RxCe - Strategies for Managing C. difficile Infection Materials

STRATEGIES FOR MANAGING CLOSTRIDIOIDES DIFFICILE INFECTIONS

Faculty:

L. Austin Fredrickson, MD, FACP

L. Austin Fredrickson is an Associate Professor of Internal Medicine at Northeast Ohio Medical University, where he serves as core faculty and teaches diagnostics, therapeutics, clinical skills, and health humanities. He is board-certified in general internal medicine and practices rural primary care. 

Liz Fredrickson, PharmD, BCPS

Liz Fredrickson, PharmD, BCPS, is an Associate Professor of Pharmacy Practice and Pharmaceutical Sciences at the Northeast Ohio Medical University (NEOMED) College of Pharmacy, where she is course director of the Parenteral Products and Basic Pharmaceutics Lab courses.

Pamela Sardo, PharmD, BS

Pamela Sardo, PharmD, BS, is a freelance medical writer and licensed pharmacist. She is the founder and principal at Sardo Solutions in Texas. Pam received her BS from the University of Connecticut and her PharmD from the University of Rhode Island. Pam’s career spans many years in retail, clinics, hospitals, long-term care, Veterans Affairs, and managed health care responsibilities across a broad range of therapeutic classes and disease states.

Abstract

Clostridioides difficile infection (CDI) is among the most prevalent hospital-acquired infections. It continues to pose significant challenges in healthcare settings, with subsequent increases in morbidity, mortality, and healthcare costs. Pharmacy teams play pivotal roles in CDI management through the application of antimicrobial stewardship and infection control and the provision of patient and caregiver education. This continuing education activity aims to provide pharmacists and pharmacy technicians with comprehensive knowledge and practical strategies for effectively managing CDI. The pathophysiology and epidemiology of CDI will be reviewed, and detailed diagnostic, prevention, and management strategies will be discussed.

Accreditation Statements

In support of improving patient care, RxCe.com LLC is jointly accredited by the Accreditation Council^TM for Continuing Medical Education (ACCME^®), the Accreditation Council for Pharmacy Education (ACPE^®), and the American Nurses Credentialing Center (ANCC^®), to provide continuing education for the healthcare team.

Joint Universal Activity Number: The Joint Accreditation Universal Activity Numbers assigned to this activity are as follows:

Pharmacists: JA4008424-0000-26-089-H01-P

Pharmacy Technicians: JA4008424-0000-26-089-H01-T

Credits: 2 contact hour(s) (0.2 CEU(s)) of continuing education credit.

Credit Types:

Pharmacy - 2 Credits

Type of Activity: Knowledge

Media: Computer-Based Training (i.e., online courses)

Estimated time to complete activity: 2 contact hour(s) (0.2 CEU(s)), including Course Test and course evaluation

Release Date: June 15, 2026 Expiration Date: June 27, 2027

Target Audience: This educational activity is for Pharmacists and Pharmacy Technicians

How to Earn Credit: From June 15, 2026, through June 27, 2027, participants must:

Read the “learning objectives” and “author and planning team disclosures;”

Take the “Educational Activity Pre-Test;”

Study the section entitled “Educational Activity;” and

Complete the Educational Activity Post-Test and Activity Evaluation. The Educational Activity Post-Test will be graded automatically. Following successful completion of the Educational Activity Post-Test with a score of 70% or higher, a statement of participation will be made available immediately. (No partial credit will be given.)

CE Credits: Credits for this course will be uploaded to CPE Monitor^® for pharmacists and pharmacy technicians.

Statement of Need

Clostridioides difficile infection is a hospital-acquired infection. It continues to pose significant challenges in healthcare settings, with subsequent increases in morbidity, mortality, and healthcare costs. Effective treatments require comprehensive knowledge and practical strategies to prevent and manage Clostridioides difficile infection.

Learning Objectives: Upon completion of this educational activity, participants should be able to:

Describe the underlying pathophysiology of and risk factors for Clostridioides difficile infection (CDI)

Identify methods by which to prevent CDI

Compare and Contrast management strategies for CDI

Recall methods by which to educate patients and caregivers on the prevention and treatment of CDI

Disclosures

The following individuals were involved in planning, developing, and/or authoring this activity: L. Austin Fredrickson, MD, FACP; and Pamela Sardo, PharmD, BS. None of the individuals involved in developing this activity has any conflicts of interest or financial relationships related to the subject matter. There are no financial relationships or commercial or financial support relevant to this activity to report or disclose by RxCe.com or any of the individuals involved in the development of this activity.

