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Markantonis, J.E.; Fallon, J.T.; Madan, R.; Alam, M.Z. Treatment of Clostridioides difficile Infection. Encyclopedia. Available online: https://encyclopedia.pub/entry/54608 (accessed on 03 May 2024).
Markantonis JE, Fallon JT, Madan R, Alam MZ. Treatment of Clostridioides difficile Infection. Encyclopedia. Available at: https://encyclopedia.pub/entry/54608. Accessed May 03, 2024.
Markantonis, John E., John T. Fallon, Rajat Madan, Md Zahidul Alam. "Treatment of Clostridioides difficile Infection" Encyclopedia, https://encyclopedia.pub/entry/54608 (accessed May 03, 2024).
Markantonis, J.E., Fallon, J.T., Madan, R., & Alam, M.Z. (2024, January 31). Treatment of Clostridioides difficile Infection. In Encyclopedia. https://encyclopedia.pub/entry/54608
Markantonis, John E., et al. "Treatment of Clostridioides difficile Infection." Encyclopedia. Web. 31 January, 2024.
Treatment of Clostridioides difficile Infection
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This entry is adapted from the peer-reviewed paper 10.3390/pathogens13020118

Clostridioides difficile is the most important cause of healthcare-associated diarrhea in the United States. The high incidence and recurrence rates of C. difficile infection (CDI), associated with high morbidity and mortality, pose a public health challenge. Although antibiotics targeting C. difficile bacteria are the first treatment choice, antibiotics also disrupt the indigenous gut flora and, therefore, create an environment that is favorable for recurrent CDI. The challenge of treating CDI is further exacerbated by the rise of antibiotic-resistant strains of C. difficile, placing it among the top five most urgent antibiotic resistance threats in the USA. The evolution of antibiotic resistance in C. difficile involves the acquisition of new resistance mechanisms, which can be shared among various bacterial species and different C. difficile strains within clinical and community settings.

Clostridioides difficile infection drug-resistant pathogen nucleic acid amplification testing host immunity enzyme immunoassays recurrent C. difficile infection

1. Introduction

With an estimated incidence rate of 110.2 cases per 100,000, C. difficile infection (CDI) is one of the leading causes of morbidity and mortality due to infectious diarrhea in the United States [1]. CDI occurs when there is a shift in the colonic microbial flora allowing toxin-producing strains of the Gram-positive, spore-forming, anaerobic bacillus to over proliferate [2]. Antibiotic exposure, the most important risk factor for CDI, results in a reduction in the population of non-pathogenic anaerobes that normally inhabit the gut [2][3]. This leads to a decrease in competition for space and resources for C. difficile allowing it to replicate unchecked [2]. Additionally, an ineffective host immune response contributes to this disease process due to the reduced elimination of this pathogenic bacterium as well as an increased inflammatory response to the bacterium and its toxins [2][4][5][6][7]. Clinical manifestations of CDI commonly include fever, leukocytosis, abdominal pain and profuse watery diarrhea [8][9]. Severe complications from CDI include dehydration, electrolyte imbalances, acute kidney injury (AKI) and pseudomembranous colitis [8][9][10]. The presence of toxic megacolon, ileus or shock indicates fulminant (severely complicated) disease which requires aggressive medical therapy [8][9][10].
The C. difficile bacterium produces clostridial toxins, which are its major virulence factors, and are responsible for CDI [2][11]. CDI generally occurs from strains that produce two exotoxins, toxin A (tcdA) and toxin B (tcdB) [2][11][12]. Rare toxigenic strains that harbor mutations in tcdA have been reported throughout the world [13][14][15]. These strains lack toxin A production; however, they still retain the ability to produce toxin B [13][14]. Interestingly, these toxin B-only producing C. difficile strains are still strongly associated with CDI [13][14]. In contrast, strains that produce only toxin A, as well as non-toxigenic strains, are rarely associated with pathogenicity [11][13][14][16]. A third toxin (clostridium binary toxin, CDT) has been identified in approximately 20% of C. difficile strains [2][11][12][17][18]. Strains that produce CDT, such as PCR ribotype 027/North American pulse-field type 1, restriction endonuclease analysis type B1 strain (NAP1/B1/027 or RT-027), are often associated with severe disease and are known as hypervirulent strains [11][15][17][18]. In addition to CDT production, mutations in the toxin regulator gene (tcdC) have been found in these strains, possibly leading to hyperproduction of toxin A and toxin B [11][18][19][20]. The NAP1/B1/027 strain is notable not only for its heightened toxin production but also for an increased sporulation rate, potentially enhancing the pathogen’s survival and promoting the spread of CDI [21].

