Adjunctive use of Saccharomyces boulardii versus bismuth subsalicylate in the management of non-Clostridioides difficile nosocomial diarrhea in severely ill patients: a three-arm randomized controlled trial

Introduction

Nosocomial diarrhea is a common complication in hospitalized patients with a reported incidence ranging from 5–38% (1-4). Infectious causes including Clostridioides difficile infection (CDI) accounted for 10–25% of cases, while most cases are due to non or unknown infectious etiologies (5,6). Although the treatment guidelines for CDI are well established, non-CDI nosocomial diarrhea management can be varied depending on the underlying causes of diarrhea. Common etiologies of non-infectious nosocomial diarrhea include antibiotic-associated diarrhea (AAD), drug-induced diarrhea, enteral feeding, and exacerbation of pre-existing gastrointestinal diseases such as lactose intolerance or inflammatory bowel disease (6-8).

Multiple etiologies of diarrhea can share similar stool characteristics. For instance, osmotic diarrhea can be caused by both medications and enteral feeding, while secretory diarrhea can be resulted from certain drugs, bacterial toxins or bile salts (9,10). Antibiotics are commonly prescribed in hospitalized patients, contribute to diarrhea directly and indirectly by alteration of intestinal microbiota. The latter effect causes dysbiosis and subsequently leads to impaired intestinal mucosal integrity, dysmotility, and impaired local immune regulation (11-14). Exploration of the etiologies of nosocomial diarrhea leads to a better understanding of the patient’s condition and helps guiding for specific management. Identifying the definite cause of nosocomial diarrhea can be challenging as hospitalized patients often expose to multiple contributing factors, resulting in the complex mechanism of diarrhea (15). Therefore, many anti-diarrheal medications focus on counteracting the underlying pathophysiology of diarrhea and have been used in clinical practice empirically regardless of etiologies.

To rectify dysbiosis, probiotics is a promising therapeutic option as it could modulate an unbalanced intestinal microbiota, restore local immune function and maintain gut homeostasis (16-18). Bismuth subsalicylate (BSS), a long-available over-the-counter anti-diarrheal agent, has been used to alleviate diarrhea due to its anti-inflammatory, anti-microbial, and anti-secretory effects. Furthermore, bismuth salt has demonstrated the ability to prevent both bacterial and viral invasion into intestinal epithelial cells (19-22). The multi-mechanisms of these agents probably handle various pathophysiology of nosocomial diarrhea and might enhance the outcomes of standard treatment.

In this study, we chose Saccharomyces boulardii (S. boulardii), a yeast-based probiotics, and BSS as the treatment of non-CDI nosocomial diarrhea. S. boulardii has not only shown to restore gut microbiota but also demonstrated anti-inflammatory and anti-secretory effects (23,24). Previous meta-analyses of randomized controlled trial (RCT) have demonstrated the efficacy of S. boulardii in treating acute gastroenteritis by reduction in both diarrheal duration and volume (25,26) and in the prevention of AAD (27,28). BSS has also been known to decrease the duration and severity of diarrhea in infectious diarrhea patients and is recommended for prevention of traveler’s diarrhea (29,30). Since the mechanisms of both probiotics and BSS are accountable for the treatment of nosocomial diarrhea, we conducted this study to evaluate the efficacy of S. boulardii versus BSS as an adjunctive treatment to standard care (SC) for non-CDI nosocomial diarrhea in hospitalized patients. We present this article in accordance with the CONSORT reporting checklist (available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-68/rc).

Methods

Study design

This is a three-arm randomized, open-label, trial, conducted in patients with new onset nosocomial diarrhea in the Department of Internal Medicine, Siriraj Hospital, a referral center in Bangkok, Thailand. The study was carried out from August 2016 to February 2018. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of Human Research Protection Unit, Siriraj Hospital (certificate of approval number Si 489/2016). All participants or legal surrogates provided written informed consent to participate in this study.

Participants

The adult patients who had nosocomial diarrhea, defined as an episode of at least 3 times/day of unformed stool, 1 time of mucous bloody stool, or significant increase in stool frequency above baseline after 72 hours of hospitalization (5), with stool test negative for polymerase chain reaction (PCR) for C. difficile toxin gene were eligible for inclusion in the study.

