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Clostridioides difficile

Clostridioides difficile (formerly known as Clostridium difficile) is a Gram-positive, anaerobic, spore-forming bacterium that causes Clostridioides difficile infection (CDI), a potentially life-threatening condition characterized by diarrhea and colitis resulting from the release of toxins that damage the intestinal mucosa.^[1] The infection typically arises when antibiotics disrupt the normal gut microbiota, allowing C. difficile spores to germinate, colonize the colon, and produce toxins A (TcdA) and B (TcdB), which inactivate Rho GTPases, leading to cytoskeletal disruption, increased intestinal permeability, and inflammation.^[1]^[2] CDI is a leading cause of healthcare-associated infections worldwide, with an estimated 500,000 cases annually in the United States (as of 2015), contributing to approximately 29,000 deaths each year (as of 2015).^[3]^[4] The incidence rose significantly in the early 2000s, from about 139,000 hospitalized cases in 2000 to over 336,000 in 2009, although it has since declined, driven by the emergence of hypervirulent strains such as BI/NAP1/027 and increasing community-acquired infections, which account for up to 41% of cases in some studies.^[2]^[5] Globally, the burden is substantial, with higher rates in regions like North America and Europe, exacerbated by factors such as the COVID-19 pandemic due to heightened antibiotic use.^[1] Symptoms of CDI range from mild to severe, including watery diarrhea (often more than three times daily), abdominal cramps, fever, and loss of appetite, progressing in fulminant cases to pseudomembranous colitis, toxic megacolon, or perforation.^[3] Transmission occurs primarily through the fecal-oral route, with resilient spores contaminating surfaces in healthcare settings and surviving standard disinfectants, making hand hygiene with soap and water essential over alcohol-based sanitizers.^[3] Risk factors prominently include recent antibiotic exposure (increasing risk up to 10-fold), advanced age (≥65 years), prolonged hospitalization, and immunocompromised states.^[3]^[2] Diagnosis relies on detecting toxins or toxin genes via nucleic acid amplification tests (NAATs) or enzyme immunoassays for glutamate dehydrogenase (GDH), while treatment involves discontinuing inciting antibiotics and administering targeted therapies like oral vancomycin or fidaxomicin, with fecal microbiota transplantation for recurrent episodes.^[1] Prevention strategies emphasize antimicrobial stewardship, contact precautions, thorough environmental cleaning with sporicidal agents, and vigilant infection control in healthcare facilities.^[1]

Taxonomy and nomenclature

Taxonomy

Clostridioides difficile is a Gram-positive, strictly anaerobic, spore-forming bacillus classified within the family Peptostreptococcaceae of the order Clostridiales in the phylum Bacillota.^[6] This placement reflects its rod-shaped morphology and ability to produce endospores, characteristics typical of many clostridia, though its phylogenetic position distinguishes it from the core Clostridium group.^[7] The species was first described in 1935 by Hall and O'Toole as Clostridium difficile, isolated from the stool of a healthy newborn infant and named for the challenges in its cultivation. In 2016, it was reclassified into the newly proposed genus Clostridioides based on molecular evidence demonstrating its divergence from the restricted genus Clostridium, which is now limited to Clostridium butyricum and closely related species sharing high 16S rRNA gene sequence similarities (>97%) and robust phenotypic coherence.^[6] This taxonomic revision was justified by phylogenetic analyses showing that C. difficile clusters separately, with average nucleotide identity values below 60% and in silico DNA-DNA hybridization estimates under 25% relative to the Clostridium type species, C. butyricum.^[8] The genus Clostridioides comprises two species: Clostridioides difficile and Clostridioides mangenotii. Evolutionary relationships of C. difficile have been elucidated through 16S rRNA gene sequencing and whole-genome comparisons, revealing its closest relative as Clostridioides mangenotii with 94.7% 16S rRNA similarity.^[6] Other relatives include Paeniclostridium sordellii and Hungatella hathewayi, all co-occurring in the Peptostreptococcaceae family and sharing ecological niches in the mammalian gut, though C. difficile's lineage shows distinct adaptations for sporulation and toxin production.^[9] No significant taxonomic revisions have occurred since 2016, with the genus Clostridioides firmly established in subsequent phylogenetic frameworks.

Etymology and pronunciation

The genus name Clostridioides is derived from the Greek klōstēr (κλωστήρ), meaning "spindle," combined with the suffix -oeidēs (οειδής), meaning "resembling" or "like," and referencing the established genus Clostridium; this reflects the bacterium's rod-shaped, spindle-like morphology similar to other clostridia.^[10] The species epithet difficile is the neuter form of the Latin adjective difficilis, translating to "difficult," a nod to the organism's fastidious growth requirements that complicated its initial isolation and cultivation.^[11] Clostridioides difficile was originally described in 1935 by Ivan C. Hall and Elizabeth O'Toole as Bacillus difficilis, isolated from the intestinal contents of healthy newborn infants during studies of neonatal gut flora.^[12] It was reclassified as Clostridium difficile in 1938 due to its anaerobic, spore-forming characteristics aligning with the Clostridium genus. In 2016, phylogenetic and genomic analyses prompted its transfer to the newly proposed genus Clostridioides to distinguish it from true clostridia in the family Peptostreptococcaceae, establishing the current binomial nomenclature.^[6] The standard pronunciation is /klɒˌstrɪdiˈɔɪdiːz dɪˈfɪsɪleɪ/ in British English and /kləˌstrɪdiˈɔɪdiːz dɪˈfɪsɪl/ in American English, with the genus stressed on the "oy" diphthong and the species on the second syllable of "difficile."^[10] It is commonly abbreviated and referred to as C. difficile or "C. diff" (/siː ˈdɪf/), though mispronunciations like /klɒˈstrɪdiəz/ (omitting the "oy") or French-influenced /di.fiˈsil/ for the species name occasionally occur in non-specialist contexts.^[13]