2. Laboratory Tests to Diagnose CDI

2.1. Toxigenic Culture

Culturing viable organisms from stool followed by the confirmation of toxin production is considered the “gold standard” for diagnosing CDI [22]. Cycloserine–cefoxitin–fructose–egg yolk agar (CCFA), or a modified version, is the standard media used for the isolation of C. difficile [9][22][23]. Fresh stool samples should be treated with alcohol or heat shock to facilitate the conversion of spores to their vegetative forms prior to inoculation on CCFA or a similar selective media [9][23]. This is followed by anaerobic incubation at 37 °C for 48 h or longer [9][22][23]. Colonies with the typical appearance of C. difficile (flat, yellow, ground-glass-appearing colonies with a yellow halo) are selected for Gram staining and confirmatory testing [23][24]. This is generally accomplished by either biochemical analysis or through matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF) [9][22]. Differentiating C. difficile from other Clostridia can be accomplished by identifying motility, gelatin hydrolysis, glucose fermentation and esculin hydrolysis, while demonstrating the negative production of lecithinase, lipase, indole and urease [25]. Chromogenic media are commercially available, allowing for direct plating and a reduced incubation time (24 h), but are generally a more costly alternative to standard selective media [22]. Confirmed isolates are then tested for toxin production using a cell cytotoxicity neutralization assay (CCNA) [9][22][23][24]. Although considered the “gold standard”, the long turn-around-time and high complexity of this testing makes its routine use in clinical labs impractical [9]. Its current use is largely confined to research labs.

2.2. Cell Cytotoxicity Neutralization Assay

In addition to testing for toxin production from cultured C. difficile isolates, CCNA can be performed directly on fresh stool which allows for the detection of in vivo toxin production. For this testing, a stool filtrate is generated followed by the application of the supernatant to a cell line monolayer, commonly a human foreskin fibroblast-derived line [9][24][26]. Additionally, a second cell culture is incubated with a toxin-specific antibody following the application of the stool filtrate supernatant [9][24][26]. The monolayers are examined under high power microscopy at designated times over 48 h for signs of cytopathic effects (CPE) [9][24][26]. CPE refers to observable cellular changes, particularly cell rounding, resulting from the inactivation of Rho proteins. C. difficile toxins induce CPE by glucosylating low-molecular-weight GTP-binding proteins from the Rho subfamily, leading to actin reorganization and cell rounding [27]. This cell culture-based test is interpreted as being positive if ≥50% of the cultures cells exhibit cell rounding (CPE) with no CPE identified in the cells from the antibody treated culture. When performed properly this testing has high clinical sensitivity and specificity; however, several factors limit its clinical utility [9]. It has a prolonged turn-around-time and subjective interpretation issues compared to antigen- and molecular-based testing [9]. Additionally, as most clinical microbiology labs have transitioned to molecular testing for most assays, maintaining cell lines for this testing is often not practical. Like toxigenic culture, this testing is best used for reference testing in a research setting [9].

2.3. Nucleic Acid Amplification Testing

Molecular testing allows for the rapid and analytically sensitive detection of toxigenic C. difficile from clinical samples. Examples of nucleic acid amplification testing (NAAT) methods routinely used in clinical microbiology labs include polymerase chain reaction and loop-mediated isothermal amplification [9][28][29][30]. NAAT detects genes specific to toxigenic C. difficile, most commonly toxin-related genes [31]. Most molecular assays contain the toxin B gene target (tcdB); however, some assays also contain a target for tcdA, cdt and/or tcdC [31]. Limitations of NAAT include a higher average cost than alternative testing for the detection of asymptomatic colonization [9]. Among healthy adults, C. difficile colonization without clinical signs of CDI ranges from 0% to 17.5%, while hospitalized adults show a higher prevalence, ranging from 0% to 51% [32][33]. Molecular testing does not detect active toxin production, thus leading to specificity issues in the diagnosis of CDI when used alone [9]. Unnecessary treatment of asymptomatic colonized individuals can lead to adverse effects [32].

