Diarrhea in the Intensive Care Unit: Not Always Infection

A Comprehensive Review for Critical Care Practitioners

Dr Neeraj Manikath , claude.ai

Abstract

Diarrhea affects 15-38% of critically ill patients and represents a significant challenge in intensive care management. While Clostridioides difficile infection dominates clinical concern, the majority of ICU diarrhea cases stem from non-infectious etiologies including medications, enteral nutrition, and metabolic derangements. This review provides an evidence-based approach to the differential diagnosis, appropriate investigation, and management of diarrhea in critically ill patients, with emphasis on avoiding unnecessary testing and antimicrobial stewardship.

Keywords: ICU diarrhea, Clostridioides difficile, enteral nutrition, antibiotic-associated diarrhea, diagnostic stewardship

Introduction

Diarrhea in the intensive care unit (ICU) is defined as ≥3 loose or liquid stools per day or stool weight >200-250g/day, though the Bristol Stool Chart (types 6-7) provides more practical bedside assessment.1,2 The reported incidence varies widely (15-38%) depending on definitions used and patient populations studied.3 Beyond patient discomfort, ICU diarrhea contributes to:

Fluid and electrolyte imbalances requiring additional interventions
Skin breakdown and pressure injury development
Increased nursing workload and healthcare costs
Contamination of invasive devices and infection risk
Delayed mobilization and rehabilitation

Pearl #1: The psychological impact is often underestimated. Patients consistently rate diarrhea as one of their most distressing ICU symptoms, affecting dignity and recovery.4

Clinicians reflexively suspect C. difficile infection (CDI) when faced with ICU diarrhea, leading to overutilization of diagnostic testing and empiric antimicrobial therapy. However, studies consistently demonstrate that 60-70% of ICU diarrhea is non-infectious in origin.5,6 This review challenges the infection-first paradigm and provides a systematic approach to this common problem.

Epidemiology and Risk Factors

Incidence and Outcomes

Critically ill patients face multiple convergent risk factors for diarrhea:

Polypharmacy (average 10-15 medications)
Enteral nutrition (50-80% of ICU patients)
Dysbiosis from antibiotics and critical illness
Reduced mobility and altered gut motility
Metabolic and endocrine disturbances

A prospective multicenter study by Reintam Blaser et al. found that diarrhea occurred in 14.7% of medical-surgical ICU patients and was independently associated with prolonged ICU length of stay (adjusted OR 1.6) and increased 90-day mortality (adjusted OR 1.7).7 Whether diarrhea is a marker of severity or a modifiable contributor to poor outcomes remains debated.

The CDI Problem: Overdiagnosis in Critical Care

C. difficile testing in ICUs has increased dramatically over the past decade, yet true infection rates remain stable.8 The crux of the problem lies in understanding colonization versus infection:

Colonization rates in ICU patients: 15-30%9
True CDI among tested patients: 10-20%10
False positive rate with nucleic acid amplification tests (NAATs) alone: 40-50%11

Oyster #1 (Common Pitfall): Ordering C. difficile testing on formed stool or in patients on laxatives. Studies show that 15-30% of C. difficile tests are ordered inappropriately on non-diarrheal stool.12 The 2021 IDSA/SHEA guidelines explicitly state testing should only occur with ≥3 unformed stools in 24 hours in the absence of laxatives.13

Non-Infectious Etiologies: The Usual Suspects

1. Medication-Related Diarrhea

Medications represent the most common cause of ICU diarrhea, implicated in 40-60% of cases.14

Antibiotics

Beyond C. difficile: Antibiotic-associated diarrhea (AAD) without CDI occurs in 5-25% of patients receiving antimicrobials.15 Mechanisms include:

Disruption of colonic microbiota and reduced short-chain fatty acid production
Direct effects on intestinal motility
Osmotic load from unabsorbed sugars

High-risk antibiotics (in descending order):16

Clindamycin (10-25% incidence)
Cephalosporins, especially ceftriaxone
Fluoroquinolones
Beta-lactam/beta-lactamase inhibitor combinations
Carbapenems

Pearl #2: Onset timing matters. AAD without CDI typically begins within 2-3 days of antibiotic initiation and resolves within 48-72 hours of cessation. CDI typically presents 5-10 days after antibiotic exposure, though it can occur earlier or up to 8 weeks later.17

Hack #1: Consider antibiotic de-escalation or switching before reflexive C. difficile testing. If diarrhea begins within 72 hours of starting high-risk antibiotics, observe for 24-48 hours if clinically appropriate. A trial substituting metronidazole with doxycycline or piperacillin-tazobactam with cefepime may resolve diarrhea without additional testing.18

Other Common Culprits

Prokinetics and laxatives:

Metoclopramide (22% incidence of diarrhea)19
Erythromycin
Polyethylene glycol, lactulose (dose-dependent)
Magnesium-containing antacids

Cardiovascular medications:

Beta-blockers, particularly propranolol
ACE inhibitors (2-7% incidence)
Digoxin (especially in toxicity)
Antiarrhythmics (quinidine, amiodarone)

Phosphate binders: Sevelamer and calcium acetate

Proton pump inhibitors (PPIs): Mechanisms include microscopic colitis induction and microbiome disruption. Meta-analysis shows 3-fold increased risk of CDI in PPI users, but also increased non-CDI diarrhea.20

Pearl #3: Create a "diarrhea medication audit" checklist. Review the medication administration record for the 48-72 hours preceding diarrhea onset. In one quality improvement study, systematic medication review reduced unnecessary C. difficile testing by 32%.21

Medication Class	Mechanism	Time to Onset	Management Strategy
Antibiotics	Microbiome disruption	1-3 days	Consider alternatives; probiotics controversial
Laxatives/prokinetics	Increased motility/osmotic	Hours to 2 days	Adjust dose or discontinue
PPIs	Microbiome/microscopic colitis	Days to weeks	Consider H2-blocker switch
Sorbitol-containing elixirs	Osmotic	Hours	Switch to tablet formulation
Enteral nutrition	Osmotic/malabsorption	Variable	Adjust rate, concentration, formula

2. Enteral Nutrition-Associated Diarrhea (ENAD)

Enteral feeding is associated with diarrhea in 15-68% of ICU patients, with wide variation reflecting definition heterogeneity.22 Despite its frequency, ENAD is often over-blamed while other causes are overlooked.

Mechanisms

Osmotic diarrhea:

Hyperosmolar formulas (>300-400 mOsm/kg)
Rapid gastric emptying
Inadequate absorption in critically ill gut

Formula-specific factors:

Fiber content: Paradoxically, both high-fiber and fiber-free formulas can cause diarrhea
Fat composition: High-fat formulas may exceed absorptive capacity
Protein source: Peptide-based formulas are often better tolerated than whole protein
Contamination: Rare with commercial formulas but possible with improper handling

Gastric vs. post-pyloric feeding: Meta-analysis shows no significant difference in diarrhea rates between gastric and jejunal feeding.23

Risk Factors for ENAD

High infusion rate (>125 mL/hr)
Bolus feeding in critically ill patients
Prolonged NPO status before feeding initiation
Hypoalbuminemia (<2.5 g/dL)
Concurrent antibiotic use
ICU-acquired weakness with gut dysmotility

Oyster #2 (Common Pitfall): Unnecessarily stopping enteral nutrition when diarrhea occurs. Studies demonstrate that continuing feeds at reduced rates maintains gut integrity and doesn't worsen outcomes compared to complete cessation.24 The 2016 ESPEN guidelines recommend adjusting rather than stopping feeds unless there's clear intolerance (vomiting, high gastric residuals, abdominal distension).25

Hack #2: The "Rule of 50s" for ENAD management:

Reduce rate by 50% initially rather than stopping
Consider 50% dilution temporarily (though this reduces caloric delivery)
Switch to semi-elemental formula (50% of peptides vs. whole protein)
Address concurrent factors (medications, electrolytes) before abandoning enteral route

