Highlights & Basics
- Clostridioides difficile-associated disease usually presents with diarrhea, abdominal pain, and leukocytosis, and a history of recent antibiotic use. Other common symptoms include fever, abdominal tenderness, and distension.
- Testing should be limited to patients with unexplained, new-onset diarrhea (defined as 3 or more unformed stools in 24 hours). Molecular testing alone or as part of a multistep algorithm is recommended depending on local institutional protocols. May be evidence of pseudomembranes on sigmoidoscopy or colonoscopy in some patients.
- Treatment is to discontinue the inciting antimicrobial agent and start therapy with oral fidaxomicin or vancomycin (metronidazole may be used as an alternative option in certain patients and some locations). Surgery may be required in fulminant disease. Fecal microbiota transplantation is an option in severe and fulminant disease, and recurrent infections.
- Up to half of treated patients have recurrence after discontinuation of therapy but most respond to a second course of therapy. Fecal microbiota transplantation is recommended in patients with multiple recurrences. Bezlotoxumab may be considered in patients at high risk of recurrence.
Quick Reference
History & Exam
Key Factors
diarrhea
abdominal pain
Other Factors
fever
abdominal tenderness
nausea and vomiting
abdominal distension
symptoms of shock
Diagnostics Tests
1st Tests to Order
CBC
stool guaiac (fecal occult blood test)
stool polymerase chain reaction (PCR)
stool immunoassay for glutamate dehydrogenase
stool immunoassay for toxins A and B
abdominal x-ray
Other Tests to consider
cell culture cytotoxicity neutralization assay
CT abdomen
sigmoidoscopy or colonoscopy
Emerging Tests
stool lactoferrin or calprotectin
Treatment Options
acute
initial episode: nonsevere
oral fidaxomicin or vancomycin or metronidazole
discontinuation of causative agent
supportive care
infection control measures
initial episode: severe
oral fidaxomicin or vancomycin
discontinuation of causative agent
supportive care
infection control measures
fecal microbiota transplantation
Definition
Classifications
Case surveillance
- Laboratory-identified Clostridioides difficile infection that occurs more than 3 days after admission to the facility (i.e., on or after day 4). Healthcare facilities should track these cases in order to detect increases in the number of cases and outbreaks.
- C difficile infection occurring within 28 days after discharge from a healthcare facility.
- C difficile infection with no documented overnight stay in a healthcare facility in the prior 12 weeks.
Vignette
Common Vignette
Other Presentations
Epidemiology
Etiology
Pathophysiology
Images
Diagnostic Approach
History
- Cephalosporins (third- and fourth-generation) and carbapenems are most strongly associated with healthcare facility-associated infection; modest associations were also noted for fluoroquinolones, clindamycin, and beta-lactamase inhibitor/penicillin combinations.[40]
- An analysis of the Food and Drug Administration adverse event reporting system found that lincosamides (e.g., clindamycin) had the greatest proportion of reports of Clostridioides difficile infection, followed by monobactams, beta-lactamase inhibitor/penicillin combinations (e.g., piperacillin/tazobactam), carbapenems, cephalosporins, tetracyclines, macrolides, fluoroquinolones, and trimethoprim/sulfamethoxazole.[41]
- However, a meta-analysis suggests that tetracyclines may be associated with a decreased risk of infection compared with other antibiotics.[42]
Physical examination
Initial investigations
Subsequent tests
Emerging tests
Risk Factors
History & Exam
Tests
Differential Diagnosis
Differentiating Signs/Symptoms
- AAD includes osmotic diarrhea associated with antibiotic use. Nausea and diarrhea present. Absence of fever.
Differentiating Tests
- All tests within normal limits. Negative tests for Clostridioides difficile toxin.
Ischemic colitis
Differentiating Signs/Symptoms
- History of stroke, hypotension, heart failure, diabetes, or abdominal radiation exposure. Symptoms of bloody diarrhea, abdominal pain, vomiting, and fever.
Differentiating Tests
- Colonoscopy reveals inflamed mucosal surface or ischemic ulcers. Angiography reveals arterial flow disruption.
Bacterial or viral gastroenteritis
Differentiating Signs/Symptoms
- History of travel, eating contaminated food, or family members also ill.
- May have history of bloody stools.
Differentiating Tests
- Blood as well as stool culture positive for invasive bacterial infection.
Inflammatory bowel disease
Differentiating Signs/Symptoms
- Chronic diarrhea that may be bloody with extraintestinal manifestations.
Differentiating Tests
- Colonoscopic and pathologic findings suggestive of inflammatory bowel disease.
Criteria
- The presence of diarrhea or evidence of megacolon or severe ileus; and
- A positive laboratory diagnostic test result or evidence of pseudomembranes on endoscopy or histopathology.
- A new primary episode of symptom onset (no episode of symptom onset with positive result in the previous 8 weeks) and a positive assay result.
- An episode of symptom onset and positive assay result following an episode in the previous 2 to 8 weeks.