Microbiology

Genome

The genome of Clostridioides difficile consists of a single circular chromosome approximately 4.3 million base pairs (Mb) in length, with a G+C content of about 28.8%. This structure encodes roughly 3,800 to 4,000 protein-coding genes, reflecting the bacterium's adaptation as an obligate anaerobe capable of spore formation and toxin production. The chromosome lacks a second chromosome or large extrachromosomal elements in the reference strain, though smaller plasmids can occur in some isolates.^[14] A defining feature is the pathogenicity locus (PaLoc), a 19.6-kilobase (kb) region containing genes for the major virulence factors, including tcdA and tcdB, which encode the large glucosyltransferase toxins TcdA and TcdB, respectively. The PaLoc also includes accessory genes such as tcdR, encoding a sigma-70-like transcription factor that positively regulates toxin expression by binding upstream promoters; tcdC, a negative regulator that inhibits TcdR activity; and tcdE, which codes for a holin-like protein aiding toxin release.^[15] Additionally, a separate 6.2-kb cdt locus encodes the binary toxin CDT, comprising cdtA and cdtB subunits that ADP-ribosylate actin, disrupting the cytoskeleton, along with cdtR, a regulator promoting expression under specific stress conditions.^[16] These loci are absent or disrupted in non-toxigenic strains, underscoring their role in pathogenesis.^[17] The first complete genome sequence was published in 2006 for the multidrug-resistant strain 630, revealing the bacterium's mosaic architecture and paving the way for comparative genomics. By 2025, over 19,000 C. difficile genomes had been sequenced and deposited in public databases like GenBank, enabling analyses of evolutionary dynamics and strain diversity.^[18] These efforts uncovered mobile genetic elements, including up to 10% of the genome composed of prophages and transposons, as well as CRISPR-Cas systems (primarily type I-B) that provide adaptive immunity against phages and plasmids.^[19] Genetic plasticity in C. difficile is driven by high recombination rates, facilitated by integrases and resolvases associated with mobile elements, allowing rapid acquisition of antibiotic resistance and toxin variants.^[14] Prophages, such as those in the φCD27 family, integrate into the chromosome and promote horizontal gene transfer, while plasmids (e.g., pCD6.8, ~6.8 kb) carry resistance genes like ermB for macrolides. This variability contributes to the pathogen's adaptability, with recombination hotspots near toxin loci enabling diversification across clades.^[14]

Epigenome

The epigenome of Clostridioides difficile is characterized by DNA methylation patterns that serve as regulatory switches, primarily involving N6-methyladenine (6mA) modifications. A key mechanism is phase-variable methylation mediated by conserved methyltransferases, such as the solitary Type II methyltransferase CamA (locus tag CD630_2758 in strain 630), which specifically targets the CAAAAA motif. This enzyme is present in all sequenced C. difficile genomes (over 300) and across 36 analyzed human isolates, contributing to epigenomic diversity while operating independently of restriction endonucleases in most cases. Multiple restriction-modification (R-M) systems are prevalent, with an average of 3.5 Type II systems per genome, where methylation patterns influence approximately 20% of these systems by modulating accessibility and expression without altering the DNA sequence.^[20] A seminal 2019 study utilizing single-molecule real-time (SMRT) sequencing revealed that these methylation patterns enable reversible switches in gene expression, with non-methylated CAAAAA sites enriched in promoter regions, transcription factor binding sites, and transcription start sites. Inactivation of camA resulted in a approximately 50% reduction in sporulation efficiency, primarily through delayed activation of the early sporulation sigma factor σ^F, highlighting methylation's role in developmental timing. Similarly, variable methylation at orthologous CAAAAA sites overlaps with genes involved in motility, such as fliZ and fliN, suggesting epigenetic control of flagellar assembly and bacterial dissemination. Although toxin production levels remained unaffected in camA mutants, these findings underscore how methylation facilitates phenotypic heterogeneity without genetic mutations.^[20] These epigenetic mechanisms provide C. difficile with adaptive advantages, enabling rapid responses to environmental stresses such as antibiotics. In mouse models of infection, camA mutants exhibited significantly reduced colonization and persistence in the presence of clindamycin, indicating that methylation supports survival and transmission in perturbed gut microbiomes. Overall, the epigenome's plasticity, mapped via SMRT sequencing, positions it as a critical layer of regulation distinct from genomic sequence variations, briefly intersecting with toxin loci to fine-tune virulence expression.^[20]