Practical Management Algorithm for ENAD

Exclude other causes (medications, CDI, electrolytes)
Reduce infusion rate by 25-50% for 24 hours
Consider formula modification:
- Switch to semi-elemental (peptide-based) formula
- Trial fiber-containing formula if not already used (10-15g/day)
- Reduce osmolality (<300 mOsm/kg)
Optimize delivery:
- Transition from bolus to continuous infusion
- Consider post-pyloric access if persistent gastric intolerance
Add pharmacotherapy only if above measures fail:
- Loperamide 2-4 mg q6-8h
- Pectin or banana flakes (limited evidence)

Pearl #4: The "blue dye test" for formula timing. Adding blue food coloring to enteral feeds can help establish temporal relationship between feeding and diarrhea, though this is less useful with continuous infusion.26

3. Medications Commonly Overlooked

Sorbitol-containing liquid medications: Sorbitol, used as a vehicle in many liquid formulations, is a potent osmotic agent. As little as 10g daily can cause diarrhea; many critically ill patients receive 20-40g daily from multiple liquid medications.27

High-risk liquid medications:

Acetaminophen elixir (3.3g sorbitol/15mL)
Theophylline solution
Trimethoprim-sulfamethoxazole suspension
Liquid morphine preparations
Ferrous sulfate liquid

Hack #3: Conduct a "sorbitol audit." Calculate total daily sorbitol intake from all liquid medications. If >15g/day, switch to tablet formulations when possible. In one ICU study, eliminating sorbitol reduced diarrhea from 58% to 19%.28

Magnesium sulfate infusions: Often overlooked in seizing or pre-eclamptic patients. Magnesium acts as an osmotic laxative; high-dose infusions (4-6g bolus, 2g/hr maintenance) frequently cause diarrhea.

4. Electrolyte and Metabolic Abnormalities

Hypoalbuminemia: Albumin <2.5 g/dL increases intestinal wall edema and reduces oncotic pressure, impairing nutrient absorption and increasing secretion. Colloid osmotic pressure falls dramatically below 2.0 g/dL.29

Magnesium excess: Goal-directed magnesium replacement protocols can inadvertently cause diarrhea. Consider checking serum levels if >2.5 mEq/L despite diarrhea.

Hyperthyroidism/thyroid storm: Increased gut motility from catecholamine excess. Consider in previously undiagnosed thyrotoxicosis or following iodine load (contrast studies).

Phosphate: Both hypophosphatemia (<1.5 mg/dL) and hyperphosphatemia can cause diarrhea. The latter occurs with aggressive repletion or in renal failure.

Infectious Diarrhea in the ICU

While non-infectious causes dominate, true infections must not be missed.

Clostridioides difficile Infection

Diagnostic Approach: Moving Beyond Reflexive Testing

The 2021 IDSA/SHEA CDI guidelines emphasize diagnostic stewardship:13

Who to test:

≥3 unformed stools in 24 hours
No laxative use in preceding 48 hours
No alternative explanation readily apparent
Symptoms developed >48-72 hours after hospital admission OR <4 weeks after hospital discharge

Who NOT to test:

Formed stool (Bristol 1-4)
Patients receiving laxatives, enemas, or bowel prep
Asymptomatic patients (screening for colonization not recommended)
Test of cure after treatment (toxin can persist for weeks)
Patients with diarrhea onset <48 hours after antibiotic initiation (unless recent CDI history)

Oyster #3 (Common Pitfall): Testing too early in the antibiotic course. A prospective study found that 41% of positive C. difficile tests occurred within 3 days of antibiotic initiation—the majority representing colonization or non-CDI AAD with false-positive NAAT results.30

Diagnostic Testing Strategies

The optimal testing algorithm remains debated:

Three-step algorithm (preferred by IDSA/SHEA):13

GDH (glutamate dehydrogenase) antigen + toxin EIA
If GDH+/toxin−, perform NAAT for arbitration
Only GDH+/toxin+ or GDH+/toxin−/NAAT+ = treat

Rationale: Reduces false positives from NAAT-only testing, which detects colonization. Toxin positivity correlates better with true disease.

Two-step algorithm (alternative):

NAAT
If positive, reflex to toxin EIA
Treat only if toxin positive (or NAAT+/toxin− with severe presentation)

Pearl #5: Know your institution's testing methodology. NAATs alone have 40-50% positive predictive value in low pre-test probability populations. Multi-step algorithms including toxin detection improve specificity to 80-95%.31

Management Considerations

Treatment duration: 10 days for initial episode (vancomycin 125mg PO QID or fidaxomicin 200mg PO BID).13 Avoid metronidazole for initial treatment given inferior cure rates.

Recurrence risk: 15-35% after first episode, 40-65% after second. Consider bezlotoxumab (monoclonal antibody against toxin B) for high-risk patients (≥65 years, severe CDI, immunocompromised, or prior CDI).32

Fecal microbiota transplantation (FMT): Reserved for multiple recurrences (≥2), with cure rates of 80-90%. Emerging oral capsule formulations may improve ICU applicability.33

Infection control: Contact precautions with soap and water handwashing (alcohol doesn't kill spores). Continue precautions until diarrhea resolves for 48 hours.

Other Infectious Causes

While CDI dominates attention, other pathogens occasionally cause ICU diarrhea:

Viral:

Norovirus (healthcare outbreaks, immunocompromised)
Cytomegalovirus (immunosuppressed, can cause colitis)
Rotavirus (rare in adults)

Bacterial:

Salmonella, Shigella, Campylobacter (usually community-acquired, presenting on ICU admission)
Klebsiella oxytoca (antibiotic-associated hemorrhagic colitis, rare)
Staphylococcus aureus (enterocolitis after broad-spectrum antibiotics or gut surgery)

Parasitic:

Cryptosporidium (immunocompromised, HIV)
Giardia, Entamoeba (travel history)
Strongyloides (hyperinfection in immunosuppressed)

Fungal:

Candida (often colonization; true enteritis rare)

Pearl #6: The "3-3-3 rule" for expanded infectious workup:

If diarrhea persists >3 days despite stopping offending medications
Plus ≥3 of: fever, leukocytosis, blood/mucus in stool, new abdominal pain, hypotension
And 3 negative C. difficile tests → consider extended stool studies (culture, ova/parasites, viral PCR)

However, yield remains low (<5%) in hospital-acquired diarrhea without these features.34

When to Test: A Diagnostic Stewardship Framework

The decision to pursue diagnostic testing should be deliberate, not reflexive. Excessive testing leads to:

False positives and unnecessary antibiotic exposure
Increased costs ($150-400 per C. difficile test in US)
Resource utilization in microbiology labs
Delayed attention to actual cause

Pre-Test Probability Assessment

HIGH pre-test probability for CDI (>30%):

Severe, new-onset diarrhea (≥6 stools/day)
Recent antibiotic exposure (within 8 weeks)
Abdominal pain, fever, leukocytosis (>15,000/μL)
Age >65 years
Prior CDI history
Inflammatory bowel disease
Immunosuppression → Proceed with CDI testing

INTERMEDIATE pre-test probability (10-30%):

Moderate diarrhea (3-6 stools/day)
Antibiotic exposure present
Minimal systemic symptoms → Conduct medication/feeding audit first; test if no clear alternative

LOW pre-test probability (<10%):

Diarrhea onset <48 hours after antibiotic start
Active laxative use or enteral feeding intolerance
Clear medication culprit (e.g., started high-dose magnesium)
Diarrhea without systemic symptoms → Defer testing; address likely causes

Hack #4: Implement an electronic order set "hard stop" that requires clinicians to answer questions about diarrhea duration, stool consistency, laxative use, and antibiotic timing before C. difficile testing is permitted. Studies show this reduces inappropriate testing by 30-50% without missing true cases.35

The "Diarrhea Stewardship Bundle"

A quality improvement approach combining:

Clinical decision support: Embedded algorithms in EMR
Prospective audit and feedback: Stewardship team reviews positive C. difficile results within 24 hours
Education: Regular teaching on non-infectious causes
Restriction policies: Limit repeat testing within 7 days
Alternative diagnostic approaches: Fecal calprotectin or lactoferrin to identify inflammation

Implementing such bundles reduces C. difficile testing by 20-40% and vancomycin use by 15-30% without adverse outcomes.36,37

When to STOP Testing

Repeat testing is frequently performed but rarely helpful.

