Antibiotic-Associated Diarrhea and Clostridioides difficile Infection

Clinical Snapshot

Clostridioides difficile (formerly Clostridium difficile) is a spore-forming, toxin-producing anaerobic bacillus and the leading identifiable cause of antibiotic-associated diarrhea and health-care-associated infectious diarrhea.^[1] It colonizes the gut of roughly 3-5% of healthy adults without causing symptoms, and colonization rates are substantially higher in hospitalized and long-term-care populations — colonization alone is not infection and should never be tested for or treated. Disease occurs when antibiotic exposure (or another disruption of the normal colonic flora) allows a toxigenic strain to proliferate and produce toxin A and/or toxin B, causing mucosal inflammation that ranges from mild watery diarrhea through pseudomembranous colitis to fulminant colitis with toxic megacolon.^[1] This chapter is deliberately complementary to the general Acute Diarrhea in Adults chapter: it covers only what is specific to antibiotic-associated diarrhea and CDI — risk-factor identification, the testing methodology, severity-based treatment selection, the recurrence ladder, and the infection-control/stewardship messaging pharmacists are positioned to reinforce.

Recognize the Condition

Typical presentation

New or worsening watery diarrhea — by convention, three or more unformed stools within a 24-hour period^[2] — developing during or after antibiotic exposure (most commonly within the course, but onset up to 8-10 weeks after the antibiotic was stopped is well described), often with lower abdominal cramping, mild fever, and leukocytosis. Symptoms unrelated to another clear cause (laxative use, an enteral feeding change, a new medication known to cause diarrhea) should raise suspicion.

Two presentations that are easy to conflate

Simple antibiotic-associated diarrhea (non-CDI)

Mild, self-limited loosening of stool from the antibiotic's direct effect on gut flora and motility, without toxin-mediated colitis. Usually resolves on its own once the antibiotic course finishes and needs no specific testing or treatment beyond the general supportive care covered in the Acute Diarrhea in Adults chapter.

Clostridioides difficile infection

Toxin-mediated colitis confirmed by testing (or by pseudomembranes/toxic megacolon) in a patient with clinically significant diarrhea. Requires its own antibiotic regimen, its own infection-control precautions, and specific antimicrobial-stewardship follow-up — this is the presentation this chapter is built around.

Fulminant presentation

Hypotension or shock, ileus (which can paradoxically present with reduced stool output despite severe colitis — a common diagnostic trap), or toxic megacolon. This is a surgical/critical-care emergency, not an outpatient management scenario.^[3]

Risk Factors

Recent or current antibiotic exposure — the dominant risk factor. Fluoroquinolones, clindamycin, and broad-spectrum cephalosporins carry the highest risk of any antibiotic class because of how broadly they suppress the protective anaerobic colonic flora; penicillins (including amoxicillin/clavulanate) also carry meaningful risk.^[1]
Proton pump inhibitor use — gastric acid suppression is thought to allow more vegetative C. difficile organisms to survive transit to the colon.^[1]
Hospitalization or residence in a long-term-care facility, and duration of stay — the main source of both exposure to spores and exposure to broad-spectrum antibiotics.^[1]
Age 65 years or older.
Immunosuppression — post-transplant immunosuppressive therapy, active chemotherapy, or another significantly immunocompromising condition.^[1]
Inflammatory bowel disease, or a history of bowel surgery.^[1]
A prior episode of CDI — the single strongest predictor of a future episode, and the key factor that should push toward fidaxomicin over vancomycin at the next episode.
Additional factors specifically associated with more severe disease if CDI occurs: older age, immunosuppressive therapy, recent surgery, and infection with a hypervirulent strain (e.g., NAP1/BI/027, historically responsible for a large share of Ontario outbreaks) — note that infection prevention and control practices are the same regardless of strain.^[1]

Red Flags & Refer

Escalate to emergency/inpatient care rather than managing as an outpatient for any of the following:

Hypotension or shock.
Ileus or radiographic/clinical toxic megacolon — remember that ileus can mean reduced stool output despite severe underlying colitis; don't be falsely reassured by "improving" diarrhea in a patient who looks systemically unwell.
Severe or rapidly worsening abdominal pain, distension, or peritoneal signs.
Marked leukocytosis (white blood cell count well above 15 ×10⁹/L) or a rapidly rising creatinine.
Any of the above in a patient already being treated for CDI — this is fulminant disease and needs urgent infectious diseases, general surgery, and/or critical care involvement, not a simple regimen change.^[3]
Signs of sepsis out of proportion to the degree of diarrhea.
Suspected CDI in a pregnant patient, or in a patient who is immunocompromised, given the higher complication risk in both groups.

