TMP-SMX, Glycopeptides Linked to High Absolute Risk for SJS/TEN in Japan

Trimethoprim-sulfamethoxazole and glycopeptides carried a high absolute risk for Stevens-Johnson syndrome/toxic epidermal necrolysis among new antibiotic users in Japan.

A high absolute risk for Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) was found to be associated with trimethoprim-sulfamethoxazole (TMP-SMX) and glycopeptides, according to study results published in The Journal of Allergy and Clinical Immunology: In Practice.

The main causes of SJS/TEN, a severe skin reaction characterized by painful blistering of the skin and mucous membranes, are certain medications (for example, antiseizure drugs, nonsteroidal anti-inflammatory drugs [NSAIDs], and antibiotics). Risk varies by geographic region owing to genetic and ethnic factors, but evidence is lacking regarding the association between antibiotic use and risk for SJS/TEN among Asian patients. Therefore, investigators in Japan sought to evaluate the risk for SJS/TEN associated with various antibiotic classes in the treatment of Japanese patients.

In a case-crossover study, the investigators used an insurance claims database (JMDC Inc, Tokyo, Japan) that covers the period from January 2005 through October 2020 and includes deidentified data from more than 10 million patients younger than 75 years of age. They used the data to evaluate the association between antibiotic use and risk for SJS/TEN, controlling for possible genetic confounding. They also conducted a cohort study using the insurance claims database from October 2012 to September 2020 to assess the absolute risk for SJS/TEN among patients exposed to antibiotic treatment.

Exposure was defined as at least a 1-day supply of any of the investigated antibiotics. The investigators compared drug exposure status in the hazard period (for 56 days immediately before the outcome) to identify possible causative drug exposure, with 3 consecutive control periods for each patient and a 28-day washout period between hazard and control periods. Patients meeting the inclusion criteria could be entered into more than 1 antibiotic class cohort. Patients (62% women) were average (SD), 45.1 (16.0) years at the end of the hazard period.

Given the risk observed in our study, concern about SJS/TEN should play a crucial role in clinical decision making about treatment with TMP-SMX and glycopeptides.

The investigators found 170 cases of SJS/TEN with increased odds ratios (ORs) for antibiotic use associated with the risk for SJS/TEN with lincomycins (OR, 33.00; 95% CI, 3.74-4332.05), TMP-SMX (OR, 21.20; 95% CI, 6.73-105.98), penicillins (OR, 14.39; 95% CI, 6.95-34.21), and glycopeptides (OR, 14.37; 95% CI, 3.17-136.10). Probable causality was 20.0% for lincomycins, 71.4% for TMP-SMX, 52.6% for penicillin, and 12.5% for glycopeptides.

Increased causal ORs for SJS/TEN were also noted for macrolides, tetracyclines, carbapenems, fosfomycin, quinolones, aminoglycosides, and cephalosporins, and ranged from 3.78 to 7.06, respectively. No SJS/TEN cases of patients exposed to aminoglycosides or fosfomycin had probable causality. Lipopeptides, metronidazole, monobactams, penems, and polypeptide exposure had nonsignificant associations with SJS/TEN.

In evaluating the 56-day cumulative incidence of SJS/TEN among new users of antibiotics, however, the investigators noted that the cumulative incidence of SJS/TEN was 86.2/100,000 new users for glycopeptides, 67.4/100,000 new users for TMP-SMX, and negligible (below 10.0) for the other antibiotic classes. A probable causal relationship only existed in 2 cases with glycopeptides.

Study limitations include time-varying confounders in the case-crossover design (such as concomitant treatment with high-risk drugs), unaccounted-for use of over-the-counter NSAIDs, and possible reverse causality in patients with SJS/TEN complicated by serious infections treated with antibiotics.

“This study newly indicates that risk of SJS/TEN is increased by exposure to lincomycin, glycopeptides, aminoglycosides, fosfomycin, and carbapenems, adding to the previously reported increase with penicillin, cephalosporins, macrolides, tetracyclines, quinolones, and trimethoprim-sulfamethoxazole,” the investigators concluded. They added, “Our study adds higher estimates of TMP-SMX-induced absolute risk among antibiotics to the accumulated evidence of risk factors for SJS/TEN, and underpins the increased ORs reported in previous case-control studies. Only TMP-SMX and glycopeptides showed a high absolute risk of SJS/TEN. Given the risk observed in our study, concern about SJS/TEN should play a crucial role in clinical decision making about treatment with TMP-SMX and glycopeptides.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

This article originally appeared on Dermatology Advisor


Fukasawa T, Urushihara H, Takahashi H, Okura T, Kawakami K. Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with antibiotic use: a case-crossover study. J Allergy Clin Immunol Pract. Published online July 15, 2023. doi:10.1016/j.jaip.2023.07.012