Educational Activity Pre-Test

Which of the following strategies can be used to prevent Clostridioides difficile infection (CDI) in hospital settings?

Allow healthcare providers to order high-risk antibiotics without approval

Avoid using private rooms for patients with CDI

Test all patients in the hospital for CDI, even those without significant diarrhea

Conduct and analyze CDI surveillance data, providing regular reports to key stakeholders

Which of the following is recommended by the American College of Gastroenterology for treating nonsevere CDI infections?

IV vancomycin 20 mg/kg Q12H for 7 days

Oral vancomycin 125 mg four times a day for 10 days

Oral fidaxomicin 1000 mg once daily for 7 days

IV metronidazole 500 mg twice daily for 10 days

The IDSA/SHEA guidelines prefer ____________ to be used to treat a first episode of CDI, given its safety and efficacy.

fidaxomicin

rifamycin

vancomycin

metronidazole

Educational Activity

Strategies for Managing Clostridioides difficile Infections

Introduction

Clostridioides difficile infection is a hospital-acquired infection. It continues to pose significant challenges in healthcare settings, with subsequent increases in morbidity, mortality, and healthcare costs. Pharmacy teams play pivotal roles in Clostridioides difficile infection management through the application of antimicrobial stewardship and infection control and the provision of patient education. This continuing education activity aims to provide pharmacists and pharmacy technicians with comprehensive knowledge and practical strategies to effectively prevent and manage Clostridioides difficile infection. The pathophysiology and epidemiology of Clostridioides difficile infection will be reviewed, and detailed diagnostic and management strategies will be discussed.

Epidemiology and Etiology

Clostridioides difficile infection (CDI) is among the most prevalent hospital-acquired infections.¹ It leads to increases in morbidity, mortality, and healthcare costs.^1,2 These infections are so serious that the Centers for Disease Control and Prevention (CDC) has deemed Clostridioides difficile (C. difficile) an urgent threat to public health which requires aggressive action.^1,2 The most recent guidelines for managing CDI were updated in 2021 by the American College of Gastroenterology (ACG) and the Infectious Diseases Society of America/Society for Healthcare Epidemiology of America (IDSA-SHEA).^3,4

Clostridioides difficile is a gram-positive, obligately anaerobic, spore-forming bacterium commonly found in hospitals and long-term care facilities due to high antimicrobial use and contamination with C. difficile spores.^5,6 In these settings, CDIs account for approximately 15-20% of all cases of antibiotic-associated diarrhea.⁶ This includes conditions ranging from mild diarrhea to severe pseudomembranous colitis (PMC).⁶

In 2017, over 460,000 cases of CDI were documented in the United States (US).⁵ While the incidence of healthcare-associated CDI has decreased in recent years, the incidence of community-acquired CDI has risen, now accounting for up to 40% of all cases.^5,6 Multiple recurrent CDI has increased disproportionately, with an 189% increase in the US between 2001 and 2012; in contrast, CDI increased by 46% at this time.⁶ The emergence of more virulent strains, such as ribotype 027, has contributed significantly to the CDI epidemic, leading to more severe illness and higher relapse rates.⁶

Clostridioides difficile is most commonly transmitted via the fecal-oral route when spores are ingested.⁷ Initially linked to clindamycin, ampicillin, and cephalosporins, CDI is often associated with second and third-generation cephalosporins and fluoroquinolones.⁵ Some antimicrobials, including piperacillin/tazobactam, are associated with fewer cases.⁵ However, all antibiotics put patients at some risk of CDI, as they can upset normal gut flora.^2,5 Infections are most likely to occur during antibiotic therapy or shortly after treatment ends.⁷ However, even after therapy, patients remain at risk and can develop C. difficile for up to three months following antibiotic exposure.² Despite the overall decline in CDI rates, the persistence of these virulent strains underscores the importance of infection prevention programs and the reduction of modifiable risk factors, such as fluoroquinolone use, to mitigate the spread of resistant C. difficile strains.⁶

Risk Factors

Numerous host—and therapy-related factors may put patients at risk of developing CDI. The most pertinent risks include older age (65 years or older), exposure to the healthcare environment, and exposure to antibiotics.² CDI risk factors are summarized in Table 1 and described in more detail below.^2,5,7,8

