Faecal Microbiota Transplant Decreases Mortality in Severe and Fulminant Clostridioides difficile Infection in Critically Ill Patients

Abstract

• Background:

Severe and fulminant Clostridioides difficile infection is associated with high mortality rates. While faecal microbiota transplant has been shown to be effective for the treatment of recurrent Clostridioides difficile infection, there is little data on the utility of faecal microbiota transplant in severe or fulminant Clostridioides difficile infection.

• Aims:

Compare outcomes of antibiotics plus faecal microbiota transplantation versus antibiotics alone (standard of care) in critically ill patients with severe or fulminant Clostridioides difficile infection.

• Methods:

This was a retrospective, matched cohort study in one, urban tertiary academic care center including 48 patients hospitalized with severe or fulminant Clostridioides difficile infection who required care in intensive care unit.

• Results:

Patients who received faecal microbiota transplantation had a 77% decrease in mortality (OR 0.23, 95%-CI 0.06–0.97) with a number needed to treat of 3 to prevent one death.

• Conclusions:

Faecal microbiota transplantation provides mortality benefit over standard of care for severe and fulminant Clostridioides difficile infection and should be considered in critically ill patients.

Introduction

Severe and fulminant Clostridioides difficile infection (CDI) is an increasingly common disease with significant associated morbidity and mortality.¹ Estimated attributable mortality rates range between 30 and 60%.² Per the 2017 IDSA/SHEA guidelines, standard of care treatment for severe and fulminant CDI includes oral vancomycin and intravenous metronidazole. If ileus is present, vancomycin may also be administered per rectum. Alternative therapies such as tigecycline and intravenous immunoglobulins have been used in such patients who do not respond to vancomycin and metronidazole, though there have been no controlled trials for these therapies and they are not included in treatment guidelines.³ Colectomy is recommended for fulminant patients but still results in mortality rates close to 50%.⁴ There are few absolute indications for surgery such as colonic ischemia and perforation. Additionally, there is a lack of clear guidelines on the optimal timing of surgical intervention for fulminant CDI. Even in patients who are discharged after subtotal colectomy for fulminant disease, long-term outcomes are poor with average survival time of 18 months.⁵ Over the past decade or more, there has been little advance made in the treatment of severe/fulminant CDI. Initial success with new surgical technique was initially reported by Neal et al using diverting loop ileostomy and colonic lavage.⁶ A multicenter retrospective analysis confirmed these findings, but this practice has not become standard of care.⁷

For cases of recurrent or refractory CDI, faecal microbiota transplant (FMT) has been shown to be extremely efficacious.^8–10 However, the utility of FMT in severe or fulminant CDI, especially for critically ill, hospitalized patients, is not well described in the current literature. While there have been several publications demonstrating FMT to be safe and effective in this population, much of this data is uncontrolled and does not directly compare patients who received antibiotics plus FMT versus antibiotics alone (standard of care, SOC).^11–14 The aim of this study was to assess outcomes of hospitalized patients with severe or fulminant CDI requiring intensive care who received antibiotics plus FMT compared to SOC.

Materials and Methods

We performed a retrospective matched cohort study of patients hospitalized with severe or fulminant CDI who received antibiotics plus FMT or SOC in a single urban tertiary care academic medical center between December 1^st, 2013 and August 31^st, 2018. CDI was defined as diarrhea with a positive stool test for Clostridioides difficile (PCR or toxin). The strain of Clostridioides difficile was not reported as this is not routine practice at our institution. Severity was classified by 2017 IDSA/SHEA guidelines.³ Severe colitis was defined by white blood cell (WBC) count of ≥ 15,000 cells/mL or a serum creatinine of > 1.5 mg/dL. Fulminant colitis was defined by presence of hypotension or shock, ileus, or toxic megacolon. Serious adverse events were defined as life-threatening events including bacteremia, aspiration, and perforation related to FMT that required medical or surgical intervention.