2.4. Enzyme Immunoassays

Antigen testing, most commonly in the form of enzyme immunoassays (EIAs), provides a rapid, simple and cost-effective alternative to other diagnostic tests for CDI. This form of testing had previously fallen out of favor due to poor analytical performance; however, newer technological advancements have significantly improved these methods’ clinical performance [34]. EIAs utilize antibodies that bind specifically to the antigen of interest [35]. EIAs that target toxin A and toxin B (toxin EIA) are considered the most specific diagnostic testing method routinely used by clinical microbiology labs for CDI diagnosis [8][9][36][37]. Since clostridial toxins degrade rapidly, the toxin EIA testing has relatively poor sensitivity [38][39]. This necessitates the use of a second, more sensitive, test alongside toxin EIA testing [9][38][40]. Glutamate dehydrogenase (GDH) is an antigen found in high levels in C. difficile and is not present in appreciable levels in other related organisms [41]. This creates an EIA that detects GDH (GDH EIA) a suitable screening target for the presence of C. difficile. The presence of GDH does not distinguish between toxigenic C. difficile and non-toxigenic strains [41]. This can be problematic as a positive result may indicate colonization as opposed to CDI, especially in individuals with a low test probability for CDI [41]. Thus, the detection of CDI by EIA is best optimized by pairing GDH and toxin detection [9][38][41].

2.5. Current Landscape of Clinical CDI Testing

Like syphilis testing, no single stand-alone test is currently recommended for the optimal clinical diagnosis of CDI [9][42][43]. An algorithmic approach is best suited for this task [8][9][38][43][44][45]. Current recommendations include a sensitive test (GDH EIA, NAAT) as the first step in CDI screening followed by a specific test (toxin EIA) to confirm in vivo toxin production [8][9]. For institutions that utilize a GDH EIA as the first part of the algorithm, a C. difficile NAAT can be used to arbitrate specimens that are GDH+/Toxin− to confirm whether the detected organism is a toxigenic strain [8][9]. This can be carried out reflexively or in all patients in whom the pre-test probability for CDI is high. Toxigenic culture and direct stool CCNA offer the best sensitivity/specificity but are practically illogical for most clinical laboratories [9]. Ultimately, there is no one test or algorithm that has a strong literature to support its use over others [46]. However, it is important to note that depending solely on molecular tests may result in overdiagnosis, unnecessary treatment and elevated healthcare costs associated with CDI. A study conducted by Polage at al. aimed to determine the natural history and treatment necessity for patients testing Tox−/PCR+ (toxin immunoassay negative, polymerase chain reaction positive) for CDI [47]. Among 1416 hospitalized adults, 21% were PCR positive, but only 44.7% of these had toxins that were detected by clinical tests. Tox−/PCR+ patients showed a lower bacterial load, less antibiotic exposure and fewer complications compared to Tox+/PCR+ patients. The median duration of diarrhea was shorter in Tox−/PCR+ patients, and no CDI-related complications or deaths occurred, unlike in Tox+/PCR+ patients. The study suggests that relying solely on molecular tests for CDI diagnosis may lead to overdiagnosis, overtreatment and increased healthcare costs. The decision for which testing should be used for the diagnosis of CDI is largely decided by the laboratory in conjunction with their associated clinical staff leadership. It is important to note that, while laboratory testing is supportive for diagnosis, CDI should not be eliminated from the differential diagnosis for individuals with significant risk factors for and a clinical presentation consistent with CDI based solely on laboratory results [8][9].

