Enabling antibiotic allergy evaluations and reintroduction of first-line antibiotics for patients with cystic fibrosis.

BACKGROUND: Patients with cystic fibrosis (CF) often have a history of antibiotic adverse drug reactions (ADRs) that pose a barrier to receiving recommended first-line treatment. Targeted antibiotic allergy evaluations are increasingly recognized as an important strategy for optimization of antimicrobial stewardship. OBJECTIVE: To improve first-line antibiotic use in patients with CF with antibiotic ADRs by streamlining access to antibiotic allergy evaluations and standardizing documentation of plans for antibiotic reintroduction. METHODS: We incorporated allergy evaluations into a multidisciplinary CF clinic and used telemedicine when allergy evaluations could not be performed during CF clinic. Standard documentation of antibiotic allergy plans was used to enable safe reintroduction of first-line antibiotics by CF providers. RESULTS: Strategies used in this study allowed 81.3% (26 of 32) of patients with CF to receive allergy evaluations and antibiotic allergy plans for prioritized antibiotics (penicillin, cephalosporin, sulfonamide), with removal of 41.0% (16 of 39) of prioritized antibiotic ADRs. Only 5.1% (2 of 39) of prioritized antibiotic ADRs evaluated required strict avoidance after evaluation. There were 9 patients who received at least 1 prioritized antibiotic, with 66.6% (6 of 9) of these patients given the antibiotic after only 1 allergy evaluation visit. Furthermore, these strategies allowed allergy evaluations of 23 nonprioritized antibiotics to occur, with removal of the ADR in 39.1% (9 of 23) and use of 77.8% (7 of 9) of nonprioritized antibiotics after removal. CONCLUSION: Incorporating allergy evaluations into a multidisciplinary CF clinic can liberalize first-line antibiotic use in patients with CF. Standard documentation of antibiotic allergy plans allowed antibiotic reintroduction to occur even before complete removal of documented antibiotic ADRs.

Single-step direct drug provocation testing is safe for delabelling selected non-low-risk penicillin allergy labels.

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.

Safety and efficacy of direct two-step penicillin challenges with an inpatient pharmacist-driven allergy evaluation.

Background: Penicillin allergy is commonly reported and has clinical and financial consequences for patients and hospitals. A penicillin evaluation program can safely delabel patients and optimize antibiotic therapy. Pharmacists who perform this task have focused on a detailed interview or penicillin skin testing (PST). Antibiotic graded challenge after PST requires more resources and is more costly than going directly to a two-step challenge. Objective: To determine whether a pharmacist-driven penicillin allergy evaluation and a testing protocol that primarily uses direct oral challenges can safely delabel patients. Methods: Adult patients (ages >18 years) with a penicillin allergy in their electronic medical record (EMR) who were admitted between September 2019 and June 2020 were eligible. Although all patients with penicillin allergy were eligible, priority was given to patients who required antibiotics. Patients were interviewed, and, if indicated, based on an institutional protocol, were tested by using PST and/or two-step oral challenge. If the patient passed the challenge, then the penicillin allergy label was removed in the EMR and the patient counseled. Demographic information, allergy questionnaire results, testing results, and changes in antimicrobial therapy were collected. Results: Fifty patients were evaluated from September 2019 to June 2020. Ninety-six percent of the patients were delabeled, and antibiotic therapy changed for 54%. Twenty patients were delabeled with an interview alone, and 30 patients underwent oral two-step challenge. Only one patient required PST. Conclusion: A pharmacist-driven penicillin allergy evaluation program focused on direct oral graded challenges and bypassing PST can effectively delabel admitted patients. However, more safety data are needed before implementation of similar programs to optimize antibiotic treatment.

Antibiotic susceptibility guided reuse of levofloxacin-based therapy in a penicillin-allergic patient for Helicobacter pylori infection: A case report.

RATIONALE: Antibiotic resistance poses a challenge for Helicobacter pylori eradication treatment. Current guidelines strongly recommend avoiding repeated treatments with the same antibiotic to prevent the emergence of drug resistance. However, for penicillin-allergic patients with recurrent H. pylori eradication failures, avoiding repeated treatments with the same antibiotic severely limits the choice of treatment. PATIENT CONCERNS: A 47-year-old woman with a penicillin allergy for whom 2 previous levofloxacin and bismuth-based therapies had failed. DIAGNOSIS: H. pylori infection. INTERVENTIONS: Agar dilution susceptibility testing and gene sequence analysis was performed to confirm levofloxacin susceptibility again. Therefore, we treated her with a 14-day regimen consisting of levofloxacin (500 mg once daily), furazolidone (100 mg twice daily), colloidal bismuth pectin (220 mg twice daily), and esomeprazole (20 mg twice daily). OUTCOMES: The patient was successfully treated with a third levofloxacin and bismuth-based regimen. LESSONS: Antibiotics included in previous failed therapies need not be eliminated if no antibiotic resistance is found on antimicrobial susceptibility testing.

