Sulfamethoxazole-trimethoprim-induced Stevens-Johnson syndrome in a NAT2 slow acetylator: A case for pre-emptive pharmacogenomic screening?

Severe Cutaneous Adverse Reactions (SCAR), such as Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), are serious complications associated with several high-risk medications and can result in significant morbidity and mortality. Although HLA-mediated SCARs have been well-characterized-particularly involving drugs like carbamazepine, abacavir, and allopurinol-there is limited data on the role of N-acetyltransferase 2 (NAT2) polymorphisms in SCAR pathogenesis. We present a case of sulfamethoxazole-trimethoprim (SMX-TMP)-induced SJS (Naranjo probability score: seven), hypothesized to be linked to NAT2 slow acetylator (SA) status. This case underscores the potential utility of preemptive pharmacogenomic screening to reduce the incidence of SCARs. NAT2 SA status has also been strongly associated with isoniazid-induced liver injury; the Clinical Pharmacogenetics Implementation Consortium (CPIC) recently published a guideline that NAT2 SA predicted for hydralazine-induced systemic lupus erythematosus (SLE) and they were at higher risk of side effects, suggesting broader clinical implications for routine NAT2 genotyping. Aside from G6PD testing, there is an emergent role to test for NAT2 genotype in preparation for SMX-TMP therapy. Clinically relevant NAT2 alleles include ∗4, ∗5, ∗6, and ∗7. Given that multiple single nucleotide variants (SNVs) must be tested, multiplex pharmacogenomic panels may offer a more cost-effective and comprehensive approach than reactive single gene testing. Some multiplex panels that may be employed include: GeneXpert NAT2-PGx Assay-a rapid assay targeting 5 key polymorphisms to predict isoniazid acetylation, nanopore sequencing-based panels--a scalable targeted sequencing panel useful for NAT2 and other antitubercular genes (rifampicin, linezolid, and bedaquiline); Fulgent Genetics pharmacogenomics comprehensive panel; CleanPlex pharmacogenomics kit; and GenoPharm.