Clostridioides difficile infection (CDI)

Overview

Clostridioides difficile (CDI) intestinal infections are among the most common nosocomial infections in high-income countries (8). Refractory Clostridioides difficile infection (CDI) = Ongoing CDI-related symptoms despite appropriate extended anti-microbial therapy (47). Clostridioides difficile infection (CDI) rates have increased significantly over the years. The Covid-19 pandemic has contributed to higher CDI rates (6). C. difficile infection (CDI) is made more complex by a high level of strain diversity and the emergence of epidemic strains, including ribotype 027-strains which induce more severe disease in patients (25, 38, 39, 40).

How does Clostridioides difficile cause and sustain serious infections?

Clostridioides difficile can cause severe infections, particularly in healthcare settings. Its success depends on bacterial evolution, toxin regulation, gut adaptation, environmental pressures, and host health (50)

How does genome diversity shape C. difficile pathogenicity?

Genome studies reveal numerous distinct C. difficile lineages. Genetic diversity can influence how dangerous individual strains become (50).

Which evolutionary forces drive the emergence of successful strains?

Mobile genetic elements contribute to genetic diversification.
Antibiotic exposure and host-associated pressures select for adaptive changes.These forces can support the spread of epidemic lineages (50).

How can genetic changes alter toxin production and disease severity?

Evolution may modify toxin genes themselves. It can also change how strongly toxin genes are expressed, potentially affecting virulence (50).

Why are nutrient utilization and spore formation important for persistence?

Adaptive genomic changes can improve nutrient use in the gut. Enhanced spore formation may increase environmental survival and persistence (50).

Clostridioides difficile infection (CDI) as significant public health threat

C difficile infection (CDI) is the leading cause of infectious diarrhea in hospitalized patients (1, 26, 27, 34, 35) and of healthcare-associated infectious enteric inflammations worldwide (8, 26, 27). In the U.S., CDI is a public health concern, labeled an urgent threat by the Centers for Disease Control and Prevention (CDC) in 2019 (3). Healthcare costs due to CDI exceed $1.5 billion each year (4, 5).

Global incidence of CDI: 49.36 per 100,000 population/year (2). Rates are increasing in both hospitals and communities, particularly in the population with inflammatory bowel disease (37).

The Centers for Disease Control and Prevention (CDC) estimates (5, 7, 9, 10, 11):
* Clostridioides difficile infection (CDI) causes 250,000 hospitalizations annually in the U.S.A.
* Annual mortality rate: 12,800
* Recurrence rate: 15–30% of patients after a primary infection, 60% after three or more episodes.
* 1 in 11 patients over 65 years die within 1 month of health care–associated CDI diagnosis annually

In 2017, nearly half a million Americans were diagnosed with CDI. Almost half of these cases required hospitalization; over a quarter resulted in death during admission. From 2011 to 2017, national CDI burden and hospitalizations decreased, but community-acquired CDIs, first recurrences, and in-hospital deaths remained high (4). It causes approximately 453,000 new cases of C. difficile infection each year and is responsible for 29,300 deaths (28, 29, 43, 44).

In Europe, approximately 198,526 cases are reported annually in acute care hospitals, with the actual number likely being significantly higher (12).

Clostridioides (Clostridium) difficile produces spores that are resistant to disinfection. This complicates treatment and increases the risks of environmental exposure (41, 42).

Influence of antibiotic use

Antibiotic resistance is a factor in the rising CDI rates. Antimicrobial use creates selective pressures that affect CDI rates (6). Antibiotic use causes low microbial diversity, or dysbiosis, which weakens colonization resistance, a key function of a healthy microbiome (30, 31, 36). Clostridium difficile infection (CDI) is the prime example of a human disease that develops as a result of critical changes to the gut microbiota (33). While antibiotics eliminate toxin-producing C. difficile bacteria, they do not affect dormant spores, which can germinate if dysbiosis continues (30).

Microbiota

At C. difficile infection higher relative abundances of Enterobacteriaceae, Lactobacillaceae, and Veillonellaceae, compared with healthy individuals (45, 46).

What are the symptoms of Clostridioides difficile infection (CDI)?