- Supportive clinical data: leukocytosis with WBC count of ≤15,000 cells/mL and serum creatinine <1.5 mg/dL (<0.13 mmol/L).
- Supportive clinical data: leukocytosis with WBC count of ≥15,000 cells/mL and serum creatinine >1.5 mg/dL (>0.13 mmol/L).
- Supportive clinical data: hypotension, shock, ileus, or megacolon.
Treatment Approach
Infection prevention and control
Discontinue causative agent
Supportive care
Initial episode: antibiotic therapy
- Supportive clinical data: leukocytosis with WBC count of ≤15,000 cells/mL and serum creatinine <1.5 mg/dL (<0.13 mmol/L)
- First-line treatment: oral fidaxomicin for 10 days
- Alternative treatment: oral vancomycin or metronidazole for 10 days
- Supportive clinical data: leukocytosis with WBC count of ≥15,000 cells/mL and serum creatinine >1.5 mg/dL (>0.13 mmol/L)
- First-line treatment: oral fidaxomicin for 10 days
- Alternative treatment: oral vancomycin for 10 days
- Supportive clinical data: hypotension, shock, ileus, or megacolon
- First-line treatment: oral vancomycin (at a higher dose than the dose for nonfulminant infection). If ileus is present, rectal installation of vancomycin can be considered. Intravenous metronidazole should be given with oral or rectal vancomycin, particularly if ileus is present as this may impair delivery of oral vancomycin to the colon
- Alternative treatments: tigecycline or immune globulins have been used in patients who are not responding to first-line treatments, but no controlled trials have been performed.
Severe and fulminant disease: surgery
Severe and fulminant disease: fecal microbiota transplantation
Recurrent infection: antibiotic therapy
- First-line treatment: a standard 10- or 20-day course of fidaxomicin
- Alternative treatment: a prolonged tapered and pulsed-dose regimen of oral vancomycin, or a standard 10-day course of oral vancomycin (if metronidazole was used for the initial episode).
- A standard 10- or 20-day course of fidaxomicin.
- A prolonged tapered and pulsed-dose regimen of oral vancomycin
- A standard 10-day course of oral vancomycin followed by rifaximin for 20 days.
Recurrent infection: bezlotoxumab
Recurrent infection: fecal microbiota transplantation
- One Cochrane review found that FMT likely leads to a large increase in the resolution of recurrent infection in immunocompetent adults compared to alternative treatments (e.g., antibiotics), based on moderate-certainty evidence. Conclusions could not be made regarding benefits or harms in immunocompromised patients due to a lack of data. FMT probably leads to a small decrease in the rates of serious adverse events (moderate-certainty evidence) and may decrease all-cause mortality (low-certainty evidence). However, an increased risk of these outcomes cannot be ruled out as the number of events was small.[72]
- Randomized controlled trials have shown high success rates.[73] [74] [75] Meta-analyses have reported efficacy rates of 82.1% to 95.6%.[76] [77] A prospective real-world analysis of a US FMT registry found that 90% of patients were considered cured (i.e., diarrhea had resolved without needing additional treatment) at 1-month follow-up. Of those cured at 1 month, 4% of patients experienced recurrence by 6 months.[78] However, FMT has been associated with lower cure rates in randomized trials compared with open-label and observational studies, and efficacy is higher for recurrent infection compared with refractory disease.[79]
- FMT appears to be the optimum approach for the treatment of recurrent disease compared with antibiotics such as vancomycin or fidaxomicin or placebo.[80] [81] [82] A systematic review of randomized controlled trials found that there was moderate-quality evidence to indicate that FMT is more effective than vancomycin or placebo.[83] Another randomized controlled trial found that FMT (applied by colonoscopy or nasojejunal tube after 4 to 10 days of vancomycin) was superior to fidaxomicin or vancomycin in terms of clinical and microbiologic resolution or clinical resolution alone.[84]
- Success of FMT may be improved by adequate bowel preparation at the time of FMT and optimizing antibiotic stewardship practices in the peri-FMT period. Nonmodifiable risk factors that increase the risk of treatment failure include advanced age, severe infection, inflammatory bowel disease, prior C difficile-related hospitalization, and inpatient status.[85]
- FMT-related adverse effects have been reported in 19% of patients undergoing FMT, and were generally considered to be mild to moderate and self-limiting. However, serious adverse effects, including infections and death, were reported in 1.4% of patients. All serious adverse effects were reported in patients with mucosal barrier injury.[91]
- Patients who received FMT via colonoscopy experienced more adverse effects compared to patients who received FMT via enema or oral capsules.[92]
- Long-term consequences are unknown.