The exclusion criteria were patients with hemodynamic instability, short bowel syndrome, had contraindication to oral or enteral diet, immunocompromised status such as neutropenia with absolute neutrophil count (ANC) less than 1,000 cells/mm³, human immunodeficiency virus (HIV) infection with CD4 count less than 200 cells/mm³, currently underwent chemotherapy sessions, or refuse to participate.

Interventions

Eligible patients were randomly allocated in a 1:1:1 ratio using computer-generated block of 6 randomization to receive either S. boulardii (Sb group), BSS (BSS group) or SC (SC group) by the researchers. In Sb group, patients were prescribed Bioflor^® 1 capsule twice daily, in which one capsule contained 250 mg of S. boulardii. The patients in BSS group received one tablet of Gastrobismol-L^® containing 1,048 mg of BSS orally twice daily. The duration of treatment was 5 days in both groups. In patients who retained nasogastric/gastrostomy tube, Bioflor^® was delivered without capsule and Gastrobismol-L^® was dissolved in water before feeding. While in the SC group, the treatments were given according to their primary physicians’ discretion without any intervention from the investigators.

The data regarding frequency, weight and consistency of stool were recorded daily by trained nurse assistants for 5 consecutive days of the treatment period. Factors that might possibly related to diarrhea such as medications, antibiotics, anti-diarrheal medications, and details of enteral nutrition received were collected.

Outcomes

The primary objective of this study was to determine the efficacy of S. boulardii and BSS as an adjunctive treatment compared to the SC in non-CDI nosocomial diarrhea. The measurement outcome was improvement of diarrhea including reduction in stool weight, frequency and improvement of stool consistency from day 1 to day 5 throughout treatment period. The quantity of stool was measured by weighing them together with the containers, either bedpans or diapers. The recorded stool quantity was obtained after subtracted by the container weight and presented in gram (g). Stool consistency was classified using Bristol Stool Form Scale (BSFS).

Sample size

Based on previous study (31), 72 patients (24 patients per treatment group) were required to provide 90% power and detect 5% difference between S. boulardii, BSS and SC, type I error rate of 0.05 and accounted for 20% of losing data.

Statistical analysis

Categorical data were summarized using descriptive statistics and are reported as frequency and percentage. Continuous variables were presented as mean [standard deviation (SD)] for normally distributed data, and median with interquartile range (IQR) for non-normally distributed data. The normality of the distribution was assessed using the Kolmogorov-Smirnov test. Comparisons between categorical variables were performed using the Chi-squared test or Fisher’s exact test when appropriate. Continuous variables were compared using Student’s t-test for normally distributed data or the Mann-Whitney U test for non-normally distributed data. A two-tailed P value of less than 0.05 was considered statistically significant. All analyses were performed using IBM SPSS Statistics software version 20 (SPSS Inc., Chicago, IL, USA).

Results

Study participants

A total of 236 patients with non-CDI nosocomial diarrhea were screened for eligibility during August 2016 through February 2018 and 72 participants were enrolled. All participants were randomly allocated to receive Bioflor^® (Sb group), BSS (BSS group), or standard of care (SC group) with 24 patients in each group. One patient in Sb group was excluded due to unexpected death on the second day of study period which left a total of 23 patients in Sb group in the final analysis (shown in Figure 1). Demographic data and clinical characteristics at baseline were collected and summarized in Table 1. The baseline characteristics were similar across the groups without significant difference. The mean ± SD of age in Sb, BSS and SC group were 70.4±14.4, 70.0±13.7 and 73.4±13.3 years, respectively. The duration of hospital stay before the onset of diarrhea was longer in the SC group comparing to Sb group (11.2±16.8 vs. 17.9±18.8 days; P=0.04) but not different compared to BSS group (12.8±19.7 days). Most of the patients (95.8%) developed diarrhea during or after the course(s) of antibiotics. Mechanical ventilation was required in 37.5–58.3% of patients. Most patients received enteral nutrition (75.0% in the Sb group, 83.3% in the BSS group, and 91.7% in the SC group). The feeding rate was mostly greater than 100 mL/hour. Only a few of them had feeding regimen modification (e.g., formula change, concentration, or rate of feeding) before the development of diarrhea. The enteral feeding formulas and protocols were not different among the three groups. Stool tests were reported after finishing a course of treatment, a patient in BSS group had parasite in stool while another one in SC group had positive Salmonella group E detected by stool culture. Medications that potentially contribute to diarrhea were commonly prescribed without significant differences observed between groups.