Outpatient Penicillin Allergy Testing in Pregnant Women Who Report an Allergy.

OBJECTIVE: To estimate the feasibility, acceptability, and safety of outpatient penicillin allergy testing among pregnant women. METHODS: We conducted a prospective cohort study at a large academic hospital from March 2019 to March 2020. We recruited pregnant women with a self-reported penicillin allergy who underwent allergy testing between 14 0/7 and 36 6/7 weeks of gestation. RESULTS: Of 127 eligible women pregnant women, 74 (58%, 95% CI 4-67%) accepted allergy testing. Fifty completed or intended to complete allergy testing, yielding a feasibility rate of 68% (95% CI 56-78%). Among the 46 women actually tested (who ranged in age from 18 to 42), 93% (95% CI 68-100%) had a negative test result. A systemic reaction (symptoms consistent with anaphylaxis) occurred in only 2 women (4%, 95% CI 0.5-15%) despite 20 (43%) reporting a severe allergy. No woman suffered an adverse event as a result of allergy testing. In multivariate analysis adjusting for age and parity, women with public insurance had decreased odds of undergoing penicillin allergy testing (adjusted odds ratio 0.24, 95% CI 0.08-0.69). CONCLUSION: Outpatient penicillin allergy testing is acceptable and feasible in pregnancy.

Diagnostic value and safety of penicillin skin tests in children with immediate penicillin allergy.

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.

Neo-antigens for the serological diagnosis of IgE-mediated drug allergic reactions to antibiotics cephalosporin, carbapenem and monobactam.

New antigens deriving from -lloyl and -llanyl, major and minor determinants, respectively, were produced for ß-lactam antibiotics cefuroxime, cefotaxime, ceftriaxone, meropenem and aztreonam. Twenty ß-lactam antigens were produced using human serum albumin and histone H1 as carrier proteins. Antigens were tested by multiplex in vitro immunoassays and evaluated based on the detection of specific IgG and IgE in the serum samples. Both major and minor determinants were appropriate antigens for detecting specific anti-ß-lactam IgG in immunised rabbit sera. In a cohort of 37 allergic patients, we observed that only the minor determinants (-llanyl antigens) were suitable for determining specific anti-ß-lactam IgE antibodies with high sensitivity (< 0.01 IU/mL; 24 ng/L) and specificity (100%). These findings reveal that not only the haptenisation of ß-lactam antibiotics renders improved molecular recognition events when the 4-member ß-lactam ring remains unmodified, but also may contribute to develop promising minor antigens suitable for detecting specific IgE-mediated allergic reactions. This will facilitate the development of sensitive and selective multiplexed in vitro tests for drug-allergy diagnoses to antibiotics cephalosporin, carbapenem and monobactam.

Skin testing and oral amoxicillin challenge in the outpatient allergy and clinical immunology clinic in pregnant women with penicillin allergy.

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.

Minimal agreement between basophil activation test and immunoassay in diagnosis of penicillin allergy.

INTRODUCTION: Basophil activation test (BAT) and immunoassays are the most widely used in vitro tests to diagnose IgE-mediated allergic reactions to penicillin. However, studies to determine if one test is interdependent from another are limited. OBJECTIVE: The present study aimed to measure the agreement between BAT and immunoassay in diagnosis of penicillin allergy. METHOD: BAT was performed using penicillin G (Pen G), penicillin V (Pen V), penicilloyl-polylysine (PPL), minor determinant mix (MDM), amoxicillin (Amx) and ampicillin (Amp) in 25 patients. Immunoassay of total IgE (tIgE) and specific IgE (sIgE) antibodies to Pen G, Pen V, Amx and Amp were quantified. Skin prick test (SPT) using PPL-MDM, Amx, Amp and Clavulanic acid were also performed. RESULTS: Minimal agreement was observed between BAT and immunoassay (k=0.25). Of two BAT-positive patients, one patient is positive to Amx (59.27%, SI=59) and Amp (82.32%, SI=82) but sIgE-negative to all drug tested. This patient is also SPT-positive to both drugs. Another patient is BAT-positive to Pen G (10.18%, SI=40), Pen V (25.07%, SI=100) and Amp (19.52%, SI=79). In sIgE immunoassay, four patients were sIgE-positive to at least one of the drugs tested. The sIgE level of three patients was between low and moderate and they were BAT-negative. One BAT-positive patient had a high level of sIgE antibodies (3.50-17.5kU/L) along with relatively high specific to total IgE ratio ≥0.002 (0.004-0.007). CONCLUSIONS: The agreement between BAT and immunoassay is minimal. Performing both tests provides little increase in the sensitivity of allergy diagnosis work-up for immediate reactions to penicillin.