Bacteriophage

Clostridioides difficile is primarily infected by temperate bacteriophages belonging to the families Myoviridae and Siphoviridae within the order Caudovirales.^[21] Myoviruses, such as phiCD27 and phiC2, represent the most abundant group, characterized by contractile tails that facilitate host attachment and genome injection.^[22] Siphoviruses, including phiCDHM1 and phiSM101-like phages, feature non-contractile tails and are less common but contribute to prophage diversity in environmental isolates.^[23] As of 2022, more than 35 distinct C. difficile phage genomes have been sequenced and publicly deposited, with ongoing discoveries suggesting dozens more by 2025, many of which integrate as prophages in bacterial genomes.^[24] Several of these phages encode accessory toxin genes, such as tcdE (a holin aiding toxin secretion) or components of the binary toxin (cdtA and cdtB), potentially enhancing host virulence during lysogeny.^[25]^[26] The lifecycle of C. difficile bacteriophages predominantly follows a temperate strategy, where upon infection, the phage genome integrates into the bacterial chromosome as a prophage via site-specific recombination, often at tRNA or conserved intergenic sites.^[21] This lysogenic state allows the phage to replicate passively with the host during cell division, conferring potential benefits like immunity to superinfection by similar phages.^[27] Induction to the lytic cycle occurs under stress conditions, such as exposure to antibiotics (e.g., mitomycin C or fluoroquinolones), DNA damage, or quorum-sensing signals, triggering prophage excision, virion assembly, and host lysis to release new particles.^[28] While most identified phages are temperate, engineered or naturally lytic variants have been isolated and show promise for targeted bacterial killing without lysogeny.^[27] Bacteriophages play a key role in the evolution of C. difficile by facilitating horizontal gene transfer through transduction, where phage particles package and transfer bacterial DNA fragments, including virulence-associated genes, between strains.^[29] This process contributes to genetic diversity, enabling the spread of factors like antibiotic resistance cassettes or regulatory elements that modulate toxin expression, though direct transduction of the core toxin genes tcdA and tcdB (located in the chromosomal PaLoc) is rare and more commonly achieved via conjugation.^[27]^[30] Prophage induction can also indirectly influence virulence by altering host physiology, such as upregulating toxin production (e.g., TcdB levels increase post-infection in some strains) or promoting biofilm formation, thereby enhancing survival in the gut microbiome.^[26] These interactions underscore phages' contribution to strain variation, with multiple prophages (up to 5–6 per genome) driving adaptive evolution in clinical and environmental isolates.^[31] Therapeutic exploitation of C. difficile phages focuses on lytic variants or engineered cocktails to selectively decolonize the pathogen without disrupting commensal microbiota. Preclinical studies, including hamster models of CDI, have demonstrated that phage mixtures (e.g., combining myoviruses like phiCDHM3 and siphoviruses) reduce bacterial loads by over 90% and attenuate toxin-mediated pathology when administered orally post-infection.^[32]

Strains

Clostridioides difficile strains are classified using methods such as PCR ribotyping, which identifies variations in the 16S-23S rRNA intergenic spacer region, and multilocus sequence typing (MLST), which analyzes seven housekeeping genes to assign sequence types (STs).^[33] PCR ribotyping has been the most widely adopted globally for surveillance, revealing over 300 ribotypes, while MLST groups strains into clades, with ST1 associated with ribotype 027 (RT027) and ST11 with RT078.^[34] Key toxigenic strains include RT001 and RT106, both producing toxins A and B (A+B+ profile) and belonging to MLST clade 1; RT001 is historically prevalent in Europe, while RT106 has emerged as a dominant type in recent years.^[35] RT017, common in Asia, features an A-B+ toxin profile due to a deletion in the toxin A gene and is linked to severe disease in that region.^[36] The hypervirulent RT027 (also known as BI/NAP1/027, ST1) produces elevated levels of toxins A, B, and binary toxin (CDT), often with fluoroquinolone resistance due to mutations like Thr82Ile in gyrA.^[34] RT078 (ST11) similarly produces CDT and is associated with community and animal sources. An emerging hypervirulent strain, RT955 (ST1), reported in the UK from late 2023 to 2025, shows increased severity, metronidazole resistance, and genetic similarity to RT027.^[37] Virulence varies significantly among strains; hypervirulent types like RT027 and RT955 produce higher toxin quantities, leading to more severe colitis and higher recurrence rates, compounded by antibiotic resistance profiles such as fluoroquinolone insensitivity.^[34] In contrast, non-toxigenic strains, which lack toxin genes, primarily facilitate asymptomatic colonization and may competitively inhibit toxigenic strains, reducing CDI risk in carriers.^[38] Globally, RT027 dominated infections in North America and Europe before the 2010s, driving epidemics, but its prevalence declined post-2010 due to enhanced infection control and reduced fluoroquinolone use.^[34] By 2025, shifts have occurred, with RT106 becoming prominent in Europe and parts of North America, while RT017 persists in Asia and RT955 emerges in the UK.^[35]^[37]

Pathogenesis and virulence

Role as a human pathogen

Clostridioides difficile acts as an opportunistic pathogen in humans, exploiting disruptions in the normal gut microbiota, most commonly following antibiotic therapy. It is the leading cause of healthcare-associated infectious diarrhea and accounts for approximately 20-30% of all antibiotic-associated diarrhea cases.^[39]^[40] Furthermore, it serves as the primary etiologic agent of pseudomembranous colitis, a severe inflammatory condition characterized by the formation of pseudomembranes on the colonic mucosa.^[41]^[42] The pathogen's virulence is primarily driven by two large glucosyltransferase toxins: toxin A (TcdA), an enterotoxin that triggers fluid secretion and inflammation, and toxin B (TcdB), a potent cytotoxin that disrupts the actin cytoskeleton of intestinal epithelial cells. About 20% of C. difficile strains also produce the binary toxin CDT (Clostridium difficile transferase), which ADP-ribosylates actin and may enhance the severity of infection when co-expressed with TcdA and TcdB. In addition, the bacterium's ability to form highly resistant endospores allows for prolonged environmental survival, facilitating colonization and reinfection in susceptible hosts.^[43]^[44]^[45] C. difficile was first recognized as a human pathogen in 1978, when studies linked its toxins to cases of antibiotic-associated pseudomembranous colitis previously attributed to other causes. The term "Clostridioides difficile infection" (CDI) was formalized in the 2010 clinical practice guidelines issued by the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA), reflecting updated understanding of its epidemiology and management.^[46]^[47]^[48] Although C. difficile exhibits zoonotic potential with isolation from various animal species, foods, and environmental sources, humans represent the principal reservoir for toxigenic strains responsible for clinical disease.^[49]^[50]

