II. 3 Why does it return? Recurrent CDI

If this is not the first time you are battling C. difficile, it is not your fault. You understand why the infection returns so stubbornly, and why it is precisely the restoration of the flora that breaks this spiral.

The numbers behind which you, too, stand

Many patients believe that once they are "over it", that's the end of it. The reality is that C. difficile infection often returns. After the first episode, the infection flares up again in roughly 20–30 per cent of patients. That is already a high rate on its own – but the situation is even more telling if someone has relapsed more than once.

This is because every relapse further increases the chance of the next. In someone in whom the infection has already recurred several times, the probability of the next recurrence can exceed 60 per cent. So it is no accident that you feel it getting harder and harder: the infection falls into a self-feeding pattern, and after each round it returns ever more easily.

So if you, too, are at your umpteenth episode, that does not mean you did something wrong, or that you are "weaker". The return stems from the nature of the disease – and it is precisely this nature that the DiffBiome course targets, attacking not only the pathogen but also the underlying problem that feeds the return.

The vicious cycle – why does it spiral?

The mechanism of recurrence is logical if we think it through step by step. The typical initial treatment of C. difficile infection is an antibiotic, which does indeed push the pathogen back – the complaints ease temporarily. The catch is that this same antibiotic further thins out the protective flora, so colonisation resistance^[G] – the natural shield discussed in the previous chapter – cannot recover.

Meanwhile the tough spores^[G] of C. difficile survive in the bowel. As soon as the antibiotic course ends, and the flora is still weak and thinned out, the surviving spores germinate, the bacterium multiplies again, and the complaints return. Another antibiotic follows – which again further weakens the flora. This is the vicious cycle: after each round the protection is weaker, the return easier, and the symptoms worse.

The solution, therefore, cannot be to try to overcome the pathogen with ever-stronger antibiotics – that only deepens the problem. The spiral can be broken where it arises: at the rebuilding of the flora^[G]. If the diverse, protective gut flora is restored, colonisation resistance returns, the surviving spores cannot germinate, and the cycle is broken. This is exactly the goal of DiffBiome FMT^[G].

What can happen, and what is not your fault

Many patients live for months or years with the diarrhoea returning again and again, with the constant uncertainty of "when the next attack will come". This is exhausting, and often leaves its mark on mood, work and social life too. It needs to be said plainly: this burden is not your fault, and it is not because you "weren't careful enough".

The good news is that it is precisely in recurrent cases that the benefit of flora restoration is most striking. The more relapses you have been through, the greater the chance that using the pathogen-targeting antibiotic only makes the situation worse – and the more important it is that you do not merely suppress the symptoms but treat the root of the return. In your diary, over the coming weeks, you will be able to see for yourself how the symptom trend turns steadily in the right direction.

🍽️ Eating during these days

During these three days you understand why the infection returns so stubbornly, and why it is the restoration of the flora that breaks the recurrence spiral – and your eating now supports your bowel settling while this flora rebuilds. Since the danger of diarrhoea and dehydration still remains, the goal is a gentle, firming diet: plenty of fluids, easily digestible foods and soluble fibre. Soluble fibre forms a gel in water, which slows the passage of bowel contents and supports a firmer stool, while plenty of fluids replace the amount lost with the looser stool. Your concrete tasks: on all three days take the daily dose according to the usual routine, drink an extra glass of water after every looser stool, and do not start a further antibiotic or probiotic course on your own that would again disturb the flora that is now rebuilding.

In this early phase there is not yet a daily plant – the Plant Calendar only starts from day 15. For now stay with easily digestible, boiled or steamed foods, and avoid raw, coarse, strongly gas-forming foods; building up a varied, diverse diet comes later, as the symptoms settle.

Why does this matter?

If you understand that the return is a self-reinforcing spiral fed by the damaged flora, then you also understand why the solution is not ever-renewed attacks on the pathogen. The DiffBiome course targets the root of the cycle: by restoring the flora it gives back colonisation resistance, and so breaks the chain of relapses.

References

[005] Kelly C, Fischer M, Allegretti J, LaPlante K, Stewart D, Limketkai B, Stollman N. ACG Clinical Guidelines: Prevention, Diagnosis, and Treatment of Clostridioides difficile Infections. The American journal of gastroenterology. 2021. Link

According to the 2021 ACG guideline, FMT is part of standard care for rCDI; strongly recommended after ≥2 recurrences — American College of Gastroenterology's latest CDI guidelines: FMT strongly recommended after ≥2 CDI recurrences; capsule and colonoscopic administration are equivalent; detailed donor screening and storage protocol; COVID-era updates regarding FMT safety also incorporated.

[007] Chilton C, Pickering D, Freeman J. Microbiologic factors affecting Clostridium. difficile recurrence. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2018. Link

Microbiological causes of C. difficile recurrence — spore persistence and dysbiosis — Low bacterial diversity correlates with clinical rCDI. Spore persistence + germination is the key to recurrence. FMT and microbiota therapies are increasingly investigated. Targeted antibiotics (fidaxomicin) + microbiota restoration form the combined approach.

[016] Cammarota G, Ianiro G, Tilg H et al. European consensus conference on faecal microbiota transplantation in clinical practice. Gut. 2017. Link

European consensus conference developing evidence-based recommendations on FMT for clinical practice, with 28 experts from 10 countries collaborating in working groups. Statements were generated through evidence-based review, evaluated electronically via a Delphi process, and finalized in a plenary consensus session. Recommendations cover FMT indications, donor selection, faecal material preparation, clinical management, faecal delivery, and minimum requirements for establishing an FMT centre. Provides the European standardization framework for safe and governed FMT delivery.