Table 1

CDI Risk Factors^2,5,7,8

Initial CDI Infections	Recurrent CDI Infections
Recent healthcare exposure	Antibiotic exposure after initial CDI episode
Advanced age (65+ years old)	Advanced age (65+ years old)
Hospitalization	Prolonged or recent stay in a healthcare facility
Acid-suppression therapy	Acid-suppression therapy
Immunosuppression	Infection with a hypervirulent strain
Abdominal surgery/nasogastric tube	Prior episode of CDI
Diabetes mellitus
End-stage renal disease
Inflammatory bowel disease

Antibiotic Use

Meta-analyses show differences in CDI risk by antibiotic-use setting and region.⁸ Clindamycin, cephalosporins, carbapenems, fluoroquinolones, and trimethoprim/sulphonamides minimally double the CDI risk in hospital settings.⁸ In community settings, clindamycin increases CDI risk by 8 to 20 times and cephalosporins and quinolones by 3 to 5 times.⁸ Macrolides significantly increase community-associated CDI risk but not hospital-associated CDI risk.⁸ Tetracyclines and aminoglycosides are not significantly associated with CDI in either setting.⁸

Use of Gastric Acid Suppressors and Other Drugs

Proton pump inhibitors (PPIs), commonly used for acid-related gastrointestinal disorders, have been linked to CDI and recurrent CDI (rCDI).⁸ Systematic reviews and meta-analyses report significant associations between PPI use and CDI, with varying strengths of association.⁸ Causality cannot be determined due to confounding variables surrounding gastric acid suppressor use, including polypharmacy and comorbidities.⁸ While it is recommended to avoid the unnecessary use of PPIs, patients do not need to stop acid suppression therapy solely to prevent CDI.² The role of NSAIDs in CDI risk is inconsistent.⁸ While aspirin is not significantly associated with CDI in the community, corticosteroids are, as noted in one meta-analysis.⁸ Non-selective NSAIDs (not including COX-2 inhibitors) have been associated with CDI.⁸

Age

Increased age is a significant risk factor for both incident CDI and recurrent CDI.⁸ In 2011, CDI rates in the USA were four times higher among adults aged 65 and older than among those aged 45–65, and thirteen times higher than among those aged 18–44.⁸ Older age has also been linked to a higher risk of CDI with the virulent BI/NAP1/027 strain and rCDI.⁸

Comorbidities

Various comorbidities increase the risk of community-associated CDI, including inflammatory bowel disease, diabetes, leukemia or lymphoma, renal failure, and solid cancer.⁸ Lower 25-hydroxyvitamin D (25(OH)D) levels are linked to increased susceptibility to infectious diseases, but the evidence for an association with CDI is limited.⁸ Some studies suggest a significant link between low 25(OH)D and rCDI, but this is based on a few studies and does not differentiate between hospital and community settings.⁸

Clinical Characteristics and Interventions

Exposure to healthcare settings is a well-known risk factor for CDI.⁸ Longer hospital stays are strongly associated with exposure to C. difficile spores and colonization. However, study results on the length of stay as a determinant for CDI are inconsistent.⁸ Some studies show that CDI patients have hospital stays 2–4 times longer than non-CDI patients, while others find no difference.⁸ Invasive procedures such as abdominal surgery, nasogastric tube placement, and mechanical ventilation are associated with prolonged hospitalization and increased CDI risk.⁸ Age, systemic antibiotic treatment, leukocyte count, albumin levels, and temperature at diagnosis are prognostic factors associated with poor outcomes.⁸

Pathophysiology of CDI

Three key events are required for CDI development: exposure to antimicrobial agents (which disrupt normal gut flora), exposure to toxigenic C. difficile, and a third factor, such as a virulent strain, specific antimicrobial exposure, or inadequate immune response.⁵ The host immune response, especially the serum IgG antibody response to toxin A, significantly influences susceptibility to CDI.⁵ Individuals with higher antibody levels tend to be asymptomatic carriers, while those with lower levels are more likely to develop symptomatic CDI and experience higher recurrence rates.¹

When toxigenic C. difficile spores are ingested, they can survive the stomach's acidity, germinate in the small intestine, and colonize the lower intestinal tract.⁵ Two major toxins are then produced, toxin A (an enterotoxin) and toxin B (a cytotoxin), that disrupt the epithelial-cell barrier, leading to diarrhea and pseudomembrane formation.⁵ Toxin A is a potent neutrophil chemoattractant.⁵ Studies indicate that toxin B is the more crucial virulence factor, as clinical disease can occur with toxin A-negative but not toxin B-negative strains.⁵ Cytoskeleton disruption results in loss of cell shape, adherence, and tight junctions, causing fluid leakage.⁵