Clostridioides difficile infection (CDI) causes severe symptoms including diarrhea (the main symptom), fluid loss, inflammation, more severe abdominal pain, leukocytosis, or in severe cases, pseudomembranous colitis or toxic megacolon (34). Symptoms include up to 20 watery bowel movements per day (diarrhea). Therefore, CDI significantly impacts health-related quality of life (HRQOL) (13, 14, 15, 16, 17, 26, 27). A UK study found a 46% reduction in HRQOL in hospitalized Clostridioides difficile infection (CDI) patients compared to population norms (32, 33). Also, the disease affects mental, physical, and relational aspects of patients' lives. It leads to anxiety and depression.

Who is responsible for the severe diarrhea and pseudomembranous colitis?

The Clostridioides (Clostridium) difficile toxin A (TcdA) and Clostridioides (Clostridium) difficile toxin B (TcdB) from C. difficile are primarily responsible for the severe diarrhea and pseudomembranous colitis (49)

Virulence

Enterococci enhance the fitness and pathogenesis of Clostridioides difficile in the gut. They alter the amino acid composition and provide signals that increase the virulence of Clostridioides difficile towards the host (20).

Collagen and other components of the extracellular matrix are degraded by matrix metalloproteinases. This degradation is a significant source of peptides and amino acids. These peptides and amino acids support the growth of C. difficile in vivo (22).

How is the lethality of a Clostridioides difficile infection (CDI) to be assessed?

The lethality of Clostridioides difficile infection (CDI) in older patients with clinically relevant comorbidities is high, and it is one of the important causes of death in the hospital for patients > 80 years (49).

Mechanism

Disease is mediated by two large Clostridioides (Clostridium) difficile toxins and the expression of their genes is induced upon nutrient depletion (22). Due to the production of these toxins Clostridioides difficile infection of the colon leads to severe inflammation and damage to the gastrointestinal epithelium (23). Both of which disrupt the Rho family of GTPases in host cells, causing cell rounding and death and leading to fluid loss and diarrhea. However, these toxins, despite their functional and structural similarity, do not contribute to disease equally (25).

The epithelial cells are primarily damaged by the C. difficile toxins. The direct reaction of the host takes place via the activation of

• Group 1 ILCs (ILC1) or Natural killer cells (NK cells) via IL-12p70, Interleukin-18 (IL-18), Interleukin-1 (IL-1) beta (IL-1F2), which in turn stimulate B cells / B Lymphocytes to secrete Immunoglobulin G (IgG) via cytokines, and of


• Group 2 ILCs (ILC2) via Interleukin-33 (IL-33), which in turn activate phagocytic eosinophils (24).

This inflammatory tissue damage causes the liberation of high concentrations of host heme at infection sites. We identify the C. difficile heme-sensing membrane protein system (HsmRA) repurposing heme to counteract antimicrobial oxidative stress responses. HsmR recognizes high concentrations of vertebrate heme at the host-pathogen interface, resulting in increased expression of the hsmRA operon and subsequent deployment of the membrane protein HsmA to scavenge heme and reduce redox damage protecting against oxidative stress (23).

Why are Clostridioides difficile infection (CDI) and their recurrence increasing so dramatically?

Clostridioides difficile has a high adaptability to exploit nutrients that become available during community disruption, including host and microbiota-derived metabolites and substrates.
This metabolic plasticity accounts for the high and growing burden of C. difficile infections (CDI), including recurrent diseases (48)

New therapeutics urgently needed

CDI is a global clinical issue. There is a rise in the incidence of primary infections. Hypertoxigenic ribotypes are occurring more frequently. Drug-resistant, recurrent, and non-hospital CDI cases are increasing. There is an urgent need to discover new therapeutic targets (21)