We identified all patients with severe or fulminant CDI who received critical care in an intensive care or step-down unit during their admission. Therapy plan for CDI was determined by the treating physicians, but all patients received oral vancomycin. Within this group, patients who received FMT were matched 1:2 to SOC patients. SOC was defined as oral vancomycin +/− intravenous metronidazole. No patients received fidaxomicin, bezlotoxumab, or other adjunctive therapy. Frozen FMT (donor-selected or OpenBiome) was administered via colonoscopy or flexible sigmoidoscopy. If pseudomembranous colitis was identified during endoscopy, FMT was repeated every 3–5 days until resolution of colitis per previously published protocol.^14,15 Matching was performed by the statistical software based on age, sex, history of CDI in prior 60 days, antibiotic use, and CDI severity. Mortality was not known during the matching process. Patient information was extracted from the hospital electronic medical record, including age, sex, comorbidities using the Charlson comorbidity index (CCI),¹⁶ number of prior Clostridioides difficile episodes, interventions, serious adverse events, and relevant dates (e.g. date of birth, admission, diagnosis of CDI, date of FMT, discharge, and death). We also calculated predicted risk of mortality from CDI using the Clostridium difficile associated risk of death score (CARDS).¹⁷ Exclusion criteria included age <18 years and absence of vancomycin treatment.

Primary outcome was death during hospital admission. Secondary outcomes included colectomy during admission, recurrent CDI, hospital readmission, and 30- and 90-day mortality rate after discharge. Descriptive statistics were performed using means, standard deviations (SD), and proportions for continuous and categorical data, respectively. Associations were assessed using student’s t-test, χ2 test or Fisher’s exact tests. Univariable and multivariable logistic regression were performed with odds ratios (OR) and 95% confidence intervals (CI) reported. For multivariable analysis, age and CCI were a priori entered into models assessing the primary outcome as well as any baseline variable significant at the p < 0.1 level. Two-sided p values < 0.05 were considered statistically significant. Given that our cohort contained both severe and fulminant patients, we conducted sensitivity analyses to investigate the impact of FMT within the fulminant cases. Analyses were performed using SAS v9.4 (Cary, NC).

Results

Four-hundred and twenty six patients who had severe or fulminant CDI and required intensive care were identified between December 2013 and August 2018. Of these patients, 16 (3.8%) received FMT in addition to antibiotics. These patients were matched 1:2 with 32 controls who received SOC antibiotics alone. Average age was 62.9 years (range 19–90, SD 20.1). Average CCI score was 7.4 (range 0–14, SD 3.5). The mean number of FMTs administered was 1.4 (range 1 – 3). Overall, 68.8% of patients had fulminant CDI and 32.2% had severe CDI. The FMT and SOC groups were similar with the exception of mean WBC count at time of diagnosis, which was 24.6 versus 13.2 in FMT versus SOC respectively (p=0.04) (Table 1). There was no significant difference between the FMT and SOC groups with respect to year in which they were admitted, pressor requirement, intubation, and CCI score. There was no significant difference with regards to antibiotics used in each group. Average time from CDI diagnosis to FMT was 9.6 days (range 1–50 days, SD 9.3 days). The FMT group had a higher rate of predicted CDI-related mortality compared to the SOC group with mean CARDS score of 10.9 versus 9.3 respectively (p = 0.03).

Table 1.

: Baseline patient characteristics

BASELINE CHARACTERISTICS	FMT (N = 16)	SOC (N = 32)	P-value
Mean age (years) (SD)	62.6 (20.4)	63.1 (19.4)	0.93
Female sex (%)	9 (56.3%)	18 (56.3%)	1.00
Mean BMI (kg/m2) (SD)	24.3 (6.2)	27.1 (7.1)	0.20
Mean CCI (SD)	7.1 (4.3)	7.5 (3.1)	0.67
Prior CDI (%)	3 (18.8%)	6 (18.8%)	1.00
Fulminant CDI (%)	11 (68.8%)	22 (68.8%)	1.00
History of IBD (%)	1 (6.3%)	0 (0%)	0.33
Immunosuppressed (%)	5 (31.3%)	12 (37.5%)	0.67
Mean WBC count at diagnosis (103 cells/uL) (SD)	24.6 (19.5)	13.2 (9.0)	*0.04
Mean creatinine at diagnosis (mg/dL) (SD)	3.0 (3.2)	3.2 (2.4)	0.80
Mean peak WBC (103 cells/uL) (SD)	30.6 (20.2)	19.5 (9.9)	0.05
Mean peak creatinine (mg/dL) (SD)	4.1 (3.7)	4.8 (3.3)	0.05
Mean hemoglobin (g/dL) (SD)	10.3 (1.7)	9.3 (1.9)	0.07
Surgical history (%)	9 (56.3%)	15 (37.5%)	0.54
Pressors required (%)	10 (62.5%)	20 (62.5%)	1.00
Intubation required (%)	10 (62.5%)	21 (65.6%)	0.83
SBP < 100 (%)	15 (93.8%)	29 (90.6%)	0.71
Oral Vancomycin Received (%)	16 (100%)	32 (100%)	1.00
Rectal Vancomycin Received (%)	3 (18.8%)	3 (9.4%)	0.36
IV Metronidazole Received (%)	12 (75.0%)	21 (65.6%)	0.51