Clinical Presentation and Diagnosis

Clinical Manifestations

Diarrhea is the most common symptom of CDI, characterized by stools that are rarely bloody and may be unformed, watery, or mucoid.⁵ CDI is often associated with a distinctive odor.⁵ Other clinical signs include fever (28% of cases), abdominal pain (22%), and leukocytosis (50%).⁵ It is important that patients who present with new and unexplained diarrhea be evaluated for potential CDI.² CDI recurs in about 15-30% of treated cases, either as relapses with the same strain or reinfections with a new strain, largely due to antibiotics' continued disruption of the normal fecal microbiota.⁵

Diagnosis

Per the ACG guidelines, only individuals with symptoms that suggest active CDI should be tested.³ This includes unexplained, new-onset diarrhea.² CDI testing algorithms should include a highly sensitive and specific testing modality to differentiate between colonization and active infection.⁵ CDI diagnosis combines clinical criteria and laboratory tests.⁵ The criteria include (1) diarrhea (≥3 unformed stools per 24 hours for ≥2 days) without another known cause and (2) detection of toxin A or B, toxin-producing C. difficile by nucleic acid amplification testing (NAAT, such as PCR), or by culture, or visualization of pseudomembranes in the colon.⁵ Endoscopy can rapidly diagnose suspected PMC in severely ill patients, but a negative result does not rule out CDI.⁵

Table 2 provides the sensitivity and specificity of diagnostic tests for CDI.⁵ Clinicians should note that no single test for C. difficile and its toxins offers high sensitivity, specificity, and rapid results.¹ Enzyme immunoassays (EIAs) for toxins often lack sensitivity, and repeated stool testing is not recommended.⁵ NAATs are rapid and sensitive but may detect colonization without active CDI.⁵ If a NAAT is negative, the patient does not have CDI, but testing should be done to confirm CDI if this test is positive.² Empirical treatment is advised if CDI is strongly suspected and stool testing is delayed. Testing asymptomatic patients is generally discouraged, and "tests of cure" post-treatment are not recommended since many patients remain carriers without active disease.⁵

Table 2

Relative Sensitivity and Specificity of Diagnostic Tests for Clostridioides difficile Infection (CDI)⁵

Type of Test	Relative Sensitivity	Relative Specificity	Notes
Stool culture for C. difficile	++++	+++	Most sensitive test; specificity of ++++ if the C. difficile isolate tests positive for toxin; turnaround time too slow for practical use
Cell culture cytotoxin test on stool	+++	++++	With clinical data, it is diagnostic of CDI; highly specific but not as sensitive as stool culture; slow turnaround time
Enzyme immunoassay for toxins A and B in stool	++ to +++	+++	With clinical data, it is diagnostic of CDI; rapid results, but not as sensitive as stool culture or cell culture cytotoxin test
Enzyme immunoassay for C. difficile common antigen in stool	+++ to ++++	+++	Detects glutamate dehydrogenase found in toxigenic and nontoxigenic strains of C. difficile and other stool organisms; more sensitive and less specific than enzyme immunoassay for toxins; requires confirmation with a toxin test; rapid results
Nucleic acid amplification tests for C. difficile toxin A or B gene in stool	++++	+++	Detects toxigenic C. difficile in stool; widely used in the United States for clinical testing; more sensitive than enzyme immunoassay toxin testing; a marked increase in CDI diagnoses when implemented
Colonoscopy or sigmoidoscopy	+	++++	Highly specific if pseudomembranes are seen; insensitive compared with other tests

Note: ++++, >90%; +++, 71–90%; ++, 51–70%; +, ~50%.

Classification of CDI

The ACG guidelines recommend various criteria for classifying severe CDI infection, including a white blood cell count >/ 15,000 or a serum creatinine >1.5 mg/dL.⁵ Additionally, they define fulminant infections as occurring in patients who meet the criteria for a severe CDI and have hypotension, shock, ileus, or megacolon.⁵ Criteria to determine CDI severity are detailed in Table 3.²

Table 3

Criteria for CDI Severity²

Definition	Supportive Data
Nonsevere infection	WBC </15,000 cells/mL and SCr <1.5 mg/dL
Severe infection	WBC >15,000 cells/mL or SCr >1.5 mg/dL
Fulminant infection	Hypotension, shock, ileus, or megacolon