- Earlier observational evidence suggested that FMT may be less effective at clearing C difficile infection in patients with inflammatory bowel disease.[93] However, one meta-analysis of cohort studies found no significant difference in cure rate after FMT in patients with C difficile infection with or without inflammatory bowel disease, but noted that further randomized controlled trials are necessary to validate its safety and efficacy in these patients.[94] Another meta-analysis found that FMT appears to be a highly effective therapy for preventing recurrent infection in these patients.[95]
- The ACG recommends that FMT should be considered for recurrent infection in patients with inflammatory bowel disease.[26]
- A systematic review of 303 immunocompromised patients found no difference between rates of serious adverse effects in immunocompromised and immunocompetent patients who undergo FMT.[96] However, the FDA has warned that FMT may transmit multidrug-resistant organisms, leading to serious or life-threatening infections, particularly in patients who are immunocompromised. This follows two cases of immunocompromised adults who received FMT and developed invasive infections caused by extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli. One of the patients died.[97]
- The FDA recommends that healthcare providers consider the potential risk of transmission of pathogenic bacteria by FMT products, including enteropathogenic Escherichia coli (EPEC) and Shiga toxin-producing Escherichia coli (STEC), and the resultant serious adverse reactions that may occur.[98]
- The FDA has warned that clinical use of FMT has the potential to transmit monkeypox virus, and that additional precautions are required for stool donated on or after 15 March 2022.[99] See Monkeypox .
- A prospective cohort study found that patients who undergo FMT compared with those taking antibiotics had a decreased risk of bloodstream infection.[100]
- Fecal products may also contain food allergens.
Treatment Options
initial episode: nonsevere
oral fidaxomicin or vancomycin or metronidazole
Primary Options
- fidaxomicin
200 mg orally twice daily for 10 days
- fidaxomicin
Secondary Options
Tertiary Options
- metronidazole
500 mg orally three times daily for 10-14 days
- metronidazole
Comments
- Supportive clinical data: leukocytosis with WBC count of ≤15,000 cells/mL and serum creatinine <1.5 mg/dL (<0.13 mmol/L).
- Antibiotic therapy should be started empirically if there is likely to be a substantial delay (>48 hours) in laboratory confirmation. For other patients, antibiotic therapy may be started after diagnosis in order to limit the overuse of antibiotics.
- The Infectious Diseases Society of America/Society for Healthcare Epidemiology of America (IDSA/SHEA) recommends oral fidaxomicin as a first-line agent for an initial episode of Clostridioides difficile infection, as it is more effective than vancomycin with respect to sustained clinical response. This recommendation is based on moderate-certainty evidence. Fidaxomicin may not be widely available and is more costly; therefore, vancomycin remains an acceptable alternative.[2][46] The ACG recommends vancomycin or fidaxomicin for the treatment of an initial episode of nonsevere disease.[26] Metronidazole is now only recommended in settings where access to first-line agents is limited.[2]
- Highest quality evidence indicates fidaxomicin is significantly better than vancomycin at achieving sustained symptomatic cure in adults with non-multiply recurrent infections. It is therefore considered a better treatment option than vancomycin in all patients except those with severe infections. Cure rates with metronidazole were significantly less compared to vancomycin and fidaxomicin. Furthermore, fidaxomicin is more effective at preventing recurrence compared with vancomycin.[51] [52] [53] [54]
- While therapeutic drug monitoring is not usually recommended with the use of oral vancomycin, it may be considered on a case-by-case basis, particularly in high-risk situations where high blood levels are anticipated (e.g., renal impairment, inflammatory bowel disease).[58]
discontinuation of causative agent
Comments
- At the first suggestion of diagnosis, the inciting antibiotic(s) should be discontinued as soon as possible.[2]
- If antibiotics cannot be withdrawn, an agent less likely to cause C difficile infection should be substituted. In particular avoid ampicillin, cephalosporins, clindamycin, carbapenems, and fluoroquinolones.
supportive care
Comments
- Patients should be evaluated for fluid status initially, especially if they are hospitalized. If necessary, hydration and electrolyte replacement should be instituted.
- Use of antimotility agents, including opioids and loperamide, should be avoided, although there is no evidence to support this recommendation.
infection control measures
Comments
- Patients should be isolated in a private room with a dedicated toilet. Priority should be given to patients with stool incontinence. Patients with suspected infection should be placed on contact precautions before test results become available. Contact precautions should be continued for at least 48 hours after diarrhea has resolved, and until discharge if C difficile infection rates remain high.[2][32]
- Healthcare professionals should use gowns and gloves on entry to a room. Hand hygiene should be performed before and after patient contact and after removing gloves. Either soap and water, or an alcohol-based product, should be used. Patients should also be encouraged to wash their hands and shower to reduce spore burden on the skin. Disposable patient equipment is preferred if available (rectal thermometers are not recommended).[2]
- The World Health Organization provides guidelines on correct hand-washing technique.[31] WHO: guidelines on hand hygiene
initial episode: severe
oral fidaxomicin or vancomycin
Primary Options
- fidaxomicin
200 mg orally twice daily for 10 days
- fidaxomicin
Secondary Options
Comments
- Supportive clinical data: leukocytosis with WBC count of ≥15,000 cells/mL and serum creatinine >1.5 mg/dL (>0.13 mmol/L).