References

(1) Khanna & Pardi 2012 Mayo Clin Proc 87(11): 1106-1117
(2) Balsells et al. 2019 J Glob Health 9(1): 010407
(3) Centers for Disease Control and Prevention. Antibiotic Resistance Threats in the United States, 2019. Atlanta, GA: US Department of Health and Human Services, CDC; 2019.
(4) Guh et al. 2020 N Engl J Med 382(14): 1320-1330
(5) Centers for Disease Control and Prevention. What is C. diff? https://www.cdc. gov/cdiff/what-is.html. Updated September 7, 2022. Accessed April 12, 2023.
(6) Chilton et al. 2026 Nat Rev Microbiol 24: 215-232
(7) Tran et al. 2025 Expert Opinion on Investigational Drugs 34(11): 869–885
(8) Li & Saavedra 2025 mBio 16: e03562-24
(9) Berry & Khanna 2023 BioDrugs 37(6): 757-773
(10) Chopra 2023 Expert Review of Anti-Infective Therapy 21(3): 243-253
(11) Garey et al. 2023 JAMA Netw Open 6: e2253570
(12) Viprey et al. 2022 Euro Surveill 27: 2100704
(13) Pakyz et al. 2016 Am J Infect Control 44(5): 554-559
(14) Heinrich et al. 2018a Dig Dis Sci 63(11): 2864-2873
(15) Barbut et al. 2019 Health Qual Life Outcomes 17(1): 6
(16) Bear et al. 2021 Microorganisms 9(4): 723
(17) Hengel et al. 2022 J Patient Rep Outcomes 6(1): 49
(18) Lurienne et al. 2020 J Patient Rep Outcomes 4(1): 14
(19) Vent-Schmidt et al. 2020 Patient Prefer Adherence 14: 33-43
(20) Smith et al. 2022b Nature 611: 780
(21) Monaghan et al. 2021 Expert Opinion on Therapeutic Targets 25(11): 949-963
(22) Fletcher et al. 2021
(23) Knippel et al. 2020 Cell Host & Microbe 28: 411-421
(24) Beck et al. 2020
(25) Mileto et al. 2019 Microbiol Spectrum 7(3): GPP3- 0015-2018
(26) Allegretti et al. 2018 Gastrointest Endosc 87: 18–29
(27) Belizário & Faintuch 2018 In: Silvestre, R., Torrado, E. (eds) Metabolic Interaction in Infection. Experientia Supplementum 109 Springer, Cham. https://doi.org/10.1007/978-3-319-74932-7_13
(28) Lessa et al. 2015 N Engl J Med 372: 825-34
(29) Magill et al. 2018 N Engl J Med 379: 1732-1744
(30) Chang et al. 2008 J Infect Dis 197: 435-8
(31) Seekatz et al. 2015 Infect Immun 83: 3838-46
(32) Herdman et al. 2011 Qual Life Res 20(10): 1727-1736
(33) Britton & Young 2014
(34) Rupnik et al. 2009 Nat Rev Microbiol 7: 526-536
(35) Takahashi et al. 2014 BMJ Open 4: e005665
(36) Buffie et al. 2019 Nature 517: 205–208
(37) Rodemann et al. 2007 Clin Gastroenterol Hepatol. 5(3): 339-344
(38) Pépin et al. 2005 Clin Infect Dis 41: 1254-1260
(39) Chandler et al. 2007 Infect Control Hosp Epidemiol 28: 116-122
(40) Kuijper et al. 2008 Euro Surveill 13(31)
(41) Clabots et al. 1992 J Infect Dis 166: 561-567
(42) Hensgens et al. 2012 Clin Microbiol Infect 18: 635-645
(43) Feuerstadt et al. 2014 Am. J. Gastroenterol. 109: 1265
(44) Lofgren et al. 2014 Epidemiology 25: 570
(45) Weingarden et al. 2013 J Clin Gastroenterol 47: 735–37
(46) Weingarden et al. 2014 Am J Physiol Gastrointest Liver Physiol 306: G310–19
(47) Mullish et al. 2021
(48) Engevik et al. 2026 Cell & Host Microbe 34(7): 1220-1240
(49) AMB 2026, 60, 55
(50) Khanna et al. 2026 Cell Reports 45

see also:
Antibiotics & Clostridioides difficile infection (CDI)
Brain-Gut-Microbiome-Axis / Gut-Brain Axis & Stress
Clostridioides (Clostridium) difficile
Clostridioides (Clostridium) Clade 3
Clostridioides (Clostridium) Clade 4
Clostridioides (Clostridium) difficile Clade 5
Clostridioides (Clostridium) difficile Hypervirulent Clade 2
Clostridioides difficile infection (CDI) & Dysbiosis
Clostridioides difficile infection (CDI) & Gut microbiota
Clostridioides difficile infection (CDI) & Lactobacillaceae
Clostridioides difficile infection (CDI) & Pathogenicity / Pathology
Clostridioides difficile infection (CDI) & Risk factors
Clostridioides difficile infection (CDI) (initial)
Clostridioides difficile infection (CDI) (recurrent)
Fecal Microbiota Transplantation (FMT) & Clostridioides difficile infection (CDI) (recurrent)