Prevention and Management of CDI

Prevention

Probiotics are live microorganisms that provide health benefits to the host when consumed in adequate amounts.⁵ They work by colonizing and normalizing disturbed intestinal microbial communities, competitively excluding pathogens, producing bacteriocins (antibiotics), and modulating the immune system and various metabolic functions to maintain gut mucosa integrity.⁵ The ACG guidelines do not recommend that probiotics be used to prevent CDI in patients being treated with antibiotics as primary prevention or to use them as secondary prevention in patients with a previous case(s) of CDI.³ Probiotics are sold as dietary supplements with claims to improve gut health, without the stringent Food and Drug Administration (FDA) oversight required for manufactured drugs.³ Consequently, manufacturers often avoid conducting clinical trials to support specific uses, leading to suboptimal quality control, product labeling, and efficacy inconsistencies.³ Furthermore, recent microbiome analyses suggest that probiotics may hinder normal colon recolonization after antibiotic treatment.³

Primary Prevention

A 2017 Cochrane review examined 31 studies on probiotics for primary prevention of CDI in adults and children receiving antibiotics, involving 8,672 participants.⁹ Most studies (27 out of 31) had a high or unclear risk of bias and missing data.⁹ The review concluded that probiotics offer a modest benefit (number needed to benefit = 42), but post hoc subgroup analysis showed benefits only in trials with baseline CDI risk >5%.⁹ Five studies were found to heavily influence results, with CDI baseline risk >15%, questioning their applicability to typical hospital settings.⁹

A meta-analysis by McFarland, et al., focused on a specific probiotic combination comprising three lactobacilli strains.¹⁰ Out of three randomized controlled trials (RCTs), only one showed efficacy for primary CDI prevention.¹⁰ Another recent meta-analysis of 19 RCTs found that probiotics reduced CDI risk in hospitalized patients, particularly when started within 2 days of starting antibiotics, with a 70% risk reduction.¹¹ However, this benefit dropped to 30% if probiotics were started after two days.¹¹ Notably, these studies excluded immunocompromised patients, those undergoing cancer treatments, ICU patients, and individuals with preexisting gastrointestinal conditions.¹¹

Secondary Prevention

The 2017 PICO trial included 33 patients with initial mild-to-moderate CDI.¹² Patients were randomized to receive either a 28-day course of a 4-strain probiotic or placebo alongside standard anti-CDI therapy.⁹ The trial found no significant difference in CDI recurrence rates between the two groups.¹² A 2000 study included 168 patients with recurrent CDI who received a 28-day course of S. boulardii or placebo in addition to anti-CDI therapy.¹³ Benefits were observed only in the subgroup treated with high-dose vancomycin and S. boulardii (16.7% recurrence vs. 50% with placebo).¹³ Due to the small sample size, firm conclusions could not be drawn.¹³

Guideline-Based Management of CDI

The American College of Gastroenterology (ACG) and the Infectious Diseases Society of America (IDSA) jointly issued guidelines for the management of CDI in adult patients. The Society for Healthcare Epidemiology of America (SHEA) also issued guidelines.^3,4 Both sets of guidelines were published in 2021.^3,4

Treatment of Nonsevere CDI

In treating CDI, it is important to stop any antibiotics that may have caused the infection, if feasible, to reduce the risk of recurrent CDI.² The ACG guidelines make three recommendations pertaining to the treatment of nonsevere CDI:³

Oral vancomycin 125 mg 4 times daily for 10 days to treat initial episodes of nonsevere CDI

Oral fidaxomicin 200 mg twice daily for 10 days to treat initial episodes of nonsevere CDI

Oral metronidazole 500 mg three times daily for 10 days to be considered for treatment of initial nonsevere CDI in low-risk patients

The IDSA/SHEA guidelines recommend fidaxomicin for a first episode over a standard course of vancomycin.⁴ They state vancomycin is acceptable, but fidaxomicin is preferred, given its safety and efficacy.⁴

Fidaxomicin and vancomycin have shown efficacy in treating nonsevere CDI.³ One double-blind, randomized controlled trial (RCT) found that fidaxomicin 200 mg twice daily for 10 days was non-inferior to vancomycin 125 mg four times daily for 10 days.¹⁴ In this study, the rate of recurrence within 30 days was significantly lower with the use of fidaxomicin.¹⁵ A second study found no difference in clinical failure or recurrence between fidaxomicin and vancomycin treatments.¹⁵ In contrast, the role of metronidazole is less definitive.³ A 2017 review of 22 trials of patients with nonsevere disease found vancomycin was more effective than metronidazole for symptomatic cure, and fidaxomicin was more effective than vancomycin.¹⁶ Vancomycin has the benefit of being relatively inexpensive, while fidaxomicin leads to lower rates of recurrence, which ultimately can result in lower costs.³ Patients who are younger and have few to no comorbidities may be able to utilize metronidazole.³