Antibiotic resistance

Clostridioides difficile exhibits both intrinsic and acquired resistance to multiple antibiotics, contributing to its persistence in healthcare settings and complicating treatment of associated infections. Intrinsic resistance to beta-lactams is mediated by chromosomal genes encoding beta-lactamases, such as CDD-1 and CDD-2, which hydrolyze the beta-lactam ring, rendering penicillins and cephalosporins ineffective.^[51] Similarly, intrinsic resistance to clindamycin and other macrolide-lincosamide-streptogramin B (MLS_B) antibiotics occurs through ribosomal methylation via the erm(B) gene, which modifies the 23S rRNA target site and is often carried on mobile genetic elements like Tn5398.^[52] These mechanisms allow C. difficile to survive exposure to antibiotics commonly used in clinical practice.^[52] Acquired resistance has emerged particularly to fluoroquinolones, driven by point mutations in DNA gyrase genes such as gyrA (e.g., Thr82Ile) and gyrB, which alter the drug's binding site and are prevalent in epidemic strains.^[51] Efflux pumps, including AcdP (encoded by CD2068) and Mef variants like mefH paired with msr(D), actively expel antibiotics such as macrolides, tetracyclines, and fluoroquinolones from the cell, conferring multidrug efflux capabilities.^[52] Ribosomal protection proteins encoded by ermB further enhance macrolide resistance by preventing drug binding to the ribosome.^[51] Resistance linked to the binary toxin, often co-occurring in hypervirulent isolates, involves genetic elements that promote overall multidrug tolerance, though direct mechanistic ties remain under investigation.^[52] The evolution of resistance in C. difficile is exemplified by hypervirulent strains like PCR ribotype 027 (RT027), which display multidrug resistance profiles encompassing fluoroquinolones, macrolides, and tetracyclines, facilitated by mobile genetic elements and selective pressure from broad-spectrum antibiotic use.^[53] Recent studies from 2023–2025 indicate emerging reduced susceptibility to vancomycin in some isolates, attributed to mutations in the vanG_CD operon (e.g., Ser313Phe in VanS_CD) and murG, leading to elevated minimum inhibitory concentrations (MICs) that challenge standard therapies, though many global isolates remain susceptible.^[52]^[53] These adaptations highlight the pathogen's genomic plasticity in response to antimicrobial exposure.^[53] Antibiotic resistance in C. difficile significantly impacts clinical outcomes, contributing to recurrence rates exceeding 20% following initial treatment, as resistant strains evade eradication and persist in the gut microbiota.^[53] The selective pressure exerted by broad-spectrum antibiotics, such as cephalosporins and clindamycin, not only promotes the proliferation of resistant C. difficile but also disrupts host microbiota, facilitating recurrent infections.^[52] This underscores the need for stewardship to mitigate resistance evolution.^[53]

Pathophysiology

Clostridioides difficile, a Gram-positive, spore-forming anaerobe, initiates infection through the germination of its resilient spores in the disrupted intestinal environment, primarily following antibiotic-induced microbiota dysbiosis. Antibiotics such as clindamycin or fluoroquinolones deplete protective commensal bacteria, reducing microbial diversity and creating a niche for C. difficile overgrowth by eliminating competitors that inhibit spore germination and vegetative cell proliferation.^[54] This dysbiosis elevates levels of primary bile acids like taurocholate in the small intestine, as gut microbes normally convert them to secondary bile acids (e.g., deoxycholate) that suppress C. difficile growth; taurocholate acts as a potent germinant, binding to the SpoVA protein complex in the spore's inner membrane to trigger calcium release and cortex hydrolysis, converting dormant spores to metabolically active vegetative cells.^[55] Germination is further potentiated by co-germinants such as glycine, which interact with pseudoproteases like CspC to sense environmental cues, enabling rapid colonization of the colon without tissue invasion.^[56] Once vegetatively growing, C. difficile produces two major exotoxins, toxin A (TcdA) and toxin B (TcdB), which are glucosyltransferases that inactivate Rho GTPases (RhoA, Rac1, Cdc42) by adding glucose moieties, disrupting actin cytoskeleton dynamics in colonic epithelial cells. TcdA primarily induces fluid secretion and mucosal inflammation by glucosylation of Rho proteins in enterocytes, leading to loss of tight junctions, increased permeability, and chemokine release that recruits neutrophils; TcdB, more potent in cytotoxicity, causes similar glucosylation but targets a broader range of Rho isoforms, resulting in cell rounding, apoptosis, and barrier disruption.^[57] A subset of hypervirulent strains also secretes binary toxin CDT (Clostridium difficile transferase), an ADP-ribosyltransferase that modifies G-actin, depolymerizing microtubules and impairing phagocytosis while enhancing TcdA/TcdB adhesion to host cells via cytoskeleton alterations. These toxin-mediated effects are purely extracellular and non-invasive, relying on receptor-mediated endocytosis (e.g., via frizzled family receptors for TcdB) to deliver the glucosyltransferase domain into the cytosol.^[58] Pathological progression begins with toxin-induced epithelial damage, progressing from superficial erosions to full-thickness mucosal injury and formation of pseudomembranes—adherent plaques composed of fibrin, mucus, inflammatory cells, and cellular debris that coalesce into a characteristic "volcano" appearance on the colonic surface. In mild cases, this manifests as localized colitis, but unchecked toxin activity exacerbates inflammation and edema, potentially leading to severe complications like toxic megacolon, where colonic dilation (>6 cm) and systemic toxicity arise from massive fluid shifts, bacterial translocation, and cytokine storms.^[59] The process is self-perpetuating in dysbiotic conditions, as ongoing microbiota imbalance sustains vegetative proliferation and toxin production, amplifying tissue destruction without direct bacterial invasion.^[60]

