Comprehensive review of Clostridium difficile infection: Epidemiology, diagnosis, prevention, and treatment

Abstract

In recent years, nosocomial infections caused by Clostridium difficile (C. difficile) have risen, becoming a leading cause of hospital-acquired diarrhea. The global prevalence of C. difficile infection (CDI) varies across regions and populations. The diagnosis relies primarily on laboratory testing, including toxin, glutamate dehydrogenase, and nucleic acid amplification tests. Treatment strategies for CDI include antimicrobial therapy (e.g., metronidazole, vancomycin, and fidamycin), fecal transplantation, and immunotherapy (e.g., belotozumab), depending on the patient’s specificity and severity. This paper reviews recent research on CDI’s epidemiological characteristics, risk factors, diagnosis, treatment, and prevention, aiming to support hospitals and public health initiatives in implementing effective detection, prevention, and treatment strategies.

Key Words: Clostridium difficile; Pseudomembranous colitis; Public health safety; Epidemiology; Prevention; Diagnosis and treatment

Core Tip: The incidence of Clostridium difficile infection (CDI) has surpassed methicillin-resistant Staphylococcus aureus as a common pathogen in hospitals. The high incidence, lethality, and widespread nature of CDI seriously affect patients' lives and induce a huge medical burden on the country. Therefore, it is of great significance to understand the epidemiological characteristics, risk factors, diagnosis, and treatment methods, as well as conduct targeted prevention and control of CDI in hospitals.

INTRODUCTION

Clostridium difficile (C. difficile) is a strictly anaerobic, Gram-positive bacterium[1]. Its spores primarily adhere to the epithelial cells of the human intestine, impairing mucosal cell function by releasing exotoxins A and B and leading to C. difficile infection (CDI)[2]. The widespread use of antibiotics in recent years has exacerbated the CDI problem, making it a significant public health concern. A recent study published in the World Journal of Gastrointestinal Surgery by Ke et al[3] emphasized the critical need for vigilance regarding CDI in patients undergoing gastrointestinal surgery, particularly those with risk factors such as a history of antibiotic use. The widespread use of antibiotics in recent years has exacerbated the CDI issue, making it a substantial public health concern. This recent study by Ke et al[3] has highlighted the critical need for vigilance regarding CDI in patients undergoing gastrointestinal surgery. This caution is mainly required for those with risk factors such as a history of antibiotic use. Furthermore, the study reported a case of CDI following colon obstruction. CDI can be triggered by intestinal hypoxia, improper antibiotic use, and bile acid circulation disorders. Ke et al[3] used vancomycin and metronidazole along with probiotics for antibacterial treatment to restore healthy intestinal microflora, inhibit resistant C. difficile strains, and achieve therapeutic efficacy. CDI is highly toxic and is associated with considerable morbidity and poor patient outcomes. Despite its impact, comprehensive clinical treatment guidelines are not available. Understanding the prevalence of CDI, identifying risk factors, and applying effective diagnostic and treatment methods are essential for enhancing clinical outcomes and alleviating the disease burden. This review examines the epidemiological characteristics, risk factors, prevention strategies, control measures, and therapeutic options for CDI in hospitals.

EPIDEMIOLOGICAL CHARACTERISTICS OF CDI

C. difficile is widely distributed across natural environments such as soil, hay, sand, and the feces of large animals, including cattle, donkeys, and horses[4]. The clinical manifestations of CDI vary significantly, ranging from mild, self-limiting diarrhea to severe conditions such as pseudomembranous enteritis, septic syndrome, toxic megacolon, and even intestinal perforation[5-7]. The incidence of CDI is rising across the globe, with hospitals getting particularly affected, where it has become a major cause of nosocomial infection. Between 2011 and 2016, the prevalence of C. difficile ribotype RT106 and RT014/020 strains has increased, with RT106 emerging as the most common strain in community-associated infections in North America and is associated with a higher risk of recurrent CDI[8,9]. In Canada alone, the infection rate of RT106 has increased from 7.3% in 2015 to 18.9% in 2019[10]. Similarly, data from Australia during 2013-2018 suggests that the RT014/020 strain was most frequently detected[11]. In China, CDI exhibited distinct epidemiological patterns, with the prevalent strains being RT017, RT046, and RT012.

