Adverse reactions to vancomycin and cross-reactivity with other antibiotics.

PURPOSE OF REVIEW: Glycopeptide antibiotics such as vancomycin are frequently utilized to treat resistant Gram-positive infections such as methicillin-resistant Staphylococcus aureus. The current literature on glycopeptide and lipoglycopeptide structure, hypersensitivity and potential cross-reactivity was reviewed, highlighting implications for safe prescribing. RECENT FINDINGS: Structurally similar, glycopeptides could theoretically cross-react. Immediate reactions to vancomycin include non-IgE-mediated reactions (e.g. red man syndrome) and IgE-mediated hypersensitivity (e.g. anaphylaxis), sharing clinical features. Vancomycin can activate mast cells via MAS-related G-protein-coupled receptor X2, an IgE-independent receptor implicated in non-IgE reactions. In-vivo and in-vitro testing for suspected IgE-mediated reactions to glycopeptides remain ill-defined. Vancomycin is increasingly recognized to cause severe cutaneous adverse reactions (SCAR), with drug reaction with eosinophilia and systemic symptoms (DRESS) predominantly reported. Vancomycin DRESS has been associated with HLA-A32:-01, with a number needed to prevent of 1 in 74. Data demonstrating cross-reactivity amongst glycopeptides and lipoglycopeptides is limited to case reports/series. SUMMARY: Further studies and in-vivo/in-vitro diagnostics are required for better differentiation between IgE and non-IgE glycopeptide reactions. Despite its association with vanomycin DRESS, utility of pharmacogenomic screening for HLA-A32: 01 is ill-defined. Although HLA-A32:01 has been associated with vancomycin DRESS, its utility for pharmacogenomic screening is ill defined. Further clinical and immunological cross-reactivity data for glycopeptide/lipoglycopeptide antibiotics is required.

HLA-B*58:01 Genotyping to Prevent Cases of DRESS and SJS/TEN in East Asians Treated with Allopurinol-A Canadian Missed Opportunity [Formula: see text].

BACKGROUND AND OBJECTIVE: East Asians exposed to the urate-lowering drug allopurinol have a predilection for severe cutaneous drug reactions such as drug-induced hypersensitivity syndrome or drug reaction with eosinophilia and systemic symptoms (DRESS) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Screening is recommended in patients of East Asian descent for the presence of HLA-B*58:01 prior to allopurinol initiation to avoid these complications. Utilization rates of the HLA-B*58:01 predictive screening test within the Greater Vancouver area, which has a population composed of 40.1% people of East Asian descent, are unknown. MEASURES: We identified cases of DRESS or SJS/TEN due to allopurinol using the Vancouver General Hospital dermatology consult service database. We next compared the frequency in which the HLA-B*58:01 screening test was ordered since 2012 to the estimated frequency of new prescriptions for allopurinol prescribed for the management of gout among the East Asians. RESULTS: We report 5 cases of East Asian patients exposed to allopurinol for management of gout between 2012 and 2016, who developed DRESS (4 patients) or SJS/TEN (1 patient). All were of HLA-B*58:01 genotype, representing preventable cases. The HLA-B*58:01 test was ordered 6 times in 2012, whereas the estimated number of new cases of allopurinol-prescribed gout among patients of East Asian descent during that time period was 13. For 2012, testing was ordered for only 46% of at-risk patients. CONCLUSION: We continue to observe cases of severe cutaneous drug reactions among high-risk individuals due to allopurinol exposure. The HLA-B*58:01 screening test for allopurinol hypersensitivity is underutilized in our geographic area.

Evaluation of Prospective HLA-B*13:01 Screening to Prevent Dapsone Hypersensitivity Syndrome in Patients With Leprosy.

