Association between Nutrition Protocol with Clostridium butyricum MIYAIRI 588 and Reduced Incidence of Clostridioides difficile Infection in Critically Ill Patients: A Single-Center,Before-and-After Study

Abstract

Background:

Clostridioides difficile infection (CDI) is associated with high mortality. Clostridium butyricum MIYAIRI 588 (CBM) is a probiotic that suppresses Clostridioides difficile proliferation. We assessed the effect of a prophylactic nutritional protocol with CBM on reducing CDI incidence in critically ill patients.

Patients and Methods:

Adult critically ill patients admitted to the intensive care unit (ICU) between 2008 and 2012 were enrolled in this single-center observational study. The original nutritional protocol was introduced in 2010. Patients admitted between 2011 and 2012 (nutrition protocol group) were compared with those admitted between 2008 and 2009 (control group). The primary outcome was CDI incidence during ICU stay.

Results:

There were 755 and 1,047 patients in the control and nutrition protocol groups, respectively. The median (interquartile range) age of the control and nutrition protocol groups was 61 (43–75) and 63 (47–76) years, respectively (p = 0.05). The Acute Physiology and Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores of the control and nutrition protocol groups were 14 (9–23) and 15 (10–22) points (p = 0.73), and four (2–7) and four (2–7) points (p = 0.48), respectively. There were 14 (1.9%) patients with CDI in the control group and one (0.1%) patient in the protocol group (p < 0.01). As a secondary outcome, there were five (0.7%) patients with recurrent CDI in the control group and zero patients in the protocol group (p = 0.01). The length of ICU stay was seven (4–14) days and six (4–13) days in the control and protocol groups (p = 0.01), respectively. Univariable analyses of the relative risk for CDI showed that the nutrition protocol reduced the risk of CDI (0.05 [0.01–0.39]; p < 0.01).

Conclusions:

The nutritional protocol using Clostridioides butyricum may reduce CDI in critically ill patients.

Clostridioides difficile infection (CDI) is one of the most common causes of hospital-acquired diarrhea in intensive care units (ICU). Its incidence and severity are increasing globally [1]. The risk of recurrent CDI has been reported to be 20%–60% [2] and is associated with high mortality [3].

The duration of hospitalization, mechanical ventilation, antibiotic use, antacid drugs, and nosocomial diarrhea are widely recognized risk factors for CDI [4 –7]. Most patients in the ICU have some of these risk factors, possibly leading to poor outcomes when they develop CDI in the presence of other comorbidities [8].

Probiotics have been found to be useful for combating CDI [9 –11]. However, the clinical efficacy of probiotics is inconsistent, and there are many differences between studies, including probiotic formulations, duration of administration, and follow-up duration. Clostridium butyricum MIYAIRI 588 (CBM) is a butyrate-producing probiotic that has been reported to modulate the gut microbiome, prevent Clostridioides difficile proliferation, and enhance the antibacterial activity of fidaxomicin against Clostridioides difficile [12,13]. Despite these basic findings, there have been no clinical studies on the effect of CBM on CDI.

Protocol-based nutritional management has been reported to increase the percentage of achievement for targeted calories and improve clinical outcomes, such as preventing nosocomial infections and reducing hospital stay among critically ill patients [14 –16]. However, the efficacy of protocol-based nutritional therapy using CBM for the prevention of CDI has not yet been evaluated.

We hypothesized that protocol-based nutrition therapy with CBM would be effective for CDI prevention in critically ill patients. Therefore, this study evaluated the effect of a nutrition protocol with CBM on preventing CDI in patients admitted to the ICU.

Patients and Methods

Study design

This was a single-center observational study conducted in the ICU.

Participants

Adult critically ill patients admitted to the ICU of a tertiary care university hospital between 2008 and 2012 were enrolled. The inclusion criteria were as follows: adult patients aged ≥20 years and patients who stayed >48 hours in the ICU. Patients were excluded if they withdrew from aggressive treatment within 48 hours of ICU admission.

Nutrition protocol

In 2010, we introduced an original nutrition protocol for patients in the ICU. Before introducing the protocol, the target energy was determined using the Harris-Benedict equation. Nutritional planning and diarrhea treatment were performed at the discretion of each attending physician. Each physician performed CDI treatment following the CDI guidelines. The essential components of the nutrition protocol are described below.

Early enteral nutrition (EN) and permissive underfeeding: Patients were managed with EN within 48 hours of ICU admission and given permissive underfeeding with EN up to 10 kcal/kg of body weight per day for the first five days. Parenteral nutrition (PN) was not administered for the first five days. After five days of ICU stay, EN was increased to the caloric target.

Caloric target: The caloric target was 30 kcal/kg of actual body weight per day. The target was modified using serial assessments, including indirect calorimetry.

Antacid drugs: The antacid drug was discontinued if EN reached >60% of the caloric target.