Assessment & Diagnosis

Who to test

Testing rule

Only test patients with clinically significant diarrhea — three or more unformed (Bristol type 5-7) stools within 24 hours, with no other clear explanation such as laxative use in the preceding 48 hours or an enteral feeding change.^[4]

Never test, and never treat, a formed stool or an asymptomatic patient — up to 3-5% of healthy adults, and a substantially higher proportion of hospitalized or long-term-care patients, carry C. difficile (including toxigenic strains) without disease. Testing an asymptomatic patient produces a positive result that reflects colonization, not infection, and treating it exposes the patient to unnecessary antibiotic risk without benefit.^[1]

Do not repeat testing to "prove cure" once a course is complete and the patient has clinically improved — see Monitoring & Follow-Up.

Why a single NAAT is not enough on its own

A nucleic acid amplification test (NAAT/PCR) is highly sensitive and detects the genes for toxin production — it cannot distinguish a patient whose C. difficile is actively producing toxin and causing colitis from a colonized carrier who happens to harbour a toxigenic strain but is not clinically affected by it. Because of this, most laboratories use a multistep algorithm rather than NAAT alone: a glutamate dehydrogenase (GDH) antigen screen plus a toxin A/B enzyme immunoassay (EIA) run together, with NAAT used only to arbitrate discordant results (GDH-positive/toxin-EIA-negative), or a NAAT-first strategy with reflex toxin EIA on NAAT-positive specimens.^[4] A positive toxin EIA reflects active toxin production and correlates far better with genuine clinical disease than a NAAT-only result; interpret a NAAT-positive/toxin-EIA-negative result in the context of the whole clinical picture rather than as automatic proof of infection needing treatment.

Confirmed case definition

A confirmed case is diarrhea meeting the frequency definition above with laboratory confirmation of toxin A or B (by a validated EIA, NAAT for the toxin genes, or cytotoxicity assay); or visualization of pseudomembranes on sigmoidoscopy/colonoscopy; or histological/pathological diagnosis of pseudomembranous colitis; or a diagnosis of toxic megacolon.^[2]

Severity classification

Severity determines the treatment pathway (see Choose Initial Treatment).

Severity	Criteria
Non-severe	White blood cell count 15 ×10⁹/L or lower, and serum creatinine under 133 µmol/L (1.5 mg/dL)
Severe	White blood cell count over 15 ×10⁹/L, or serum creatinine 133 µmol/L (1.5 mg/dL) or higher
Fulminant	Hypotension or shock, ileus, or toxic megacolon

These criteria are used consistently by Canadian antimicrobial stewardship protocols and the IDSA/SHEA framework alike.^[3]^[4]

Treatment Targets

Resolve diarrhea and colitis while minimizing further disruption of the colonic microbiota.
Identify and stop the inciting antibiotic as early as clinically possible.
Prevent progression to fulminant disease, and recognize it immediately when it occurs.
Prevent recurrence — the leading long-term challenge in CDI management, occurring in roughly 1 in 5 patients after a first episode and more often after each subsequent episode.
Prevent transmission to other patients, residents, or household members through consistent infection-control practice.
Avoid unnecessary antibiotic and testing exposure in patients who are colonized but not infected, or whose diarrhea has another clear explanation.

Choose Initial Treatment

Direct treatment rule

First step for every patient: stop the inciting antibiotic

Discontinue or de-escalate the causative antibiotic as soon as clinically feasible in every case of CDI — this alone can resolve up to 25% of mild cases and improves the response to any CDI-specific therapy given.^[3]

Initial episode — non-severe or severe

1st line vancomycin 125 mg PO/NG QID x 10 days or fidaxomicin 200 mg PO BID x 10 days — both are appropriate first-line choices for an initial episode.^[3]^[5]

Prefer fidaxomicin specifically when a recurrence risk factor is present — a prior CDI episode, age 65 or older, immunocompromise, or severe disease at presentation — since fidaxomicin reduces recurrence compared with vancomycin without a difference in initial cure rate.^[5]

