I recently evaluated a 50 year-old female with a history of chronic sinusitis. Her ENT physician would like to treat her with a sulfa antibiotic. Her daughter years ago had what sounds like a Stevens-Johnson reaction to sulfa and her mother also had some sort of allergic reaction to sulfa. For this reason, the patient has never taken sulfa antibiotics as far as she knows. No other known antibiotic sensitivities. So wondering how to approach this issue? First dose in office, challenge in office, or just prescribe and have patient call if reaction? ENT would really like to use sulfa.


There is a growing body of data linking drug reactions with genetic factors. These include thiopurine S-methyltransferase deficiency and azathioprine toxicity, acetylator status affecting risk of sulfonamide reations (Wang) and HLA markers linking dapsone, abacavir, nevirpaine, carbamazepine and allopurinol adverse effects (Sukasem; Zhang). This is probably just the beginning of the story. There are also recognized metabolic factors, such as glutathione depletion which could have some genetic basis, which increase the risk of reactions to drugs including sulfonamides. The controversial concept of multiple drug intolerance syndrome may also have familial relationship suggesting that either metabolism or other inherited factors may influence drug intolerance. Most of the reactions reported with multidrug intolerance are not likely immunologic.

Polymorphisms of sulfonamide detoxification genes have been associated with sulfonamide hypersensitivity (Sacco). This would suggest there is an increased risk of sulfonamide reactions with a positive family history. I am not aware of epidemiologic data supporting a familial associated risk of sulfonamide reactions.

I would document a discussion with your patient and explain there may be some increased risk of sulfonamide sensitivity with a family history of sulfonamide reactions. I am not aware of a familial relationship with Stevens-Johnson reactions. I would discuss the risk of using a less effective or more expensive antibiotic. I would offer an open challenge/administration in clinic, observe for 2 hours and advise the patient to report any symptoms. Otherwise would discuss with ENT physician that there may be an increased risk of sulfonamide but you cannot verify or refute.

Asian Pac J Allergy Immunol. 2014 Jun;32(2):111-23.
Pharmacogenomics of drug-induced hypersensitivity reactions: challenges, opportunities and clinical implementation.
Sukasem C1, Puangpetch A, Medhasi S, Tassaneeyakul W.
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1Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Drug hypersensitivity reactions affect many patients leading to a variety of clinical manifestations, mainly the cutaneous adverse reactions ranging from milder skin reactions to severe cutaneous adverse reactions (SCARs). Hypersensitivity reactions are unpredictable and are thought to have an underlying genetic etiology, as suggested by case reports. With the scientific knowledge of pharmacogenomics and the evidence based on the genomic testing, it is possible to identify genetic predisposing factors for these serious adverse reactions and personalize drug therapy. The most significant genetic associations have been identified in the major histocompatibility complex (MHC) genes encoded for human leukocyte antigens (HLA) alleles. Drugs associated with hypersensitivity reactions with strong genetic predisposing factors include abacavir, nevirapine, carbamazepine, and allopurinol. In this review, strong genetic associations of drug-induced SCARs are highlighted so as to improve drug safety and help to select optimal drugs for individual patients. Further investigation, however, is essential for the characterization of other genes involved in the hypersensitivity reactions with the use of several genetic strategies and technologies.