CBM: CBM was administered prophylactically before or simultaneously at the start of EN until ICU discharge. The standard prescription was 1.0 g MIYA-BM^® (Miyarisan Pharmaceutical Co., Ltd., Tokyo, Japan) three times a day.

Nutritional assessment: Nutritional assessment was performed once per week, including body weight, organ function, diarrhea status, nitrogen balance, levels of rapid turnover proteins, and indirect calorimetry, when applicable.

Diarrhea management: The administration of broad-spectrum antibiotic agents was changed or discontinued when diarrhea was observed for three days or more. Patients with unexplained and three or more new-onset unformed stools in 24 hours were examined using stool test for Clostridioides difficile toxin(s). Following the Japanese guidelines for CDI during study period, nucleic acid amplification test was not used to diagnose CDI. Antidiarrheal drugs were not recommended, but the diarrhea cause was determined. When necessary, EN was reduced and/or changed from intermittent to continuous mode, and antacid drugs were discontinued in patients without definite indications of bleeding peptic ulcer.

Comparison of two cohorts

Patients admitted between 2011 and 2012 were assigned to the protocol group, and those admitted between 2008 and 2009 were assigned to the control group. The year 2010 was considered the transition period.

Data collection and variables

Data were collected from the medical records. Clinical background characteristics, including age, gender, body mass index (BMI), initial diagnosis, Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores, use of mechanical ventilation, tube feeding, and oral intake were collected. The time of starting tube feeding and prescriptions of carbapenem, tazobactam/piperacillin, levofloxacin, clindamycin, fourth- and third-generation cephalosporins, CBM, antibiotic-resistant lactic acid bacteria, antacid drugs, and antidiarrheal drugs were recorded. We collected information on the incidence of CDI, recurrent CDI, and bleeding digestive ulcers treated endoscopically. The attending physicians evaluated diarrhea during the ICU stay.

Outcomes

The primary outcome was CDI incidence during ICU stay. Secondary outcomes included length of ICU stay, recurrent CDI, the incidence of bleeding digestive tract ulcers, ventilator-free days, and hospital mortality.

Definitions

Clostridioides difficile infection was defined as a symptom of diarrhea with a positive result on a Clostridioides difficile toxin assay of stool specimens [6], except for the initial diagnosis of CDI. Intensive care unit-acquired CDI was diagnosed after admission for at least 48 hours and had an onset of diarrhea in the ICU (>3 loose stools within a 24-hour period) without other etiologies [17]. Incidence was expressed as CDI cases per 10,000 patient-days. Recurrent CDI was defined as CDI recurrence after a 10-day course of CDI-specific antimicrobial therapy within the same admission period or for eight weeks [18].

The following drugs were assessed as days of administration because the dose was modified with organ functions: MIYA-BM, antibiotic agents, carbapenems, tazobactam/piperacillin, levofloxacin, clindamycin, fourth- and third-generation cephalosporins, antacid drugs, intravenous histamine-receptor-2 (H2) blockers, and proton-pump inhibitors, and antidiarrheal drugs including loperamide, aluminum silicate, albumin tannate, and antibiotic-resistant lactic acid bacteria (ARL).

Enteral nutrition energy indicated enteral tube feeding but did not include oral intake. Diarrhea was defined as the elimination of at least three liquid stools per day or a Bristol scale of five or more [19], and continued for three days.

Statistical analysis

Numerical data were presented as median (interquartile range [IQR]) or mean (± standard deviation), and categorical data were presented as numbers (%). Continuous data were compared using the Wilcoxon rank-sum test based on the distributions. Categorical data were compared using Fisher exact test. Numerical data were divided into two groups with median values to evaluate the association between the implementation of the nutrition protocol and CDI incidence. Univariable analysis was performed using known risk factors for CDI: mechanical ventilation, length of ICU stay, antibiotic use, and nutrition protocol with CBM. Statistical analyses were performed using JMP Pro ver. 14.0.0 for windows (SAS Institute Inc., Cary, NC). All statistical tests were two-sided, and statistical significance was set at p < 0.05.

Ethical consideration

The Institutional Review Board of the Tohoku University Hospital ethical committee approved the study protocol (2021-1-800). This study was conducted following the principles of the Declaration of Helsinki. The requirement for informed consent was waived because of the retrospective observational nature of the study and the use of the standard of care in daily clinical practice following the Japanese guidelines (Ministry of Education, Culture, Sports, Science and Technology, and Ministry of Health, Labor, and Welfare, Japan. Ethical guidelines for medical and health research involving human subjects, March 2015). This article is consistent with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement [20].

