25 mg, and 4 (4.2%) after 250-mg doses. Overall, 195 participants (94.7%) successfully completed the study and 11 (5.3%) experienced mild symptoms. Of 14 providers, 12 (85.7%) completed surveys and 11 (93%) agreed on the safety/effectiveness of penicillin allergy assessment in STI clinics. CONCLUSIONS: An easy-to-administer risk-assessment questionnaire can safely identify patients for penicillin allergy evaluation in STI clinics by PST or GOC, with GOC showing operational feasibility. Using this approach, 67% of participants with reported penicillin allergy could safely receive first-line treatments for gonorrhea or syphilis. Clinical Trials Registration. Clinicaltrials.gov (NCT04620746).

Diagnosis and Clinical Management of Drug Allergies in Obstetrics and Gynecology: An Expert Review.

Drug allergies, specifically antibiotic allergies, are frequently encountered in obstetrics and gynecology as10% of the United States population reports a penicillin allergy. This poses a particular challenge to the obstetrician-gynecologist as beta-lactam antibiotics are indicated as first-line therapy for the treatment and prevention of most specialty-specific infections. Alternative antibiotic use in the setting of a reported allergy, is not benign and has been associated with increased cesarean delivery, endometritis, wound complications, and increased lengths of hospital stay in pregnant patients, increased Group B Streptococcus sepsis, neonatal length of stay and neonatal lab draws in neonates born to allergic patients and increased surgical site infections in gynecologic patients. Furthermore, alternative antibiotic use leads to increased antibiotic resistance, toxicity and healthcare cost. . Administration of antibiotics in a patient with a history of a Type I immediate hypersensitivity reaction, however, poses the risk of anaphylaxis with repeat exposure. Fortunately, over 90% of patients who report a penicillin allergy are not truly allergic and would tolerate penicillins if administered. This can be due to either mislabeling of the index reaction as an allergy (when it was due to a drug intolerance or a viral exanthem) or due to waning Immunoglobulin E-mediated immunity over time. Given this, allergy evaluation is widely recommended, even in pregnancy. Allergy evaluation involves a detailed patient history and when appropriate allergy testing with skin testing and/or oral challenge. These tools when used appropriately have been found to be safe and effective in gravid as well as non-gravid individuals and result in increased use of first line antibiotics. Furthermore, even in the setting of a true penicillin allergy, cross-reactivity with cephalosporins is extremely low and estimated at 2-3% among patients with a verified penicillin allergy and significantly lower than this among patients with an unverified penicillin allergy. Guidelines support routine use of cephalosporins without testing or additional precautions in patients with an unverified nonanaphylactic penicillin allergy as well as routine use of structurally dissimilar cephalosporins (specifically ancef) even in patients with an anaphylactic penicillin allergy. In cases where there is no appropriate alternative antibiotic than to the one which the patient is allergic such as with syphilis in a penicillin allergic pregnant patient, desensitization can be performed. This process involves temporary induction of drug tolerance through exposure of small amounts of the allergen until a therapeutic dose is achieved and has been safely performed in pregnancy. Desensitization requires expert supervision and is most often performed in the intensive care setting with a multidisciplinary team. The other two most common antibiotic allergies encountered in obstetrics and gynecology are to cephalosporins and metronidazole. Cephalosporin allergies are managed similarly to penicillin allergies with readily available skin testing and oral challenge. Skin testing for metronidazole allergy lacks sensitivity and specificity and thus oral challenge or desensitization procedure is the preferred approach for low risk and high-risk patients respectively. When it comes to drug allergies, and specifically antibiotic allergies, the role of the obstetrician-gynecologist is to identify patients with a reported allergy and to refer patients to a specialist for further evaluation as soon as possible. Allergy evaluation by means of a detailed patient history and allergy testing (skin testing and/or oral challenge) when indicated has been shown to be safe and effective and is an important part of antibiotic stewardship.

Antepartum vs postpartum amoxicillin oral challenge in pregnant patients with a reported penicillin allergy: A two-center prospective cohort study.