During the coronavirus disease 2019 pandemic, CDI incidence increased due to constrained hospital resources, increased patient mobility, and the extensive use of antimicrobial drugs. However, as the outbreak was brought under control and hospital resources were recovered, enhanced monitoring and prevention efforts led to a reduction in the CDI prevalence[12-14]. Some hospitals have successfully lowered the CDI rates through improved disinfection methods and have reinforced hand-hygiene practices.

Individuals at high risk for CDI include the elderly, immunocompromised patients (such as those with malignancies or organ-transplant recipients), long-term antibiotic users, and those with inflammatory bowel disease. The widespread application of antimicrobial agents and the emergence of highly resistant and virulent C. difficile strains have exacerbated the incidence and mortality of CDI, presenting a significant global public health challenge. The complex and evolving epidemiological characteristics of C. difficile necessitate the undertaking of comprehensive measures for effective prevention and control.

PATHOGENIC MECHANISM OF C. DIFFICILE

The pathogenic mechanism of C. difficile predominantly involves releasing TcdA (toxin A) and TcdB (toxin B)[15]. Both are protein toxins with high molecular weights and are composed of four key domains. Specifically, the molecular weight of TcdA is approximately 308 kDa, whereas that of TcdB is approximately 270 kDa[16]. These toxins contain domains associated with glycosyltransferase activity. TcdA and TcdB, as glycosyltransferases, can irreversibly inactivate Rho family proteins, inhibit actin polymerization, disrupt the cytoskeleton, and therefore trigger cytotoxicity[17]. The cytotoxicity of TcdB is particularly significant as it can directly damage intestinal wall cells[18]. In contrast, the cytotoxicity of TcdA mainly involves massive intestinal water loss and hemorrhagic necrosis. In addition, these toxins induce an inflammatory response by immune cells, exacerbating tissue damage. Moreover, they bind to surface receptors on the host cell membrane and enter the cells via endocytosis. While TcdA binds to cell surface receptors such as gp96, sGAGs, and LDLR[19], TcdB targets receptors including CSPG4 and TFPI[20]. Once inside the cell, the toxins undergo a structural rearrangement due to the indoor zone’s acidic environment. As a result, pores are formed in the endosomal membrane, allowing the release of the glucosyltransferase binding domain (GTD)[21]. Subsequently, the GTD enzyme transfers glucose to small GTPases, activating them. This process disrupts actin polymerization, compromises the structural integrity of the cell, and ultimately leads to apoptosis of the target cells[22]. Cellular tight junctions are compromised by cellular damage, increasing intestinal permeability. This disruption contributes to intestinal edema and other related lesions (see Figure 1 created with BioRender.com)[23-25].

Figure 1 The molecular mechanism of the Clostridium difficile infection. CDI: Clostridium difficile infection; Tcd A: Toxin A; Tcd B: Toxin B; LDLR: Low-density lipoprotein receptor; sGAGs: Sulfated glycosaminoglycans; CSPG4: Chondroitin sulfate proteoglycan 4; TFPI: Tissue factor pathway inhibit; Rho: Ras homologous; GTPase: Guanosine triphosphate hydrolase; GTD: Glucosyltransferase domain (Created in BioRender, Supplementary material).

RISK FACTORS ASSOCIATED WITH CDI

Several factors contribute to the risk of developing CDI, including age, antibiotic use, nonsteroidal anti-inflammatory drugs (NSAIDs), prolonged hospitalization, gastrointestinal diseases, immune suppression, and proton pump inhibitors (PPIs). In addition, malignancies, organ transplantation, and chronic kidney disease are key risk factors owing to their effects on immune function[1,26].

Antibiotic use and advanced age are the most critical risk factors. The extensive use of antibiotics mainly contributes to CDI. Broad-spectrum antibiotics disrupt the normal gut flora and create conditions favorable for C. difficile overgrowth[27]. Quinolones, cephalosporins, penicillins, and clindamycin are chiefly linked to a heightened risk of CDI[7,9,28]. Cephalosporins are often used owing to their conducive pharmacodynamic properties, but they contribute to CDI risk as C. difficile strains are intrinsically resistant to third-generation cephalosporins. Moreover, prolonged antibiotic therapy disrupts gut flora, aggravating the risk of CDI.