Other antibiotics, including rifaximin and tigecycline, are not recommended for treating CDI.³ Additionally, loperamide without concurrent antibiotic use is not recommended.³ In some studies, patients either experienced complications of therapy or died after receiving antimotility agents without concurrent antibiotics.³ The guidelines state that loperamide or antimotility agents could be used as needed in patients who have been started on anti-CDI therapy.³ However, they should be avoided in fulminant CDI.³ Other agents that may be helpful in the recovery phase include psyllium husk, as fiber helps to regulate intestinal barrier function and inflammation, and has shown benefits for post-infection IBS symptoms.³

Treating Severe CDI

The following treatment options are recommended by the ACG guidelines:³

As initial therapy for severe CDI, we recommend vancomycin 125 mg 4 times a day for 10 days

As initial therapy for severe CDI, we recommend fidaxomicin 200 mg twice daily or 10 days

One meta-analysis aimed to compare treatments for non-multiple recurrent CDI in adults, examining both primary cure and recurrence rates.¹⁷ This study included 24 randomized controlled trials with 5,361 patients, assessing 13 different treatments. Fidaxomicin had higher sustained cure rates than vancomycin, but vancomycin was more cost-effective.¹⁸ In terms of medication dosing, another study that included 46 hospitalized patients with C. diff colitis showed no differences in rates of cure, response time, or recurrence rates between vancomycin 125 mg and 500 mg given four times daily for 10 days.¹⁸

Fidaxomicin was shown not to be inferior to vancomycin for clinical cure at the end of therapy in patients with severe C. difficile infections.¹⁹ A retrospective study of critically ill patients indicated a similar response to fidaxomicin as in general medical wards, but one-third of the 36 patients with severe or fulminant CDI experienced treatment failure.²⁰ A larger retrospective chart review comparing fidaxomicin and oral vancomycin found no significant difference in clinical failure or recurrence rates and no differences in mortality at 30 or 180 days.²¹ Most studies utilized 10-day treatment courses for both drugs, which seems adequate for the majority of patients.³

Metronidazole is not recommended for severe CDI as it is inferior to vancomycin in multiple randomized controlled trials and cohort studies.³ A retrospective study revealed that patients with severe CDI who received vancomycin only after failing metronidazole had longer hospital stays, higher rates of acute kidney injury, and lower cure rates compared to those who received vancomycin from the start.²² Additionally, a large cohort study found that vancomycin reduced the 30-day all-cause mortality rate from 19.8% to 15.3% compared to metronidazole.²³

Fulminant CDI

The following are ACG guidelines for the management of fulminant CDI:³

Patients with fulminant CDI should receive medical therapy that includes adequate volume resuscitation and treatment with 500 mg of oral vancomycin every 6 hours daily for the first 48–72 hours. Combination therapy with parenteral metronidazole 500 mg every 8 hours can be considered

For patients with ileus, the addition of vancomycin enemas (500 mg every 6 hours) may be beneficial

A multidisciplinary care team is necessary to ensure optimal patient outcomes in patients with fulminant CDI. This team should include the following specialties: critical care, gastroenterology, and infectious disease, among others.³ A dearth of evidence recommends vancomycin 500 mg every 6 hours to treat fulminant CDI, but numerous guidelines have suggested this.³ The guidelines suggest treating with this higher dosage for 48-72 hours is reasonable.³ If clinical improvement is achieved, the dose of vancomycin can be decreased to 125 mg every 6 hours for 10 more days.³ Patients who do not respond should be reevaluated for a different approach.³

A vancomycin enema at a concentration of 500 mg per 100 mL of saline is recommended for patients with ileus.³ However, there is little literature to support this decision.³ Theoretically, delivering the drug via enema is beneficial over orally administered medications, as these may not pass beyond the upper GI tract.³

While vancomycin monotherapy is superior to metronidazole for severe CDI, guidelines recommend adding intravenous metronidazole to oral vancomycin for fulminant disease.³ A single-center retrospective study found lower mortality rates in ICU patients with fulminant CDI who received vancomycin and metronidazole compared to vancomycin alone.³ However, a more recent multicenter study found no added benefit of intravenous metronidazole regarding colectomy, death, or recurrence rates.³ Intravenous metronidazole may still be beneficial in cases of paralytic ileus, where oral vancomycin transit is impaired, as it can achieve therapeutic concentrations in the inflamed colon.³

Fidaxomicin is not inferior to vancomycin for severe CDI, but no data support its use in fulminant CDI.³ While case reports suggest that adjunctive intravenous immunoglobulin might help in refractory fulminant CDI, a larger study showed no improvement in outcomes.³ Additionally, a retrospective cohort study indicated that bedside colonic lavage with polyethylene glycol solution might reduce in-hospital mortality compared to colectomy, although this is not recommended for routine use.³ Table 4 summarizes the IDSA-SHEA treatment recommendations for various CDI conditions.