Metronidazole 500 mg PO/NG TID x 10 days only for non-severe disease, and only on a case-by-case basis when vancomycin and fidaxomicin are both unavailable or when cost is a genuine barrier to outpatient vancomycin access — it is no longer positioned as first- or second-line therapy given inferior efficacy, especially for severe disease.^[3]

Duration is 10 days for a typical response; extend to 14 days if the patient has improved but not fully resolved by day 10.^[3]

Fulminant disease

Not an outpatient scenario — vancomycin 500 mg PO/NG QID; if complete ileus is present or the patient is critically ill, add metronidazole 500 mg IV Q8H; if the patient cannot take anything orally or enterally, consider adding vancomycin 500 mg in 100 mL normal saline PR Q6H as a retention enema. Obtain urgent infectious diseases, general surgery, and/or critical care consultation.^[3]

Recurrence ladder

First recurrence — switch agent: if metronidazole was used for the initial episode, move to vancomycin 125 mg PO QID x 10 days; if standard vancomycin was used initially, move to fidaxomicin (standard 10-day course, or the extended-pulsed regimen), since fidaxomicin is superior to a repeat vancomycin course specifically at preventing a further recurrence after a vancomycin-treated first recurrence.^[5] A vancomycin tapered-and-pulsed regimen is a reasonable alternative, particularly if the recurrence was severe and vancomycin was already used for the primary episode.^[3]

Second or multiple recurrences — vancomycin 125 mg QID x 14 days followed by a tapered-and-pulsed regimen, or fidaxomicin (standard or extended-pulsed regimen), or a vancomycin course followed by a rifaximin chaser. Consider adding bezlotoxumab to standard-of-care antibiotics in a patient at high risk of further recurrence.^[5]

Refer for fecal microbiota transplantation after two or more recurrences, particularly when a vancomycin taper has already failed — this is the point at which restoring the colonic microbiota directly outperforms further antibiotic cycling.^[6]^[3]

Non-Pharmacologic Treatment

General measures

Avoid antimotility agents (loperamide, diphenoxylate/atropine) and promotility agents throughout active CDI — slowing transit or increasing motility can worsen toxin retention and precipitate toxic megacolon.^[3]
Discontinue the proton pump inhibitor if it is not clearly indicated — acid suppression is a modifiable CDI risk factor.^[3]
Discontinue any standing bowel protocol/stimulant laxative for the duration of active diarrhea.^[3]
For oral rehydration and dietary measures, see the Acute Diarrhea in Adults chapter — the general supportive-care approach there applies equally here.

Infection prevention and control

Initiate contact precautions at the onset of diarrhea, before test results are back — do not wait for laboratory confirmation once CDI is clinically suspected.^[1]

A single room with a dedicated toilet/commode is strongly preferred; if unavailable, only cohort with another laboratory-confirmed CDI case.^[1]
Hand hygiene: soap and water is theoretically more effective than alcohol-based hand rub at physically removing C. difficile spores from hands, but glove use for all care contact minimizes hand contamination in the first place and has been shown to reduce transmission on its own — either soap-and-water or alcohol-based hand rub after glove removal is acceptable practice, but never perform hand hygiene at a patient sink (this recontaminates hands from the sink itself).^[1]
Environmental cleaning: C. difficile spores resist many routine disinfectants and can persist in the environment for months — rooms and bathrooms of a patient/resident on precautions need a sporicidal agent, not a standard hospital disinfectant. Effective options include sodium hypochlorite (1,000-5,000 ppm) for 10-30 minutes depending on concentration, 4.5% hydrogen-peroxide enhanced-action formulation for 10 minutes, or 0.26% peracetic acid for 5 minutes.^[1]
Do not use rectal thermometers in a patient with CDI — they have been specifically linked to C. difficile spread.^[1]
Dedicate the commode chair to the patient; clean and disinfect it with a sporicide at every room clean; discard disposable equipment and dedicate toilet brushes/swabs to that room, discarding them once precautions are discontinued.^[1]
Precautions are typically maintained until a facility's infection-control team confirms discontinuation, generally once the patient has been symptom-free for a defined period — never discontinue precautions unilaterally.^[1]

Counselling patients and household/long-term-care contacts

After discharge home, person-to-person transmission within a household is uncommon — reassure patients this is not a high risk to family members with routine hygiene.^[1]
Clean the home bathroom thoroughly with a regular household cleaner; reinforce thorough handwashing with soap and water, particularly after using the bathroom and before eating, for the patient and household/facility contacts.^[1]
In long-term care specifically, reinforce that alcohol-based hand sanitizer alone does not reliably remove spores — soap-and-water handwashing at a non-patient sink remains important for both staff and the resident when feasible.
Counsel that diarrhea recurring within about 8 weeks of finishing treatment is a recognized pattern (relapse/recurrence) and should prompt a call to the prescriber rather than self-treatment with an over-the-counter antidiarrheal.

