Introduction
Over the past few years, there has been a growing interest in changes in gut bacteria in different disorders. Faecal microbiota transplant (FMT), also known as faecal microbiota transplantation or stool transplant, is a medical procedure that involves transferring faecal material from a healthy donor into the gastrointestinal tract of a recipient. The transplant can be delivered into the upper gastrointestinal (GI) tract (via esophagogastroduodenoscopy (EGD), or a nasogastric, nasojejunal or nasoduodenal tube), the lower GI tract (via colonoscopy) or in the form of an oral capsule [1–3]. The efficacy of either fresh or frozen FMT has been described as similar [4]. FMT has been applied as an effective tool for re-establishing the structure of gut microbiota and has been shown to be a highly effective treatment, even more so than antibiotics, for recurrent or resistant Clostridioides difficile infection (CDI), a nosocomial infection which has been more frequent over the last few years [5]. C. difficile colonisation occurs in 4–15% of healthy adults, up to 21% of hospitalized adults, and 15–30% of residents in long-term care facilities [6, 7]. Amongst the most well-described risk factors for developing an active infection are contact within a healthcare environment, advanced age (65 years or older), and antibiotic use. Recurrent CDI (rCDI) is defined as the recurrence of diarrhoea and a confirmatory positive test within 8 weeks of treatment for an initial episode of CDI. Approximately 20% of patients may experience recurrence, and rates of further recurrence may increase after each incident [8]. Although patients in hospitals and long-term care facilities remain at highest risk, the rise of community-associated infections, which now account for 35–48% of CDI diagnoses, is a great medical problem [9, 10]. Risk factors of community-acquired infections, apart from antibiotic treatment, include cardiac disease, chronic kidney disease and inflammatory bowel disease (IBD).
Aim
The aim of this study was to evaluate the efficacy and safety of FMT in recurrent C. difficile infection in the studied population.
Material and methods
Study population
This was a retrospective analysis of electronic medical records of FMT due to recurrent CDI. All 74 patients tested positive for C. difficile toxin and/or had a positive culture. In all patients, FMT was performed through a nasoenteric tube placed during gastroscopy. Frozen donor faeces were used for FMT from unrelated healthy donors. FMT material was received from healthy donors, with exclusion criteria of HBV, HCV, HIV infection, and autoimmunological or bacterial infection. To avoid the effect of a single donor, FMT from 2–3 unrelated donors was used. Three days earlier, FMT vancomycin had been applied, and a preparation with macrogol was administered, according to European guidelines [11]. A good response to a single FMT was considered as an improvement. Needing more than 1 FMT was considered a suboptimal response.
The clinical history charts of the subjects were analysed for comorbidities, including cardiovascular risk factors – hypertension (HT), hyperlipidaemia (HLA) – as well as bowel pathology such as IBD, cancer history and hypothyroidism. Additionally, concomitant medication such as antibiotics, steroids, immunosuppressives and proton pump inhibitors (PPI) used 30 days prior to CDI was analysed. In the case of CDI, previous use of vancomycin, metronidazole or fidaxomicin was analysed.
Statistical analysis
Descriptive statistics are presented as counts and percentages (for categorical variables) and mean and standard deviation, as well as median, minimum and maximum values (for numerical variables). Analysis of factors influencing treatment failure (the need for repeat FMT) was performed using univariate logistic regression; results are presented as odds ratios (OR) along with 95% confidence intervals, and p-values for significance tests. Calculations were performed using R statistical software v4.3.1 (R Core Team (2023). R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria (https://www.R-project.org/).
Results
Data from the 98 patients who had received FMT in the studied department between 2015 and 2022 were analysed. 110 FMTs were performed for 74 patients with recurrent CDI. 41 (55.4%) were women. Most were aged > 55 years (77%) and the remaining 23% (17) were aged 19–55 years. The youngest was 19 years old and the eldest 97 (Table I).
Table I
Patient characteristics (n = 74)
| Patient characteristic | Result | |
|---|---|---|
| Sex | ||
| Female | 41 (55.5%) | |
| Male | 33 (44.5%) | |
| Age | ||
| Mean | 68 | |
| Median | 72 | |
| Range | 19–97 | |
Clinical improvement after the first FMT procedure was observed in 44. Twenty-three of 30 initially non-responding patients had a clinical resolution after a second FMT, leading to an increased overall cure rate of 90.1%. Three of the remaining 5 patients needed 3 FMTs and 1 needed 5 FMTs. 58.1% (43) of patients had cardiovascular risk factors, 13.5% (10) DM, 12.2% (9) IBD history and 5.4% (4) patients had thyroid alterations.
In terms of the previous use of medications, 41 (55.4%) had previously, before CDI infection, used an antibiotic, 4 (5.4%) PPI and 2 (2.7%) steroids. 88% (65) had used vancomycin, 22.9% (17) metronidazole and 5.4% (4) fidaxomicin. 55.4% of patients had previous history of use of antibiotics, 2.7% of steroids and 5.4% of PPI (Tables II, III).
Table II
Patient characteristics: previous use of medications (n = 74)
| Previous use of medication | Result |
|---|---|
| Medications used | |
| Antibiotics | 41(55.4%) |
| Steroids | 2 (2.7%) |
| Proton pump inhibitors | 4 (5.4%) |
Table III
Patient characteristics: antibiotics used for treatment of CDI before FMT (n = 74)
| Antibiotics used for treatment of CDI before FMT | Result |
|---|---|
| Vancomycin | 65 (87.8%) |
| Metronidazole | 17 (23%) |
| Fidaxomicin | 4 (5.4%) |
According to analysed factors only heart disease and/or any of the cardiovascular factors such as hypertension or hyperlipidaemia were associated with an unsatisfactory response (the need to undergo more than 1 FMT) (Tables IV, V).