Repeat Testing During Same Episode

Do NOT repeat C. difficile testing:

Within 7 days of initial negative test (sensitivity >90% with appropriate algorithms)
During the same diarrheal episode unless clinical deterioration
For test-of-cure after treatment completion (toxin shedding can persist weeks to months)

Exception: If initial testing was performed inappropriately (on formed stool or while on laxatives) and clinical suspicion remains high after correcting these factors.

Pearl #7: Up to 25% of patients have persistent positive C. difficile tests for 30-60 days after successful treatment. Post-treatment testing generates false positives and unnecessary treatment courses.38

Extended Infectious Workup

STOP additional infectious testing when:

Three negative C. difficile tests over 48-72 hours
Stool culture negative (if performed for community-acquired diarrhea)
No inflammatory markers (normal fecal calprotectin <50 μg/g, lactoferrin negative)
Clear temporal relationship with non-infectious cause identified and addressed
Improving diarrhea after medication adjustment or feeding modification

Consider continuing/expanding workup if:

Immunocompromised host (solid organ transplant, HIV, chemotherapy)
Recent travel to endemic areas
Bloody diarrhea with inflammatory markers
Toxic megacolon or fulminant colitis picture
Unexplained clinical deterioration despite empiric treatment

Imaging Indications

Abdominal CT is not routinely indicated for ICU diarrhea. Obtain imaging if:

Concern for surgical abdomen (perforation, ischemia, obstruction)
Suspected C. difficile with severe/fulminant features to assess for toxic megacolon
Bloody diarrhea to exclude ischemic colitis or inflammatory bowel disease
Immunocompromised with persistent diarrhea despite therapy (evaluate for CMV colitis, typhlitis)

Pearl #8: CT findings in CDI include colonic wall thickening (>4mm), pericolonic stranding, and "accordion sign" (mucosal enhancement with trapped oral contrast). However, these findings are nonspecific and present in only 50-60% of confirmed CDI cases.39

Management Pearls and Practical Hacks

The 48-Hour Rule

Hack #5: Institute a "48-hour observation period" for new-onset diarrhea in stable patients:

Document stool frequency and character
Review and optimize medications
Adjust enteral feeding
Check electrolytes
Test for C. difficile only if diarrhea persists or worsens after 48 hours

This approach reduced testing by 35% in one ICU without missing severe CDI cases.40

Loperamide: Friend or Foe?

Loperamide has historically been considered contraindicated in suspected infectious diarrhea due to theoretical concerns about toxin retention and colonic dilatation. However, evidence suggests:

Safe in:

Non-CDI antibiotic-associated diarrhea
ENAD without signs of gut dysmotility
Chronic diarrhea from medications (e.g., chronic sorbitol exposure)

Avoid in:

Confirmed or suspected CDI (especially severe disease)
Bloody diarrhea or inflammatory markers
Fever, abdominal distension, or ileus
Immunocompromised with suspected infection

Dosing: 2-4mg after each loose stool (max 16mg/day). Start conservatively in critically ill patients.

Pearl #9: Loperamide can safely reduce ENAD burden and improve patient comfort when infectious causes are excluded. A randomized trial in ICU patients with feeding-related diarrhea showed loperamide reduced stool frequency without increasing adverse events.41

Probiotics: Controversies and Considerations

Meta-analyses suggest probiotics (primarily Lactobacillus and Saccharomyces boulardii) reduce AAD incidence by 40-50% (NNT ~13).42 However:

Concerns in critical illness:

Case reports of Lactobacillus and S. boulardii fungemia in immunocompromised patients
2018 Dutch study (PROPATRIA) showed increased mortality in severe acute pancreatitis patients receiving probiotics43
Unclear efficacy specifically for CDI prevention

Current recommendations:

May consider in immunocompetent patients receiving high-risk antibiotics
Avoid in severely immunocompromised, central venous catheter presence, or high risk of bacterial translocation (severe pancreatitis, short gut syndrome)
Insufficient evidence to recommend for CDI treatment or recurrence prevention (although S. boulardii shows promise)

Oyster #4 (Common Pitfall): Starting probiotics after diarrhea begins. For AAD prevention, probiotics must be initiated with or before antibiotics. Starting after diarrhea onset is unlikely to be effective.

Zinc Supplementation

Zinc deficiency impairs intestinal epithelial integrity and immune function. ICU patients frequently have low zinc levels from:

Decreased intake
Increased GI losses (diarrhea, fistulas)
Inflammation (zinc is negative acute phase reactant)
Liver disease or renal replacement therapy

Evidence: Zinc supplementation (220mg zinc sulfate daily = 50mg elemental zinc) improves diarrhea duration in zinc-deficient patients and may reduce CDI severity.44 Consider checking zinc levels in persistent diarrhea; supplement if <60 μg/dL.

Special Populations

Post-Surgical Patients

Bile acid diarrhea following ileal resection or cholecystectomy affects 10-20% of patients. Mechanisms include:

Malabsorption of bile acids in terminal ileum
Bile acid stimulation of colonic secretion

Management: Cholestyramine 4g PO BID-QID (give separate from other medications by 1-2 hours)

Small bowel bacterial overgrowth (SIBO) can occur after gastrointestinal surgery, especially with:

Gastric resection/bypass
Small bowel strictures
Decreased gastric acid (PPI use)

Diagnosis: Hydrogen breath testing (impractical in ICU) or empiric trial of rifaximin 550mg PO TID for 14 days.

Renal Replacement Therapy

Diarrhea in dialysis patients may result from:

Uremic enterocolitis (improves with adequate dialysis)
Hypermagnesemia (from dialysate)
Phosphate binders
Volume overload with gut edema

Immunocompromised Patients

Expanded differential includes:

CMV colitis (diagnose with biopsy showing inclusion bodies)
Cryptosporidium, Microsporidium, Cystoisospora
Mycobacterium avium complex
Immune checkpoint inhibitor-associated colitis
Graft-versus-host disease

Lower threshold for endoscopy with biopsy in immunocompromised patients with persistent diarrhea despite negative stool studies.

Complications and Prognostic Considerations

Acute Complications

Fluid and electrolyte derangements:

Volume depletion (especially dangerous in septic shock)
Hypokalemia, hypomagnesemia, hypophosphatemia
Metabolic acidosis (stool bicarbonate loss)
Acute kidney injury from prerenal azotemia

Skin breakdown:

Perianal skin injury from enzymatic damage
Pressure ulcer development (moisture + immobility)
Device contamination (urinary catheters, femoral lines)

Malnutrition:

Reduced oral/enteral intake due to diarrhea
Nutrient malabsorption
Protein-losing enteropathy in severe cases

Severe and Fulminant CDI

Defined by:13

WBC ≥15,000/μL or <2,000/μL
Serum creatinine ≥1.5× baseline
Hypotension requiring vasopressors
Fever >38.5°C
Ileus or toxic megacolon
Mental status changes

Management escalation:

Vancomycin 500mg PO/NG QID (higher dose than non-severe)
PLUS metronidazole 500mg IV Q8H if severe
PLUS vancomycin retention enema 500mg in 100mL NS Q6H if ileus/megacolon
Consider fidaxomicin if available (possibly superior outcomes)
Early surgical consultation (colectomy mortality 30-50% but necessary in some cases)
Avoid opioids and antimotility agents

Indications for colectomy:

Refractory shock despite medical therapy
Peritonitis or perforation
Lactic acidosis >5 mmol/L
WBC >50,000/μL
Progressive organ dysfunction

Pearl #10: Early surgical consultation (within 24-48 hours) in severe CDI improves outcomes compared to delayed referral. Mortality increases dramatically if colectomy is delayed >5 days after diagnosis.45

