Danish national guideline for the treatment of Clostridioides difficile infection and use of faecal microbiota transplantation (FMT)

Figures & data

Figure 1. Classification of Clostridioides difficile infection (CDI).

Table 1. Treatment algorithm in patients with Clostridioides difficile infection (CDI).

CDI classification	Recommended treatment
All cases of CDI	Revise ongoing antibiotics and proton pump inhibitors
First CDI	Mild/moderate: First choice: Oral vancomycin 125 mg × 4 for ten days Second choice: If vancomycin is not available (non-hospitalised): Oral metronidazole 500 mg × 3 for ten days Severe and/or inpatient: First choice: Oral vancomycin 125 mg × 4 for ten days Second choice: Oral fidaxomicin 200 mg × 2 for ten days Consider faecal microbiota transplantation (FMT)
Recurrent CDI: First recurrence	Mild/moderate (not requiring hospitalisation): First choice: Oral vancomycin 125 mg × 4 for ten days FMT may be considered Severe and/or inpatient: First choice: Oral vancomycin p.o. 125 mg × 4 for ten days Second choice: Oral fidaxomicin 200 mg × 2 for ten days FMT should be offered as an extension of antibiotic treatment*
Recurrent CDI: Second recurrence and above	All degrees of disease: First choice: FMT should be offered in continuation of antibiotic treatment* If FMT cannot be completed: First choice: Oral vancomycin. A tapering regimen may. Be applied, e.g.: 125 mg × 4 daily for two weeks, 125 mg × 2 daily for one week, 125 mg × 1 daily for one week, 125 mg × 1 every two days for one week 125 mg × 1 every three days for two weeks
Fulminant CDI (regardless of number of episodes)	All: Multidisciplinary** assessment should be made with regard to treatment plan. First choice: FMT (possibly repeated at 3-day intervals) Antibiotics: Intravenous metronidazole 1,000 mg × 1 or 500 mg × 3 daily in addition to oral/rectal vancomycin Surgery considered: Colonoscopic desuffling with vancomycin flushing/FMT, loop ileostomy with vancomycin flushing/FMT – or colectomy.
Refractory CDI (regardless of number of episodes)	Revision of antibiotic treatment, both CDI-related and non-CDI-related First choice: FMT (possibly repeated at 3-day intervals) Consider multidisciplinary assessment**

*FMT is preceded by 4–10 days of oral vancomycin (/fidaxomycin) with discontinuation 1–2 days before FMT. With a longer waiting time for FMT, vancomycin/fidaxomycin is continued, possibly with tapering to the lowest possible dose that provides symptom relief. Thus, when referring to FMT, no end date is set for antibiotic treatment.

**Multidisciplinary assessment: gastroenterology, possibly infectious disease medicine, colorectal surgery, clinical microbiology.

Table 2. Evaluation of treatment effects in patients with Clostridioides difficile infection (CDI).

Definition of diarrhoea: ≥3 liquid stools per day (Bristol score 6–7), assessed over at least two days. CD test: PCR-based toxin test or faecal culture for Clostridioides difficile. CD testing is performed in clinical routine only in patients with diarrhoea and not during ongoing antibiotic treatment.
A] Clinical evaluation during treatment
Continued or worsened diarrhoea ≥3 liquid stools per day (Bristol 6–7) Failure Refractory CDI, change treatment as shown in Table 1	Clinical improvement < 3 stools per day, no or decreased pain Effect Complete treatment
B] General evaluation following treatment
<3 stools per day: no diarrhoea Effect CD test is not recommended (if a CD test has been performed and is positive, this indicates carrier status without clinical disease)
New-onset diarrhoea: ≥3 liquid stools per day (Bristol 6–7) and a positive CD test: Failure (CDI recurrence)	New-onset diarrhoea: ≥3 liquid stools per day (Bristol 6–7) and a negative CD test: Effect (Diarrhoea of other cause)

Table 3. Clinical recommendations for the treatment of patients with Clostridioides difficile infection (CDI).

Clinical recommendations for the treatment of patients with Clostridioides difficile infection (CDI)