- Antibiotic therapy should be started empirically if there is likely to be a substantial delay (>48 hours) in laboratory confirmation.[2]
- IDSA/SHEA recommends fidaxomicin as a first-line agent for an initial episode of C difficile infection as it is more effective than vancomycin with respect to sustained clinical response. This recommendation is based on moderate-certainty evidence. Fidaxomicin may not be widely available and is more costly; therefore, vancomycin remains an acceptable alternative.[2] [46] The ACG recommends vancomycin or fidaxomicin for the treatment of an initial episode of severe disease.[26]
- While therapeutic drug monitoring is not usually recommended with the use of oral vancomycin, it may be considered on a case-by-case basis, particularly in high-risk situations where high blood levels are anticipated (e.g., renal impairment, severe disease, inflammatory bowel disease).[58]
discontinuation of causative agent
Comments
- At the first suggestion of diagnosis, the inciting antibiotic(s) should be discontinued as soon as possible.[2]
- If antibiotics cannot be withdrawn, an agent less likely to cause C difficile infection should be substituted. In particular avoid ampicillin, cephalosporins, clindamycin, carbapenems, and fluoroquinolones.
supportive care
Comments
- Patients should be evaluated for fluid status initially, especially if they are hospitalized. If necessary, hydration and electrolyte replacement should be instituted.
- Use of antimotility agents, including opioids and loperamide, should be avoided, although there is no evidence to support this recommendation.
infection control measures
Comments
- Patients should be isolated in a private room with a dedicated toilet. Priority should be given to patients with stool incontinence. Patients with suspected infection should be placed on contact precautions before test results become available. Contact precautions should be continued for at least 48 hours after diarrhea has resolved, and until discharge if C difficile infection rates remain high.[2][32]
- Healthcare professionals should use gowns and gloves on entry to a room. Hand hygiene should be performed before and after patient contact and after removing gloves. Either soap and water, or an alcohol-based product, should be used. Patients should also be encouraged to wash their hands and shower to reduce spore burden on the skin. Disposable patient equipment is preferred if available (rectal thermometers are not recommended).[2]
- The World Health Organization provides guidelines on correct hand-washing technique.[31] WHO: guidelines on hand hygiene
fecal microbiota transplantation
Comments
- The ACG recommends considering fecal microbiota transplantation (FMT) in patients with severe and fulminant disease who are refractory to antibiotic therapy, in particular, when patients are deemed poor surgical candidates.[26] However, IDSA/SHEA do not currently recommend FMT in these patients as yet.[2]
initial episode: fulminant
vancomycin plus metronidazole, or tigecycline, or intravenous immune globulin (IVIG)
Primary Options
- vancomycin
500 mg orally (or by nasogastric tube) four times daily; or 500 mg in 100 mL of normal saline rectally (as a retention enema) every 6 hours
and
- metronidazole
500 mg intravenously every 8 hours
- vancomycin
Secondary Options
- tigecycline
100 mg intravenously initially as a loading dose, followed by 50 mg every 12 hours
- tigecycline
- immune globulin (human)
150-400 mg/kg intravenously as a single dose
- immune globulin (human)
Comments
- Supportive clinical data: hypotension, shock, ileus, or megacolon. Also known as severe, complicated infection.
- Antibiotic therapy should be started empirically if there is likely to be a substantial delay (>48 hours) in laboratory confirmation.
- Oral vancomycin (at a higher dose than the dose used for nonfulminant infection) is the recommended first-line treatment. If ileus is present, rectal installation of vancomycin can be considered. Intravenous metronidazole should be given with oral or rectal vancomycin, particularly if ileus is present as this may impair delivery of oral vancomycin to the colon.[2]
- In patients who are not responding to first-line therapy, tigecycline or IVIG have been used, but no controlled trials have been performed.[2] IVIG has been effective in a small number of patients with fulminant disease, presumably by providing neutralizing antibodies against toxins A and B.[21] [22] IVIG may be considered in fulminant disease in those who have a high surgery risk; however, there are no definite data or guidelines to support this recommendation.
- While therapeutic drug monitoring is not usually recommended with the use of oral vancomycin, it may be considered on a case-by-case basis, particularly in high-risk situations where high blood levels are anticipated (e.g., renal impairment, combination oral and enteral therapy, severe disease, inflammatory bowel disease).[58]
discontinuation of causative agent
Comments
- At the first suggestion of diagnosis, the inciting antibiotic(s) should be discontinued as soon as possible.[2]
- If antibiotics cannot be withdrawn, an agent less likely to cause C difficile infection should be substituted. In particular avoid ampicillin, cephalosporins, clindamycin, carbapenems, and fluoroquinolones.
supportive care
Comments
- Patients should be evaluated for fluid status initially, especially if they are hospitalized. If necessary, hydration and electrolyte replacement should be instituted.