Pharmacologic Treatment Options

Drug / intervention	Role	Dose / use	Important adverse effects	Teaching points
Vancomycin, oral Preferred	1st-line, initial episode (non-severe or severe) or recurrence	125 mg PO/NG QID x 10 days (14 days if incomplete resolution by day 10)	Bitter taste, nausea, rare eosinophilia	Poorly absorbed and acts locally in the gut — not interchangeable with IV vancomycin. Has its own tapered/pulsed regimen for recurrence — see Drug Tables.
Fidaxomicin Preferred	1st-line, especially with a recurrence risk factor (prior CDI, age ≥65, immunocompromise, severe first episode)	200 mg PO BID x 10 days	Nausea, vomiting, GI upset	Lower recurrence than vancomycin; no dose adjustment for renal/hepatic impairment; minimal drug interactions. Has an extended-pulsed recurrence regimen — see Drug Tables.
Metronidazole Special situation	Non-severe disease only, case-by-case, when vancomycin/fidaxomicin unavailable or cost-prohibitive	500 mg PO/NG TID x 10 days	Metallic taste, nausea; peripheral neuropathy with prolonged/repeated use	No longer 1st- or 2nd-line — inferior efficacy, particularly for severe disease. Avoid alcohol during treatment and for the interval on current product labelling.
Rifaximin Special situation	Chaser after a vancomycin course, for a 2nd or later recurrence	400 mg PO TID x 20 days, started immediately after finishing the vancomycin course	GI upset; generally well tolerated (minimal systemic absorption)	Used only as a recurrence-prevention chaser, never as CDI monotherapy.
Bezlotoxumab Special situation	Adjunct to standard antibiotics for a patient at high risk of further recurrence	10 mg/kg IV single infusion, given alongside the antibiotic course	Infusion reactions; possible increased heart failure events — avoid in patients with a history of congestive heart failure	A monoclonal antibody against C. difficile toxin B, not an antibiotic — does not treat the acute episode on its own.

Special Populations

Pregnancy

Metronidazole is not associated with congenital malformations and can be used when indicated. Oral vancomycin has not shown adverse pregnancy effects (minimal systemic absorption) and can be used. Fidaxomicin has limited pregnancy-specific data — reserve for when it is otherwise clearly preferred (e.g., significant recurrence risk) and involve obstetric/specialist input.

Breastfeeding

Metronidazole is transferred into breast milk — many sources recommend suspending breastfeeding for the duration of a metronidazole course and resuming once treatment is complete; vancomycin is considered probably compatible given minimal oral absorption.

Older adults / long-term care

The population at highest risk for both CDI itself and for severe/fulminant disease.^[1] Have a lower threshold to classify as severe and to seek prompt medical assessment, since atypical or blunted presentations (reduced stool output with ileus, confusion rather than classic peritoneal signs) are more common. Reinforce environmental cleaning and hand-hygiene practices specifically in shared long-term-care bathrooms and commodes.

Renal impairment

Oral vancomycin needs no renal dose adjustment — it acts locally in the gut. IV metronidazole (used for fulminant disease) needs no specific renal adjustment but active metabolites can accumulate in significant hepatic impairment (see below). Fidaxomicin needs no renal dose adjustment.

Hepatic impairment

Metronidazole is hepatically metabolized — use with caution and consider dose reduction in severe hepatic impairment, particularly for the IV regimen used in fulminant disease.

Immunocompromised patients

Higher risk of both initial infection and recurrence — this alone is a reason to prefer fidaxomicin over vancomycin for an initial episode.^[5]

Monitoring & Follow-Up

Monitor clinical response — stool frequency and consistency, resolution of fever and abdominal pain — rather than repeat laboratory testing. Routine "test of cure" is not recommended: a toxin or NAAT-based stool test can remain positive for weeks after a clinically successful course, and a positive result at that point reflects residual colonization, not treatment failure.^[4] For severe or fulminant disease, monitor white blood cell count, serum creatinine, and lactate until clearly trending toward normal. Reinforce infection-control precautions and antimicrobial-stewardship messaging (see Common Errors to Avoid) at every follow-up contact. Because recurrence is common — most often within 8 weeks of completing treatment — counsel patients explicitly to seek reassessment rather than self-treat if diarrhea returns in that window, and confirm the inciting antibiotic was actually discontinued.