If necessary, discontinue antibiotic therapy, in particular cephalosporins, clindamycin and fluorquinolone, which may trigger CDI (EL 1a, RG A). The first mild-to-moderate severity CDI is treated with vancomycin 125 mg orally × 4 for ten days. In mild initial cases, in the unaffected patient seen in the primary sector and where vancomycin is unavailable, metronidazole 500 mg orally × 3 for ten days is used (EL 1a, RG A). Vancomycin is dispensed free of charge from the country’s hospitals. Please see regional guidelines and guidelines from the Danish Regions. Vancomycin is superior to metronidazole in terms of efficacy, recurrence rate and mortality in CDI (EL 1a, RG A). First cases of severe CDI (or mild-to-moderate CDI in a hospital) are treated with vancomycin 125 mg orally × 4 for ten days (first choice) or fidaxomicin 200 mg orally × 2 for ten days (EL 1a, RG A). In case of CDI recurrence, vancomycin 125 mg orally x 4 for ten days (first choice) or fidaxomicin 200 mg orally × 2 for ten days (EL 3a, RG B). At the first recurrence of CDI, FMT can be offered (EL 1b, RG A). Patients with two or more recurrences of CDI should be offered FMT (EL 1a, RG A). In case of multiple CDI recurrences, where FMT is not indicated or cannot be performed, vancomycin tapering may be tried, for example 125 mg four times daily for two weeks, 125 mg twice daily for one week, 125 mg once daily for one week , 125 mg once every two days for one week, 125 mg once every three days and then discontinuation, corresponding to a total of seven weeks of treatment (EL 3b, RG B). No clinical recommendation can be given for the use of rectal bacterial installation (RBI) (EL 1b, RG A). In the case of fulminant CDI with paralytic ileus or toxic megacolon where a threatening surgical indication is considered: metronidazole 1,000 mg IV x 1 or 500 mg IV x 3 daily in addition to vancomycin (EL 3b, RG C). In case of severe or fulminant CDI, the patient should undergo multidisciplinary evaluation to consider a surgical intervention (endoscopic desuffling, endoscopic rinsing with vancomycin or FMT, colectomy, loop ileostomy with perioperative rinsing and antegrade vancomycin and possibly FMT; for toxic megacolon or colon perforation, a total/subtotal colectomy is performed) (EL 3a, RG C). FMT is currently not recommended for treatment of mild-to-moderate first CDI (EL 1b, RG B). In case of treatment refractory CDI, FMT should be considered (EL 2b, RG B). In case of severe/fulminant CDI, FMT should be considered (EL 2b, RG B). Bezlotoxumab may be considered as an adjuvant treatment for antibiotics by CDI in patients who are at a high risk of recurrence of CDI and where FMT is not desired, but its place in the treatment algorithm currently remains unknown and limited by high treatment cost (EL 1b, RG B). To prevent recurrence in selected fragile patients with recurrent CDI where other treatment attempts have been unsuccessful or the patient does not want other treatment, long-term vancomycin may be used, reduced to the lowest possible dose at which the patient remains free of diarrhoea (EL 4, RG C). Prophylactic vancomycin during other antibiotic therapy may be used in elderly patients who have had at least one previous CDI. The dose is 125 mg orally twice daily until seven days after completion of other antibiotic therapy (EL 4, RG C). During waiting time for FMT, either due to a temporary relative contraindication or other antibiotic treatment, long-term vancomycin in the lowest possible dose may be used as a bridge until FMT is available or contraindications for FMT have ceased (EL 5, RG D). Treatment effect after completion of treatment is assessed by clinical resolution of diarrhoea. Only in case of renewed diarrhoea should the treatment be supplemented with a CD test (EL 2, RG B). CD testing during treatment is not recommended (EL 4, RG C).

Table 4. Clinical recommendations for the use of faecal microbiota transplantation (FMT).

Clinical recommendations for the use of faecal microbiota transplantation (FMT).
Contraindications and precautions	In conditions other than CDI, FMT should only be offered as part of clinical trials (EL 5, RG D). There are no known absolute contraindications to FMT (EL 5, RG D).
Patient preparation before FMT	In case of disclosure of health information, written patient consent is required (legal requirements). Remediation of antibiotics and proton pump inhibitor is performed as part of FMT (EL 5, RG D). Vancomycin is given 4–10 days before FMT and discontinued 1–2 days before FMT (EL 1a, RG A). In case of intolerance to vancomycin, fidaxomicin may be used as pre-treatment (EL 5, RG D). No evidence exists for the use of FMT without pre-treatment with antibiotics (EL 5, RG D). Purification before FMT is performed according to the application form but hardly has an independent clinical effect in FMT (EL 3b, RG C).
Clinical application and follow-up	Colonoscopic administration of FMT has a higher effect than the other application forms, and rectal installation has a lower effect than the other application forms (EL 1a, RG A). In rectal installation, repeated/repetitive treatment after/within 7–14 days produces an overall effect that may be in line with the other forms of application (EL 2a, RG B). In patients with fulminant CDI, repeated/repetitive treatment after 3–5 days may increase the clinical effect (EL 2a, RG B). In FMT for rCDI, the faecal component corresponds to 50 grams of stool from one donor (EL 2a, RG B). Patients who have received FMT for CDI are observed for 30 minutes after colonoscopic FMT in a right-sided position, for 1 hour in a left-sided position after rectal infusion, and sitting for 30 minutes after upper application (EL 5, RG D). The primary endpoint of FMT for CDI is the absence of CDI defined as normal bowel movements (three or fewer bowel movements per day), or in case of diarrhoea (more than three thin (Bristol 6–7) bowel movements daily) (EL 5, RG D). Long-term follow-up of all patients who have received FMT is generally performed for at least one year (EL 5, RG D). In patients who have recurrence after previous FMT, new FMT preceded by vancomycin may be offered (EL 5, RG D). Adverse reactions and complications are recorded (EL 5, RG D).
Special situations	In patients with known chronic inflammatory bowel disease and CDI, FMT can be used for common indications, but the patient must be informed of the risk of flare-up (EL 3b, RG C). In patients with severe immune incompetence, FMT can be used, but special caution and close follow-up need to be agreed (EL 3b, RG C). Organ transplants and other patients undergoing immunosuppressive therapy may be offered FMT in line with other patients (EL 3b, RG C). Patients with liver cirrhosis may be offered FMT on the usual indication, but additional treatments may be needed (EL 3b, RG C). In patients who are colectomized and develop CDI, FMT may be considered in the same way as in patients with preserved colon (EL 4, RG D).