Immune response

The innate immune response to Clostridioides difficile infection begins with recognition of bacterial flagella by Toll-like receptor 5 (TLR5), which signals through the adaptor protein MyD88 to activate NF-κB and, to a lesser extent, MAPK pathways in epithelial cells, promoting an early proinflammatory state.^[61]^[62] This TLR5-MyD88 axis is crucial for restoring intestinal innate defenses disrupted by antibiotics, as demonstrated in mouse models where TLR5 stimulation ameliorates inflammation and prevents mortality from C. difficile colonization.^[63] Additionally, C. difficile toxins A and B induce IL-8 production from intestinal epithelial cells and monocytes, recruiting neutrophils to the site of infection and amplifying local inflammation.^[64] Toxins also activate the NLRP3 and pyrin inflammasomes in macrophages and epithelial cells, leading to caspase-1-mediated processing and release of IL-1β, which drives neutrophil influx and contributes to mucosal injury during acute infection.^[65]^[66] Adaptive immunity against C. difficile involves Th17 cells, which differentiate in response to infection and produce IL-17 and IL-22 to enhance barrier integrity and protect the microbiota from dysbiosis.^[62]^[67] IL-17 correlates with disease severity in humans and promotes recruitment of neutrophils and antimicrobial peptide production, while IL-22 supports epithelial repair and restricts pathogen expansion in mouse models of colitis-associated infection.^[68]^[69] Circulating IgG antibodies specific to toxins A and B neutralize toxin activity, reducing recurrence risk by preventing toxin-mediated damage; levels of toxin-specific IgG post-infection predict protection against reinfection.^[70] Regulatory T cells (Tregs) mitigate excessive inflammation by suppressing Th17 responses and IL-17 production, balancing immunity to limit tissue destruction without compromising pathogen clearance.^[67] Dysregulation of the immune response exacerbates C. difficile infection outcomes, with overactive innate and adaptive signaling—particularly excessive IL-1β and IL-17—causing collateral tissue damage, barrier disruption, and worsened colitis in animal models.^[66] In elderly hosts, age-related immunosenescence impairs adaptive responses, including reduced Th17 differentiation and toxin-specific IgG production, leading to higher susceptibility, severe disease, and recurrence rates.^[71]^[72] Recurrent cases often show persistent Treg dysfunction and diminished memory B cell responses, failing to sustain protective humoral immunity.^[73]^[74] Insights from vaccine development highlight immune correlates of protection, such as bezlotoxumab, a monoclonal antibody targeting toxin B (TcdB), which neutralizes toxin cytotoxicity, reduces systemic inflammation, and prevents recurrence by preserving thymic function and limiting extraintestinal damage in preclinical models.^[75]^[76] Recent 2024 clinical trials, including those for adjuvanted toxoid vaccines like GSK's candidate and multivalent mRNA-LNP platforms, demonstrate robust induction of toxin-neutralizing IgG and Th17-associated cytokines (IL-17/IL-22) as key correlates, with AS01-adjuvanted formulations eliciting superior systemic and mucosal responses in healthy adults.^[77]^[78]

Possible role in colon cancer

Emerging research has proposed that Clostridioides difficile may contribute to colorectal cancer (CRC) development through its toxins, which induce chronic inflammation and DNA damage in colonic tissues. Specifically, toxins TcdA and TcdB disrupt the epithelial barrier by targeting tight junction proteins such as claudins and occludins, leading to increased permeability and persistent low-grade inflammation that activates oncogenic pathways like NF-κB and STAT3. Additionally, the binary toxin CDT has been linked to genotoxicity, causing DNA damage in intestinal epithelial cell lines by disrupting microtubule assembly and promoting double-strand breaks. These hypotheses stem from observations that chronic C. difficile exposure creates a pro-tumorigenic microenvironment, though direct causation in humans remains unproven.^[79] Studies from 2018 to 2025 have provided evidence of elevated C. difficile abundance in CRC tumors and its association with accelerated tumorigenesis. Metagenomic analyses of CRC patient biopsies have detected higher levels of C. difficile DNA and toxins in tumor tissues compared to healthy controls, with one epidemiological study reporting a 2.7-fold increased CRC risk following C. difficile infection. In mouse models, chronic colonization with patient-derived toxigenic C. difficile strains in germ-free Apc^Min/+ mice significantly increased tumor burden, with tumor counts rising by up to 3-fold in the presence of toxin-producing strains. These effects were toxin-dependent, as non-toxigenic mutants failed to promote tumor growth.^[79]^[80]^[81] Mechanistically, C. difficile toxins foster oncogenesis by generating reactive oxygen species (ROS) via TcdB, which upregulates Wnt/β-catenin signaling and induces senescence in colonic stem cells, while CDT exacerbates genotoxic stress. This leads to epithelial barrier disruption, allowing microbial translocation and microbiome shifts that reduce short-chain fatty acid production while elevating secondary bile acids, both of which favor carcinogenesis. Chronic inflammation from these processes recruits IL-17-producing immune cells, further amplifying tumor progression in preclinical models. However, no direct causal link has been established in human cohorts.^[79]^[81] Controversies persist regarding whether C. difficile acts as a primary driver or merely an opportunist in dysbiotic environments predisposed to CRC. While animal and in vitro data support a promotional role, human studies largely show correlations, such as enriched C. difficile in metastatic CRC, without isolating it from confounding microbiome alterations or antibiotic exposures. The variability in toxin production across strains complicates interpretations, and longitudinal clinical trials are needed to clarify causality.^[79]