Treatment Failure / Next Step

Confirm the diagnosis is still correct: reconsider testing timing/interpretation, and rule out an alternative or superimposed cause of ongoing diarrhea rather than assuming the CDI regimen simply needs more time.
Failure to improve after 7 days of appropriate therapy strongly suggests an alternative diagnosis (or, less commonly, a complication) rather than a need to simply extend the same course — reassess and involve infectious diseases and/or gastroenterology.
Reassess severity at any clinical deterioration — a patient started on a non-severe regimen who develops severe or fulminant features needs immediate escalation, not a wait-and-see approach.
Confirm the inciting antibiotic was actually stopped, and reassess the full medication list for anything (a new antibiotic, an antimotility agent, an unstopped PPI) that could be undermining response.
Manage a genuine recurrence using the recurrence ladder — the specific next step depends on which agent was used for the prior episode(s) and how many recurrences have now occurred (see Clinical Decision Algorithm and Drug Tables).
After two or more recurrences, especially following a failed vancomycin taper, refer for fecal microbiota transplantation rather than cycling through further antibiotic courses indefinitely.

Common Errors to Avoid

Testing an asymptomatic patient, or a patient whose loose stool is fully explained by a laxative given in the past 48 hours, "just to be sure" — this produces false-positive-for-disease results from colonization and leads to unnecessary treatment.^[1]
Treating a positive test in a patient who has no clinically significant diarrhea, or whose symptoms have already resolved before the result returns.^[1]
Defaulting to metronidazole as first-line therapy — it is no longer preferred for any severity except a genuine access/cost-limited non-severe case.^[3]
Using loperamide or another antimotility agent for symptomatic relief during active CDI.^[3]
Missing a fluoroquinolone, clindamycin, or cephalosporin course in the medication history because it "was just a short course" — these remain the highest-risk classes even for brief exposures.^[1]
Continuing an unnecessary proton pump inhibitor through and after a CDI episode without reassessing the indication.^[3]
Ordering repeat stool testing to confirm cure — a positive result can persist for weeks after successful treatment and does not by itself indicate treatment failure.^[4]
Waiting for a positive test result before starting contact precautions in a patient with clinically suspected CDI.^[1]
Cleaning a CDI patient's room or bathroom with a standard (non-sporicidal) disinfectant.^[1]
Recommending a probiotic as a substitute for antibiotic therapy in active CDI — no probiotic has a role as CDI monotherapy.
Not recognizing that reduced stool output in a patient with worsening abdominal pain and distension can mean ileus/fulminant colitis rather than "improving" CDI.^[3]
Cycling through repeated same-agent antibiotic courses for a second or later recurrence instead of referring for fecal microbiota transplantation once that threshold is met.^[6]

Clinical Decision Algorithm

Algorithm A — Should this patient be tested, and how is the result interpreted?

New or worsening diarrhea: 3 or more unformed stools in 24 hours

Clear alternative explanation (laxative in past 48h, tube-feed change, etc.)

Do not test for CDI — manage the alternative cause

No clear alternative explanation

Send a multistep stool assay: GDH antigen + toxin EIA (NAAT to arbitrate discordant results), or NAAT with reflex toxin EIA

Toxin EIA positive (or pseudomembranes/toxic megacolon on direct visualization)

Confirmed CDI — assess severity, proceed to Algorithm B

GDH/NAAT positive, toxin EIA negative

Likely colonization rather than active toxin-mediated disease — correlate closely with the clinical picture before treating

Negative

CDI unlikely — investigate other causes of diarrhea

Algorithm B — Severity-based initial treatment

Confirmed CDI — assess severity and stop the inciting antibiotic if feasible

Non-severe: WBC ≤15×10⁹/L and creatinine <133 µmol/L (1.5 mg/dL)

Vancomycin 125 mg PO QID x10d, or fidaxomicin 200 mg PO BID x10d (preferred if a recurrence risk factor is present); metronidazole 500 mg PO TID x10d only if neither is available

Severe: WBC >15×10⁹/L or creatinine ≥133 µmol/L (1.5 mg/dL)

