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. 2025 Jul 8;14(14):4819.
doi: 10.3390/jcm14144819.

Evaluation of Adverse Events Associated with the Sulfamethoxazole/Trimethoprim Combination Drug

Takaya Sagawa  1   2 , Tomoaki Ishida  3 , Kohei Jobu  1   2 , Shumpei Morisawa  1 , Keita Akagaki  1   2 , Takahiro Kato  1 , Takumi Maruyama  1 , Yusuke Yagi  1   4 , Tomomi Kihara  5   6 , Sanae Suzuki  7 , Mio Endo  7 , Nobuaki Matsunaga  7 , Yukihiro Hamada  1   2
Affiliations

Evaluation of Adverse Events Associated with the Sulfamethoxazole/Trimethoprim Combination Drug

Takaya Sagawa et al. J Clin Med. .

Abstract

Background/Objectives: The combination drug sulfamethoxazole/trimethoprim (ST) is a broad-spectrum antibiotic used against various infections; however, it is associated with several serious adverse events. The ST package inserts contain warnings about these adverse events. However, warnings vary internationally, and specific measures to address ST-related adverse events are unclear. Therefore, we aimed to comprehensively evaluate ST-related adverse events using the Japanese Adverse Drug Event Report (JADER) database and analyze the onset time for each event. Methods: Adverse events due to ST were analyzed using the JADER database between April 2004 and June 2023. The reported odds ratio and 95% confidence interval (95% confidence interval [CI]) were calculated, with a signal detected if the 95% CI lower limit exceeded 1. The Weibull distribution was used to characterize the onset time of adverse events with detected signals. Results: The total number of cases in the JADER database during the study period was 862,952, and the number of adverse events involving ST as a suspected drug was 4203. Adverse events associated with ST include hyperkalemia, syndrome of inappropriate antidiuretic hormone secretion, hematopoietic cytopenia, acute renal failure, hypoglycemia, disseminated intravascular coagulation syndrome, hepatic disorder, and the Stevens-Johnson syndrome/toxic epidermal necrolysis. Conclusions: Weibull analysis indicated an early failure-type onset time for all adverse events, suggesting the need for intensive adverse event monitoring of ST, especially in the first month of use. These findings may support revising drug package inserts in Japan to better reflect the identified risks.

Keywords: Japanese adverse drug event report; Weibull; confidence intervals; spontaneous reporting system; sulfamethoxazole/trimethoprim.

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Conflict of interest statement

The authors declare no conflicts of interest. The funding agency had no role in the design, execution, analysis, or interpretation of the data.

Figures

Figure 1
Figure 1
Time-to-onset analysis of adverse events by sulfamethoxazole/trimethoprim administration. Histograms for (A) hyperkalemia, (B) syndrome of inappropriate secretion of antidiuretic hormone, (C) hematopoietic cytopenia, (D) Stevens–Johnson syndrome/toxic epidermal necrolysis, (E) acute renal failure, (F) hypoglycemia, and (G) hepatic disorders are shown. Abbreviations: 95% CI, 95% confidence interval; IQR, interquartile range; SIADH, syndrome of inappropriate antidiuretic hormone secretion; SJS/TEN, Stevens–Johnson syndrome/toxic epidermal necrolysis.
Figure 1
Figure 1
Time-to-onset analysis of adverse events by sulfamethoxazole/trimethoprim administration. Histograms for (A) hyperkalemia, (B) syndrome of inappropriate secretion of antidiuretic hormone, (C) hematopoietic cytopenia, (D) Stevens–Johnson syndrome/toxic epidermal necrolysis, (E) acute renal failure, (F) hypoglycemia, and (G) hepatic disorders are shown. Abbreviations: 95% CI, 95% confidence interval; IQR, interquartile range; SIADH, syndrome of inappropriate antidiuretic hormone secretion; SJS/TEN, Stevens–Johnson syndrome/toxic epidermal necrolysis.
Figure 2
Figure 2
Cumulative incidence of adverse events over time. Kaplan–Meier-like curves illustrate the time to reporting of (A) hyperkalemia, (B) syndrome of inappropriate secretion of antidiuretic hormone, (C) hematopoietic cytopenia, (D) Stevens–Johnson syndrome/toxic epidermal necrolysis, (E) acute renal failure, (F) hypoglycemia, (G) disseminated intravascular coagulation, and (H) hepatic disorder following drug administration, based on data from the spontaneous reporting system. The x-axis represents the number of days from the start of drug administration to adverse event onset, and the y-axis indicates the cumulative reported rate. Shaded areas represent 95% confidence intervals.
Figure 2
Figure 2
Cumulative incidence of adverse events over time. Kaplan–Meier-like curves illustrate the time to reporting of (A) hyperkalemia, (B) syndrome of inappropriate secretion of antidiuretic hormone, (C) hematopoietic cytopenia, (D) Stevens–Johnson syndrome/toxic epidermal necrolysis, (E) acute renal failure, (F) hypoglycemia, (G) disseminated intravascular coagulation, and (H) hepatic disorder following drug administration, based on data from the spontaneous reporting system. The x-axis represents the number of days from the start of drug administration to adverse event onset, and the y-axis indicates the cumulative reported rate. Shaded areas represent 95% confidence intervals.
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