Older adults, particularly those > 65 years of age, and individuals with severe underlying conditions such as inflammatory bowel disease, chronic kidney disease, or immune deficiencies are at a substantially higher risk of CDI. These patients tend to be immunocompromised and are more susceptible to C. difficile invasion. Furthermore, the decline in bifidobacteria, an essential component of the gut microbiota that decreases with age, contributes to the heightened susceptibility in the elderly. Research has shown that the relative abundance of bifidobacteria decreases from 60%-70% in infancy to 10% in late adulthood and to 0%-5% in the elderly[7].

Healthcare settings such as hospitals and nursing homes are significant sites for C. difficile transmission. Patients in these environments face an increased risk owing to frequent exposure to pathogens and medical equipment. Poor hand hygiene and environmental contamination also contribute to nosocomial infections.

Additionally, damage to the gastric mucosa and the use of PPIs can exacerbate the susceptibility to CDI. PPIs reduce gastric acid secretion, which diminishes the acid’s bactericidal effect. In contrast, NSAIDs can impair gastric mucosal protection by inhibiting COX-1. Gastrointestinal diseases further expose patients to CDI risk by changing the gastric environment and stimulating bacterial colonization and infection.

DIAGNOSIS AND TREATMENT OF CDI

The diagnosis of CDI is pertinent in the clinical setting, and the methods mainly include glutamate dehydrogenase (GDH) detection and nucleic acid amplification tests (NAATs)[29]. Of these, GDH detection is extensively employed to rapidly identify potential infections owing to its high sensitivity[30]. However, its specificity is low and should be combined with follow-up testing. NAATs exhibit high sensitivity and specificity in detecting toxin genes (such as tcdA and tcdB) in stool samples. These tests have become an important method to confirm the diagnosis of CDI, especially in patients with positive GDH and negative toxin A/B tests or severe symptoms[31].

In clinical practice, multistep assays such as GDH followed by toxin A/B or simultaneous combined testing, cytotoxicity testing, toxin-producing cultures, or NAATs are used for confirmation when the results are inconsistent and to enhance diagnostic accuracy. Moreover, sample selection, frequency of repeat testing, and patient management are key to ensuring diagnostic validity and preventing the spread of nosocomial infections[32].

Accurate and timely diagnosis is crucial for effective treatment and infection control in healthcare settings. CDI can lead to metabolic acidosis, hypoalbuminemia, and electrolyte imbalances, necessitating careful management of water and electrolyte balance. Rehydration is essential, and antibiotics, antiperistaltic agents, and gastric inhibitors that could exacerbate the infection should be avoided[33].

Antibiotic therapy remains the primary treatment for CDI. Vancomycin and metronidazole are the first-line therapies; metronidazole is used for mild to moderate cases and oral vancomycin for severe or recurrent CDI[34,35]. Fidaxomicin, a macrolide with minimal effect on normal intestinal flora and a low recurrence rate, was approved by the Food and Drug Administration for CDI in 2011. This drug is recommended for patients with recurrent CDI and provides a therapeutic effect comparable to that of vancomycin[35,36].

Recurrent CDI poses a considerable clinical challenge and occurs in approximately 20% of the patients. A second recurrence is expected in 45% of these patients. According to international guidelines, fidaxomicin is preferred over vancomycin for recurrent CDI. Fecal microbiota transplantation (FMT) is an emerging therapy for recurrent or severe CDI and involves the transfer of feces from healthy donors to restore normal gut flora. FMT has shown promising results, and studies have demonstrated its efficacy[37]. In patients with CDI complicated by colonic perforation or toxic megacolon, surgical intervention, such as colectomy, may be required[38]. Furthermore, adjunct therapies such as oral probiotics and intravenous immunoglobulin can support CDI treatment. Probiotics aid in maintaining microbial balance and preventing CDI in patients with prior antibiotic use[39]. Intravenous immunoglobulin can improve immune function and delay disease progression; however, its clinical application remains controversial[40]. CDI has become a significant public health threat, and the development of vaccines against this condition has attracted immense attention[41]. Given the high genetic diversity and antigenic polymorphisms of C. difficile, vaccine development is challenging. Multivalent mRNA-LNP vaccines have recently demonstrated robust and long-term immune responses in animal models[42]. These vaccines have not only prevented first and repeat CDI infections but also promoted the decolonization of C. difficile. Nonetheless, further clinical trials are required to confirm the safety and efficacy of the vaccine, and antigen selection and production processes should be optimized. In the future, effective prevention and control of CDI are expected to be achieved via comprehensive measures such as vaccination combined with antimicrobial drug management, environmental cleaning, and disinfection. Overall, effective CDI management necessitates continuous monitoring and adjustment of treatment plans to augment outcomes and minimize complications.