Figure 1 Study flow diagram. BSS, bismuth subsalicylate; NPO, nil per os; Sb, Saccharomyces boulardii; SC, standard care.

Efficacy

The median stool weight at baseline between the groups were comparable; 467 [350–625] g in Sb group, 487 [313–618] g in BSS group and 430 [280–725] g in SC group. Baseline BSFS were 6 in all groups with the median frequency of 4.0-4.4 times/day. After 5 days of intervention, all studied groups showed improvement of stool parameters. On the fifth day of treatment compared to the baseline, the median reduction of stool weight was 68 [24–276], 170 [18–274] and 156 [132–248] g in Sb group, BSS group and SC group respectively (shown in Figure 2), while stool frequency gradually decreased overtime in every group. Stool consistency remained largely unchanged with the BSFS of 6 in all groups. The details of daily change in stool weight, stool frequency and stool consistency across three groups were displayed in Table 2. No adverse events were observed in all studied population except for a patient in Sb group who passed away from worsening sepsis on the second day of treatment.

Figure 2 Comparison of stool weight between the groups. BSS, bismuth subsalicylate; Sb, Saccharomyces boulardii; SC, standard care.

Discussion

Nosocomial diarrhea remains a common yet challenging clinical problem. Given the heterogeneity of the etiologies of this condition, multimodal interventions have to be selected and implemented properly to improve patient’s outcomes. To account for this problem, we aimed to identify an adjunctive treatment for nosocomial diarrhea. In this study, we evaluated the effect of S. boulardii and BSS, the well-recognized medications used in the treatment of out-patient acute gastroenteritis. Unfortunately, the results of the study revealed that neither S. boulardii nor BSS had additional beneficial effect on non-CDI nosocomial diarrhea compared to SC alone. However, our study provided some findings which worth to mention.

Treatment outcomes of nosocomial diarrhea depend on not only treatment medications but also the patient characteristics. The patients in this cohort exhibited typical characteristics including advanced age, severe illness, substantial comorbidities, prolonged length of hospital stay, and antibiotics exposure which are known to increase risk as well as severity of nosocomial diarrhea. These characteristics are consistent with prior report (5). These reflected more severe illness typically seen in tertiary hospitals, or even in intensive care unit. Moreover, most patients in this cohort required nasogastric tube feeding with high infusion rate (more than 100 mL/hour) and high concentration (more than 1:1). Various medications which caused diarrhea were prescribed in up to 50% of the participants. Although these factors are well-established, they are inevitable among hospitalized patients. Hence, the other effective management strategies of non-CDI nosocomial diarrhea are needed.

Severe illness (including patients in intensive care unit and patients with enteral nutrition-related diarrhea) further contributes to the disruption of microbial balance. The alteration of microbiota toward dysbiosis has been linked to adverse outcomes including increased rate of systemic infection and mortality and potentially exacerbate diarrheal symptoms (32-34). These data signified the importance of treatment direct to gut microbiota restoration and enhanced intestinal barrier integrity in patients with nosocomial diarrhea. There is growing evidence highlights the crucial role of gut microbiota in maintaining local immune function and intestinal epithelial integrity (35). Hence, it is interesting to know if probiotics supplementation would alleviate this condition. In contrary with probiotics, BSS is speculated to relieve diarrhea through anti-inflammatory, local anti-microbial and anti-secretory effects. The prior study demonstrated that BSS could significantly inhibit fluid accumulation in the intestinal lumen (19), restrain bacterial growth, neutralize bacterial toxin, and prevent gut epithelium from bacterial invasion (20-22,36). These brought us the rationale to conduct a RCT to evaluate the efficacy of S. boulardii and BSS as an adjunctive treatment in hospitalized patients with diarrhea and negative stool test for C. difficile.