INTRODUCTION: While 10% of pregnant individuals report a penicillin allergy, there is no established best practice for penicillin allergy delabeling in pregnancy. To better understand options for penicillin delabeling, we aimed to evaluate two penicillin allergy delabeling protocols in pregnancy regarding efficacy, adverse events, and patient satisfaction. MATERIAL AND METHODS: From July 2019 to December 2022, we completed a two-center prospective cohort study, where each site recruited pregnant patients over 24 weeks gestational age with a reported penicillin allergy. One center offered antepartum amoxicillin oral challenges, either directly or after negative skin testing (i.e., antepartum oral challenge site). Our other centers completed a two-step approach with antepartum penicillin skin testing only and deferred oral challenges to the postpartum period (i.e., postpartum oral challenge site). Our primary outcome was the rate of penicillin allergy delabeling, defined as tolerating an antibiotic challenge with penicillin or amoxicillin. Univariate analyses were completed using chi-squared, Fisher's exact, and Wilcoxon rank tests. RESULTS: During the study period, 276 pregnant patients were assessed, with 207 in the antepartum oral challenge site and 69 in the postpartum oral challenge site. Among the 204 patients who completed antepartum oral challenges, 201 (98%) passed without reactions. Deferring oral challenges to the postpartum period led to a loss of follow-up for 37/53 (70%) of eligible individuals. Overall, 97% (201/207) of patients at the antepartum oral challenge site were delabeled from their penicillin allergy-compared to 38% (26/69) of patients referred to the postpartum oral challenge site (p < 0.0001). Three antepartum oral challenge reactions were noted, including two mild cutaneous reactions and a case of transient abdominal discomfort. CONCLUSIONS: Antepartum amoxicillin oral challenge is a more effective method to delabel pregnant patients from their penicillin allergy. Deferral of oral challenges to the postpartum period introduces a significant barrier for penicillin allergy delabeling.

Adult penicillin allergy programmes in Australian hospitals: a practical guide from the National Antibiotic Allergy Network.

Penicillin allergy is a significant burden on patient, prescribing and hospital outcomes. There has been increasing interest in the incorporation of penicillin allergy testing (i.e. delabelling) into antimicrobial stewardship (AMS) programmes to reduce the burden of penicillin allergy labels and improve prescribing. In particular, there has been a focus on point-of-care penicillin allergy assessment and direct oral challenge for low-risk phenotypes. The National Antibiotic Allergy Network has provided a guide to assist AMS clinicians with the incorporation of penicillin allergy programmes, in particular direct oral challenge, into Australian hospitals.

Risk Factors of Challenge-Proven Beta-Lactam Allergy in Children with Immediate and Non-Immediate Mild Cutaneous Reactions.

INTRODUCTION: Beta-lactam (BL) antibiotics are the most often involved drugs in allergic reactions. Mild cutaneous reactions such as maculopapular exanthema or urticaria are the most common presenting complaints of BL allergy in the pediatric population. However, it can be challenging to distinguish BL-induced allergy from reactions due to infections or other reasons. In this study, we aimed to determine the clinical characteristics and potential risk factors of true BL allergy in children with suspected mild cutaneous reactions to BLs. METHODS: We evaluated children who were admitted to our pediatric allergy clinic with suspected BL allergy in between January 2015 and March 2020. Patients with a history suggestive of immediate and non-immediate mild cutaneous reactions were included in the study. The oral challenge test (OCT) with the culprit drug was performed on all patients to confirm the diagnosis. RESULTS: Two hundred fourteen (119 male and 95 female) patients with a median age of 4.9 years were evaluated. BL allergy was confirmed in 10.7% (23) of the patients, according to the OCT results. Most of the proven allergic reactions were of the immediate type (73.9%), and urticaria was the most common presenting complaint (60.8%) in proven BL-allergic patients. The negative predictive value of penicillin-G skin testing was 89.7% for immediate-type penicillin allergy and 93.4% for non-immediate reactions. Also, positive predictive value of penicillin-G skin testing was 50% for immediate and 25% for non-immediate reactions. In the multivariate logistic regression analysis, a history of proven drug allergy (Exp (B): 7.76, 95% CI: 1.88-31.97, p = 0.005) was found to be the risk for BL allergy. CONCLUSION: This study highlighted that OCTs should be performed to confirm the diagnosis in patients suspected of immediate and non-immediate mild cutaneous reactions to BLs and remove the overestimated "BL allergy" label. In these patients, a history of proven drug allergy might be a risk factor for true BL allergy.