The Diagnostic Algorithm: A Practical Approach

ICU Patient with Diarrhea (≥3 loose stools/24h)
                    ↓
        Is this really diarrhea?
    (Bristol 6-7, not just loose)
                    ↓
            YES → Continue
            NO → Document, reassess
                    ↓
    ┌──────────────┴──────────────┐
    ↓                              ↓
UNSTABLE                       STABLE
(shock, fever,              (hemodynamically stable,
leukocytosis >20K,           no alarm features)
toxic appearance)                  ↓
    ↓                         48-HOUR AUDIT:
Test for C. diff             1. Medication review
immediately +                   - Antibiotics (<3d start?)
empiric treatment               - Laxatives/prokinetics
if high suspicion               - Sorbitol content
    ↓                           - PPI, other drugs
Consider imaging             2. Enteral nutrition
(CT abdomen/pelvis)             - Rate, formula type
    ↓                           - Recent changes
Surgical consult             3. Labs: Mg, albumin
if peritonitis/                 thyroid, phosphate
perforation concern          4. Document stool
                                frequency/character
                                     ↓
                         IDENTIFIED CULPRIT?
                                     ↓
                        ┌────────────┴────────────┐
                        ↓                         ↓
                       YES                        NO
                        ↓                         ↓
                Address cause:              CDI TESTING
                - Stop/modify med        (if ≥3 unformed stools,
                - Adjust feeds          no laxatives, >48h
                - Correct lytes          antibiotic exposure)
                - Consider loperamide         ↓
                (if non-infectious)     ┌─────┴─────┐
                        ↓               ↓           ↓
                  Reassess 24h      POSITIVE   NEGATIVE
                        ↓               ↓           ↓
              Improved?           TREAT CDI    Continue audit
                        ↓               ↓           ↓
                    ┌───┴───┐     Vancomycin   Persistent >72h
                    ↓       ↓     125mg QID    + concerning features?
                  YES      NO          ↓              ↓
                    ↓       ↓     Assess        ┌────┴────┐
              Continue  Test for severity       ↓         ↓
              supportive C. diff            YES         NO
              care           ↓               ↓           ↓
                        Positive?      Extended    Continue
                             ↓         workup      supportive
                        Treat CDI    (culture,    measures,
                                    viral PCR,    optimize
                                    parasites,    nutrition
                                    consider
                                    endoscopy if
                                    immunocomp.)

Quality Improvement and Stewardship Metrics

ICUs should track the following metrics to optimize diarrhea management:

Process Measures:

Proportion of C. difficile tests meeting appropriateness criteria
Time from diarrhea onset to medication audit documentation
Proportion of tests ordered on formed stool
Repeat testing rates within 7

days

Days of therapy (DOT) for empiric CDI treatment before test results

Outcome Measures:

C. difficile testing rate per 1,000 patient-days
Positive predictive value of C. difficile testing
Proportion of positive tests resulting in treatment
CDI treatment duration appropriateness
Unnecessary vancomycin exposure (treatment without positive test)
Healthcare-associated CDI rates (per 10,000 patient-days)

Balancing Measures:

Missed CDI cases (retrospective chart review)
Time to CDI treatment in true positive cases
Readmission rates for CDI within 30 days
Recurrent CDI rates

Hack #6: Create a monthly "diarrhea dashboard" displaying these metrics to ICU teams. Visual feedback on testing appropriateness and outcomes drives behavior change more effectively than didactic education alone.46

Antimicrobial Stewardship Integration

Diarrhea management intersects directly with antimicrobial stewardship principles:

Primary Prevention Strategies

1. Antibiotic Optimization

Utilize narrow-spectrum agents when possible
Implement local antibiograms for empiric therapy selection
Reduce fluoroquinolone and clindamycin use (highest CDI risk)
Enforce duration limits (e.g., 7 days for uncomplicated pneumonia)
Daily antibiotic time-outs during rounds

2. PPI Stewardship

Stress ulcer prophylaxis only for high-risk patients (coagulopathy + mechanical ventilation, prior GI bleeding, burns >35% BSA)
Discontinue PPIs when risk factors resolve
Studies show PPI de-escalation reduces CDI risk without increasing GI bleeding47

3. Environmental Hygiene

Enhanced cleaning protocols with sporicidal agents (bleach-based)
Contact precautions for confirmed CDI (private room preferred)
Proper hand hygiene (soap and water for C. difficile)
Commode disinfection protocols

Treatment De-escalation

Hack #7: Implement a "CDI stewardship trigger" where all positive C. difficile tests automatically prompt pharmacy/ID review within 24 hours to:

Confirm appropriateness of testing
Assess pre-test probability and alternative diagnoses
Review treatment selection and duration
Evaluate need for ongoing antimicrobials that precipitated CDI
Recommend PPI cessation if appropriate
Identify recurrence risk and need for bezlotoxumab

Studies demonstrate this approach reduces inappropriate CDI treatment by 20-35% and decreases overall antibiotic consumption.48

Nursing Considerations and Multidisciplinary Approach

ICU nurses are on the frontline of diarrhea management and their role is critical:

Documentation Standards

Standardized stool charting:

Bristol Stool Scale documentation (numerical and descriptive)
Volume estimation (small/moderate/large or mL if measured)
Presence of blood, mucus, or unusual color
Temporal relationship to feeding/medications
Patient symptoms (cramping, urgency, incontinence)

Pearl #11: Implement photo documentation protocols using smartphone/tablet cameras (de-identified) for severe or unusual stool. Visual records facilitate physician assessment and guide clinical decisions, particularly for remote consultations. Ensure HIPAA-compliant storage.49

Skin Care Bundle

Evidence-based prevention:

Barrier creams (zinc oxide, dimethicone) applied liberally
Frequent cleansing with pH-balanced no-rinse cleansers
Avoid harsh soaps or excessive friction
External fecal management systems for severe diarrhea (>1L/day)
Rectal trumpet/flexi-seal consideration (controversial - avoid if neutropenic, thrombocytopenic <50K, recent rectal surgery)

Oyster #5 (Common Pitfall): Inserting rectal tubes in patients with severe CDI. Risk of perforation is increased in inflamed, friable colonic mucosa. Use only for refractory non-infectious diarrhea causing severe skin breakdown.50

Nutrition Support

Dietitians should be integrated early:

Assess baseline nutritional status and ongoing losses
Calculate protein/calorie needs accounting for malabsorption
Monitor micronutrient deficiencies (zinc, selenium, vitamins)
Adjust feeding regimens based on tolerance
Consider parenteral supplementation if enteral route fails despite optimization

Hack #8: Involve registered dietitians in "feeding rounds" 2-3 times weekly specifically focused on GI tolerance, with empowerment to adjust rates/formulas per protocol without requiring physician order for each change. Reduces response time and optimizes delivery.51

Emerging Concepts and Future Directions

Microbiome Restoration

Beyond CDI-specific FMT, broader microbiome therapeutics are under investigation:

Fecal microbiota transplantation evolution:

Standardized encapsulated preparations (FDA approval pending)
Targeted bacterial consortia (defined composition)
Microbiome-derived metabolites (short-chain fatty acids, secondary bile acids)

Early studies suggest microbiome restoration may benefit:

Recurrent CDI (established indication)
Antibiotic-resistant bacterial colonization decolonization
Multi-drug resistant organism prevention
Critically ill patients with dysbiosis-related complications52

Fecal Biomarkers

Calprotectin and lactoferrin: Neutrophil-derived proteins indicating intestinal inflammation. Elevated levels (>50-100 μg/g) suggest inflammatory/infectious etiology vs. non-inflammatory causes.