In this study, lack of benefit from probiotics probably due to patient population and antibiotics exposure status differ from prior studies. The meta-analysis demonstrated that S. boulardii improved diarrhea presented in acute setting and studied population were mainly healthy children and adolescent (25,26). Retrospective study of out-patient setting, adult patients with diarrhea demonstrated more resolution of diarrhea with the median follow up duration of 5 days in patients received S. boulardii (37). A RCT in hospitalized patients, evaluated the effect of S. boulardii as an adjunctive treatment of mild to moderate CDI, failed to demonstrate the benefit of S. boulardii treatment in term of diarrheal outcome (38). This probably indicated that higher dose and longer duration of probiotics may be needed in hospitalized patients who received long term antibiotics to restore dysbiosis. Previous study also showed that probiotics may have dose-dependent effect, further supporting the use of higher doses (39). Regarding BSS, although meta-analysis of 11 RCTs showed the efficacy of this treatment in infectious diarrhea significantly improved within a few days compared to placebo with an odd ratio of 3.7 [95% confidence interval (CI): 2.6–6.3, P<0.001] (29). However, the benefit was limited only in the studies using the BSS dosage of 4.2 g/day, but not with 2.1 g/day. The ineffective results of BSS in this study might be from overestimation of BSS. Previous study showed that higher dosages were associated with enhancement of anti-secretory and antimicrobial effects (20).

Interestingly, there were gradual improvements of diarrhea observed in every group over the 5-day period including in the SC group. Most of the patients received enteral feeding, which is well-known cause of nosocomial diarrhea. In our cohort, adjustment of feeding regimens including formulas, concentrations and infusion rates were largely unchanged, suggesting its minor effects. Other factors mainly medications which potentially affect diarrhea were not different across the three groups. These findings emphasize the natural course of non-CDI nosocomial diarrhea which self-limiting resolved and highlight the complexity and multifactorial nature of this condition especially in severely ill patients. Different approach should be considered and more specific studies are needed.

To our knowledge, this is the first randomized-controlled trial to evaluate the effect of S. boulardii versus BSS as adjunctive therapy compared to SC in non-CDI nosocomial diarrhea. However, the study had several limitations worth mentioned: First, there was notably a considerable range of the severity of the participants. In this study, almost half of the patients were on mechanical ventilator indicating severe medical illness which may affect the severity of diarrhea. Further stratification of patients based on illness severity using standardized tools such as APACHE II score might correlate better with the diarrheal outcomes. Second, we did not exclude the patients with other plausible explanation for diarrhea especially drug-induced diarrhea and the enteral feeding protocol could not be standardized which might affect the study outcomes. Further RCT with strict protocol could partially rectify this limitation. Third, the measurement of stool weight might be inaccurate owing to potential urine contamination in some circumstances. Lastly, the lack of placebo made it impossible to blind the primary physicians and may potentially lead to bias.

Conclusions

In conclusion, although generally safe, addition of S. boulardii and BSS yielded no benefit in the treatment of non-Clostridioides difficile nosocomial diarrhea. These were consistent across all diarrheal outcomes. Nonetheless, this trial represented the real-world clinical practice in which nosocomial diarrhea can be contributed from various causes in each patient. Addressing individual factor and manage accordingly should be the utmost importance. Future studies to identify specific subgroups who might gain benefit from probiotics, optimal duration and dosage of both probiotics and BSS in hospitalized patients are awaited.

Acknowledgments

The authors thank Mrs. Khemajira Karaketklang for guiding statistical analysis.

Footnote

Reporting Checklist: The authors have completed the CONSORT reporting checklist. Available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-68/rc

Trial Protocol: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-68/tp

Data Sharing Statement: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-68/dss

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-68/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-68/coif). All authors report that the drugs used in this study were supported by DKSH, Thailand (Saccharomyces boulardii) and Farmaline Co., Ltd. (BSS). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of Human Research Protection Unit, Siriraj Hospital (certificate of approval number Si 489/2016). All participants or legal surrogates provided written informed consent to participate in this study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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