Predicting the Outcome of the Buckwheat Oral Challenge Test: A First Evaluation Assuming a Single Serving of Boiled Buckwheat Noodles.

Summary: Background. Global increase in buckwheat consumption has led to a surge in buckwheat allergy reports. However, studies scrutinizing the predictive accuracy of buckwheat-specific immunoglobulin E (IgE) antibody levels in correlation with symptom manifestation remain limited. A critical concern is the discrepancy between the total buckwheat amount featured in prior studies and the quantity consumed per occasion. We aimed to determine open Oral Food Challenge (OFC) positivity rates with buckwheat, using a single serving of boiled buckwheat noodles, and assess the predictability of positive responses using buckwheat-specific IgE levels. Methods. Patients aged 20 years or younger, suspected of buckwheat allergy, were subjected to an OFC involving consumption of 100 g (4800 mg of protein) of boiled buckwheat noodles for those under six years, and 200 g (9600 mg of protein) for those six years or older. The predictive accuracy of the OFC, corresponding with buckwheat-specific IgE antibody levels, was evaluated using Receiver Operating Characteristic (ROC) analysis. Results. Our study involved 80 patients who undertook a buckwheat OFC. Among these, 14 (17.5%) tested positive for a buckwheat allergy, with 3 (3.8%) developing anaphylaxis. The comparative analysis of buckwheat-specific IgE antibody levels did not offer a reliable predictive measure for OFC outcomes. However, a past history of symptom manifestation following buckwheat consumption was significantly correlated with a positive OFC. Conclusions. Forecasting OFC outcomes based on buckwheat-specific IgE antibody levels poses a challenge, even when taking into account the total quantity of buckwheat that can be consumed in a single occasion.

Antibiotic allergy labels in immunocompromised populations.

Antibiotic allergy labels (AALs) are commonly reported, with well-defined prevalence in the general population; several studies have now focused efforts on immunocompromised hosts. Understanding the prevalence of reported allergy labels and methods of antibiotic allergy evaluation and delabeling strategies has the potential to improve prescribing practices and clinical outcomes in this high-antibiotic use group. In this review, we will discuss the current literature on the prevalence, impact, and evaluations of AALs in immunocompromised hosts with a focus on beta-lactam (penicillin) allergy and sulfa-antibiotic (antimicrobial sulfurs) allergy labels.

The Penicillin Allergy Delabeling Program: A Multicenter Whole-of-Hospital Health Services Intervention and Comparative Effectiveness Study.