Table IV
Factors influencing unsatisfactory effect of therapy (need for > 1 FMT). Univariate analysis
Table V
Odds of unsatisfactory effect of therapy (needing >1 FMT) associated with the use of antibiotics before FMT.
| Antibiotics used for treatment of CDI before FMT and its relationship with repeated FMT | N | OR | 95% CI | P-value |
|---|---|---|---|---|
| Vancomycin | 98 | 1.02 | 0.43, 2.49 | 0.957 |
| Metronidazole | 98 | 3.02 | 1.05, 9.19 | 0.043 |
| Rifaximin | 98 | 0.22 | 0.01, 1.34 | 0.171 |
Among the patients who had received FMT because of CDI, those who had received metronidazole had a greater chance of needing more than 1 FMT (p = 0.043).
According to the evidenced side effects after FMT, only 1 patient reported abdominal pain after FMT, and this was insignificant. There was no death attributed to FMT in the studied population.
Discussion
To our knowledge, this is the first retrospective study of a Polish population detailing the efficiency of FMT in recurrent Clostridioides difficile infection. While FMT is the most efficacious treatment for recurrent rCDI, in 10–20% of cases a single FMT fails to provide a cure, with the reasons for this still unknown. According to our data, 59.4% of patients had resolution of CDI-associated diarrhoea after one FMT, which is similar to the study by Yoon et al. [12]. There is evidence that FMT for rCDI is efficient, and although a single FMT resulted in a cure in 66%–91% of patients in case reports [13, 14], for many patients with severe and fulminant presentation, multiple FMTs in short succession provided a lasting cure. According to randomised trials, donor FMTs were more efficient then autologous [15], with a high symptom resolution of 75–94% [16, 17]. Multiple FMT was more effective than a single faecal transplant [18].
It is known that several factors (modifiable and non-modifiable) may be associated with FMT failure [19–21]. Our study highlights that cardiovascular disease, hypertension and hyperlipidaemia may be risk factors for such unsatisfactory effects. In contrast, a recent meta-analysis showed that Charlson Comorbidity Index, female gender, immunosuppressed status and number of CDI recurrences were not associated with FMT failure [22]. Fragile patients such as those with cardiac disease or hyperlipidaemia may be at higher risk of not responding to the first FMT, and therefore should be under supervision and care. Recent studies have also shown that gut microbiota changes, not only in obese or diabetic type 2 patients, but also in patients with non-alcoholic fatty liver disease (NAFLD), may be related to a worse outcome of FMT in rCDI [23–26].
Among the patients with IBD who had a concomitant rCDI, 60% responded to the first FMT, which is in concordance with data from a European multicentre cohort study of FMT provided for rCDI in patients with IBD, according to which the resolution rate after 8 weeks was 71%, and it was safe [25]. All of these patients tolerated FMT well, and an outbreak was not observed after FMT.
Among the modifiable factors, the use of an antibiotic for the first CDI episode should be mentioned. 22.7% of our patients had been previously treated with metronidazole, which according to our univariant analysis made them more vulnerable and in need of more than one FMT. According to AGA guidelines, metronidazole may be applied for patients with non-severe CDI and low risk (young with no comorbidities). It was also shown that vancomycin is overall more effective than metronidazole [27]. Neither of the antimicrobial agents, metronidazole and vancomycin, can reliably inhibit C. difficile spores [28]. For that reason, according to the first-line treatment, it is not advisable to apply metronidazole, as it may later influence responses to CDI treatment. In compliance with a recent meta-analysis by Beran et al., some significant predictors of FMT failure were advanced age, severe CDI, inflammatory bowel disease, pre-FMT use of non-CDI antibiotics, prior CDI-related hospitalizations, inpatient status, and poor quality of bowel preparation [22]. The causes of failure of the first FMT treatment are unknown, but knowing the risk factors may help develop a risk stratification model to predict FMT failure in CDI patients, and to try and avoid sepsis or colectomy in patients with high risk [29].
According to previously used medications in our group of patients, antibiotics seemed to be the most significant factor for a worse outcome of FMT, followed by steroids and PPI, although there were no patients receiving immunosuppressive treatment. Gastric suppressants were not a significant factor related to the FMT response [29]. According to this analysis, there was no relationship between a worse outcome of FMT and taking antibiotics before CDI or PPI.
No serious adverse events were noted in our study, and only one patient reported abdominal pain. Serious adverse effects directly attributable to FMT in patients with normal immune function are uncommon, but may be similar to irritable bowel (constipation, cramping, bloating) and can last up to 48 h [3]. While it is known that FMT for rCDI in IBD patients is safe and effective, IBD exacerbation after FMT is infrequent. In this group, none of the patients reported side effects. Further studies should investigate the effects of FMT on the course of IBD.
This study has some limitations. First of all, it was a single-centre study, and the data, even though comparing well with other studies, may be limited. Secondly, being a retrospective study, exact follow-up data were missing.
Conclusions
In our study, FMT was an effective and safe treatment of recurrent CDI in the studied Polish population. Use of metronidazole was identified as a risk factor of a suboptimal response to FMT in the studied cohort. At the same time, according to our results, heart disease or cardiovascular risk factors (such as hypertension or hyperlipidaemia) were associated with a suboptimal response to the first FMT in the studied cohort, which may help physicians to identify high risk groups and in further decision making.