FMT = Faecal Microbiota Transplant, SOC = Standard of Care, SD = Standard Deviation, BMI = Body Mass Index, CCI = Charlson Comorbidity Index, CDI = Clostridioides difficile infection, IBD = Inflammatory Bowel Disease, WBC = White Blood Cell, SBP = Systolic Blood Pressure, IV = intravenous

Nineteen of 48 patients died during hospital admission, leading to an overall mortality rate of 39.6%. Only 3 out of 16 patients (18.8%) in the FMT group died during hospital admission compared to 16 out of 32 patients (50%) in the SOC group (p=0.045). There was a 31.2% absolute risk reduction in mortality for patients undergoing FMT corresponding to a number needed to treat of 3.2 to prevent one death. In multivariable regression analysis, which adjusted for age and CCI score, FMT was still associated with a significant mortality benefit (adjusted OR 0.23, 95%-CI 0.05–0.97, p=0.045). Five of 48 patients underwent colectomy (10.4%). There were no differences in secondary outcomes between the groups, including colectomy rate (univariable OR 0.76, 95%-CI 0.11–5.08, p=0.77), repeat CDI (univariable OR 1.30, 95%-CI 0.22–7.87, p=0.78), and readmission (univariable OR 0.37, 95%-CI 0.07–1.98, p=0.24) (Table 2).

Table 2:

Study Outcomes - Univariable Analysis

OUTCOMES	FMT	SOC	OR, 95%-CI	P-value
Death during admission (%)	3 (18.8%)	16 (50.0%)	0.23 (0.06 – 0.97)	*0.045
Colectomy during admission (%)	2 (12.5%)	3 (9.4%)	0.76 (0.11 – 5.08)	0.77
Repeat CDI (%)†	3 (23.1%)	3 (18.8%)	1.30 (0.22 – 7.87)	0.78
Readmission (%)†	8 (61.5%)	13 (81.3%)	0.37 (0.07 – 1.98)	0.24

FMT = Faecal Microbiota Transplant, SOC = Standard of Care, OR = Odds Ratio, CI = Confidence Interval, CDI = Clostridioides difficile infection

^†These outcomes were analyzed in the subset of patients who did not die during their initial admission (N = 29)

Sensitivity analyses to investigate the impact of FMT in fulminant cases alone yielded similar results, although they did not reach statistical significance. Of the 33 patients with fulminant CDI, 15 died during hospital admission (45.5%); 3 of 11 (27.3%) in the FMT group and 12 out of 22 (54.4%) in the SOC group (univariable OR = 0.31, 95%-CI 0.07–1.50, p = 0.15). There were no differences in secondary outcomes within this fulminant subset. Of the 13 patients who received FMT and were discharged from the hospital, 3 (23.1%) were lost to follow-up. Of the remaining 10 FMT patients, none died within 30 days and 2 (20.0%) died within 90 days of hospital discharge. Of the 16 patients who received SOC treatment and were discharged from the hospital, 3 (18.8%) were lost to follow-up. Of the remaining 13 SOC patients, none died within 30 days and 1 (7.7%) died within 90 days of hospital discharge.

Only four of 32 patients in the SOC group were evaluated for FMT. Of these four patients, two were found to be clinically improving, one had bacteremia that precluded FMT, and one acutely decompensated requiring emergent colectomy.

Of the patients who underwent FMT, two out of 16 (12.5%) experienced serious adverse events. One patient developed Klebsiella bacteremia shortly after FMT that was successfully treated with a course of antibiotics and was ultimately discharged home. One patient developed a bowel perforation after FMT requiring colectomy, and died during the hospital admission. Of the patients in the SOC group, 12 of 32 (37.5%) patients developed bacteremia and two of 32 patients (6.3%) developed a bowel perforation.