Results

The sources and distribution of study participants are shown in Figure 1. There were 2,412 patients during the study period. There were 112 patients aged less than 20 years, and those who withdrew from aggressive treatment within 48 hours of ICU admission were excluded. In 2010, there were 484 patients, excluding those in the transition period. The number of patients excluded because of missing data on BMI, APACHE II, or SOFA scores of the control and protocol groups were 10 and three, respectively. The total number of eligible patients in both the protocol and control groups was 1,802 during the study period. There were 755 patients in the control group (2008–2009) and 1,047 in the protocol group (2011–2012).

FIG. 1.

Flow chart of the patient selection. ICU = intensive care unit; BMI = body mass index; APACHE = Acute Physiology and Chronic Health Evaluation; SOFA, Sequential Organ Failure Assessment.

Characteristics

The clinical characteristics of the patients are summarized in Table 1. The median (IQR) age of the control and protocol groups was 61 (43–75) and 63 (47–76), respectively (p = 0.05). The APACHE II and SOFA scores of the control and nutrition protocol groups were 14 (9–23) and 15 (10–22) points (p = 0.73), and 4 (2–7) and 4 (2-7) points (p = 0.48), respectively, with no significant difference between the two groups. Total amount of the antibiotic agent use was not different between groups. The most used antibiotic agent, carbapenem, was used for 11.0 ± 0.9 and 8.59 ± 0.7 days, respectively, in the control and nutrition protocol groups (p = 0.03).

Table 1.

Clinical Characteristic of Patients

	Control (n = 755)	Nutrition protocol (n = 1,047)	p
Age	61 (43–75)	63 (47–76)	0.05
Gender, male	489, 65%	655, 63%	0.35
Body mass index	21.7 (19.0–24.7)	21.6 (18.9–24.4)	0.67
APACHE II score	14 (9–23)	15 (10–22)	0.82
SOFA score	4 (2–7)	4 (2–7)	0.48
Mechanical ventilation	239, 32%	293, 28%	0.09
Tube feeding	264, 35%	384, 37%	0.49
Oral intake	383, 51%	513, 49%	0.47
Number of the antibiotics^a use	231, 31%	305, 29%	0.53
Amount of the antibiotics^a (days/100 patient-days)	18.8 ± 1.2	17.3 ± 1.0	0.32
Carbapenem	11.0 ± 0.9	8.59 ± 0.7	0.03
Tazobactam/piperacillin	2.99 ± 0.4	2.75 ± 0.4	0.67
Levofloxacin	1.01 ± 0.3	1.45 ± 0.2	0.24
Clindamycin	1.23 ± 0.3	1.35 ± 0.3	0.81
Cephalosporin, fourth-generation	0.88 ± 0.2	0.28 ± 0.1	0.01
Cephalosporin, third-generation	2.54 ± 0.5	3.14 ± 0.4	0.33
Initial diagnosis
Trauma	195, 26%	264, 25%	0.32
Stroke	135, 18%	197, 19%
CNS disease	66, 9%	99, 9%
Sepsis	55, 7%	79, 8%
Post-cardiac arrest syndrome	45, 6%	39, 4%
Pulmonary disease	42, 6%	57, 5%
Cardiovascular disease	31, 4%	39, 3%
Burn	27, 4%	33, 3%
Digestive disease	41, 5%	85, 8%
Others	18, 2%	21, 2%

Data are shown as number and %, or median (IQR).

IQR = interquartile range; APACHE II = Acute Physiology and Chronic Health evaluation II; SOFA = Sequential Organ Failure Assessment; CNS = central nervous system; SD = standard deviation.

Antibiotics data are expressed as mean ± SD.

Nutritional management

The treatments, including the nutritional components of both groups, are shown in Table 2. Enteral nutrition was started earlier in the protocol group than in the control group. In the protocol group, the prescription of CBM increased, and the prescription of H2 blockers decreased. The incidence rates of diarrhea were 24.1% and 22.1%, respectively (p = 0.63).

Table 2.

Nutritional Management

	Control	Nutrition protocol	p
EN (kcal/ kg of body weight/d)	3.2 ± 1.4	9.5 ± 0.7	< 0.01
PN (kcal/ kg of body weight/d)	3.5 ± 0.6	2.4 ± 0.3	0.12
Total energy intake (kcal/ kg of body weight/ d)	6.7 ± 1.5	11.8 ± 0.8	0.01
Time to start tube feeding (d)	4.6 ± 0.3	3.7 ± 0.2	0.01
Start EN within 48 h	78, 30%	165, 43%	0.01
CBM (d/100 patient-days)	12 ± 2.0	49 ± 1.7	< 0.01
ARL (d/100 patient-days)	10.4 ± 1.1	9.4 ± 1.0	0.50
H2 blocker (d/100 patient-days)	29.8 ± 11	23.1 ± 0.9	< 0.01
Proton pomp inhibitor (d/100 patient-days)	5.93 ± 0.7	6.33 ± 0.6	0.67
Antidiarrheal drugs (d/100 patient-days)	0.75 ± 0.3	0.57 ± 0.2	0.64
Incidence of diarrhea (%)	24.1%	22.1%	0.63

EN = mean enteral nutrition energy intake, except for oral intake during intensive care unit (ICU) stay; PN = mean parenteral nutrition energy intake during ICU stay. Total energy intake; total energy intake, except for oral intake during ICU stay CBM, Clostridium butyricum MIYAIRI 588, ARL; antibiotic-resistant lactic acid bacteria; data are expressed as mean ± standard deviation (SD).