N Engl J Med. 2013 Oct 24;369(17):1620-8. doi: 10.1056/NEJMoa1213096.
HLA-B*13:01 and the dapsone hypersensitivity syndrome.
Zhang FR1, Liu H, Irwanto A, Fu XA, Li Y, Yu GQ, Yu YX, Chen MF, Low HQ, Li JH, Bao FF, Foo JN, Bei JX, Jia XM, Liu J, Liany H, Wang N, Niu GY, Wang ZZ, Shi BQ, Tian HQ, Liu HX, Ma SS, Zhou Y, You JB, Yang Q, Wang C, Chu TS, Liu DC, Yu XL, Sun YH, Ning Y, Wei ZH, Chen SL, Chen XC, Zhang ZX, Liu YX, Pulit SL, Wu WB, Zheng ZY, Yang RD, Long H, Liu ZS, Wang JQ, Li M, Zhang LH, Wang H, Wang LM, Xiao P, Li JL, Huang ZM, Huang JX, Li Z, Liu J, Xiong L, Yang J, Wang XD, Yu DB, Lu XM, Zhou GZ, Yan LB, Shen JP, Zhang GC, Zeng YX, de Bakker PI, Chen SM, Liu JJ.
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1The authors' full names, degrees, and affiliations are listed in the Appendix.
Background: Dapsone is used in the treatment of infections and inflammatory diseases. The dapsone hypersensitivity syndrome, which is associated with a reported mortality of 9.9%, develops in about 0.5 to 3.6% of persons treated with the drug. Currently, no tests are available to predict the risk of the dapsone hypersensitivity syndrome.
Methods: We performed a genomewide association study involving 872 participants who had received dapsone as part of multidrug therapy for leprosy (39 participants with the dapsone hypersensitivity syndrome and 833 controls), using log-additive tests of single-nucleotide polymorphisms (SNPs) and imputed HLA molecules. For a replication analysis, we genotyped 24 SNPs in an additional 31 participants with the dapsone hypersensitivity syndrome and 1089 controls and performed next-generation sequencing for HLA-B and HLA-C typing at four-digit resolution in an independent series of 37 participants with the dapsone hypersensitivity syndrome and 201 controls.
Results: Genomewide association analysis showed that SNP rs2844573, located between the HLA-B and MICA loci, was significantly associated with the dapsone hypersensitivity syndrome among patients with leprosy (odds ratio, 6.18; P=3.84×10(-13)). HLA-B*13:01 was confirmed to be a risk factor for the dapsone hypersensitivity syndrome (odds ratio, 20.53; P=6.84×10(-25)). The presence of HLA-B*13:01 had a sensitivity of 85.5% and a specificity of 85.7% as a predictor of the dapsone hypersensitivity syndrome, and its absence was associated with a reduction in risk by a factor of 7 (from 1.4% to 0.2%). HLA-B*13:01 is present in about 2 to 20% of Chinese persons, 1.5% of Japanese persons, 1 to 12% of Indians, and 2 to 4% of Southeast Asians but is largely absent in Europeans and Africans.
Conclusions: HLA-B*13:01 was associated with the development of the dapsone hypersensitivity syndrome among patients with leprosy. (Funded by the National Natural Science Foundation of China and others.).

Pharmacogenet Genomics. 2012 Oct;22(10):733-40. doi: 10.1097/FPC.0b013e328357a735.
Evaluation of polymorphisms in the sulfonamide detoxification genes NAT2, CYB5A, and CYB5R3 in patients with sulfonamide hypersensitivity.
Sacco JC1, Abouraya M, Motsinger-Reif A, Yale SH, McCarty CA, Trepanier LA.
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1Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin 53706-1102, USA.
Objective: To determine whether polymorphisms in the sulfonamide detoxification genes, CYB5A (encoding cytochrome b(5)), CYB5R3 (encoding cytochrome b(5) reductase), or NAT2 (encoding N-acetyltransferase 2) were over-represented in patients with delayed sulfonamide drug hypersensitivity, compared with control patients who tolerated a therapeutic course of trimethoprim-sulfamethoxazole without adverse event.
Methods: DNA from 99 nonimmunocompromised patients with sulfonamide hypersensitivity who were identified from the Personalized Medicine Research Project at the Marshfield Clinic, and from 99 age-matched, race-matched, and sex-matched drug-tolerant controls, were genotyped for four CYB5A and five CYB5R3 polymorphisms, and for all coding NAT2 SNPs.
Results: CYB5A and CYB5R3 SNPs were found at low allele frequencies (<3-4%), which did not differ between hypersensitive and tolerant patients. NAT2 allele and haplotype frequencies, as well as inferred NAT2 phenotypes, also did not differ between groups (60 vs. 59% slow acetylators). Finally, no difference in NAT2 status was found in a subset of patients with more severe hypersensitivity signs (drug reaction with eosinophilia and systemic symptoms) compared with tolerant patients.
Conclusion: We found no evidence of a substantial involvement of these nine CYB5A or CYB5R3 polymorphisms in sulfonamide hypersensitivity risk, although minor effects cannot be completely ruled out. Despite careful medical record review and full resequencing of the NAT2 coding region, we found no association of NAT2 coding alleles with sulfonamide hypersensitivity (predominantly cutaneous eruptions) in this adult Caucasian population.