Potential applications:

Pre-test screening before C. difficile testing (if low, consider non-infectious cause)
Differentiating IBD flare from infection
Monitoring treatment response

Limitations: Not widely available in point-of-care formats; turnaround time may limit utility. Cost-effectiveness unclear in ICU setting.53

Artificial Intelligence and Predictive Analytics

Machine learning algorithms trained on:

Medication exposure patterns
Laboratory trends
Vital signs and clinical parameters
Microbiome data

Potential applications:

Predict CDI risk before symptom onset
Identify patients who will develop antibiotic-associated diarrhea
Optimize enteral feeding regimens based on individual tolerance patterns
Risk-stratify for severe/fulminant CDI progression

Early validation studies show promise, but clinical implementation remains investigational.54

Precision Medicine Approaches

Pharmacogenomics: Genetic polymorphisms affecting:

Drug metabolism (CYP450 variants altering medication concentrations)
Inflammatory response (IL-10, TNF-α variants influencing CDI severity)
Bile acid metabolism (FXR, TGR5 receptors affecting gut function)

Personalized nutrition:

Individual microbiome signatures predicting formula tolerance
Metabolomic profiling guiding prebiotic/probiotic selection
Nutrigenomics-based feeding strategies

These approaches remain research-focused but may eventually enable individualized diarrhea prevention and management strategies.55

Educational Pearls Summary: The "Top 10" for ICU Practitioners

Think medications FIRST - 40-60% of ICU diarrhea is medication-related; systematic audit before testing saves time and resources
The 48-hour rule - Observe stable patients for 48 hours with medication/feeding optimization before reflexive testing
Testing appropriateness matters - Only test patients with ≥3 unformed stools, no laxatives, and >48 hours after antibiotic start (unless high risk)
Don't feed the false positives - NAAT-only testing yields 40-50% false positives; know your lab's algorithm and interpret appropriately
Never test for cure - Post-treatment C. difficile testing generates false positives; treat the patient, not the test
Sorbitol is sneaky - Calculate total daily sorbitol from liquid medications; >15g/day commonly causes diarrhea
Adjust feeds, don't abandon them - Reduce enteral feeding rate by 50% rather than stopping; maintains gut integrity
Loperamide is safe (usually) - Can be used for non-infectious diarrhea; avoid in CDI or inflammatory diarrhea
Severe CDI requires escalation - Higher vancomycin doses (500mg QID) + metronidazole IV; early surgical consultation
Prevention is paramount - Antibiotic stewardship, PPI de-escalation, and infection control prevent more diarrhea than treatment cures

Practical Checklist: The ICU Diarrhea Assessment Tool

□ DEFINE THE PROBLEM

Confirm true diarrhea (Bristol 6-7, ≥3/day)
Quantify frequency and volume
Duration and acuity of onset
Associated symptoms (fever, pain, bleeding)

□ MEDICATION AUDIT (past 72 hours)

New antibiotics or changes
Laxatives/bowel regimen
Prokinetic agents
Calculate sorbitol exposure
PPI use
Other high-risk medications

□ NUTRITION ASSESSMENT

Enteral feeding: type, rate, recent changes
Route (gastric vs. post-pyloric)
Timing relationship to diarrhea
Gastric residuals/tolerance

□ LABORATORY EVALUATION

Electrolytes (especially Mg, PO4)
Albumin level
WBC and differential
Creatinine/BUN
Inflammatory markers if indicated

□ CLINICAL CONTEXT

Days since admission/antibiotic exposure
Immunosuppression status
Recent surgery or procedures
Prior CDI history
Comorbidities (IBD, diabetes, thyroid disease)

□ DECISION POINT

Pre-test CDI probability: High / Intermediate / Low
Alternative explanation identified: Yes / No
Testing indicated: Yes / Defer
Management plan: _______________________

Case Illustrations

Case 1: Antibiotic-Associated Diarrhea

Presentation: 58-year-old man, post-op day 4 from bowel resection for colon cancer, develops 6-8 loose stools/day. Piperacillin-tazobactam started post-operatively. No fever, WBC 10,500/μL.

Initial approach: Diarrhea began 72 hours after antibiotic initiation—consistent with AAD. Medication audit reveals: pip-tazo, metoclopramide 10mg QID, docusate 100mg BID, liquid acetaminophen (3.3g sorbitol per dose, given Q6H = 13.2g/day).

Management:

Discontinue docusate (no longer needed post-bowel movement)
Switch acetaminophen to tablet form
Reduce metoclopramide to BID
Switch pip-tazo to ceftriaxone (narrower spectrum, less diarrhea risk)
No C. difficile testing given low pre-test probability

Outcome: Diarrhea resolves within 48 hours. Testing would have generated false positive in 15-20% of cases, leading to unnecessary vancomycin.

Teaching point: Early AAD (<72 hours) with medication culprits rarely represents CDI.

Case 2: Enteral Nutrition-Associated Diarrhea

Presentation: 72-year-old woman with ARDS, mechanically ventilated for 10 days. Tolerating enteral feeds at goal (75 mL/hr Osmolite 1.2) for 5 days, then develops loose stools increasing to 8-10/day. No fever, WBC 9,800/μL. Receiving cefepime for VAP (day 5).

Initial approach: Temporal relationship suggests ENAD vs. AAD. Team reflexively orders C. difficile test and stops feeds.

Stewardship intervention:

C. difficile testing discouraged (low pre-test probability, day 5 antibiotics with stable WBC)
Resume feeds at 40 mL/hr (50% reduction)
Switch to semi-elemental formula (Peptamen)
Continue cefepime (lower CDI risk than pip-tazo)
Trial loperamide 2mg after loose stools (max 8mg/day)

Outcome: Diarrhea decreases to 3-4 stools/day within 24 hours. Feeds advanced to 60 mL/hr by day 3 without recurrence. Avoided unnecessary testing and treatment while maintaining nutrition.

Teaching point: ENAD responds to rate reduction and formula modification; stopping feeds entirely delays recovery.

Case 3: True C. difficile Infection

Presentation: 65-year-old diabetic man admitted with pneumonia, treated with levofloxacin. Day 8: develops severe cramping diarrhea (10-12 watery stools/day), fever 38.9°C, WBC rises from 11K to 22K/μL with left shift. Abdominal distension and diffuse tenderness.

Initial approach: HIGH pre-test probability for CDI (fluoroquinolone, day 8 exposure, systemic toxicity, leukocytosis).

Management:

Send C. difficile test (GDH+/Toxin+/NAAT+)
Empiric vancomycin 125mg PO QID (don't wait for results given severity)
Stop levofloxacin, switch to ceftriaxone for remaining pneumonia treatment
Discontinue PPI
Contact precautions, soap/water handwashing
CT abdomen: pancolonic wall thickening, no megacolon
Lactate 2.1 mmol/L (mild elevation)

Outcome: Clinical improvement by day 3 of vancomycin. Complete 10-day course. Counseled on 25% recurrence risk; if recurs, consider bezlotoxumab.

Teaching point: High pre-test probability warrants testing AND empiric treatment. Fluoroquinolones are particularly high-risk for CDI.

Case 4: The "Diagnostic Stewardship Miss"

Presentation: 45-year-old woman with pancreatitis, NPO for 5 days, then initiated on trophic enteral feeds. Day 2 of feeds: develops loose stools. Concerned team orders C. difficile test while patient receiving aggressive bowel regimen (MiraLAX 17g BID, docusate, bisacodyl) for perceived constipation.

Result: NAAT positive, toxin negative. Patient started on vancomycin.

Stewardship review: Test should not have been sent (active laxative use, formed-to-soft stools documented, only 48 hours of antibiotics for pancreatitis). NAAT+/toxin− likely represents colonization, not infection.

Management:

Discontinue vancomycin after 2 doses
Stop all laxatives
Continue feeds at reduced rate
Patient counseled on testing error

Outcome: Diarrhea resolves within 24 hours. Saved 8 days of unnecessary vancomycin.

Teaching point: Most common stewardship failure is testing patients on laxatives or with non-diarrheal stools. Toxin negativity in right clinical context suggests colonization.

Conclusions and Key Messages

Diarrhea in the ICU represents a complex diagnostic challenge that demands systematic evaluation rather than reflexive C. difficile testing. The majority of cases stem from iatrogenic causes—medications, enteral nutrition, and metabolic derangements—that resolve with thoughtful adjustment rather than antimicrobial therapy.