- Use of antimotility agents, including opioids and loperamide, should be avoided, although there is no evidence to support this recommendation.
infection control measures
Comments
- Patients should be isolated in a private room with a dedicated toilet. Priority should be given to patients with stool incontinence. Patients with suspected infection should be placed on contact precautions before test results become available. Contact precautions should be continued for at least 48 hours after diarrhea has resolved, and until discharge if C difficile infection rates remain high.[2][32]
- Healthcare professionals should use gowns and gloves on entry to a room. Hand hygiene should be performed before and after patient contact and after removing gloves. Either soap and water, or an alcohol-based product, should be used. Patients should also be encouraged to wash their hands and shower to reduce spore burden on the skin. Disposable patient equipment is preferred if available (rectal thermometers are not recommended).[2]
- The World Health Organization provides guidelines on correct hand-washing technique.[31] WHO: guidelines on hand hygiene
surgery
Comments
- Early diagnosis and treatment are essential for a good outcome, and early surgical intervention should be considered in patients who are unresponsive to medical therapy or who have rising WBC count or lactate level.
- The surgical procedure of choice is a subtotal colectomy with preservation of the rectum. Diverting loop ileostomy (with colonic lavage followed by antegrade vancomycin flushes) is an alternative approach.[2][63] Both procedures have similar survival rates; however, loop ileostomy is associated with a lower risk of surgical site infections, and an increased rate of colonic preservation. Evidence is limited.[64] [65]
fecal microbiota transplantation
Comments
- The ACG recommends considering fecal microbiota transplantation (FMT) in patients with severe and fulminant disease who are refractory to antibiotic therapy, in particular, when patients are deemed poor surgical candidates.[26] However, IDSA/SHEA do not currently recommend FMT in these patients as yet.[2] A meta-analysis of randomized controlled trials found that there was no statistically significant difference between medical therapy and FMT in patients with primary infection.[66]
- See subsequent recurrence section below for more information on FMT.
first recurrence
repeat course of antibiotic therapy
Primary Options
- fidaxomicin
200 mg orally twice daily for 10 days; or 200 mg orally twice daily for 5 days, followed by 200 mg on alternate days for 20 days.
- fidaxomicin
Secondary Options
- vancomycin
standard regimen: 125 mg orally four times daily for 10 days; tapered and pulsed regimen: 125 mg orally four times daily for 10-14 days, followed by 125 mg twice daily for 7 days, then 125 mg once daily for 7 days, then 125 mg every 2-3 days for 2-8 weeks
- vancomycin
Comments
- IDSA/SHEA recommends that a first recurrence should be treated with a 10- or 20-day course of fidaxomicin first line. A prolonged tapered and pulsed-dose regimen of oral vancomycin, or a standard 10-day course of oral vancomycin (if metronidazole was used for the initial episode) are alternative options.[2][46] The ACG recommends a tapered and pulsed-dose regimen of oral vancomycin (after an initial course of fidaxomicin, vancomycin, or metronidazole) or fidaxomicin (after an initial course of vancomycin or metronidazole) for a first recurrence.[26]
- Taper and pulsed-dose regimens of vancomycin were superior to taper alone and pulsed-dose alone regimens (resolution rates of 83% versus 68% and 54%, respectively) for recurrent infection. However, evidence is limited.[69]
- While therapeutic drug monitoring is not usually recommended with the use of oral vancomycin, it may be considered on a case-by-case basis, particularly in high-risk situations where high blood levels are anticipated (e.g., renal impairment, severe disease, inflammatory bowel disease).[58]
bezlotoxumab
Primary Options
- bezlotoxumab
10 mg/kg intravenously as a single dose
- bezlotoxumab
Comments
- Bezlotoxumab, a human monoclonal antibody that binds to Clostridioides difficile toxin B, has been approved to reduce the recurrence of C difficile infection in adults who are receiving antibacterial treatment for C difficile infection and who have a high risk of recurrence. It is not indicated for the treatment of C difficile infection and is not an antibacterial drug so must be used in combination with antibiotic therapy. Bezlotoxumab should be used under specialist guidance.