3. Treatment of C. difficile Infection

3.1. Treatment of the Initial Episode of CDI

The treatment of CDI, which was initially considered relatively straight forward, has become more challenging as antibiotic resistant and hypervirulent strains have emerged [19][48][49][50]. The current standard of care (SOC) for CDI treatment is largely based on recently published recommendation guidelines from the Infectious Disease Society of America/Society for Healthcare Epidemiology of America (IDSA/SHEA), American College of Gastroenterology (ACG) and the European Society of Clinical Microbiology and Infectious Disease (ESCMID) [8][9][10][51]. However, it should be noted these recommendations are based on low levels of evidence and lack high-quality research evidence [46].
The management of CDI primarily relies on three antibiotics: metronidazole, vancomycin and fidaxomicin, which are routinely employed in its treatment [8][10][51]. Metronidazole belongs to the nitroimidazole class of drug that is highly effective in the treatment of anaerobic bacterial infections and certain parasites [52]. Its mechanism of action is based on generation of reactive free radicals that damage nucleic acid. For the treatment of CDI, it can be administered orally or intravenously [8][10][51]. Vancomycin, a glycopeptide, prevents crosslinking of D-Ala-D-Ala moieties in peptidoglycan leading to impairment in cell wall synthesis and stability [53]. It has activity predominantly towards Gram-positive bacteria [53]. Vancomycin is minimally absorbed by the intact gastrointestinal tract and concentrates at high levels in the colon lumen, the site of its intended antimicrobial effect [54]. Although relatively new for CDI treatment, fidaxomicin has established an important role in the treatment of this disease [8][10][51][55]. Belonging to the macrocyclic lactones (macrolide) class of antimicrobial agents, fidaxomicin is unique in its narrow spectrum of anti-bacterial activity [55]. It effectively targets C. difficile without disrupting much of the remaining colonic flora [55][56]. Research studies have shown a decreased rate of treatment failure and recurrence compared to treatment with metronidazole or vancomycin [57][58][59]. In addition to initiating C. difficile-targeted antimicrobial therapy discontinuing non-CDI antimicrobials, if being administered, allows for the re-establishment of the normal colonic flora [8][10][51]. Fluid resuscitation is also important in CDI treatment to prevent complications associated with dehydration [8][10][51].
Standard-of-care (SOC) treatment for an initial episode of CDI involves a treatment course based on either fidaxomicin or oral vancomycin [8][10][51]. Per IDSA guidelines, fidaxomicin and vancomycin are recommended as the SOC for adults, while vancomycin and metronidazole continue to be considered standard for pediatric patients [9][51]. Fidaxomicin (200 mg) taken orally twice a day for 10 days is the preferred first-line treatment in these cases as its narrow spectrum likely leads to less gut dysbiosis and lower C. difficile recurrence rates [8][10][51]. ESCMID guidelines recommends the consideration of an extended course of fidaxomicin (200 mg twice daily for 5 days, then 200 mg every other day for 7–25 days) for patients at high risk for recurrence (e.g., geriatric patients, continued use of antibiotics and/or proton pump inhibitors, etc.) [10]. Fidaxomicin is significantly more expensive than oral vancomycin and not available at all treatment facilities [8][10][51]. An acceptable alternative is 125 mg vancomycin taken orally fourtimes a day for ten days [8][10][51]. If both agents are unavailable, 500 mg metronidazole taken by mouth three times a day for 10–14 days can be considered in initial, non-severe, cases [8][10][51]. Per ACG guidelines, metronidazole can also be considered over fidaxomicin and oral vancomycin for use in initial episodes of non-severe CDI in low-risk patients [8]. Severe cases are generally defined by a high fever, marked leukocytosis and the development of acute kidney injury [8][10][51].
For fulminant (severe complicated) CDI, treatment is the same regardless of whether it is an initial episode or a recurrence [8][10][51]. Fulminant CDI is largely defined as the development of profound hypotension/shock, toxic megacolon, ileus or other signs of rapid deterioration in medical condition [8][10][51]. IDSA/SHEA and ACG guidelines suggest the administration of 500 mg vancomycin by mouth or nasogastric tube every 6 h combined with 500 mg metronidazole administered intravenously every 8 h [8][51]. If ileus is present, rectal vancomycin administration (500 mg every 6 h) should be considered [8][51]. ESCMID guidelines differ from IDSA/SHEA and ACG, in that there is no recommendation to increase the dose or frequency of the administration of vancomycin [10]. The guidelines cite concerns for increased adverse effects and the development of antimicrobial resistance [10]. The basis of this recommendation is that, as the standard dose already results in high colonic intraluminal concentrations, the therapeutic benefits of the higher dose are uncertain [10]. The ESCMID guidelines also state the adjunctive additions of intravenous metronidazole and/or intravenous tigecycline for individual’s with a deteriorating SOC and CDI antimicrobial agents can be considered on a case-by-case basis; however, their routine use is not recommended [10]. Early surgical consultation is recommended for severe and fulminant cases of CDI as prompt surgical intervention when indicated may lead to less aggressive surgical procedures and better surgical outcomes [8][9][10].