Update on penicillin allergy delabeling.

PURPOSE OF REVIEW: To review phenotyping and risk classification of penicillin allergy and provide an update on penicillin allergy delabeling strategies for primary care. RECENT FINDINGS: Beta-lactams are considered the treatment of choice for a wide range of bacterial pathogens; however, many patients receive second-line agents due to being labeled as having an allergy to penicillin. This approach can lead to antibiotic resistance and inferior health outcomes. While 10% of the population is labeled as penicillin allergic, penicillin anaphylaxis occurs in less than 1% of patients. For patients with delayed benign skin rashes (e.g., urticaria or maculopapular exanthem >1 h after administration) attributable to beta-lactam administration occurring more than 12 months ago, direct oral challenge (rechallenge with antibiotic in the clinical setting) can be a safe and effective strategy, with immediate reactions occurring in less than 5% of such low-risk patients and delayed reactions appearing infrequently. In patients with penicillin-associated immediate urticaria, other IgE-mediated features, or anaphylaxis, further allergy evaluation and penicillin skin testing is warranted. Any severe idiosyncratic cutaneous adverse reaction is rare, but can be dangerous so prompt removal of the inciting agent is required. SUMMARY: Penicillin allergy delabeling is a high-value service that can be effectively delivered through a multidisciplinary collaborative approach.

Hypersensitivity to antibiotics in drug reaction with eosinophilia and systemic symptoms (DRESS) from other culprits.

BACKGROUND: Antibiotics have been implicated in the reactivation of exanthema and systemic involvement in drug reaction with eosinophilia and systemic symptoms (DRESS); however, it is not clear whether these patients become sensitized to the antibiotic. OBJECTIVE: To evaluate if, after DRESS, patients become sensitized to antibiotics. METHODS: We retrospectively reviewed the patch test (PT) data and clinical files of DRESS patients who were administered antibiotics during DRESS from other culprits. RESULTS: Nine patients out of 17 (53%) were positive to antibiotics in PT: six to the penicillin group and three to cephalosporins (including one patient with additional positivity to vancomycin). Considering the eight patients who were negative to antibiotics in PT, seven were exposed to a fluoroquinolone. Four cases were patch tested again and three remained positive to antibiotics 2 to 5 years thereafter. Two patients with positive PT results had an accidental re-exposure to antibiotics and developed a maculopapular exanthema without systemic symptoms. CONCLUSION: Exposure to antibiotics during DRESS or its prodromal phase could enhance sensitization to antibiotics, as confirmed by a positive PT. Reproducibility of positive PTs to antibiotics after several years and reactivation after re-exposure support that T-cell-mediated hypersensitivity to antibiotics in the setting of DRESS is a specific reaction.

Drug allergy is associated with the development of extraintestinal manifestations in patients with ulcerative colitis.

Summary: Drug allergies are developed by antibody or cell-mediated reactions as immunologic mechanisms. It has been demonstrated that hypersensitivity reaction to certain allergens may play a role in the pathogenesis of inflammatory bowel disease (IBD) focused on food allergies. A total of 256 patients with UC were divided in two groups: 203 patients with active UC and 53 in remission UC were included in the present study. In the present study we found that 11.7% had allergy to at least one drug distributed. The most frequent drug-allergies were sulfonamides in 2.8% and penicillin in 3.1%. Sulfonamide allergy was associated with several extraintestinal manifestations such as: peripheral arthritis/arthralgia (OR = 9.06, 95% CI 1.71 - 48.00, p = 0.002); pyoderma gangrenosum (OR = 24.10, 95% CI 3.55 - 163.48, p minor 0.0001) and uveitis (OR = 15.93, 95% CI 2.55 - 99.23, p minor 0.0001). The frequency of drug allergy was 11.7% in Mexican UC patients, most frequently to sulfonamides and penicillin drugs. The presence of sulfonamide allergy was associated with the presence of several extra-intestinal manifestations.