Importance: Dapsone hypersensitivity syndrome (DHS) is the most serious adverse reaction associated with dapsone administration and one of the major causes of death in patients with leprosy, whose standard treatment includes multidrug therapy (MDT) with dapsone, rifampicin, and clofazimine. Although the HLA-B*13:01 polymorphism has been identified as the genetic determinant of DHS in the Chinese population, no studies to date have been done to evaluate whether prospective HLA-B*13:01 screening could prevent DHS by identifying patients who should not receive dapsone. Objective: To evaluate the clinical use of prospective HLA-B*13:01 screening for reduction of the incidence of DHS by excluding dapsone from the treatment for patients with HLA-B*13:01-positive leprosy. Design, Setting, and Participants: A prospective cohort study was conducted from February 15, 2015, to April 30, 2018, in 21 provinces throughout China. A total of 1539 patients with newly diagnosed leprosy were enrolled who had not received dapsone previously. After excluding patients who had a history of allergy to sulfones or glucose-6-phosphate dehydrogenase deficiency, 1512 individuals underwent HLA-B*13:01 genotyping. All of the patients were followed up weekly for the first 8 weeks after treatment to monitor for adverse events. Exposures: Patients who were HLA-B*13:01 carriers were instructed to eliminate dapsone from their treatment regimens, and noncarrier patients received standard MDT. Main Outcomes and Measures: The primary outcome was the incidence of DHS. The historical incidence rate of DHS (1.0%) was used as a control. Results: Among 1512 patients (1026 [67.9%] men, 486 [32.1%] women; mean [SD] age, 43.1 [16.2] years), 261 (17.3%) were identified as carriers of the HLA-B*13:01 allele. A total of 714 adverse events in 384 patients were observed during the follow-up period. Dapsone hypersensitivity syndrome did not develop in any of the 1251 patients who were HLA-B*13:01-negative who received dapsone, while approximately 13 patients would be expected to experience DHS, based on the historical incidence rate of 1.0% per year (P = 2.05 × 10-5). No significant correlation was found between other adverse events, including dermatologic or other events, and HLA-B*13:01 status. Conclusions and Relevance: Prospective HLA-B*13:01 screening and subsequent elimination of dapsone from MDT for patients with HLA-B*13:01-positive leprosy may significantly reduce the incidence of DHS in the Chinese population.

Association of HLA-A*31:01 Screening With the Incidence of Carbamazepine-Induced Cutaneous Adverse Reactions in a Japanese Population.

Importance: Carbamazepine, a commonly used antiepileptic drug, is one of the most common causes of cutaneous adverse drug reactions (cADRs) worldwide. The allele HLA-A*31:01 is reportedly associated with carbamazepine-induced cADRs in Japanese and European populations; however, the clinical utility of HLA-A*31:01 has not been evaluated. Objective: To assess the use of HLA-A*31:01 genetic screening to identify Japanese individuals at risk of carbamazepine-induced cADRs. Design, Setting, and Participants: This cohort study was conducted across 36 hospitals in Japan from January 2012 to November 2014 among 1202 patients who had been deemed suitable to start treatment with carbamazepine. Preemptive HLA-A*31:01 genetic screening was performed for 1187 participants. Patients who did not start treatment with carbamazepine or alternative drugs were excluded. Participants were interviewed once weekly for 8 weeks to monitor the development of cADRs. Data analysis was performed from June 8, 2015, to December 27, 2016. Exposures: Neuropsychiatrists were asked to prescribe carbamazepine for patients who tested negative for HLA-A*31:01 and alternative drugs for those who tested positive for HLA-A*31:01. Main Outcomes and Measures: Incidence of carbamazepine-induced cADRs. Results: Of the 1130 included patients who were prescribed carbamazepine or alternative drugs, the mean (range) age was 37.4 (0-95) years, 614 (54.3%) were men, and 198 (17.5%) were positive for HLA-A*31:01. Expert dermatologists identified 23 patients (2.0%) who had carbamazepine-induced cADRs, of which 4 patients required hospitalization. Drug-induced hypersensitivity syndrome was observed for 3 patients, maculopapular eruption for 9 patients, erythema multiforme for 5 patients, and an undetermined type of cADR for 6 patients. No patient developed Stevens-Johnson syndrome or toxic epidermal necrolysis. Compared with historical controls, the incidence of carbamazepine-induced cADRs was significantly decreased (for BioBank Japan data: incidence, 3.4%; odds ratio, 0.60; 95% CI, 0.36-1.00; P = .048; for the Japan Medical Data Centre claims database: incidence, 5.1%; odds ratio, 0.39; 95% CI, 0.26-0.59; P < .001). Conclusions and Relevance: Preemptive HLA-A*31:01 genetic screening significantly decreased the incidence of carbamazepine-induced cADRs among Japanese patients, which suggests that it may be warranted in routine clinical practice.

HLA-B*5801: utility and cost-effectiveness in the Asia-Pacific Region.

Gout is a common condition which is mainly treated with the hypo-uricemic agent, allopurinol. Although allopurinol is generally a well-tolerated drug, there is a small risk of developing potentially fatal complications, such as allopurinol hypersensitivity syndrome. Recent advances in pharmacogenomics have made possible the identification of genes which confer susceptibility to specific drugs. A recent multi-national case-control study has reported allopurinol as the most common drug associated with Stevens-Johnson syndrome and toxic epidermal necrolysis. Several studies have established a strong association between the human leukocyte antigen (HLA)-B*5801 gene and development of Stevens-Johnson syndrome and toxic epidermal necrolysis. The allele frequency of HLA-B*5801 is highest in the South East Asian population.Since other hypo-uricemic agents are available, patients may wish to have HLA-B*5801 testing before being started on allopurinol. As the test for HLA-B*5801 is expensive, time-consuming and only available in selected laboratories, there is a need to evaluate the utility and cost-effectiveness of this test in our region.