[017] van Prehn J, Reigadas E, Vogelzang EH, Bouza E, Kuijper EJ et al. European Society of Clinical Microbiology and Infectious Diseases: 2021 update on the treatment guidance document for Clostridioides difficile infection in adults. Clinical Microbiology and Infection. 2021. Link

ESCMID 2021 treatment guidance for C. difficile infection in adults. Metronidazole is no longer recommended where fidaxomicin or vancomycin is available; fidaxomicin is the preferred agent for an initial episode and for the first recurrence; for a second or further recurrence, faecal microbiota transplantation (FMT) or bezlotoxumab in addition to standard-of-care antibiotics is preferred. Compared with the previous edition, emphasis shifts from disease severity to risk of recurrence: treatment strategy is determined by the individual patient's recurrence risk. This supports triage that measures prognostic risk alongside current symptoms.

[023] McDonald LC, Gerding DN, Johnson S, Bakken JS, Carroll KC et al. Clinical Practice Guidelines for Clostridium. difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clinical Infectious Diseases. 2018. Link

Comprehensive IDSA/SHEA clinical practice guideline on the diagnosis, treatment and prevention of C. difficile infection in adults and children. It defines severity categories (non-severe, severe, fulminant) and characterises fulminant disease by hypotension or shock, ileus or toxic megacolon — findings that require inpatient care, intravenous therapy and surgical consultation. For multiply recurrent infection in which antibiotic therapy has repeatedly failed, faecal microbiota transplantation is recommended. This document provides the international frame to which the book's red flags and hospital-referral signs are aligned.

[024] Hoffmann DE, Javitt GH, Kelly CR, Keller JJ, Baunwall SMD, Hvas CL. Fecal microbiota transplantation: a tale of two regulatory pathways. Gut Microbes. 2025. Link

A joint analysis by lawyers and clinicians of how faecal microbiota transplantation came to sit on two divergent regulatory pathways. In the United States it is handled as a drug (investigational new drug, or licensed product); in Europe it falls under the framework for substances of human origin (SoHO). The authors work through what this means for donor screening, traceability, access and liability. What both pathways share: FMT is not a freely available preparation but a procedure tied to medical supervision and a controlled institutional setting — whichever legal route a given country follows.

[025] Rodriguez J, Cordaillat-Simmons M, Pot B, Druart C. The regulatory framework for microbiome-based therapies: insights into European regulatory developments. npj Biofilms and Microbiomes. 2025. Link

Review of the European regulatory framework for microbiome-based therapies. The paper separates live biotherapeutic products (LBPs), which can be authorised as medicines, from donor-derived substances, which fall under the EU framework for substances of human origin (SoHO) — faecal microbiota transplantation among them. It stresses that donor screening, traceability and clinical oversight are minimum requirements, and that member-state practice can differ within the common frame. This is the international background to which the book's phrasing „tied to medical supervision and an institutional setting" is aligned.

[028] Johnson S, Lavergne V, Skinner AM, Gonzales-Luna AJ, Garey KW, Kelly CP, Wilcox MH. Clinical Practice Guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 Focused Update Guidelines on Management of Clostridioides difficile Infection in Adults. Clinical Infectious Diseases. 2021. Link

A focused update of the 2017 IDSA/SHEA guideline, limited to treatment recommendations. The principal change is that fidaxomicin is now preferred over vancomycin for an initial episode — a conditional recommendation with moderate certainty — because although initial cure is similar, sustained cure is better. For recurrent episodes fidaxomicin is likewise preferred, as is a tapered and pulsed vancomycin regimen. Bezlotoxumab is offered as an adjunct for patients at high risk of recurrence. The guideline states explicitly that vancomycin remains an acceptable choice where fidaxomicin is unavailable, and metronidazole has receded even for mild disease. For the SIS the guideline matters because it confirms that the treatment decision depends not only on current severity but on the risk of recurrence — the duality that underlies the acute and prognostic subscores of the SIS.

[029] van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, Visser CE, Kuijper EJ, Bartelsman JF, Tijssen JG, Speelman P, Dijkgraaf MG, Keller JJ. Duodenal infusion of donor feces for recurrent Clostridium. difficile. The New England Journal of Medicine. 2013. Link

The first randomised controlled trial comparing faecal microbiota transplantation with standard antibiotic therapy in recurrent *Clostridioides difficile* infection. Patients were assigned to three arms: donor faeces given through a duodenal tube after a short course of vancomycin, vancomycin alone, or vancomycin with bowel lavage. The trial was stopped early because the difference was so large: in the transplantation arm 81 percent of patients were cured after the first infusion and 94 percent including repeat infusions, against 31 and 23 percent in the two vancomycin arms. After treatment the diversity of the patients' faecal flora came to resemble that of the donors. This paper turned microbiota transplantation into an evidence-based treatment and is the starting point for the dosing regimen of the present protocol.

[777] Mullish BH, Merrick B, Quraishi MN et al. The use of faecal microbiota transplant as treatment for recurrent or refractory Clostridioides difficile infection and other potential indications: second edition of joint British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS) guidelines. Gut. 2024. Link

The 2024 second edition of the joint British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS) guidelines on faecal microbiota transplant (FMT) for recurrent or refractory Clostridioides difficile infection and other potential indications. It updates the 2018 first edition with evidence from national FMT registries. It also sets out the UK regulatory framework: the MHRA treats FMT as a medicinal product for human use, centres processing and distributing FMT must obtain MHRA licences, and a pharmacy exemption may apply when FMT is supplied on a named-patient basis within a single organisation. Detailed recommendations cover donor screening, product manufacture, delivery routes and patient follow-up.