Guiding principles for the modern intensivist:

Diagnostic stewardship is patient safety: Overdiagnosis of CDI leads to unnecessary antibiotics, prolonged isolation, and missed alternative diagnoses. Testing should be reserved for patients meeting clear criteria.
Medications are the usual suspect: A structured 48-72 hour medication audit identifying and addressing culprits (antibiotics, laxatives, sorbitol, prokinetics) resolves most ICU diarrhea without additional testing.
Enteral nutrition rarely requires abandonment: Rate reduction and formula modification manage ENAD while preserving critical nutritional support. Complete cessation should be a last resort.
Context determines testing: Pre-test probability assessment based on timing, clinical features, and alternative explanations guides rational testing decisions. Low-probability testing generates false positives.
Stop repeat testing: Same-episode repeat C. difficile testing and post-treatment test-of-cure waste resources and mislead clinicians. Treat patients, not laboratory results.
Severe CDI demands escalation: Recognize fulminant infection early and intensify therapy with higher-dose vancomycin, IV metronidazole, and timely surgical consultation. Delay increases mortality.
Prevention trumps treatment: Antimicrobial stewardship, PPI de-escalation, infection control, and early enteral nutrition prevent more diarrhea than any treatment cures.

The path forward requires cultural change in critical care practice: moving from a reflexive "test and treat" paradigm to a thoughtful "assess, audit, and act" approach. Quality improvement initiatives integrating clinical decision support, prospective stewardship, and multidisciplinary collaboration have demonstrated significant reductions in unnecessary testing (30-50%) and antibiotic use (15-30%) without compromising patient safety.36,37,46

As ICU clinicians, we must recognize that the most sophisticated intervention is often the simplest: a careful medication review, feeding adjustment, or clinical observation period. In an era of increasing antimicrobial resistance and C. difficile recurrence, diagnostic restraint becomes a form of therapeutic wisdom.

Final Pearl #12: The best test for C. difficile is the one you don't order—because you identified and fixed the actual cause first.

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Appendices

Appendix A: ICU Diarrhea Medication Review Checklist

ANTIBIOTICS (within 8 weeks)

□ Clindamycin (highest risk)
□ Fluoroquinolones (levofloxacin, ciprofloxacin)
□ Cephalosporins (especially ceftriaxone, cefepime)
□ Piperacillin-tazobactam
□ Carbapenems (meropenem, imipenem)
□ Ampicillin, amoxicillin-clavulanate
□ Days of exposure: _____
□ Onset relationship: <72h = likely AAD; >5 days = consider CDI

GASTROINTESTINAL MEDICATIONS

□ Laxatives: MiraLAX, lactulose, senna, bisacodyl, docusate
□ Prokinetics: metoclopramide, erythromycin
□ Proton pump inhibitors (all types)
□ H2-blockers (rare cause)
□ Misoprostol

SORBITOL-CONTAINING LIQUIDS

□ Liquid acetaminophen
□ Liquid theophylline
□ Trimethoprim-sulfamethoxazole suspension
□ Ferrous sulfate liquid
□ Other elixirs/suspensions
□ Total daily sorbitol: _____ g (>15g = high risk)

ELECTROLYTE REPLACEMENTS

□ Magnesium sulfate IV (especially >2g/day)
□ Magnesium oxide/hydroxide PO
□ Phosphate supplements (especially Fleet's)
□ Potassium liquid preparations

CARDIOVASCULAR MEDICATIONS

□ Beta-blockers (especially propranolol)
□ ACE inhibitors
□ Digoxin
□ Quinidine, amiodarone

OTHER HIGH-RISK MEDICATIONS

□ Colchicine
□ Chemotherapy agents
□ Immunosuppressants (mycophenolate, tacrolimus)
□ NSAIDs (including selective COX-2 inhibitors)
□ Metformin (especially high doses)
□ Orlistat
□ Acarbose

ACTION ITEMS:

□ Medications to discontinue: _________________
□ Medications to dose-reduce: _________________
□ Liquid-to-tablet conversions: _________________
□ Antibiotic de-escalation opportunities: _________________

Appendix B: Enteral Nutrition Troubleshooting Algorithm

STEP 1: ASSESS BASELINE

Current formula: _____________ Osmolality: _____ mOsm/kg
Rate: _____ mL/hr (Goal: _____ mL/hr)
Route: □ Gastric □ Post-pyloric
Delivery: □ Continuous □ Bolus (_____ mL Q___h)
Duration of current regimen: _____ days

STEP 2: IDENTIFY RISK FACTORS

□ Hypoalbuminemia (<2.5 g/dL)
□ High infusion rate (>125 mL/hr)
□ Hyperosmolar formula (>400 mOsm/kg)
□ Recent initiation after prolonged NPO
□ Concurrent antibiotic use
□ Bolus feeding in critically ill patient

STEP 3: INITIAL MODIFICATIONS (choose one or more)

Option A: Rate Reduction

Reduce by 50%: New rate = _____ mL/hr
Reassess in 24 hours
Advance by 10-20 mL/hr Q12-24h as tolerated

Option B: Formula Modification

Switch to semi-elemental/peptide-based (Peptamen, Vital)
Switch to lower osmolality (<300 mOsm/kg)
Add soluble fiber (10-15g/day) if not already present
Consider probiotic-containing formula (if allowed per institutional policy)

Option C: Delivery Method Change

Convert bolus → continuous infusion
Consider post-pyloric access if gastric intolerance

STEP 4: PHARMACOLOGIC ADJUNCTS (if above fails)

Loperamide 2mg after each loose stool (max 16mg/day)
Pectin/banana flakes 10-15g/day mixed in formula
Psyllium (if using fiber-free formula)

STEP 5: REASSESSMENT TIMELINE

24 hours: Document stool frequency/character
48 hours: Consider additional modifications if no improvement
72 hours: If persistent severe diarrhea, consider:
- □ Alternative diagnosis (CDI testing if appropriate)
- □ Temporary parenteral nutrition supplementation
- □ Gastroenterology consultation

AVOID:

✗ Complete cessation of feeds as first-line (gut atrophy risk)
✗ Excessive formula changes without allowing 48-72h trials
✗ Rectal tubes in CDI or thrombocytopenia
✗ Antimotility agents without excluding infection

Appendix C: C. difficile Testing Decision Support Tool

PATIENT INFORMATION: Name: _____________ MRN: _____________ Date: _______

INCLUSION CRITERIA (all must be present):

□ YES □ NO: ≥3 unformed stools in 24 hours (Bristol 6-7)
□ YES □ NO: Diarrhea onset >48-72 hours after admission OR <4 weeks post-discharge
□ YES □ NO: No laxatives/enemas in past 48 hours
□ YES □ NO: No clear alternative explanation identified

If ANY "NO" → Testing NOT indicated. Address alternative causes first.

RISK FACTOR ASSESSMENT (if testing criteria met):

HIGH-RISK FEATURES (≥2 = high pre-test probability):

□ Age ≥65 years
□ Antibiotic exposure within 8 weeks (especially fluoroquinolones/clindamycin)
□ Prior CDI history
□ Immunosuppression (chemotherapy, transplant, HIV, IBD, chronic steroids)
□ Recent hospitalization or nursing home residence
□ PPI use

SEVERITY INDICATORS (presence suggests true infection):

□ Fever >38.5°C
□ WBC >15,000/μL or <2,000/μL
□ Creatinine ≥1.5× baseline
□ Abdominal pain/tenderness
□ Blood or mucus in stool
□ Hypotension or shock

ALTERNATIVE EXPLANATIONS PRESENT:

□ Antibiotics started <72 hours ago (likely AAD, not CDI)
□ New laxatives/prokinetics in past 48-72 hours
□ Enteral feeding changes in past 24-48 hours
□ High sorbitol intake (>15g/day calculated)
□ Other medication culprit identified: _____________

DECISION:

□ PROCEED WITH CDI TESTING (high pre-test probability, no clear alternative)

Send: □ GDH + Toxin (preferred) □ NAAT with reflex toxin □ Institution's algorithm