3.2. Treatment of Recurrent CDI

Recurrent CDI (rCDI) is generally defined as the return of symptoms consistent with CDI within 8 weeks of an initial episode with laboratory confirmation [8][9][10][60]. For rCDI episodes, anti-C. difficile antimicrobial agents remain the backbone of medical therapy [8][10][51]. Novel treatment strategies incorporating toxin-binding monoclonal antibodies and fecal microbiota transplantations have now become established in treatment courses for rCDI cases [8][10][51][61]. For a first recurrence of CDI, fidaxomicin remains the preferred treatment option per most societal guidelines [8][10][51]. The standard 200 mg dose can be given twice a day for 10 days, or an extended course where the standard dose is given twice a day for 5 days followed every other day for 20 days based on IDSA/SHEA guidelines or 7–25 days if following ESCMID guidelines [10][51]. Alternatively, oral vancomycin in a standard 10-day course or in a tapered/pulsed-dosed regiment can be considered [8][10][51]. The ACG guidelines strongly recommend the use of fidaxomicin if oral vancomycin or metronidazole was the treatment agent used in the initial CDI episode and tapered/pulsed dosing of oral vancomycin over a standard course when used in recurrence [8].
For second and subsequent recurrences, the IDSA/SHEA guidelines recommend either a standard or extended course of fidaxomicin, a tapered/pulsed-dose oral vancomycin regiment or a standard course of oral vancomycin followed by rifaximin 400 mg three times daily for 20 days [51]. The ACG and ESCMID guidelines recommend fecal microbiota transplantation (FMT) as the first-line treatment option for second and subsequent recurrences [8][10]. FMT has been shown to be effective in preventing recurrence in individuals who have failed SOC antimicrobials in the past [62][63][64][65][66]. The goal of FMT is to restore a functioning gut microbiome to suppress the growth of C. difficile by competing for resources and epithelial surface area [64]. If FMT is not a feasible option, SOC antimicrobials can be considered [10]. In the FMT procedure, stool samples from healthy donors are chosen for transplantation into the recipient’s colon. The preferred methods for this transplantation include ingestion through an oral capsule or administration via a colonoscopy [62][66]. It is important to note that a rectal enema is another option, although it is not recommended according to ACG guidelines [8][66]. The ACG and ESCMID guidelines state that FMT can also be considered for severe and fulminant CDI cases where individuals on SOC therapy are failing, and a surgical intervention is not feasible [8][67].
On 30 November 2022, the FDA announced the approval of Rebyota as a preventive measure for rCDI in individuals aged 18 and above who have undergone antibiotic treatment [68]. Rebyota is a rectally administered, pre-packaged, single-dose microbiota suspension of 150 mL. Its effectiveness has been evaluated through randomized, double-blind, placebo-controlled, multicenter studies, demonstrating that Rebyota is well-tolerated and safe for use in adults with rCDI [69][70]. Additionally, the FDA recently approved Vowst as the first orally administered fecal microbiota product for preventing CDI recurrence following antibacterial treatment [71]. Vowst, containing live bacteria, is derived from human fecal matter donated by qualified individuals, with a dosing regimen of four capsules taken orally once a day for three consecutive days [71].
While effective in managing rCDI, FMT poses a potential risk of transmitting infectious agents. IDSA/SHEA guidelines recommend reserving FMT for individuals with two prior recurrences based on the concern for adverse events. These include the inadvertent transplantation of antimicrobial-resistant or pathogenic organisms and the development of sepsis due to these newly introduced gut microorganisms. It should be noted that these are rare occurrences with this procedure [51][63][64][72][73]. Additionally, although FMT poses the risk of transmitting multi-drug resistant pathogens, the FDA’s approval ensures that these products meet certain safety and efficacy standards for clinical use, potentially reducing associated risks [74].
Bezlotoxumab is a monoclonal antibody that binds and neutralizes toxin A and toxin B [75]. Several studies have shown decreased recurrence rates when it is administered alongside SOC antimicrobial therapy for CDI [76][77]. This is especially evident in the case of oral vancomycin, as this was the antimicrobial agent largely used in these clinical studies [8][51][67]. Data on its use with fidaxomicin are limited [8][51][67]. Congestive heart failure (CHF) is also a relative contraindication for its use; its benefit in prevention of CDI recurrence needs to be weighed against the potential risk of CHF exacerbation [8][51][67]. Its incorporation into the treatment course as a one-time dose administered intravenously for both the first and subsequent recurrence is highly recommended [8][51][67]. It should also be considered in patients at high risk for recurrence even during an initial CDI episode [8][51][67]. Managing recurrent CDI poses a significant challenge, requiring attention in both treating the underlying infection and implementing preventive measures for future episodes in every treatment plan.

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Subjects: Infectious Diseases
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
John E. Markantonis
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John T. Fallon
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Rajat Madan
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Md Zahidul Alam
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Entry Collection: Biopharmaceuticals Technology
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