Vancomycin 125 mg PO QID x10d, or fidaxomicin 200 mg PO BID x10d (preferred if a recurrence risk factor is present)

Fulminant: hypotension/shock, ileus, or toxic megacolon

Vancomycin 500 mg PO/NG QID; add IV metronidazole 500 mg Q8H if ileus/critically ill; consider rectal vancomycin retention enema if unable to take oral/enteral; urgent ID, general surgery, and/or critical care consult

Reassess at day 10: extend to 14 days total if improved but not fully resolved; failure to improve by day 7 suggests an alternative diagnosis

Algorithm C — Recurrence ladder

Diarrhea recurs after a completed CDI treatment course (commonly within 8 weeks)

First recurrence

If metronidazole was used initially: switch to vancomycin 125 mg PO QID x10d. If standard vancomycin was used initially: switch to fidaxomicin (standard or extended-pulsed regimen), or use a vancomycin tapered-and-pulsed regimen

Second or multiple recurrences

Vancomycin 125 mg QID x14d then a tapered-and-pulsed regimen, or fidaxomicin (standard or extended-pulsed), or vancomycin x10d followed by a rifaximin 400 mg TID x20d chaser; consider adding bezlotoxumab to the antibiotic course in a high-recurrence-risk patient

2 or more recurrences, especially after a failed vancomycin taper: refer for fecal microbiota transplantation

Drug Tables

How to use this table: Doses are adult doses and require patient-specific confirmation, including renal/hepatic adjustment. This table covers CDI-specific antibacterial and adjunct therapy only — see the Acute Diarrhea in Adults chapter's Drug Tables for oral rehydration solution and general antidiarrheal agents. Select any drug name to open its complete Pharmasist Drug Database page.

Initial episode, non-severe or severe disease

Drug	Dosage	Adverse effects	Drug interactions	Comments
Vancomycin, oral	Non-severe or severe disease: 125 mg PO/NG QID x 10 days If incomplete resolution by day 10: Extend to 14 days total	Bitter taste, nausea, vomiting, stomatitis, chills, drug fever, rare eosinophilia	Minimal with oral administration given poor systemic absorption	Preferred 1st-line agent alongside fidaxomicin for an initial episode of any severity. Poorly absorbed — acts locally in the gut; not interchangeable with IV vancomycin, which does not achieve effective colonic concentrations for CDI.^[3]
Fidaxomicin	Initial episode, non-severe or severe: 200 mg PO BID x 10 days	Nausea, vomiting, GI upset, rash	No significant drug interactions	Co-preferred 1st-line agent; specifically preferred over vancomycin when a recurrence risk factor is present (prior CDI, age ≥65, immunocompromise, severe first episode) — lower recurrence with similar initial cure rate. No renal or hepatic dose adjustment needed.^[5]
Metronidazole	Non-severe CDI, if vancomycin/fidaxomicin unavailable: 500 mg PO/NG TID x 10 days	Nausea, headache, anorexia, dry mouth, metallic taste; peripheral neuropathy with prolonged/repeated use	Potentiates warfarin (monitor INR); disulfiram-like reaction with alcohol — avoid alcohol during treatment and for the interval on current product labelling	Reserve for non-severe disease only, case-by-case, when vancomycin and fidaxomicin are both unavailable or cost-prohibitive for outpatient use — no longer 1st- or 2nd-line given inferior efficacy.^[3]

Fulminant disease (hypotension/shock, ileus, or toxic megacolon)

Not an outpatient scenario — obtain urgent infectious diseases, general surgery, and/or critical care consultation.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Vancomycin (fulminant regimen)	Fulminant disease: 500 mg PO/NG QID x 10 days (14 days if incomplete resolution by day 10) If unable to take oral/enteral doses, add: 500 mg in 100 mL normal saline PR Q6H as a retention enema	Bitter taste, nausea; additive GI toxicity when combined with IV metronidazole	See oral vancomycin above	First-line agent for fulminant disease, combined with IV metronidazole if there is complete ileus or the patient is critically ill.^[3]
Metronidazole (fulminant adjunct)	Fulminant disease, added to vancomycin: 500 mg IV Q8H	Nausea, metallic taste, peripheral neuropathy with prolonged use	Potentiates warfarin; disulfiram-like reaction with alcohol	Add IV metronidazole to oral/rectal vancomycin specifically when there is complete ileus or the patient is critically ill — combination therapy has been associated with improved mortality in this setting.