Pharmacogenet Genomics. 2011 Oct;21(10):652-64. doi: 10.1097/FPC.0b013e3283498ee9.
Human N-acetyltransferase 1 *10 and *11 alleles increase protein expression through distinct mechanisms and associate with sulfamethoxazole-induced hypersensitivity.
Wang D1, Para MF, Koletar SL, Sadee W.
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1Department of Pharmacology, Program in Pharmacogenomics, School of Biomedical Science, Ohio State University, Columbus, Ohio 43210, USA.
Objectives: N-acetyltransferase 1 (NAT1) metabolizes drugs and environmental carcinogens. NAT1 alleles *10 and *11 have been proposed to alter protein level or enzyme activity compared with wild-type NAT1 *4 and to confer cancer risk, through uncertain pathways. This study characterizes regulatory polymorphisms and underlying mechanisms of NAT1 expression.
Methods: We measured allelic NAT1 mRNA expression and translation, as a function of multiple transcription start sites, alternative splicing, and three 3'-polyadenylation sites in human livers (one of which was discovered in this study), B lymphocytes, and transfected cells. In a clinical study of 469 patients with HIV/AIDS treated with the NAT1/NAT2 substrate sulfamethoxazole (SMX), associations were tested between SMX-induced hypersensitivity and NAT1 *10 and *11 genotypes, together with known NAT2 polymorphisms.
Results: NAT1 *10 and *11 were determined to act as common regulatory alleles accounting for most NAT1 expression variability, both leading to increased translation into active protein. NAT1 *11 (2.4% minor allele frequency) affected 3'-polyadenylation site usage, thereby increasing formation of NAT1 mRNA with intermediate length 3'-untranslated region (major isoform) at the expense of the short isoform, resulting in more efficient protein translation. NAT1 *10 (19% minor allele frequency) increased translation efficiency without affecting 3'-untranslated region polyadenylation site usage. Livers and B-lymphocytes with *11/*4 and *10/*10 genotypes displayed higher NAT1 immunoreactivity and NAT1 enzyme activity than the reference genotype *4/*4. Patients who carry *10/*10 and *11/*4 (fast NAT1 acetylators) were less likely to develop hypersensitivity to SMX, but this was observed only in individuals who are also carrying a slow NAT2 acetylator genotype.
Conclusion: NAT1 *10 and *11 significantly increase NAT1 protein level/enzyme activity, enabling the classification of carriers into reference and rapid acetylators. Rapid NAT1 acetylator status seems to protect against SMX toxicity by compensating for slow NAT2 acetylator status.

Pharmacogenetics. 2000 Nov;10(8):705-13.
Association analysis of drug metabolizing enzyme gene polymorphisms in HIV-positive patients with co-trimoxazole hypersensitivity.
Pirmohamed M1, Alfirevic A, Vilar J, Stalford A, Wilkins EG, Sim E, Park BK.
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1Department of Pharmacology and Terapeutics, The University of Liverpool, UK.
The use of co-trimoxazole in HIV-positive patients has been associated with a high frequency (40-80%) of hypersensitivity reactions. This has been attributed to the bioactivation of the sulphonamide component, sulphamethoxazole (SMX), to its toxic hydroxylamine and nitroso metabolites. The aim of this study was to determine whether functionally significant polymorphisms in the genes coding for enzymes involved in SMX metabolism influence susceptibility to SMX hypersensitivity. HIV-positive patients with (n = 56) and without (n = 89) SMX hypersensitivity were genotyped for allelic variants in CYP2C9, GSTM1, GSTT1, GSTP1 and NAT2 using polymerase chain reaction (PCR) and/or PCR-restriction fragment length polymorphism analysis. The CYP2C9*2/*3 genotype and CYP2C9*3 allele frequencies were nine- and 2.5-fold higher in the hypersensitive group compared to non-sensitive patients, respectively, although they were not statistically significant when corrected for multiple testing. There were no differences in the frequencies of the GSTM1 and GSTT1 null genotypes, and the slow acetylator genotype, between hypersensitive and non-sensitive patients, while GSTP1 frequency was lower (although non-significant) in the hypersensitive group [21% versus 32%, odds ratio (OR) = 0.5, Pc = 0.24]. Comparison of the genotype frequencies in HIV-positive and -negative patients showed that the NAT2 slow acetylator genotype frequency in the HIV-positive patients (74%) was significantly (Pc = 0.0003, OR = 2.3) higher than in control subjects (56%). Our results show that genetic polymorphisms in drug metabolizing enzymes are unlikely to be major predisposing factors in determining individual susceptibility to co-trimoxazole hypersensitivity in HIV-positive patients.
I hope this information is of some help to you and your patient.

All my best.
Dennis K. Ledford, MD, FAAAAI

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