Table 5. Donor screening in faecal microbiota transplantation (FMT).

Pre-screening	Age 18–65 years Body Mass Index (BMI) 18–28 kg/m^2 Without/No allergy or chronic disease, without fixed medication consumption
Questionnaire	Without/No risk factors as with blood donation, according to the Tissue Act Without risk factors for MRSA and CPO Without current, chronic or previous oncological diseases Without intestinal symptoms (diarrhoea, constipation, bloody stools, abdominal pain, nausea, flatulence) Without previous bowel surgery (phased removal of appendix) Without depression or psychiatric disorder that requires medication Without hereditary incidence of bowel cancer, inflammatory bowel disease, celiac disease 0-3 months: No antibiotic treatment 0-6 months: No risk behaviour, blood transfusion, acute intestinal disease, travel history outside Northern Europe
Blood tests	Creatinine, alanine aminotransferase, haemoglobin, albumin, C-reactive protein. CMV (anti-CMV IgM/IgG), EBV (VCA-IgM, VCA-IgG and EBNA IgG), HAV IgM, HBV (HBs Ag, HBc Ab), HCV (HCV Ab), HIV (HIV1-2 Ab/Ag), Syphilis Ab and NAT test (HBV, HCV, HIV)
Stool samples	Intestinal pathogenic bacteria • Clostridioides difficile • Salmonella • Shigella • Campylobacter jejuni/coli • Yersinia enterocolitica • Diarrhoea-causing Escherichia coli: o Verotoxin-producing E. coli (VTEC), o Enteropathogenic E. coli (EPEC), o Enterotoxigen E. coli (ETEC), o Enteroinvasive E. coli (EIEC) o Intimin-producing E. coli (attaching and effacing E. coli (A/EEC)) Intestinal pathogenic viruses: • Adenovirus, astrovirus, sapovirus, enterovirus, parechovirus, norovirus, rotavirus Intestinal pathogenic parasites: • Entamoeba histolytica • Cryptosporidium parvum/hominis • Giardia lamblia • Worms Multi-resistant microorganisms: • ESBL-producing E. coli, Klebsiella pneumoniae and Proteus mirabilis • Carbapenemase-producing organisms (CPO) • Vancomycin-resistant enterococci (VRE) Others • Helicobacter pylori antigen • SARS-CoV-2 RNA

Table 6. Mininum standards for implementing a faecal microbiota transplantation (FMT) service.

Mininum standards for implementing a faecal microbiota transplantation (FMT) service

An FMT service has a defined organisation, including a description of the persons involved and the division of responsibilities between them. An FMT service complies with the principles of the Tissue Act, including principles for traceability and anonymity as well as documentation of clinical activity and safety parameters. An FMT service has ensured access to qualified medical conference and development. Faecal donation is voluntary and unpaid. Donor recruitment, donor screening and faecal donation are established and managed in public blood banks. Faeces donors provide their written consent for the registration of personally identifiable data in the database. Donor screening includes clinical information, blood tests and stool samples with an updated donor screening panel before or in connection with any commenced and completed donation round. Laboratory processing follows published protocols and guidelines and is performed by specially trained personnel. The processing of each faecal donation is documented. Archive samples from faecal donations are stored for at least two years. Critical equipment and critical processes are defined and documented. Release of FMT components presupposes that the overall donor screening has been approved, that the donor has signed consent declarations and donation delivery notes and that both declarations and notes have been processed correctly. Distribution takes place according to written cooperation agreements in which the parties' tasks and responsibilities are described. FMT is used within the framework agreed with the relevant health authorities. Traceability between donor and recipient as well as full anonymity are ensured. Documentation regarding traceability is stored for 30 years. Clinical trials are monitored by a local GCP unit. Clinical application takes place in the relevant medical specialty, which handles patient assessment, clinical application, follow-up on and management of any complications. Critical events are recorded and evaluated.