Outcomes

As shown in Table 3, there were 14 (1.9%) patients with CDI in the control group and one (0.1%) patient in the protocol group (p < 0.01). As a secondary outcome, there were five (0.7%) patients with recurrent CDI in the control group and zero patients in the protocol group (p = 0.01). The median (IQR) length of ICU stay was seven (4–14) days in the control group and six (4–13) days in the protocol group (p = 0.01).

Table 3.

Outcomes

	Control	Nutrition protocol	p
CDI	14, 1.9%	1, 0.1%	< 0.01
Recurrent CDI	5, 0.7%	0, 0%	0.01
Bleeding digestive ulcer	1, 0.15%	0, 0%	0.42
Hospital mortality	72, 9.5%	98, 9.4%	0.94
Ventilator-free days	21 (11–24)	21 (14–24)	0.31
LOS in ICU, d	7 (4–14)	6 (4–13)	0.01

Data are expressed as median (IQR) or n, %.

IQR = interquartile range; CDI = Clostridioides difficile infection; LOS = length of stay.

Relative risk of CDI occurrence

Univariable analyses of the relative risks of CDI are presented in Table 4. The nutrition protocol reduced the CDI risk substantially.

Table 4.

Relative Risk of CDI Occurrence

	Relative risk	p
IPPV	15.5 (3.51–68.5)	< 0.01
ICU stay ≥8 d	16.8 (2.2–127)	0.01
Antibiotic agents^a	15.4 (3.48–67.8)	< 0.01
Nutrition protocol with CBM	0.05 (0.01–0.39)	< 0.01

CDI = Clostridioides difficile infection; IPPV = invasive positive pressure ventilation; ICU = intensive care unit; CBM = Clostridium butyricum MIYAIRI 588.

Carbapenem; tazobactam/piperacillin; levofloxacin; clindamycin, fourth- and third-generation cephalosporins.

Discussion

In a single-center retrospective observational study, we found that a nutrition protocol with CBM was associated with a reduced incidence of both CDI and recurrent CDI. Previous studies have reported that the incidence rates of CDI were 7.4/10,000 patient-days in Japan [21], 7.0/10,000 patient-days in Europe [22], and 10.1/10,000 patient-days in the United States [23]. After implementing the nutrition protocol, the incidence rate reduced from 13.8 to 1.2/10,000 patient-days in this study. To the best of our knowledge, the current study is the first to show an association between the implementation of a nutrition protocol with CBM and reduced CDI incidence.

The major risk factors for CDI have been documented in other studies as the duration of hospitalization, hypoalbuminemia, tube feeding, and receipt of antacid and antibiotic agents [3,7]. The risk factors for recurrent CDI include continued use of antibiotic agents after CDI diagnosis, concomitant receipt of antacid medications, and older age [24]. In our study, the reduction in antacid drug use and protocol-based nutrition therapy might be factors in reducing the risk of CDI. Though the total amount of antibiotic agents used was not different between groups, carbapenem might affect the outcome, but the risk of each antibiotic for CDI is still unknown. In addition, we assumed that CBM administration was the critical factor in reducing CDI incidence because of the previously suggested competitive effect of C. butyricum against C. difficile [25].

Limitations

There are several limitations to this study. First, the design of the before and after study could not avoid some biases in estimating the effect of the nutrition protocol. Second, the sample size was small, and the incidence of CDI (0.1%) in the protocol group was too low for robust statistical analysis. Finally, the generalizability of our results is limited because this was a single-center study.

Conclusions

The CBM nutrition protocol using C. butyricum may be associated with a reduction in CDI incidence. Further multicenter prospective studies with larger sample sizes are required to determine the optimal treatment protocol for critically ill patients.

Footnotes

Acknowledgments

The authors would like to thank Editage for the English language review.

Authors' Contributions

T.S. contributed to the conception, acquisition, and interpretation of data and drafted the manuscript. D.K. analyzed the data and drafted the manuscript. S.K. helped to draft the manuscript. All authors have read and approved the final version of the manuscript.

Data Availability

The data supporting the findings of this study are available at . All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding authors.

Funding Information

This manuscript was funded by Tohoku-Kyui-Kai.

Author Disclosure Statement

The authors have no conflicts of interest to declare.

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