PREVENTION AND CONTROL OF CDI

The increasing incidence of CDI globally has resulted in substantial morbidity and mortality, adversely affecting patients’ quality of life and imposing a heavy medical burden[43-45]. Effective prevention and control measures are imperative to mitigate this burden.

CDI can be categorized into endogenous and exogenous infections. Endogenous infections occur when carrier strains within the patient’s flora cause disease. In contrast, exogenous infections arise from contact with infected individuals, contaminated healthcare workers, hospital environments, or surfaces contaminated with C. difficile spores. Fecal contamination of surfaces or equipment (e.g., toilets, bathtubs, and electronic rectal thermometers) can harbor C. difficile spores, which may be transmitted to patients via the hands of healthcare workers[46]. C. difficile spores are particularly resistant and persist in the environment for weeks to months, showing considerable resistance to standard cleaning and disinfection procedures. Therefore, preventing hospital transmission is paramount in CDI control. This prevention requires various interventions such as contact isolation, hand hygiene, cleaning and disinfection of the environment and equipment, and management of asymptomatic carriers. A comprehensive approach combining these methods is vital for effective CDI prevention and control (Table 1).

Table 1 Treatment and prevention for Clostridium difficile infection.

	Treatment and prevention methods	Action mechanism	Ref.
Treatment	Discontinue antibiotics	Avoid the risk of recurrence	Mullane et al[33]
	Antibiotics	Inhibition of C. difficile cell wall synthesis and C. difficile deoxyribonucleic acid replication	Zhao et al[34], Dai et al[35], Louie et al[51]
	Fecal microflora transplantation therapy	Restore microbiota balance	van Nood et al[52]
	Surgical treatment	Excision of the lesion	Rajack et al[38]
	Oral probiotic therapy	Establish the normal intestinal microflora	Yang et al[39]
	Intravenous immunoglobulin	Enhance immunity	Woods et al[40]
Prevention and control	Contact isolation	Prevent C. difficile transmission	Kundrapu et al[47]
	Hand hygiene	Remove C. difficile and spores	Jabbar et al[48]
	Clean and disinfect the environment	Kill C. difficile and spores	Surawicz et al[49]
	Antimicrobial management	Reduce the risk of C. difficile infection	McDonald et al[36]
	Training and testing	Raise awareness of prevention and control	Surawicz et al[49]

C. difficile: Clostridium difficile.

Patient isolation and placement

Patients with CDI are an important source of infection transmission within medical facilities. A study has reported that CDI rates are 17% in double wards compared with 7% in single isolation units[47]. Therefore, contact isolation should be implemented for patients with CDI for effective infection control. When isolation rooms are limited, placing patients with fecal incontinence in these rooms should be prioritized. Patients infected with the same pathogen can be housed together in a single room to minimize the risk of transmission. Healthcare personnel and visitors entering patient's room must adhere to contact isolation protocols, including using suitable protective equipment such as gloves and isolation gowns. After interacting with these patients, protective gear should be carefully removed and hands thoroughly cleaned and disinfected to prevent pathogens from spreading among medical staff. For patients with suspected CDI, continuous contact precautions should be adopted during the infection period and for at least 48 h after the diarrhea resolves. These measures include proper handling of patient excreta (e.g., disinfectant treatment), regular cleaning and disinfection of the ward environment, and restriction of unnecessary visits.

Hand hygiene

Infections such as CDI, transmitted via the fecal-oral route, require rigorous hand hygiene practices for effective prevention and control. Medical staff, visitors, and patients must understand the importance of hand hygiene and adhere to established guidelines as it is crucial for reducing pathogen transmission. Proper hand hygiene is instrumental in minimizing the spread of pathogens among healthcare workers, patients, and visitors. Effective hand hygiene practices considerably alleviate the risk of cross-infection, particularly in high-risk environments such as hospitals. Given that C. difficile spores are resistant to ethanol-based hand sanitizers, the 2017 United States Infectious Diseases Society of America and Society for Healthcare Epidemiology of America (IDSA/SHEA) guidelines recommend hand washing with soap and water as the preferred method[47,48]. Furthermore, patients with CDI must maintain high standards of personal hygiene. Regular hand washing and bathing help reduce the presence of C. difficile spores on the skin, decreasing the transmission risk.