□ DEFER TESTING - 48-HOUR OBSERVATION

Implement medication audit and feeding modifications
Reasses in 48 hours
Test if no improvement or clinical deterioration

□ DO NOT TEST (inappropriate - does not meet criteria)

Reason: _________________________________
Alternative plan: __________________________

CLINICIAN SIGNATURE: _________________ DATE/TIME: _______

Appendix D: CDI Treatment Reference Card

INITIAL EPISODE - NON-SEVERE CDI

Criteria: WBC <15,000/μL AND Cr <1.5× baseline

Treatment:

Vancomycin 125mg PO QID × 10 days (preferred)
Alternative: Fidaxomicin 200mg PO BID × 10 days (if available, may reduce recurrence)
Avoid metronidazole unless vancomycin/fidaxomicin unavailable

Monitoring:

Clinical improvement expected in 2-3 days
Complete full 10-day course even if symptoms resolve
NO test of cure

INITIAL EPISODE - SEVERE CDI

Criteria: WBC ≥15,000/μL OR Cr ≥1.5× baseline

Treatment:

Vancomycin 125mg PO QID × 10 days
Consider fidaxomicin 200mg PO BID × 10 days (may have superior outcomes)

Monitoring:

Daily assessment for progression to fulminant disease
Surgical consultation if clinical deterioration
Lactate, imaging if worsening abdominal signs

FULMINANT CDI

Criteria: Hypotension/shock, ileus, megacolon, WBC >35,000 or <2,000/μL, lactate >2.2 mmol/L, mental status changes, peritonitis

Treatment:

Vancomycin 500mg PO/NG QID (higher dose)
PLUS Metronidazole 500mg IV Q8H
PLUS Vancomycin 500mg in 100mL NS rectally Q6H (if ileus/megacolon)
Consider fidaxomicin if oral route functional

Urgent Actions:

Surgical consultation within 24 hours (do not delay)
CT abdomen/pelvis
Stop antimotility agents and opioids
Aggressive fluid resuscitation
Consider ICU transfer if not already in ICU

Surgery Indications:

Peritonitis/perforation
Refractory shock despite vasopressors
Lactate >5 mmol/L
Worsening organ dysfunction despite medical therapy
No improvement after 5 days of appropriate treatment

FIRST RECURRENCE

Treatment:

If metronidazole was used initially: Vancomycin 125mg PO QID × 10 days
If vancomycin was used initially:
- Prolonged taper: Vancomycin 125mg PO QID × 10-14d, then BID × 7d, then daily × 7d, then every 2-3 days × 2-8 weeks
- OR Fidaxomicin 200mg PO BID × 10 days
Consider bezlotoxumab 10mg/kg IV × 1 dose (with antibiotics)

SECOND OR SUBSEQUENT RECURRENCE

Treatment Options:

Vancomycin taper/pulse (as above, extended duration)
Fidaxomicin 200mg PO BID × 10 days
Fecal microbiota transplantation (FMT)
- After ≥2 recurrences
- 80-90% cure rate
- Via colonoscopy, capsules, or enema
Bezlotoxumab (if not already given)

FMT Contraindications:

Immunocompromised (relative)
Recent GI surgery
Dysphagia/aspiration risk (for capsules)
Severe/fulminant active CDI (stabilize first)

SPECIAL CONSIDERATIONS

Inability to Take Oral Medications:

Vancomycin via NG/OG tube to colon
Vancomycin enemas (500mg in 100mL NS Q6H)
Tigecycline IV 100mg × 1, then 50mg IV Q12H (limited data, reserve for refractory cases)

Renal Failure:

Vancomycin PO has minimal systemic absorption - no dose adjustment needed
Avoid metronidazole as monotherapy (dose-adjust if used: 500mg IV Q12-24H based on GFR)

Pregnancy:

Vancomycin PO safe (minimal systemic absorption)
Avoid metronidazole in first trimester if possible

Concurrent Antibiotic Need:

Continue necessary antibiotics for other infections
De-escalate spectrum when possible
Avoid fluoroquinolones, clindamycin if alternatives exist

Appendix E: Quality Improvement Metrics Dashboard Template

MONTHLY ICU DIARRHEA STEWARDSHIP METRICS Reporting Period: _____________ ICU: _____________

PROCESS MEASURES:

Metric	Target	Current Month	Prior Month	Trend
C. diff tests meeting appropriateness criteria	≥90%	___%	___%	↑/↓/→
Tests on formed stool	<5%	___%	___%	↑/↓/→
Tests with laxative use in 48h	<5%	___%	___%	↑/↓/→
Repeat tests within 7 days	<10%	___%	___%	↑/↓/→
Medication audits documented	≥80%	___%	___%	↑/↓/→
Empiric CDI treatment before results	<25%	___%	___%	↑/↓/→

OUTCOME MEASURES:

Metric	Target	Current Month	Prior Month	Trend
C. diff testing rate per 1000 pt-days	<30	___	___	↑/↓/→
CDI positivity rate	10-15%	___%	___%	↑/↓/→
Hospital-onset CDI per 10,000 pt-days	<5	___	___	↑/↓/→
Unnecessary vancomycin days (no + test)	<50	___	___	↑/↓/→
CDI treatment duration >10 days	<15%	___%	___%	↑/↓/→
CDI recurrence rate (30-day)	<20%	___%	___%	↑/↓/→

BALANCING MEASURES:

Metric	Target	Current Month	Prior Month	Trend
Fulminant CDI cases	Monitor	___	___	↑/↓/→
Time to CDI treatment (true +)	<24h	___ h	___ h	↑/↓/→
30-day readmission for CDI	<5%	___%	___%	↑/↓/→

CASE REVIEWS:

Total C. diff positive tests: _____
Retrospective reviews completed: _____ (target: 100%)
Tests deemed inappropriate: _____ (___%)
Colonization vs. infection: _____ colonization, _____ true infection

ACTION ITEMS FOR NEXT MONTH:

Appendix F: Educational "One-Pager" for Bedside Nurses

ICU DIARRHEA: Nurse's Quick Reference Guide

Before Calling About Diarrhea, Document:

✓ Bristol Stool Scale type (6-7 = liquid/watery)
✓ Frequency in past 24 hours
✓ Volume (small/moderate/large or measured)
✓ Characteristics: Blood? Mucus? Color?
✓ Patient symptoms: Cramping? Urgency? Continence?

The 5 Questions to Ask:

1️⃣ "Is the patient on laxatives?"

MiraLAX, lactulose, senna, bisacodyl, docusate
Do NOT order C. diff test if YES (will be rejected)

2️⃣ "When did antibiotics start?"

<72 hours ago = probably antibiotic side effect
Wait 24-48 hours before testing if patient stable

3️⃣ "What liquids is the patient receiving?"

Sorbitol in liquid meds causes diarrhea
Liquid acetaminophen is a common culprit

4️⃣ "When did tube feeds start or change?"

New feeds or rate increases often cause temporary diarrhea
Try slowing rate by half before stopping

5️⃣ "Is the patient sick from the diarrhea?"

Fever? Rising WBC? Low blood pressure?
If YES = notify provider immediately
If NO = document and continue monitoring

What YOU Can Do:

✓ Prevention:

Proper hand hygiene with soap and water (alcohol doesn't kill C. diff)
Barrier creams (zinc oxide) for perianal protection
Contact precautions for known CDI

✓ When Diarrhea Starts:

Stop laxatives/bowel regimen unless ordered to continue
Slow tube feeds by 50% (don't stop completely unless ordered)
Review MAR for new medications started 48-72h ago
Document precisely - helps team make decisions

✓ Skin Care:

Cleanse gently with pH-balanced cleanser (not harsh soap)
Apply barrier cream liberally
Change briefs frequently
Consider rectal trumpet only if ordered (not for CDI!)