Epidemiology

Transmission

Clostridioides difficile is transmitted primarily through the fecal-oral route, with its infectious spores serving as the key vehicle for spread between hosts. These spores are shed in the feces of infected or colonized individuals and can contaminate hands, surfaces, clothing, and medical equipment, facilitating indirect transmission.^[82] Once ingested, the spores resist stomach acid and germinate in the colon, leading to infection.^[83] The durability of C. difficile spores significantly contributes to environmental persistence and transmission. Spores can survive on dry surfaces such as hospital floors, bed rails, and toilets for up to five months, remaining viable under diverse conditions including heat, desiccation, and many disinfectants. Notably, they are resistant to alcohol-based hand sanitizers, which fail to inactivate them, underscoring the importance of soap-and-water handwashing in prevention efforts.^[84] In healthcare settings, where approximately 50% of cases are healthcare-associated, transmission is amplified by contaminated healthcare worker hands (detected in up to 50% of interactions with infected patients) and shared equipment like commodes and thermometers.^[85]^[86]^[87] Community-acquired infections have risen notably, now accounting for approximately 50% of cases, often linked to prior outpatient antibiotic exposure or unrecognized environmental contact.^[88] Environmental reservoirs beyond healthcare include water, soil, sediments, and wastewater, as well as various animals such as livestock, pets, and wildlife, which may harbor toxigenic strains.^[45] Foodborne transmission remains rare but has been documented, particularly in pork and processed meats during studies in the 2010s, where viable spores were isolated from retail samples at rates up to 5%.^[89]^[90] Asymptomatic carriers play a critical role in sustaining transmission chains, with carriage rates of 5-15% among hospitalized patients serving as a major source of spore shedding into the environment.^[91] These individuals, often comprising 10-20% of admissions, can unknowingly disseminate spores via fecal contamination, contributing to both healthcare-associated and community outbreaks without developing symptoms themselves.^[92]

Host range

Clostridioides difficile primarily infects humans, where it is a leading cause of antibiotic-associated diarrhea, particularly affecting vulnerable populations such as infants and the elderly.^[60] In infants, an immature gut microbiota with limited microbial diversity allows for high rates of asymptomatic colonization, often exceeding 50% in the first months of life, though disease is rare due to low toxin production.^[60] Among the elderly, age-related decline in microbiota diversity and shifts toward pro-inflammatory taxa reduce colonization resistance, increasing susceptibility to symptomatic infection.^[60] The bacterium also colonizes a wide range of animals, establishing it as a potential zoonotic pathogen with evidence of interspecies transmission.^[93] In food-producing animals, pigs serve as major reservoirs, with prevalence rates up to 43% in piglets and adults, often carrying hypervirulent ribotype 078 (RT078), which is genetically similar to strains causing human infections and suggesting farm-to-human zoonotic spread.^[50] Horses, dogs, and cattle are also common hosts; neonatal foals and piglets exhibit high shedding (up to 100%) due to underdeveloped microbiota, while adult horses develop severe enterocolitis post-antibiotics.^[93] Companion animals like dogs and cats show variable carriage rates (0-38%), with some isolates matching human-associated ribotypes, though direct household transmission appears infrequent.^[93] Non-mammalian hosts are rare, but C. difficile has been detected in reptiles and birds, typically without causing overt disease. In reptiles such as lizards, snakes, and chelonians, isolation rates are low (around 4%), yet toxigenic strains linked to human ribotypes (e.g., RT081) indicate potential public health risks from captive or wild specimens.^[94] Among birds, prevalence is similarly low (e.g., 4% in shelter samples), confined to species like poultry and wild avians, with shared ribotypes like RT078 and RT002 between birds, animals, and humans.^[95] Insects do not serve as natural hosts or vectors; however, houseflies (Musca domestica) can mechanically transmit spores for up to 4 hours after exposure, facilitating environmental spread in settings like farms or hospitals.^[96] Across host species, colonization and disease risk are governed by gut microbiota composition, which provides competitive exclusion against C. difficile, and antibiotic exposure, which universally disrupts this barrier regardless of host.^[93] Neonates in both humans and animals are particularly susceptible due to microbiota immaturity, while antibiotics like clindamycin or fluoroquinolones precipitate overgrowth in adults of multiple species.^[93]

Incidence and prevalence

Clostridioides difficile infection (CDI) imposes a significant global burden, with an estimated global incidence of 49 cases per 100,000 person-years, equating to approximately 4 million cases annually, with an estimated 500,000 cases annually in the United States alone, contributing to approximately 30,000 deaths each year and a mortality rate ranging from 6% to 10% among infected individuals.^[97]^[88]^[98] In the European Union/European Economic Area (EU/EEA), healthcare-associated CDI affects nearly 124,000 patients yearly, resulting in about 3,700 deaths, with an incidence rate of approximately 3.7 cases per 10,000 patient-days in acute care hospitals.^[99]^[100] Epidemiological trends indicate a post-COVID-19 surge in CDI cases, driven by increased antibiotic use during the pandemic, which disrupted gut microbiota and heightened susceptibility.^[101] In the United Kingdom, CDI cases rose by 33% from the 2020/2021 period to 2023/2024, reaching 19,239 reported infections in the year ending January 2025.^[102]^[103] In the US, community-onset CDI has been increasing, accounting for over 50% of cases by 2019 and continuing to rise, reflecting a shift from predominantly healthcare-associated infections.^[88] Hospitalized elderly individuals over 65 years old face a 10-fold higher risk of CDI compared to younger adults, with this age group representing the majority of severe cases and deaths.^[98] In high-burden regions such as Poland's Silesian Voivodeship, the 2023 incidence reached 65.1 cases per 100,000 population, underscoring disparities in Eastern Europe.^[104] Emerging patterns show a growing divide between healthcare-associated and community-acquired CDI, with the latter increasingly driven by non-hospital sources and a diversification beyond traditional hypervirulent strains like ribotype 027, including non-027/078 variants causing severe disease in community settings.^[105]^[106]