BACKGROUND: Penicillin allergies are associated with inferior patient and antimicrobial stewardship outcomes. We implemented a whole-of-hospital program to assess the efficacy of inpatient delabeling for low-risk penicillin allergies in hospitalized inpatients. METHODS: Patients ≥ 18 years of age with a low-risk penicillin allergy were offered a single-dose oral penicillin challenge or direct label removal based on history (direct delabeling). The primary endpoint was the proportion of patients delabeled. Key secondary endpoints were antibiotic utilization pre- (index admission) and post-delabeling (index admission and 90 days). RESULTS: Between 21 January 2019 and 31 August 2019, we assessed 1791 patients reporting 2315 antibiotic allergies, 1225 with a penicillin allergy. Three hundred fifty-five patients were delabeled: 161 by direct delabeling and 194 via oral penicillin challenge. Ninety-seven percent (194/200) of patients were negative upon oral penicillin challenge. In the delabeled patients, we observed an increase in narrow-spectrum penicillin usage (adjusted odds ratio [OR], 10.51 [95% confidence interval {CI}, 5.39-20.48]), improved appropriate antibiotic prescribing (adjusted OR, 2.13 [95% CI, 1.45-3.13]), and a reduction in restricted antibiotic usage (adjusted OR, 0.38 [95% CI, .27-.54]). In the propensity score analysis, there was an increase in narrow-spectrum penicillins (OR, 10.89 [95% CI, 5.09-23.31]) and ß-lactam/ß-lactamase inhibitors (OR, 6.68 [95% CI, 3.94-11.35]) and a reduction in restricted antibiotic use (OR, 0.52 [95% CI, .36-.74]) and inappropriate prescriptions (relative risk ratio, 0.43 [95% CI, .26-.72]) in the delabeled group compared with the group who retained their allergy label. CONCLUSIONS: This health services program using a combination of direct delabeling and oral penicillin challenge resulted in significant impacts on the use of preferred antibiotics and appropriate prescribing.

Behind the scene: Paracetamol hypersensitivity in children.

BACKGROUND: Paracetamol, a non-steroidal anti-inflammatory drug, is commonly being used for fever and pain relief worldwide. The aim of this study was to evaluate children with a suspected history of paracetamol hypersensitivity. METHODS: Sixty patients who were referred to our clinic in between January 2015 and December 2018 with a suspected history of paracetamol hypersensitivity were included. Reactions were classified according to the European Network for Drug Allergy (ENDA)/Global Allergy and Asthma European Network classification and European Academy of Allergy and Clinical Immunology (EAACI)/ENDA Position Paper. Diagnoses were confirmed by skin tests and oral challenge tests (OCTs). In those with verified paracetamol hypersensitivity, an OCT with a strong COX-1 inhibitor was performed to classify the type of the reaction to refer as either selective or cross-intolerance hypersensitivity. A subsequent OCT with a selective COX-2 inhibitor was performed in those cross-intolerant patients to find out a safe alternative drug. RESULTS: Sixty OCTs with paracetamol were performed to patients with a median age of 8.5 years, and hypersensitivity to paracetamol was verified in 8 patients. Four children were classified as selective responders, and 3 were classified as cross-intolerant after OCT with a COX-1 inhibitor. Overall, skin test positivity for paracetamol was detected in only one patient, in whom OCT with paracetamol was negative. In all 3 cross-intolerant patients, a safe alternative non-steroidal anti-inflammatory drug was identified after an OCT with a selective COX-2 inhibitor. CONCLUSION: OCT stands as the gold-standard procedure in verifying the diagnosis of patients with paracetamol-induced drug hypersensitivity, as well as, in defining the type of reactions and finding out safe alternative drugs.

De-labelling penicillin allergy in acutely hospitalized patients: a pilot study.

BACKGROUND: Penicillin allergy prevalence is internationally reported to be around 10%. However, the majority of patients who report a penicillin allergy do not have a clinically significant hypersensitivity. Few patients undergo evaluation, which leads to overuse of broad-spectrum antibiotics. The objective of this study was to monitor prevalence and implement screening and testing of hospitalized patients. METHODS: All patients admitted to the medical department in a local hospital in Oslo, Norway, with a self-reported penicillin allergy were screened using an interview algorithm to categorize the reported allergy as high-risk or low-risk. Patients with a history of low-risk allergy underwent a direct graded oral amoxicillin challenge to verify absence of a true IgE-type allergy. RESULTS: 257 of 5529 inpatients (4.6%) reported a penicillin allergy. 191 (74%) of these patients underwent screening, of which 86 (45%) had an allergy categorized as low-risk. 54 (63%) of the low-risk patients consented to an oral test. 98% of these did not have an immediate reaction to the amoxicillin challenge, and their penicillin allergy label could thus be removed. 42% of the patients under treatment with antibiotics during inclusion could switch to treatment with penicillins immediately after testing, in line with the national recommendations for antibiotic use. CONCLUSIONS: The prevalence of self-reported penicillin allergy was lower in this Norwegian population, than reported in other studies. Screening and testing of hospitalized patients with self-reported penicillin allergy is a feasible and easy measure to de-label a large proportion of patients, resulting in immediate clinical and environmental benefit. Our findings suggest that non-allergist physicians can safely undertake clinically impactful allergy evaluations.