- IDSA/SHEA recommends using bezlotoxumab alongside standard of care antibiotics for the prevention of recurrence in patients who have had a recurrent episode within the last 6 months, particularly those who are at high risk of recurrence (e.g., age ≥65 years, immunocompromised, severe disease on presentation) and provided logistics for intravenous administration is not an issue. This recommendation is based on very low certainty evidence.[46] The ACG also recommends considering bezlotoxumab for the prevention of recurrence in patients who are at high risk of recurrence.[26]
- A single intravenous dose of bezlotoxumab (given in combination with standard antibiotic treatment) for primary or recurrent C difficile infection was associated with a 38% lower rate of recurrent infection compared with antibiotic treatment alone in 2 phase III trials. Sustained cure (no recurrent infection in 12 weeks) was achieved by 64% of patients compared with 54% of patients in the placebo group. The most common adverse effects were nausea and diarrhea, and the drug had a similar adverse effect profile to placebo.[70] Bezlotoxumab was no better at resolving recurrent infection compared with fecal microbiota transplant.[71] Data on the use of bezlotoxumab when fidaxomicin is used as the standard of care antibiotic are limited.[46]
- In patients with a history of congestive heart failure, bezlotoxumab should be reserved for use when the benefits outweigh the risks. Heart failure was reported more commonly with bezlotoxumab compared to placebo in clinical trials, primarily in patients with underlying congestive heart failure.[46]
subsequent recurrence
repeat course of antibiotic therapy
Primary Options
- fidaxomicin
200 mg orally twice daily for 10 days; or 200 mg orally twice daily for 5 days, followed by 200 mg on alternate days for 20 days
- fidaxomicin
Secondary Options
- vancomycin
standard regimen: tapered and pulsed regimen: 125 mg orally four times daily for 10-14 days, followed by 125 mg twice daily for 7 days, then 125 mg once daily for 7 days, then 125 mg every 2-3 days for 2-8 weeks
- vancomycin
- vancomycin
standard regimen: 125 mg orally four times daily for 10 days
and
- rifaximin
400 mg orally three times daily for 20 days; start after 10-day course of vancomycin is complete
- vancomycin
Comments
- IDSA/SHEA recommends subsequent recurrences may be treated with the following antibiotic regimens: a standard 10- or 20-day course of fidaxomicin; a prolonged tapered and pulsed-dose regimen of oral vancomycin; or a standard 10-day course of oral vancomycin followed by rifaximin for 20 days.[2][46] The ACG recommends that oral vancomycin may be considered for subsequent recurrences.[26]
- Taper and pulsed-dose regimens of vancomycin were superior to taper alone and pulsed-dose alone regimens (resolution rates of 83% versus 68% and 54%, respectively) for recurrent infection. However, evidence is limited.[69]
- While therapeutic drug monitoring is not usually recommended with the use of oral vancomycin, it may be considered on a case-by-case basis, particularly in high-risk situations where high blood levels are anticipated (e.g., renal impairment, severe disease, inflammatory bowel disease).[58]
bezlotoxumab
Primary Options
- bezlotoxumab
10 mg/kg intravenously as a single dose
- bezlotoxumab
Comments
- Bezlotoxumab, a human monoclonal antibody that binds to Clostridioides difficile toxin B, has been approved to reduce the recurrence of C difficile infection in adults who are receiving antibacterial treatment for C difficile infection and who have a high risk of recurrence. It is not indicated for the treatment of C difficile infection and is not an antibacterial drug so must be used in combination with antibiotic therapy. Bezlotoxumab should be used under specialist guidance.
- IDSA/SHEA recommends using bezlotoxumab alongside standard of care antibiotics for the prevention of recurrence in patients who have had a recurrent episode within the last 6 months, particularly those who are at high risk of recurrence (e.g., age ≥65 years, immunocompromised, severe disease on presentation) and provided logistics for intravenous administration is not an issue. This recommendation is based on very low certainty evidence.[46] The ACG also recommends considering bezlotoxumab for the prevention of recurrence in patients who are at high risk of recurrence.[26]
- A single intravenous dose of bezlotoxumab (given in combination with standard antibiotic treatment) for primary or recurrent C difficile infection was associated with a 38% lower rate of recurrent infection compared with antibiotic treatment alone in 2 phase III trials. Sustained cure (no recurrent infection in 12 weeks) was achieved by 64% of patients compared with 54% of patients in the placebo group. The most common adverse effects were nausea and diarrhea, and the drug had a similar adverse effect profile to placebo.[70] Bezlotoxumab was no better at resolving recurrent infection compared with fecal microbiota transplant.[71] Data on the use of bezlotoxumab when fidaxomicin is used as the standard of care antibiotic are limited.[46]
- In patients with a history of congestive heart failure, bezlotoxumab should be reserved for use when the benefits outweigh the risks. Heart failure was reported more commonly with bezlotoxumab compared to placebo in clinical trials, primarily in patients with underlying congestive heart failure.[46]
fecal microbiota transplantation (FMT)
Comments
- IDSA/SHEA recommends fecal microbiota transplantation (FMT) as an option in patients with at least two recurrences and where antibiotic therapy has failed.[2] However, the ACG recommends considering FMT as a first-line option in patients experiencing their second or further recurrence of disease to prevent further recurrences.[26] The ACG recommends that FMT should be considered for recurrent infection in patients with inflammatory bowel disease.[26]
- Involves implanting processed stool collected from a healthy donor into the intestinal tract of infected patients to correct intestinal dysbiosis. The Food and Drug Administration (FDA) has approved two proprietary fecal microbiota products for the prevention of recurrence of C difficile infection in patients ≥18 years of age. Rebyota® is administered as a single rectal dose, and Vowst® is administered orally for three days. Other proprietary products may be available in other countries. A short induction course of oral vancomycin may be used prior to FMT to reduce C difficile burden in patients who are not receiving antibiotic therapy prior to planned FMT.
