Clostridioides difficile infection in nucleic acid amplification test–positive/toxin-negative patients: to treat or not to treat

Article information

Korean J Intern Med. 2026;41(2):181-182

Publication date (electronic) : 2026 March 1

doi : https://doi.org/10.3904/kjim.2026.081

Tae-Geun Gweon

Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea

Correspondence to: Tae-Geun Gweon, M.D., Ph.D., Department of Internal Medicine, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea, Tel: +82-32-340-2228, Fax: +82-32-340-2255, E-mail: gweontae@naver.com, https://orcid.org/0000-0002-0884-7228

Received 2026 February 20; Accepted 2026 February 21.

Clostridioides difficile infection (CDI) is a major cause of nosocomial diarrhea. Stool-based diagnostic tests for CDI include toxin assays, toxigenic culture, and the nucleic acid amplification test (NAAT) [1]. The NAAT has been widely adopted for CDI diagnosis due to its high sensitivity [2]. However, the positive predictive value of NAAT is lower than that of the toxin test [3]. To date, the clinical characteristics of CDI diagnosed using NAAT have rarely been investigated. In this issue of the Korean Journal of Internal Medicine, Choi et al. [4] investigated the clinical outcomes of NAAT (+)/toxin (−) CDI by comparing them with those of toxin (+) CDI in hospitalized patients. Among the 295 patients with CDI, 128 (43.4%) were NAAT (+)/toxin (−). The authors demonstrated that the severity of CDI and clinical outcomes, including cure rates, were comparable between the two groups. However, the results of the present study should be interpreted with caution. Although the clinical cure rate of NAAT (+)/toxin (−) CDI approaches 95%, approximately one-quarter of affected patients do not receive CDI-specific treatment. This finding raises concerns regarding the accurate diagnosis of CDI. As a substantial proportion of patients achieved resolution without treatment, these cases may have represented self-limiting nosocomial diarrhea rather than true CDI. This finding reflects a high rate of false-positive NAAT results [5]. A previous United States (US) study investigated the clinical outcomes of 417 patients with NAAT (+)/toxin (−) CDI. Although only 15.1% of the patients received a CDI-specific treatment regimen, diarrhea resolved 7 days after diagnosis in the majority of cases (86.3%) [6]. The authors suggested the possibility of safety of withholding anti-CDI treatment in patients who showed NAAT (+), but not toxin (−).

The clinical characteristics of CDI in Eastern countries differ from those in Western countries, with lower overall incidence, a smaller proportion of hypervirulent strains, and reduced rates of community-acquired infection [7,8]. The incidence of CDI has recently increased in South Korea. In a multicenter cohort study that included 18 academic centers, the incidence of CDI was reported to be as high as that in Western countries [9]. Details of the diagnostic methods were not provided due to the retrospective nature of the study. The adoption of the NAAT for CDI diagnosis may have contributed to the increase in the incidence of CDI. In the US, the incidence of CDI has increased since the development of NAAT [5]. Therefore, the incidence of CDI in Korea should be investigated using standardized diagnostic methods.

In addition, the authors suggested that NAAT (+)/toxin (−) CDI was associated with the use of high-dose corticosteroids, whereas prior antibiotic exposure was inversely correlated. The use of antibiotics, which cause microbial disruption, is the most common precipitating factor for CDI [10]. Although the authors demonstrated that antibiotic use was inversely associated with NAAT (+)/toxin (−) CDI, 89.8% of patients in this group had received antibiotics. Therefore, antibiotics were used in most patients, even in NAAT (+)/toxin (−) CDI.

Differentiating between true and false-positive CDI results remains challenging. Therefore, patients with NAAT (+)/toxin (−) CDI should not be excluded from treatment. To make an accurate diagnosis, sigmoidoscopy to investigate pseudomembranous colitis may be useful, where applicable. Furthermore, metronidazole can be administered to manage mild-to-moderate CDI, as vancomycin use is associated with vancomycin-resistant Enterococcus [11]. A nationwide Korean prospective study comparing metronidazole and vancomycin for mild-to-moderate CDI is ongoing.

False-positive results can occur with NAAT. When the treatment proves ineffective in this patient subset, physicians should consider other causes of diarrhea. For inpatients, factors contributing to diarrhea should be considered. This study has inherent limitations owing to the retrospective design. The clinical characteristics and treatment strategies for NAAT (+)/toxin (−) CDI should be investigated in future studies.