Clinical aspects

Signs and symptoms

Clostridioides difficile infection (CDI) most commonly manifests as watery diarrhea, often accompanied by abdominal cramping and tenderness, typically beginning 5 to 10 days after initiation of antibiotic therapy, though onset can occur as early as the first day or up to 2 months later.^[107] The diarrhea is usually nonbloody but may contain mucus or occult blood, with patients experiencing three or more unformed stools per 24 hours.^[108] Additional symptoms can include fever, nausea, loss of appetite, and dehydration, particularly in more pronounced cases.^[109] In mild CDI, patients remain hemodynamically stable without systemic signs of infection, presenting primarily with the aforementioned diarrhea and mild abdominal discomfort, often without fever or significant tenderness on examination.^[108] Severe CDI, by contrast, involves systemic illness with marked leukocytosis (white blood cell count ≥15,000 cells/μL) or elevated serum creatinine (≥1.5 mg/dL), alongside hypoalbuminemia, intense abdominal pain, and fever.^[110]^[111] Endoscopic evaluation in severe cases may reveal pseudomembranous colitis, characterized by yellowish plaques on the colonic mucosa.^[108] Fulminant CDI represents a life-threatening progression, featuring hypotension or shock, ileus (absence of bowel sounds), or toxic megacolon (colonic dilation >6 cm), often necessitating intensive care admission and carrying a mortality rate of up to 30–40%.^[110]^[112] Rare extraintestinal manifestations, such as bacteremia, can occur, particularly in immunocompromised individuals or those with gastrointestinal breaches.^[113] Recurrent CDI affects approximately 20–30% of patients within 2 months of initial resolution, presenting with symptoms similar to the primary episode, including watery diarrhea and abdominal pain, though severity can vary.^[114] Asymptomatic carriage of toxigenic C. difficile occurs in 3–5% of the general population, without diarrhea or other symptoms, representing colonization rather than active infection.^[115]

Diagnosis

Diagnosis of Clostridioides difficile infection (CDI) begins with clinical suspicion, typically in patients presenting with new-onset diarrhea—defined as three or more unformed stools in 24 hours—particularly following recent antibiotic exposure or hospitalization, after excluding other potential causes such as laxative use or alternative infections.^[110]^[116] Testing is not recommended for asymptomatic individuals, as up to 15% of hospitalized patients may carry toxigenic C. difficile without symptoms, leading to unnecessary treatment and increased resistance risks.^[117]^[110] Laboratory confirmation relies on stool-based tests targeting the presence of toxigenic C. difficile or its toxins. Nucleic acid amplification tests (NAAT), such as PCR, detect the toxin-encoding genes tcdA and tcdB with high sensitivity (typically 95–100%) and specificity (90–100%), providing rapid results within hours; however, they cannot distinguish active infection from colonization.^[118]^[116] Enzyme immunoassays (EIA) for toxins A and B offer high specificity (around 90–100%) but lower sensitivity (70–90%), making them suitable for confirming toxin production in symptomatic patients.^[118]^[117] The cell cytotoxicity neutralization assay (CCNA), which detects toxin B's cytopathic effects on cell cultures, serves as the historical gold standard with sensitivity of 80–95% and specificity exceeding 99%, though it is labor-intensive and requires 24–48 hours.^[118]^[116] Glutamate dehydrogenase (GDH) antigen tests, with sensitivity up to 100%, are often used as initial screens due to their speed but require follow-up with toxin or NAAT confirmation owing to lower specificity (85–95%).^[118]^[117] Diagnostic algorithms typically employ a two-step approach to balance sensitivity and specificity while minimizing overdiagnosis. The Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) recommend starting with GDH or NAAT screening, followed by toxin EIA for positives; discordant results may be arbitrated by NAAT or CCNA.^[110]^[117] In severe or fulminant cases where stool testing is inconclusive or unobtainable, sigmoidoscopy or colonoscopy can visualize characteristic yellow-white pseudomembranes on the colonic mucosa, confirming pseudomembranous colitis with near-100% specificity when present, though this is not routine due to procedural risks.^[2]^[119] Key challenges in CDI diagnosis include differentiating colonization from true infection, as NAAT positivity alone can occur in 5–15% of asymptomatic carriers, potentially leading to overtreatment.^[116]^[117] Current guidelines, including the 2021 IDSA/SHEA update and 2025 institutional protocols aligned with them, emphasize prioritizing toxin-positive tests (e.g., EIA or CCNA) over NAAT alone to confirm active disease, particularly in low-prevalence settings or non-severe cases.^[110]^[117] Repeat testing within seven days of a negative result is discouraged unless symptoms worsen significantly, to avoid false negatives from toxin instability in unrefrigerated samples.^[110]^[116]

