There is an urgent need to identify therapies that prevent SARS-CoV-2 infection and improve the outcome of COVID-19 patients. Although repurposed drugs with favorable safety profiles could have significant benefit, widely available prevention or treatment options for COVID-19 have yet to be identified. Efforts to identify approved drugs with in vitro activity against SARS-CoV-2 resulted in identification of antiviral sigma-1 receptor ligands, including antihistamines in the histamine-1 receptor binding class. We identified antihistamine candidates for repurposing by mining electronic health records of usage in population of more than 219,000 subjects tested for SARS-CoV-2. Usage of diphenhydramine, hydroxyzine and azelastine was associated with reduced incidence of SARS-CoV-2 positivity in subjects greater than age 61. We found diphenhydramine, hydroxyzine and azelastine to exhibit direct antiviral activity against SARS-CoV-2 in vitro. Although mechanisms by which specific antihistamines exert antiviral effects is not clear, hydroxyzine, and possibly azelastine, bind Angiotensin Converting Enzyme-2 (ACE2) and the sigma-1 receptor as off-targets. Clinical studies are needed to measure the effectiveness of diphenhydramine, hydroxyzine and azelastine for disease prevention, for early intervention, or as adjuvant therapy for severe COVID-19.

Background and Aims Trimethoprim (TMP)–sulfamethoxazole (SMX) is an important cause of idiosyncratic drug‐induced liver injury (DILI), but its genetic risk factors are not well understood. This study investigated the relationship between variants in the human leukocyte antigen (HLA) class 1 and 2 genes and well‐characterized cases of TMP‐SMX DILI. Approach and Results European American and African American persons with TMP‐SMX DILI were compared with respective population controls. HLA sequencing was performed by Illumina MiSeq (Illumina, San Diego, CA) for cases. The HLA genotype imputation with attribute bagging program was used to impute HLA alleles for controls. The allele frequency difference between case patients and controls was tested by Fisher’s exact tests for each ethnic group. For European Americans, multivariable logistic regression with Firth penalization was used to test the HLA allelic effect after adjusting for age and the top two principal components. Molecular docking was performed to assess HLA binding with TMP and SMX. The European American subset had 51 case patients and 12,156 controls, whereas the African American subset had 10 case patients and 5,439 controls. Four HLA alleles were significantly associated in the European American subset, with HLA‐B*14:01 ranking at the top (odds ratio, 9.20; 95% confidence interval, 3.16, 22.35; P = 0.0003) after covariate adjustment. All carriers of HLA‐B*14:01 with TMP‐SMX DILI possessed HLA‐C*08:02, another significant allele (P = 0.0026). This pattern was supported by HLA‐B*14:01–HLA‐C*08:02 haplotype association (P = 1.33 × 10−5). For the African American patients, HLA‐B*35:01 had 2.8‐fold higher frequency in case patients than in controls, with 5 of 10 patients carrying this allele. Molecular docking showed cysteine at position 67 in HLA‐B*14:01 and phenylalanine at position 67 in HLA‐B*35:01 to be the predictive binding sites for SMX metabolites. Conclusions HLA‐B*14:01 is associated with TMP‐SMX DILI in European Americans, and HLA‐B*35:01 may be a potential genetic risk factor for African Americans.

Cross-reactivity between vancomycin, teicoplanin, and telavancin in patients with HLA-A*32:01-positive vancomycin-induced DRESS sharing an HLA class II haplotype To the Editor: Vancomycin is a glycopeptide antibiotic used to treat resistant gram-positive infections. It is associated with a life-threatening, delayed T-cell-mediated reaction, drug reaction with eosinophilia and systemic symptoms (DRESS) presenting with fever, rash, hematologic abnormalities, lymphadenopathy, and organ involvement that occurs 2 to 6 weeks after initiation of vancomycin treatment. 1 We demonstrated that HLA-A*32:01 is strongly associated with vancomycin-induced DRESS in European populations. 2 All glycopeptide antibiotics contain a heptapeptide core structure, and cross-reactivity should be considered when treating patients who have had a previous hypersensitivity reaction to vancomycin (see Fig E1 in this article's Online Repository at www.jacionline. org). 3 Cross-reactivity remains controversial, as some patients presenting with teicoplanin-induced DRESS showed subsequent tolerability to vancomycin 4-7 and patients with teicoplanin-induced DRESS confirmed by a positive intradermal skin test result had a negative result of a skin test to vancomycin. 8 To examine the immunologic cross-reactivity among 4 glycopeptide antibiotics (ie, vancomycin, teicoplanin, dalbavancin, and telavancin), adults who were at least 18 years old with a probable diagnosis of vancomycin-induced DRESS defined as having a corresponding Naranjo adverse drug reaction score of 5 or higher (probable adverse drug reaction), having a Registry of Severe Cutaneous Adverse Reactions score of 4 or higher (probable DRESS), and carrying HLA-A*32:01 (the recently described risk allele for vancomycin-induced DRESS) were recruited between January 2010 and September 2019 through drug allergy clinics and inpatient facilities at participating institutions (