Discussion

In this retrospective study of critically ill patients admitted with severe or fulminant CDI, we observed that FMT had a significant mortality benefit over SOC with an absolute risk reduction of 31.2% corresponding to an NNT of 3.2 to prevent one death. With an average CCI score of 7.4, our population represented a group of severely ill patients in critical care or step-down settings. By utilizing both the CCI and IDSA/SHEA guidelines, we were able to objectively classify patients regarding the severity of their CDI as well as their global illness severity. One prior study observed a similar mortality benefit for early FMT in patients with severe CDI but did not include patients with fulminant CDI and had a median CCI of 2, indicating a less severe cohort of patients.¹⁸

There is very little published data on safety outcomes of FMT in patients with severe or fulminant CDI with rates of serious adverse events ranging from 0 to 28%.^13,14,19 In our cohort, we found a small number of serious adverse events in patients who underwent FMT including one occurrence of bacteremia (6.3%) and one perforation (6.3%). Our reported rates of severe adverse events do not differ from what has been reported to date in patients undergoing FMT. In the SOC group, there was a higher rate of bacteremia (37.5%) and similar rate of perforation (6.3%) compared to the FMT group. Given that our study population was comprised of critically ill patients, at high risk of morbidity and mortality, the low rate of serious adverse events with FMT is encouraging. Further studies specifically looking at safety outcomes are imperative, especially with the recent report of two immunocompromised patients who developed infections with multi-drug resistant organisms traced back to their FMT donor.²⁰

There are several limitations to this study. This study was conducted using a retrospective matched cohort design which may have introduced selection bias. We attempted to control for confounding factors that could have impacted mortality other than CDI by matching for CCI and CDI severity, which classifies patients based on objective markers during hospitalization. We also utilized the CARDS tool to assess the predicted mortality of each group. We found that patients who received FMT had a higher predicted rate of mortality compared to patients who received SOC treatment, with a CARDS score of 10.9 and 9.3 respectively (p=0.03). This difference potentially strengthens the findings of our study as the FMT group had a statistically significant decrease in mortality compared to SOC, despite a higher CARDS score.

The decision to pursue FMT was primarily decided by the treatment team. Though it is possible that there was selection bias in who received FMT, we found no significant difference between the FMT and SOC group with regards to demographics, severity indices, percentage of patients who had systolic blood pressures < 100, required pressor support or required intubation. Only 4 of the 32 patients in the SOC group were evaluated for FMT. We suspect that the majority of SOC patients were not offered FMT due to lack of knowledge about FMT as an option for severe or fulminant CDI as it is not part of current treatment guidelines. Given our findings, we believe that there should be increased awareness across specialties regarding the utility of FMT in severe and fulminant CDI. In fact, some groups have reported decrease in CDI-related colectomy rates when initiating an inpatient FMT program.²¹

The small number of patients included may have affected secondary outcomes including colectomy and readmission rates. For the sub-analysis of fulminant cases alone, we were likely underpowered to show statistical significance. Prior studies have shown that hospitalized patients with severe and fulminant CDI have a significant rate of recurrence, which likely accounts for the high rate of recurrent CDI in both cohorts.¹⁴ While colectomy is part of standard of care guidelines for fulminant CDI, very few patients in our cohort underwent colectomy. It is possible that the inclusion of severe patients reduced the absolute number of colectomies as typically these patients do not proceed to surgical intervention. In our fulminant cohort, 15.1% went to surgery with no difference between FMT and SOC. While there was no difference in mortality rates at 30 and 90 days post hospitalization, we were unable to derive any statistically significant conclusions based on small number of patients with follow up information. Further studies on long-term outcomes in this cohort are warranted.

Many studies have reported improved mortality for patients with fulminant CDI who underwent early operative intervention.^22–25 While the average time to FMT in our study was 9 days, it is possible that earlier time to FMT could have improved survival rates. In one retrospective study, early FMT (defined as 2–4 days after initiating antibiotics) was associated with improved mortality in severe CDI.¹⁸

In conclusion, FMT was associated with a 77% decrease in mortality compared to SOC in hospitalized patients with severe or fulminant CDI requiring critical care. As evidence for FMT in this high risk cohort is still emerging, selection criteria for who receives FMT has yet to be definitively determined. Our study contributes to the growing body of literature that argues for the use of FMT in severe and fulminant patients either in place of or in conjunction with surgical intervention.^11,18,19 Most importantly, we firmly believe that early intervention in this high risk cohort is key. Further prospective studies are needed to confirm our findings, assess the overall safety of FMT, and ensure that results are applicable to larger cohorts of patients with severe and fulminant CDI.