Management

Treatment

The primary treatment for an initial episode of non-fulminant Clostridioides difficile infection (CDI) involves antibiotics that target the pathogen while minimizing disruption to the gut microbiota. Fidaxomicin, administered at 200 mg orally twice daily for 10 days, is recommended as the preferred first-line therapy due to its lower recurrence rate compared to alternatives, with clinical trials demonstrating sustained response rates of approximately 70% at one month post-treatment.^[120] Alternatively, oral vancomycin at 125 mg four times daily for 10 days is used, particularly when fidaxomicin is unavailable, achieving initial cure rates exceeding 85% in randomized controlled trials.^[120] For mild, non-severe cases in low-risk patients, oral metronidazole 500 mg three times daily for 10 days may be considered when preferred agents are inaccessible, though its use has declined due to emerging resistance concerns and inferior outcomes in comparative studies. For recurrent CDI, fidaxomicin remains the preferred option, with the standard 10-day regimen or an extended-pulsed regimen (200 mg twice daily for 5 days, followed by once daily on alternate days for days 21–25) reducing recurrence by up to 50% relative to vancomycin in phase 3 trials.^[120] Vancomycin tapered and pulsed regimens (e.g., 125 mg four times daily for 10–14 days, then twice daily for 7 days, once daily for 7 days, and every 2–3 days for 2–8 weeks) serve as an alternative for first recurrences, with observational data showing recurrence prevention in about 60% of cases.^[120] For patients with multiple recurrences (≥2 episodes), fecal microbiota transplantation (FMT) is recommended, achieving cure rates of 80–90% in meta-analyses of over 40 studies involving more than 1,000 patients, typically delivered via colonoscopy after a course of antibiotics to clear C. difficile. Adjunctive therapies enhance outcomes in high-risk recurrent cases. Bezlotoxumab, a monoclonal antibody against toxin B, is administered as a single 10 mg/kg intravenous infusion during antibiotic treatment, reducing recurrence risk by 40% in phase 3 trials of over 2,600 patients with prior CDI episodes. Approved microbiome-based products include Rebyota (fecal microbiota, live-jslm), a single rectal administration following antibiotics for recurrent CDI prevention, with phase 3 data showing 70.6% treatment success at 8 weeks compared to 57.5% with placebo. Vowst (fecal microbiota spores, live-brpk), an oral capsule regimen of four capsules daily for three days post-antibiotics, similarly prevents recurrence in 88% of recipients versus 60% with placebo in pivotal trials. Supportive measures are integral to management. Discontinuing the inciting antibiotic is prioritized to allow microbiota recovery, as this alone resolves up to 20% of mild cases without further intervention, per cohort studies. For fulminant CDI (characterized by hypotension, shock, ileus, or megacolon), high-dose oral or nasogastric vancomycin (500 mg four times daily) combined with intravenous metronidazole (500 mg every 8 hours) is used, with surgical intervention such as subtotal colectomy considered for refractory toxic megacolon, improving survival from <30% to over 50% in severe cases.^[120] Emerging therapies include investigational microbiome modulators and targeted antimicrobials. As of 2025, Idorsia's synthetic glycan-based vaccine candidate for C. difficile, covering over 90% of circulating strains, has advanced in early clinical development following positive phase 1 immunogenicity data.^[121] Phage therapy, using bacteriophages specific to C. difficile ribotypes, shows promise in preclinical models and early-phase studies for reducing toxin production without broad microbiota disruption.^[122]

Prevention

Prevention of Clostridioides difficile infection (CDI) primarily focuses on infection control measures in healthcare settings, where the majority of cases occur due to transmission via contaminated surfaces and hands.^[123] Key strategies include isolating patients with suspected or confirmed CDI and implementing contact precautions, such as wearing gloves and gowns, to limit spread.^[123] Hand hygiene with soap and water is emphasized over alcohol-based sanitizers because soap effectively removes C. difficile spores, which are resistant to alcohol.^[124] Environmental cleaning using sporicidal agents like sodium hypochlorite (bleach) or hydrogen peroxide-based disinfectants is crucial for terminal room disinfection, as these agents inactivate spores on high-touch surfaces.^[125] Antibiotic stewardship programs are essential to reduce CDI risk by limiting unnecessary prescriptions and restricting high-risk antibiotics such as clindamycin, cephalosporins, and fluoroquinolones, which disrupt the gut microbiota and promote C. difficile overgrowth.^[111] These programs, recommended by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA), involve prospective audit and feedback to clinicians, resulting in decreased CDI incidence in hospitals implementing them.^[126] The 2022 SHEA compendium update recommends targeted interventions such as enhanced environmental cleaning and antimicrobial stewardship to reduce CDI incidence in healthcare settings.^[127] Probiotics, particularly Saccharomyces boulardii, have been investigated as adjuncts to prevent CDI in patients receiving antibiotics, with some trials showing reduced risk of healthcare-onset CDI when administered prophylactically.^[128] However, major guidelines, including those from the American College of Gastroenterology, do not routinely recommend probiotics for primary or secondary prevention due to inconsistent evidence and potential risks in immunocompromised patients.^[129] For high-risk individuals, such as those with prior CDI episodes, bezlotoxumab—a monoclonal antibody against toxin B—can prevent recurrence when administered during antibiotic treatment, reducing recurrence rates by about 10% compared to placebo in clinical trials.^[130] Experimental vaccines targeting C. difficile toxins, such as Pfizer's PF-06425090 toxoid vaccine evaluated in the phase 3 CLOVER trial, have shown potential in reducing disease severity and duration despite not meeting primary efficacy endpoints for infection prevention.^[131] As of 2025, no vaccine is licensed, but ongoing research explores multivalent approaches, including mRNA-based platforms.^[78] Public health efforts include surveillance through the CDC's Emerging Infections Program (EIP), which tracks CDI incidence and trends to inform prevention policies, revealing shifts toward more community-associated cases.^[132] Reducing community spread involves education on hygiene practices, such as prompt handwashing and avoiding antibiotic overuse in outpatient settings. Guidelines emphasize antibiotic stewardship, including the judicious use of narrow-spectrum antibiotics, to support gut microbiota health and prevent CDI, though microbiome restoration strategies are not yet standardized for routine prevention.^[133]

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