Cleaning and disinfection of the environment and equipment

Environmental contamination and equipment surface significantly influence the risk of C. difficile transmission. Effective cleaning and disinfection are critical for reducing this risk. The 2013 American Gastroenterological Association guidelines recommend using C. difficile spore-killing disinfectants or 5000 ppm chlorine solutions for deep cleaning of environments[49]. When combined with optimized hand hygiene practices, hydrogen peroxide vapor disinfection has been shown to significantly lower CDI incidence. In addition, ultraviolet disinfection devices have proven effective, reducing CD levels by 22%. To further mitigate the risk, disposable items should be used whenever possible. Strict cleaning and disinfection protocols must be followed for reused equipment. A comprehensive approach that encompasses effective disinfectants, steam disinfection, UV devices, and rigorous equipment management must be adopted in healthcare institutions. This approach can create a robust system for preventing and controlling CDI, thereby enhancing the safety of the medical environment[49].

Antimicrobial management

An in-depth antimicrobial stewardship plan (ASP) and a combination of prevention and control measures are needed to alleviate the risk of CDI[50]. To start with, antimicrobial use must be managed. The indications for antimicrobial drugs must be strictly understood and used only when there is a clear indication for bacterial infection. Unnecessary broad-spectrum antimicrobial drugs must be avoided, especially those highly correlated with CDI, such as clindamycin and cephalosporins. Moreover, the therapeutic regimen must be optimized. Sensitive antimicrobial drugs should be selected according to the patient’s pathogen culture results and drug susceptibility test. The course and dose of antimicrobial drugs should be minimized, and long-term or excessive use should be avoided. In addition, strengthening prescription review is the key to ensuring rational drug use, and physicians or pharmacists with antimicrobial prescribing authority should be responsible for reviewing, timely intervening, and adjusting irrational drug use. The 2017 United States IDSA/SHEA guidelines advocate implementing an ASP to control the use of high-risk antimicrobials and minimize their frequency, duration, and number[36].

Training and testing

Enhancing knowledge and control capabilities via targeted training on CDI prevention and control is essential. Educational programs for healthcare staff, patients, and visitors can improve awareness and adherence to preventive measures[49]. Hospitals should establish robust testing systems and feedback mechanisms to promptly identify patients with CDI. Prevention and control measures should be regularly monitored and evaluated to detect issues and implement timely improvements, ensuring effective CDI management.

CONCLUSION

This literature review thoroughly analyzes CDI’s epidemiological characteristics, systematically addressing its complex risk factors, diagnostic methods, therapeutic strategies, and prevention measures. Given CDI’s escalating incidence, more efficient, accurate, and targeted treatment strategies are urgently needed. Addressing this need requires an in-depth understanding of C. difficile’s pathogenic mechanisms. Innovative therapeutic approaches, such as new antibacterial agents, immunotherapies, and microecological regulators, should be explored to overcome current treatment challenges. Establishing robust infection prevention and control measures is crucial in addition to advancing treatment. Environmental cleaning and disinfection should be enhanced, patient isolation practices should be optimized, hand hygiene compliance among healthcare workers should be improved, and proactive infection monitoring and reporting systems should be implemented. Future research should focus on elucidating the pathogenic and drug resistance mechanisms of C. difficile using advanced technologies such as high-throughput sequencing and proteomics. Such investigations are expected to support the development of precision treatments. Moreover, efforts should be made to encourage the development of new drugs, particularly those targeting virulence factors and metabolic pathways, and microecological therapies should be examined. Molecular diagnostic techniques should be refined to improve the efficiency and accuracy of CDI diagnosis. Strengthening prevention and control involves fostering multidisciplinary collaboration, improving prevention systems, effectively managing antimicrobial use, raising public health awareness, and establishing a comprehensive prevention and control network involving all societal sectors. In summary, addressing the numerous challenges posed by CDI requires a multifaceted approach. Continuous innovation and coordinated efforts are needed to curb its spread and protect public health.

ACKNOWLEDGEMENTS

We express our sincere gratitude to all colleagues, reviewers, and editors for their valuable contributions in enhancing the quality of this manuscript.