- One Cochrane review found that FMT likely leads to a large increase in the resolution of recurrent infection in immunocompetent adults compared to alternative treatments (e.g., antibiotics), based on moderate-certainty evidence. Conclusions could not be made regarding benefits or harms in immunocompromised patients due to a lack of data. FMT probably leads to a small decrease in the rates of serious adverse events (moderate-certainty evidence) and may decrease all-cause mortality (low-certainty evidence). However, an increased risk of these outcomes cannot be ruled out as the number of events was small.[72]
- Randomized controlled trials have shown high success rates.[73] One meta-analysis of over 4600 patients reports a final cure rate of 95.6% (with a mean of 1.2 treatments and follow-up of 7.7 months).[76] A prospective real-world analysis of a US FMT registry found that 90% of patients were considered cured (i.e., diarrhea had resolved without needing additional treatment) at 1-month follow-up. Of those cured at 1 month, 4% of patients experienced recurrence by 6 months.[78] However, FMT has been associated with lower cure rates in randomized trials compared with open-label and observational studies, and efficacy is higher for recurrent infection compared with refractory disease.[79]
- FMT appears to be the optimum approach for the treatment of recurrent disease compared with antibiotics such as vancomycin or fidaxomicin or placebo.[80] [81] [82] A systematic review of randomized controlled trials found that there was moderate-quality evidence to indicate that FMT is more effective than vancomycin or placebo.[83] Another randomized controlled trial found that FMT (applied by colonoscopy or nasojejunal tube after 4 to 10 days of vancomycin) was superior to fidaxomicin or vancomycin in terms of clinical and microbiologic resolution or clinical resolution alone.[84]
- The ACG recommends FMT preferably through colonoscopy or oral capsules (or enema if other methods are unavailable), and suggest repeat FMT for patients experiencing a recurrence of CDI within 8 weeks of an initial FMT.[26] Cure rates with FMT via colonoscopy are superior to FMT via enema and nasogastric tube, and comparable to FMT via oral capsules.[86] Frozen or lyophilized FMT is as effective as fresh FMT in achieving resolution of diarrhea, and lower gastrointestinal delivery may be more effective than upper gastrointestinal delivery.[74] [87] [88] [89] Oral capsules are promising due to their ease of administration, and an overall efficacy of 82% has been reported with this method of delivery.[77]
- FMT is generally well tolerated, but adverse effects may include fever, abdominal tenderness or discomfort, flatulence, nausea/vomiting, diarrhea/constipation, and infections.[90] FMT-related adverse effects have been reported in 19% of patients undergoing FMT, and were generally considered to be mild to moderate and self-limiting. However, serious adverse effects, including infections and death, were reported in 1.4% of patients. All serious adverse effects were reported in patients with mucosal barrier injury.[91] Patients who received FMT via colonoscopy experienced more adverse effects compared to patients who received FMT via enema or oral capsules.[92] Long-term consequences are unknown.
- The Food and Drug Administration (FDA) have warned that FMT may transmit multidrug-resistant organisms, leading to serious or life-threatening infections, particularly in patients who are immunocompromised. This follows two cases of immunocompromised adults who received FMT and developed invasive infections caused by extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli. One of the patients died.[97] The FDA recommends that healthcare providers consider the potential risk of transmission of pathogenic bacteria by FMT products, including enteropathogenic Escherichia coli (EPEC) and Shiga toxin-producing Escherichia coli (STEC), and the resultant serious adverse reactions that may occur.[98]
- The FDA has warned that clinical use of FMT has the potential to transmit monkeypox virus, and that additional precautions are required for stool donated on or after 15 March 2022.[99] See Monkeypox .
- Fecal products may also contain food allergens.
Emerging Tx
Oral microbiome therapeutics
Biologic agents
Small molecules
Ribaxamase
Teicoplanin
Resins
Prevention
Primary Prevention
- The use of probiotics might be helpful in primary prevention. Current evidence suggests that the use of certain probiotic strains or combinations of probiotic strains may prevent C difficile infection in patients on antibiotic treatment, and the American Gastroenterology Association (AGA) guidelines recommend their use in this situation. However, the quality of evidence is low and the reporting of potential harms was not always consistent.[25]
- Guidelines from the Infectious Diseases Society of America/Society for Healthcare Epidemiology of America (IDSA/SHEA) and the American College of Gastroenterology (ACG) do not recommend probiotics for the primary prevention of C difficile infection outside of clinical trials due to insufficient data.[2][26] The reason for the difference between recommendations between the AGA and the ACG is because the AGA accounted for strain specificity in their analysis of the evidence.[27]
- A Cochrane review of 31 randomized controlled trials (8672 patients) found that there was moderate-quality evidence that probiotics were both safe and effective for preventing C difficile-associated diarrhea when used with antibiotics in patients who are not immunocompromised or severely debilitated.[28]
- Administering probiotics close to the first dose of antibiotics has been found to reduce the risk of C difficile infection by more than 50% in hospitalized adults.[29]
- In one systematic review and meta-analysis, Lactobacillus casei ranked as the best intervention out of 9 probiotic interventions for the prevention of C difficile-associated disease.[30]
- Infection control advice and hand washing with soap and water will help prevent patient-to-patient spread. The World Health Organization provides guidelines on correct hand-washing technique. A structured washing technique was found to be more effective than an unstructured technique against C difficile.[31] WHO: guidelines on hand hygiene Patients should receive care with contact precautions for at least 48 hours after resolution of diarrhea.[32]
- Environmental cleaning in hospitals is imperative to prevent the introduction or spread of pathogens.[33] [34] Decontamination methods include the use of hydrogen peroxide, chlorine-releasing agents, and ultraviolet light. Hydrogen peroxide significantly reduced the frequency of C difficile contamination compared with hypochlorite, and reduced the incidence of hospital-acquired C difficile infection compared to other cleaning methods. UV decontamination significantly reduced the frequency of hospital-acquired C difficile infection compared with hypochlorite.[35]
- It is not clear whether bathing critically ill patients with chlorhexidine reduces hospital‐acquired infections, mortality, or length of stay in the intensive care unit due to the very low‐certainty evidence available.[36]
- Antimicrobial stewardship should be a central component of C difficile infection control programs.[37] Benefits of stewardship programs include reduced adverse effects and improved patient outcomes.