Table 4

IDSA-SHEA Treatment Recommendations

Infection Type	Preferred Regimen	Alternative Regimen	Additional Recommendations	ADEs and Use Considerations
Initial	Fidaxomicin: 200 mg PO BID x 10 days	Vancomycin: 125 mg PO QID x 10 days	For nonsevere CDI: metronidazole 500 mg PO TID x 10-14 days (if other agents not available)	Fidaxomicin: minimal systemic absorption; hypersensitivity potential if macrolide allergy present Oral vancomycin: Minimal systemic absorption; consider monitoring trough levels for systemic absorption and drug accumulation in patients with renal failure or duration of use more than 10 days Metronidazole: avoid repeated or prolonged courses owing to the risk of neurotoxicity. Avoid alcohol during treatment and for 3 days after therapy completion
First Recurrence	Fidaxomicin: 200 mg PO BID x 10 days or Fidaxomicin 200 mg PO BID x 5 days, then once every other day for 20 days	Vancomycin: 125 mg PO BID x 10 days or vancomycin 125 mg PO QID x 10-14 days, then BID x 7 days, then once daily x 7 days, then every 2-3 days for 2-8 weeks	Adjunctive bezlotoxumab 10 mg/kg IV given once during antibiotic therapy in select patients	Bezlotoxumab: use only in patients with a history of CHF when benefits > risks.
Second Recurrence	Fidaxomicin: 200 mg PO BID x 10 days or Fidaxomicin 200 mg PO BID x 5 days, then once every other day for 20 days or Vancomycin: 125 mg PO BID x 10 days or vancomycin 125 mg PO QUID x 10-14 days, then BID x 7 days, then once daily x 7 days, then every 2-3 days for 2-8 weeks		Reserve FMT for patients who received appropriate antibiotics for 2+ episodes of recurrence (or 3 CDI) Adjunctive bezlotoxumab 10 mg/kg IV given once during antibiotic therapy in select patients
Fulminant	Vancomycin 500 mg PO or via nasogastric tube QID and metronidazole 500 mg IV Q8H		Surgical intervention may be needed	Rectal vancomycin may be systemically absorbed in cases of inflamed intestinal mucosa

Surgical Options and Fecal Microbiota Transplantation

for Severe and Fulminant CDI

The ACG guidelines suggest that for patients who require surgical intervention, either a total colectomy with an end ileostomy and a stapled rectal stump or a diverting loop ileostomy with colonic lavage and intraluminal vancomycin be used depending on clinical circumstances, the patient's estimated tolerance to surgery, and the surgeon's clinical judgment.³ Fecal microbiota transplant (FMT) be considered for patients with severe and fulminant CDI refractory to antibiotic therapy, in particular when patients are deemed poor surgical candidates.³

Data from surgical registries suggest that diversion does not provide a clear survival advantage over total colectomy for fulminant CDI.³ It is crucial to avoid delayed surgical intervention, which increases postoperative mortality and premature surgery, assuming that diversion is low risk.³ Institutions should review their outcomes with diversion to ensure mortality or recurrence rates do not exceed those for total colectomy.³

For patients with fulminant CDI, after pseudomembrane resolution is confirmed by colonoscopy, a final FMT should complete therapy.³ If hospital discharge occurs before complete resolution, oral vancomycin or fidaxomicin should continue for at least five days, followed by outpatient FMT.³ The availability of donor stool from stool banks has improved treatment promptness.³ Clinical response to FMT can be monitored by stool form, frequency, presence of pseudomembrane, leukocytosis, and C-reactive protein levels. FMT should be considered after 48–72 hours of maximum medical therapy for severe and fulminant CDI, as it is less invasive and avoids surgical risks.³ Nonetheless, surgery remains standard for refractory cases, especially with colonic toxic megacolon, ischemia, or perforation.³

Antimicrobial Stewardship and Prevention Strategies

The following are recommendations to assist hospital facilities with CDI prevention:²⁴

Essential Practices for CDI Prevention: Conduct and analyze CDI surveillance data, provide regular reports to key stakeholders, reduce the risk of CDI by recommending they avoid unnecessary antibiotic exposure, and select lower-risk antibiotics.