Controversies in drug allergy: Testing for delayed reactions.

Controversies exist with regard to in vivo approaches to delayed immunologically mediated adverse drug reactions, such as exanthem (maculopapular eruption), drug reaction with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis, Stevens-Johnson syndrome/toxic epidermal necrolysis, and fixed drug eruptions. In particular, widespread differences exist between regions and practice on the availability and use of intradermal and patch testing, the standard drug concentrations used, the use of additional drugs in intradermal and patch testing to help determine cross-reactivity, the timing of testing in relation to the occurrence of the adverse drug reaction, the use of testing in specific phenotypes, and the use of oral challenge in conjunction with delayed intradermal and patch testing to ascertain drug tolerance. It was noted that there have been advances in the science of delayed T cell-mediated reactions that have shed light on immunopathogenesis and provided a mechanism of preprescription screening in the case of HLA-B*57:01 and abacavir hypersensitivity and HLA-B*15:02 and carbamazepine Stevens-Johnson syndrome/toxic epidermal necrolysis in Southeast Asian subjects. Future directions should include the collaboration of large international networks to develop and standardize in vivo diagnostic approaches, such as skin testing and patch testing, combined with ex vivo and in vitro laboratory approaches.

Advances in Food Allergy Treatment.

Food allergies represent life-threatening diseases which are increasing in prevalence with no definitive treatments currently in place. Current treatments are no more than preventative avoidance and symptom management. Research within the field has focused on therapeutic developments to modify the immune response in allergen-specific and non-specific methods. This review of the advances made in treatments intends to cover methods such as oral immunotherapy, modified food protein vaccines as well as the use of alternative medicine. Thus, this review aims to inform and further extend discussion surrounding the potential clinical applications as well as novel routes for further research into an, as of yet, unsolved question.

Oral challenge with Streptococcus sanguinis induces aortic inflammation and accelerates atherosclerosis in spontaneously hyperlipidemic mice.

Atherosclerosis is exacerbated by periodontal pathogens, which induce vascular inflammation after entering the bloodstream. Among oral indigenous bacteria, Streptococcus sanguinis and S. anginosus are related to systemic disorders, such as infective endocarditis and abscess, and are sometimes detected in human atherosclerotic plaques or blood. Thus, these oral streptococci may contribute to the progression of atherosclerosis. To test this hypothesis, apolipoprotein E-deficient spontaneously hyperlipidemic mice were intraorally challenged with S. sanguinis or S. anginosus. Atherosclerotic plaque formation increased significantly in the S. sanguinis-challenged group compared with the carboxymethylcellulose-treated control group. Expression levels of mRNAs of proinflammatory cytokines in the aorta and levels of atherosclerosis-related mediators in blood increased upon S. sanguinis challenge. Adaptor molecule TNF receptor-associated factor 6 was also enhanced in the aorta when mice were challenged with S. sanguinis. Furthermore, challenge with S. anginosus induced systemic inflammation, but inflammation-related mRNA expression levels in the aorta only increased slightly and were accompanied by minimal expansion of the lesion area. By contrast, with the exception of IL-1α, the expression levels of inflammation-related genes did not change in gingival tissues of both bacteria- and sham-challenged groups. These results reveal that S. sanguinis causes aortic inflammation that leads to accelerated progression of atherosclerosis.

Evaluating Penicillin Allergies Without Skin Testing.