- Recommendations include:[2]
- Minimizing the frequency and duration of high-risk antibiotics, as well as the number of antibiotics prescribed, to reduce the risk of C difficile infection
- Implementing an antibiotic stewardship program
- Considering restriction of fluoroquinolones, clindamycin, and cephalosporins (except for surgical prophylaxis).
- One meta-analysis found that stewardship programs have been shown to significantly reduce the incidence of C difficile infections by 32% in hospital inpatients, and were more effective when implemented with infection-control measures.[38]
- There is insufficient evidence to recommend discontinuing proton-pump inhibitors to prevent C difficile infection; however, they should be discontinued if they are not necessary.[2]
- Vaccines are not available but several are in development.[39]
Secondary Prevention
Follow-Up Overview
Prognosis
Monitoring
Complications
Citations
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Key Articles
Other Online Resources
Referenced Articles
Guidelines
Diagnostic
Summary
Provides recommendations for the diagnosis and management of patients with C difficile, as well as for the prevention and control of outbreaks; supplements previously published guidelines.Published by
American College of Gastroenterology
Published
2021
Summary
Covers diagnosis of C difficile infection in adults.Published by
American Society of Transplantation Infectious Diseases Community of Practice
Published
2019
Summary
Covers diagnosis of C difficile infection in adults.Published by
Infectious Diseases Society of America; Society for Healthcare Epidemiology of America
Published
2018
Summary
Guidance for management of C difficile infection in surgical patients.Published by
World Society of Emergency Surgery
Published
2019
Summary
This guideline evaluates the available literature, discusses criteria for disease severity, and provides recommendations for the diagnosis of C difficile.Published by
European Society of Clinical Microbiology and Infectious Diseases
Published
2018
Treatment
Summary
Provides information on the basic principles and interventions recommended for the prevention of C difficile infection in acute care facilities.Published by
Centers for Disease Control and Prevention
Published
2021
Summary
Focused update on management of C difficile infection in adults, specifically addressing the use of fidaxomicin and bezlotoxumab for the treatment of C difficile infection.Published by
Infectious Diseases Society of America; Society for Healthcare Epidemiology of America
Published
2021
Summary
Provides recommendations for the diagnosis and management of patients with C difficile, as well as for the prevention and control of outbreaks; supplements previously published guidelines.Published by
American College of Gastroenterology
Published
2021
Summary
Covers management of C difficile infection in adults.Published by
Infectious Diseases Society of America; Society for Healthcare Epidemiology of America
Published
2018
Summary
Covers management of C difficile infection in adults.Published by
The American Society of Colon and Rectal Surgeons
Published
2021
Summary
These updated guidelines address the prevention and management of C difficile infection in solid organ transplant recipients.Published by
American Society of Transplantation Infectious Diseases Community of Practice
Published
2019
Summary
These updated guidelines address the management of C difficile infection in hematopoietic cell transplant recipients in the format of frequently asked questions.Published by
American Society for Transplantation and Cellular Therapy
Published
2022
Summary
Clinical practice guideline for the prevention and treatment of C difficile infection in children and adolescents with cancer.Published by
American Society of Clinical Oncology
Published
2018
Summary
These guidelines review the diagnosis, prevention, and management of diarrhea in the pre- and post-transplant period.Published by
American Society of Transplantation Infectious Diseases Community of Practice
Published
2019
Summary
Guidance for management of C difficile infection in surgical patients.Published by
World Society of Emergency Surgery
Published
2019
Summary
This guideline evaluates the available literature, discusses criteria for disease severity, and provides recommendations for C difficile treatment, indicating level of evidence and strength of recommendation.Published by
European Society of Clinical Microbiology and Infectious Diseases
Published
2021
Summary
This guideline sets out an antimicrobial prescribing strategy for managing Clostridioides difficile infection in adults, young people and children aged 72 hours and over in community and hospital settings.Published by
National Institute for Health and Care Excellence
Published
2021