Antimicrobial Stewardship: Implement programs that require prior approval for the administration of high-risk antibiotics, such as fluoroquinolones and cephalosporins, particularly during CDI outbreaks. Target patients with a history of CDI for special attention.

Diagnostic Stewardship: Develop criteria for C. difficile testing, avoid testing in patients without significant diarrhea or recent testing, and educate healthcare providers on appropriate test use and interpretation.

Contact Precautions: Use hand hygiene, gowns, gloves, and private rooms for CDI patients. Cohort patients when private rooms are unavailable and ensure proper cleaning and disinfection of shared equipment.

Environmental Cleaning: Implement protocols for cleaning and disinfecting patient environments and equipment. Consider using sporicidal agents in outbreak settings and monitor the adequacy of cleaning practices.

Alert System: Establish a laboratory-based alert system to notify infection preventionists and clinical personnel of CDI cases immediately, ensuring timely implementation of contact precautions.

CDI Surveillance: Conduct and analyze CDI surveillance data, providing regular reports to key stakeholders to inform and improve prevention efforts.

Education: Educate healthcare personnel, environmental service staff, patients, and their families about CDI, including its risks, transmission, and prevention measures.

Hand Hygiene Compliance: Measure and ensure compliance with hand hygiene practices in accordance with CDC or WHO guidelines, emphasizing glove use and appropriate handwashing after patient contact.

The Role of the Pharmacist and Pharmacy Technicians

Pharmacists and pharmacy technicians play important roles in caring for patients with CDI. One study assessed whether a pharmacist-led antimicrobial stewardship program (ASP) could improve adherence to CDI treatment guidelines and clinical outcomes.²⁵ Conducted at a single center, the retrospective, quasi-experimental study analyzed patients with CDI before and after implementing an ASP initiative, which involved prospective audits and feedback.²⁶ Guideline-based treatment recommendations were communicated to treatment teams and documented in pharmacy progress notes for all CDI patients.²⁶ The primary goal was to measure the proportion of patients receiving guideline-compliant treatments within 72 hours of diagnosis. Secondary objectives included evaluating clinical outcomes such as length of stay (LOS), infection-related LOS, 30-day readmission rates, and in-hospital mortality.² Out of 233 patients evaluated, the post-intervention group showed a significant increase in guideline-adherent treatments within 72 hours (42% before vs. 58% after, p=0.02).²⁶ However, there were no differences in clinical outcomes or the use of laxatives, promotility agents, or proton pump inhibitors within 72 hours of diagnosis. The authors concluded that a pharmacist-led stewardship initiative successfully improved adherence to CDI treatment guidelines.²⁶

Pharmacists can provide education on proper hand hygiene, emphasizing the importance of washing with soap and water to reduce transmission.²⁶ Another role is to promote gut health through dietary advice and the cautious use of probiotics.²⁶ Pharmacists can also advocate for targeted antibiotic therapy, recommend discontinuing unnecessary PPIs, and stress the importance of completing prescribed courses.²⁶ Additionally, they can help patients access affordable medication regimens and facilitate smooth transitions between different phases of care by educating post-acute facilities and caretakers on proper medication management and adherence.²⁶ Pharmacy technicians can help pharmacists identify patients with diarrhea who may need referral to their primary care provider. They can also encourage proper hand hygiene for patients presenting with symptoms of diarrhea.

Summary

Clostridioides difficile infection is among the most prevalent hospital-acquired infections. It continues to pose significant challenges in healthcare settings, with subsequent increases in morbidity, mortality, and healthcare costs. Pharmacy teams play pivotal roles in CDI management through the application of antimicrobial stewardship and infection control and the provision of patient and caregiver education.

References

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Johnson S, Lavergne V, Skinner AM, et al. Clinical Practice Guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 Focused Update Guidelines on Management of Clostridioides difficile Infection in Adults. Clin Infect Dis. 2021;73(5):e1029-e1044. doi:10.1093/cid/ciab549

Gerding DN, Johnson S. Clostridioides difficile Infection, Including Pseudomembranous Colitis. In: Loscalzo J, Fauci A, Kasper D, Hauser S, Longo D, Jameson J. eds. Harrison's Principles of Internal Medicine, 21e. McGraw-Hill Education; 2022.

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Surawicz CM, McFarland LV, Greenberg RN, et al. The search for a better treatment for recurrent Clostridium difficile disease: Use of high-dose vancomycin combined with Saccharomyces boulardii. Clin Infect Dis. 2000;31:1012–7.

Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364:422–31.

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