PURPOSE OF REVIEW: An unconfirmed penicillin allergy is known to confer significant risk to patients. Only a small minority of patients labeled with penicillin allergy will be confirmed to be hypersensitive with the current reference standard test, an oral amoxicillin therapeutic dose challenge. Skin testing has been recommended prior to oral challenges to reduce the risk of severe acute challenge reactions. The rate of severe acute anaphylactic reactions with oral amoxicillin is currently extremely low. Unfortunately, penicillin skin testing, as commonly performed, has a high rate of false positive results. RECENT FINDINGS: Encouraging skin testing in all individuals with an unconfirmed penicillin allergy, prior to a confirmatory oral challenge, would be technically difficult, make testing all individuals with an unconfirmed penicillin allergy very unlikely, and ultimately increase the risk to patients because of suboptimal antibiotic use. Most patients, who are appropriate candidates for a direct oral amoxicillin challenge, to confirm current penicillin tolerance, can be safely identified by their clinical histories. Higher risk individuals, those with a history of anaphylaxis or other acute onset potentially IgE-mediated reaction such as hives within 6 h of the first dose of the last course of a penicillin, may benefit from properly performed puncture and intradermal skin testing, using commercially available penicilloyl-polylysine, prior to an oral challenge, if skin test negative. Direct oral amoxicillin challenges in low-risk individuals are well accepted by patients and a safe and effective part of penicillin allergy delabeling.

Prevalence of Drugs as Triggers of Exacerbations in Chronic Urticaria.

BACKGROUND AND OBJECTIVE: Many patients with chronic spontaneous urticaria (CSU) report various drugs as triggers of their symptoms and often avoid medication unnecessarily. Objective: To estimate the clinical impact of the drugs patients most frequently suspect of inducing CSU exacerbations. METHODS: The prevalence of self-reported drug reactions was evaluated by questioning patients about their clinical history of urticaria and drug reactions and performing challenge tests with the suspect drugs. A group of healthy persons were included as controls to evaluate the prevalence of self-reported drug reactions. RESULTS: The study population comprised 245 patients with CSU and 127 healthy individuals. At least 1 adverse drug reaction was reported by 92 (37.5%) patients and 30 (23.6%) controls. Nonsteroidal anti-inflammatory drugs (NSAIDs) (27.7%) and ß-lactams (9.4%) were the most commonly reported drugs in the CSU group and the control group, respectively. Positive results in the challenge tests were less common than self-reports in the CSU group (13%) and the control group (0.7%). CONCLUSIONS: Self-reporting is generally not sufficient to confirm a drug reaction. Drug reactions to NSAIDs and ß-lactams are more frequent among patients who experience CSU than in those who do not. Drug challenge tests should be offered early during medical evaluation to avoid unnecessary restrictions.

Oral challenge without skin tests in children with non-severe beta-lactam hypersensitivity: Time to change the paradigm?

Suspected allergy to penicillins and cephalosporins is very common in childhood. After a proper evaluation, allergy will be confirmed only in a small portion of them. Intradermal tests are usually part of the allergy workup, but they are painful for children and time-consuming, and their role has been debated. A systematic review found only two studies reporting a positive predictive value of skin tests in children of 36% and 33%, respectively, leading to a high rate of inaccurate diagnosis. Moreover, considering that skin tests are negative in more than 90%-95% of cases, an oral provocation test (OPT) is finally needed to confirm tolerance in most of these children. Positive OPT are rare, and even where children demonstrate reproducible signs on challenge, they rarely constitute immediate or serious symptoms. Therefore, OPT to the index antibiotic without skin tests are increasingly being considered an accepted procedure for children with a suspected mild non-immediate reaction related to a beta-lactam antibiotic. Furthermore, a recent research has taken the same approach including children with suspected mild immediate reactions, with similar safety and positive results. In light of recent evidence highlighted, it is now the time for large and multicentric studies to confirm that OPT with the index antibiotic, without skin tests, are safe and convenient for children with a history of a mild reaction with a beta-lactam antibiotic before it can be recommended in pediatric allergy guidelines.