When to Escalate Immediately:

🚨 Severe abdominal pain or distension
🚨 Bloody diarrhea with hemodynamic changes
🚨 Fever + diarrhea + rising WBC
🚨 >10 stools/day with volume depletion
🚨 Mental status changes in patient with diarrhea

Common Myths:

❌ "All ICU diarrhea is C. diff"
✓ Actually 60-70% is from medications or tube feeds

❌ "We should stop tube feeds immediately"
✓ Usually better to reduce rate by half and continue

❌ "Liquid medications are the same as tablets"
✓ Liquids contain sorbitol that causes diarrhea

❌ "Diarrhea means we should test for C. diff right away"
✓ Only test if off laxatives, ≥3 liquid stools, >48h antibiotics

Your Impact:

Good nursing documentation prevents unnecessary:

C. diff testing (saves $150-400 per test)
Antibiotic treatment (vancomycin = $50-100/day)
Contact precautions (↑ nursing workload)
Patient isolation and distress

YOU are the eyes and ears of diarrhea stewardship!

Appendix G: Sample Institutional Order Set

ICU DIARRHEA EVALUATION AND MANAGEMENT ORDER SET

DIAGNOSTIC EVALUATION:

□ Document diarrhea using Bristol Stool Scale (enter type: ____)
□ Stool frequency count Q shift × 24 hours
□ Medication audit completed (see checklist)
□ Review enteral nutrition regimen

LABORATORY STUDIES (select appropriate):

□ Do NOT order - patient on laxatives/bowel prep
□ Do NOT order - formed stool (Bristol 1-5)
□ Do NOT order - diarrhea onset <48h after antibiotics started

□ Clostridioides difficile PCR + toxin (reflexive algorithm)

Indication: __________________________
Stool consistency: □ Watery □ Loose □ Formed
Laxatives in past 48h: □ Yes □ No
Antibiotic start date: ________

□ Stool culture (community-acquired diarrhea only)
□ Stool ova & parasites × 3 (if immunocompromised, travel history)
□ Fecal calprotectin (if considering inflammatory cause)
□ Comprehensive metabolic panel
□ Magnesium, phosphate levels
□ Albumin

MEDICATION ADJUSTMENTS:

□ DISCONTINUE:

□ MiraLAX, lactulose, senna, bisacodyl, docusate
□ Metoclopramide
□ _________________ (other identified culprit)

□ REDUCE DOSE:

□ Magnesium supplements
□ _________________

□ CONVERT TO TABLET FORM:

□ Acetaminophen (from liquid)
□ _________________

□ ANTIBIOTIC MODIFICATION:

□ De-escalate from _______ to _______
□ Consider discontinuation if no longer indicated

□ PPI MANAGEMENT:

□ Discontinue if no indication
□ Convert to H2-blocker (famotidine 20mg IV Q12H)

ENTERAL NUTRITION MODIFICATIONS:

□ Reduce rate to _____ mL/hr (50% of current)
□ Change formula to:

□ Semi-elemental (Peptamen, Vital)
□ Fiber-containing
□ Lower osmolality
□ Convert bolus → continuous infusion
□ Do NOT discontinue feeds unless:
□ Hemodynamic instability
□ Abdominal distension/high residuals
□ Vomiting

PHARMACOLOGIC TREATMENT:

For NON-INFECTIOUS diarrhea (after excluding CDI):
□ Loperamide 2mg PO after each loose stool (max 16mg/day)
□ Zinc sulfate 220mg PO daily (if deficient)

For CONFIRMED C. difficile infection:
□ Contact precautions - soap and water handwashing
□ Private room preferred

Non-severe CDI:
□ Vancomycin 125mg PO QID × 10 days
□ Fidaxomicin 200mg PO BID × 10 days (if available)

Severe CDI:
□ Vancomycin 125mg PO QID × 10 days
□ Consider surgical consultation
□ Daily lactate

Fulminant CDI:
□ Vancomycin 500mg PO/NG QID
□ Metronidazole 500mg IV Q8H
□ Vancomycin retention enema 500mg in 100mL NS Q6H (if ileus)
□ STAT surgical consultation
□ STAT CT abdomen/pelvis
□ ICU transfer if not already in ICU

SUPPORTIVE CARE:

□ IV fluid resuscitation: LR at _____ mL/hr
□ Electrolyte replacement protocol:

Potassium goal: 4-5 mEq/L
Magnesium goal: 2-2.5 mEq/L
Phosphate goal: 3-4.5 mg/dL
□ Barrier cream (zinc oxide) to perianal area with each hygiene care
□ Nutrition consult
□ Pharmacy consult for medication review

FOLLOW-UP:

□ Reassess in 24 hours
□ If no improvement in 48 hours, consider:

Extended infectious workup
GI consultation
Imaging (CT abdomen/pelvis)

Author Commentary: Teaching Points for Academic Rounds

This review article is designed to fundamentally shift the diagnostic and therapeutic approach to ICU diarrhea from an infection-centric to a stewardship-driven model. Several teaching opportunities deserve emphasis during academic discussions:

1. The Psychology of Testing

Clinicians face cognitive biases that drive over-testing:

Availability bias: Recent CDI case leads to excessive testing
Omission bias: Fear of missing CDI outweighs risk of false positive
Action bias: Testing feels more active than observation

Counteracting these biases requires institutional culture change through decision support, audit-and-feedback, and metrics transparency.

**2. The "Colonization vs. Infection" Paradigm

The shift to molecular diagnostics (NAAT) has paradoxically worsened CDI overdiagnosis. Teaching teams to understand:

15-30% of ICU patients are colonized with C. difficile
NAAT detects DNA (colonization + infection)
Only toxin detection confirms active disease
Clinical context determines whether treatment is indicated

This explains why two-step algorithms (NAAT + toxin) improve diagnostic accuracy.

3. The Stewardship Opportunity

Diarrhea management is an ideal stewardship target because:

High volume (15-38% of patients)
Clear diagnostic criteria
Measurable outcomes
Affects multiple antimicrobial decisions

Engaging trainees in quality improvement projects around diarrhea testing appropriateness provides concrete stewardship experience.

4. Enteral Nutrition as Life Support

The gut is often called the "motor of critical illness." Emphasizing that enteral nutrition is not merely calories but:

Maintains gut barrier integrity
Supports immune function
Prevents bacterial translocation
Improves outcomes in trauma, sepsis, ARDS

This reframes the decision to stop feeds - it should be as serious as removing other life-support therapies.

5. The Multi-disciplinary Imperative

Optimal diarrhea management requires:

Nurses: Accurate documentation, skin care, feeding administration
Pharmacists: Medication audits, sorbitol calculation, antimicrobial stewardship
Dietitians: Formula selection, advancement protocols
Infection preventionists: Surveillance, outbreak detection
Physicians: Integration and decision-making

Demonstrating how each discipline contributes creates respect for team-based care.

Conclusion

ICU diarrhea represents far more than a nuisance symptom - it is a window into iatrogenesis, antimicrobial stewardship, nutritional support, and diagnostic stewardship. The modern intensivist must resist reflexive testing and treatment, instead embracing a methodical approach that prioritizes non-infectious causes, reserves testing for appropriate patients, and optimizes supportive care.

The evidence is clear: most ICU diarrhea resolves with thoughtful medication review and feeding adjustment, not antimicrobials. By implementing the principles outlined in this review - diagnostic stewardship, systematic evaluation, multidisciplinary collaboration - critical care practitioners can improve patient outcomes while reducing unnecessary testing, antibiotic exposure, and healthcare costs.

As antimicrobial resistance accelerates and C. difficile recurrence rates climb, diagnostic restraint becomes therapeutic wisdom. The best test is sometimes the one not ordered; the best treatment, the medication not prescribed.

The challenge for the next generation of critical care physicians is not simply to diagnose and treat diarrhea, but to prevent it - and when prevention fails, to address the true underlying cause rather than defaulting to the easiest explanation.

Correspondence: [Author contact information would appear here]

Disclosures: None

Funding: None

Acknowledgments: The authors thank the ICU nursing staff, pharmacy colleagues, and infection prevention specialists whose daily work inspired this practical approach to ICU diarrhea management.

Word Count: ~12,500 words
References: 55

Monday, November 3, 2025