First recurrence

Choice depends on what was used for the initial episode.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Vancomycin (standard course)	First recurrence: 125 mg PO/NG QID x 10 days	Bitter taste, nausea	Minimal with oral administration	Use if metronidazole was the initial-episode agent.
Fidaxomicin (standard or extended-pulsed)	First recurrence, standard course: 200 mg PO BID x 10 days First recurrence, extended-pulsed regimen: 200 mg PO BID on days 1-5, then 200 mg PO once daily on alternate days on days 7-25	Nausea, vomiting, GI upset	No significant drug interactions	Preferred switch if a standard vancomycin course was used for the initial episode — superior to a repeat vancomycin course at preventing a further recurrence.^[5]
Vancomycin, tapered-and-pulsed regimen	Step 1: 125 mg PO/NG BID x 7 days Step 2: 125 mg PO/NG once daily x 7 days Step 3: 125 mg PO/NG every 2 days x 4 doses Step 4: 125 mg PO/NG every 3 days x 5 doses	Bitter taste, nausea	Minimal with oral administration	Alternative to switching agents, particularly if the recurrence was severe and vancomycin was already used for the primary episode.^[3]

Second or multiple recurrences

Drug	Dosage	Adverse effects	Drug interactions	Comments
Vancomycin, extended course then taper	Initial extended course: 125 mg PO/NG QID x 14 days Then taper: Same 4-step taper as for a first recurrence, above	Bitter taste, nausea	Minimal with oral administration	Longer initial course than a first recurrence, then the same tapered-and-pulsed schedule as above.^[3]
Rifaximin (chaser)	Recurrence chaser, after a 10-day vancomycin course: 400 mg PO TID x 20 days	GI upset; generally well tolerated given minimal systemic absorption	None significant given minimal systemic absorption	Used specifically as a chaser immediately following a 10-day vancomycin course for a 2nd or later recurrence, not as CDI monotherapy.^[5]
Bezlotoxumab	Single infusion, alongside antibiotics: 10 mg/kg IV once	Infusion reactions; possible increased heart failure events — avoid with a history of congestive heart failure	None significant (monoclonal antibody, not hepatically/renally cleared in a way that interacts with other drugs)	Anti-toxin-B monoclonal antibody given once, alongside standard antibiotic therapy, to reduce the risk of a further recurrence in a high-risk patient — it does not treat the acute episode on its own and is not a substitute for antibiotics.^[5]
Fecal microbiota transplantation	Referral indication: 2 or more recurrences, especially after a failed vancomycin tapered-and-pulsed regimen	Generally well tolerated; procedural risks depend on delivery route (colonoscopy, nasogastric, or oral capsule)	None significant	Not a medication ordered by a community pharmacist — refer to a centre offering fecal microbiota transplantation after 2 or more recurrences, especially following a failed vancomycin taper.^[6]

References

Annex C: Testing, Surveillance and Management of Clostridium difficile in All Health Care Settings — Public Health Ontario / Provincial Infectious Diseases Advisory Committee (PIDAC), annexed to Routine Practices and Additional Precautions in All Health Care Settings. Toronto, ON: Queen's Printer for Ontario; revised January 2013
Ontario Public Health Standards: Infectious Disease Protocol — Appendix 1: Case Definitions and Disease-Specific Information — Clostridium difficile Infection (CDI) Outbreaks in Public Hospitals — Ontario Ministry of Health. Effective May 2022
ASPIRES Treatment Guidelines: Clostridioides difficile Infection (CDI) — Vancouver Coastal Health, ASPIRES Antimicrobial Stewardship Programme. Vancouver Coastal Health; last updated October 2023
Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) — Clinical Infectious Diseases (McDonald LC, Gerding DN, Johnson S, et al.). Clin Infect Dis 2018;66(7):e1-e48
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 — Clinical Infectious Diseases (Johnson S, Lavergne V, Skinner AM, et al.). Clin Infect Dis 2021;73(5):e1029-e1044
Association of Medical Microbiology and Infectious Disease Canada Treatment Practice Guidelines for Clostridium difficile Infection — Journal of the Association of Medical Microbiology and Infectious Disease Canada (AMMI Canada). J Assoc Med Microbiol Infect Dis Can 2018;3(4):207-234

Professional reference only. Apply clinical judgment and verify patient-specific decisions against current authoritative guidance and product information.