The diagnosis is Clostridioides difficile infection following recent
antibiotic exposure.
1. Definition
Clostridioides difficile infection (CDI) is a toxin-mediated
inflammatory disease of the colon caused by toxigenic C. difficile,
usually after disruption of the normal intestinal microbiota. Disease ranges
from mild diarrhea to severe colitis, pseudomembranous colitis, and
fulminant colitis.
2. Etiology and Risk Factors
1. Caused
by Clostridioides difficile, a gram-positive,
spore-forming, anaerobic bacterium
2. The
most important modifiable risk factor is recent antibiotic exposure
3. Antibiotics
strongly associated with CDI include:
o Clindamycin
o Fluoroquinolones
o Cephalosporins
o Broad-spectrum
penicillins
4. Other
important risk factors include:
o Older
age, particularly ≥65 years
o Recent
hospitalization or healthcare exposure
o Previous
CDI
o Immunosuppression
o Significant
comorbidity
5. Proton
pump inhibitor use is associated with CDI, although unnecessary
acid-suppressive therapy should be discontinued rather than stopping therapy
that has a valid indication
3. Pathophysiology
1. Antibiotic
exposure disrupts the normal intestinal microbiota
2. Ingested
C. difficile spores can germinate and permit colonization and
bacterial overgrowth
3. Toxigenic
strains produce:
o Toxin
A
o Toxin
B
4. These
toxins glucosylate and inactivate Rho-family GTPases
5. This
causes:
o Cytoskeletal
disruption
o Loss
of epithelial barrier integrity
o Fluid
secretion
o Neutrophilic
inflammation and colonic injury
6. Severe
mucosal injury can result in pseudomembrane formation
4. Clinical Features
1. Watery
diarrhea, typically ≥3 unformed stools within 24 hours
2. Abdominal
pain and cramping
3. Fever
4. Leukocytosis
5. Nausea
and anorexia may occur
6. Severe
or fulminant disease may cause:
o Marked
abdominal pain or distension
o Ileus
o Toxic
megacolon
o Hypotension
or shock
o Colonic
perforation
o Sepsis
5. Diagnosis
Diagnosis requires compatible clinical symptoms together with
laboratory evidence of toxigenic C. difficile.
5.1 Who Should Be Tested
1. Test
patients with unexplained new-onset diarrhea, generally defined
as ≥3 unformed stools in 24 hours
2. Test
only unformed stool, except in selected patients with
suspected ileus or toxic megacolon
3. Do
not routinely test asymptomatic patients
4. Do
not perform a test of cure, because patients may remain colonized
after clinical recovery
5.2 Stool Testing
1. Nucleic
acid amplification testing (NAAT/PCR)
o Detects
genes encoding C. difficile toxins
o Highly
sensitive
o Does
not directly demonstrate free toxin production
2. A
positive NAAT can occur with asymptomatic colonization, so results
must be interpreted in the appropriate clinical context
3. A
multistep testing algorithm is often preferred for diagnostic
accuracy, such as:
o GDH
antigen plus toxin assay
o GDH
plus toxin assay with NAAT arbitration
o NAAT
plus toxin assay
4. NAAT
alone may be used when strict preagreed stool-submission criteria
are applied
5.3 Endoscopy
1. Colonoscopy
is not routinely required
2. It
may demonstrate characteristic yellow-white pseudomembranes
3. Endoscopy
may be considered when the diagnosis remains uncertain and direct visualization
is clinically necessary
6. Severity Classification
6.1 Nonsevere CDI
1. WBC
≤15,000 cells/µL
2. Serum
creatinine ≤1.5 times baseline
6.2 Severe CDI
1. WBC
>15,000 cells/µL, and/or
2. Serum
creatinine >1.5 times baseline
6.3 Fulminant CDI
Characterized by one or more of the following:
1. Hypotension
or shock
2. Ileus
3. Toxic
megacolon
In this patient, fulminant CDI is not evident, but exact
severity cannot be classified without the absolute WBC count and serum
creatinine.
7. Management
7.1 Initial CDI Episode
1. Discontinue
the inciting antibiotic when clinically feasible
2. Maintain
appropriate fluid and electrolyte replacement
3. Preferred
treatment:
o Fidaxomicin
200 mg orally twice daily for 10 days
4. Acceptable
alternative:
o Vancomycin
125 mg orally four times daily for 10 days
5. Fidaxomicin
is preferred because it provides similar initial cure with a lower risk
of recurrence, although access and cost may influence treatment choice
7.2 Fulminant CDI
1. Vancomycin
500 mg orally or enterally every 6 hours
2. Add
IV metronidazole 500 mg every 8 hours
3. If
ileus is present, add rectal vancomycin 500 mg every 6 hours
4. Manage
with a multidisciplinary team, with early surgical involvement
when there is:
o Toxic
megacolon
o Perforation
o Shock
o Progressive
organ failure
o Clinical
deterioration
7.3 Recurrent CDI
1. First
recurrence
o Fidaxomicin,
or
o A
tapered and pulsed oral vancomycin regimen
2. Second
recurrence or subsequent episodes
o Fidaxomicin
or an appropriate vancomycin regimen
o Fecal
microbiota-based therapy should be offered after treatment of a second
recurrence
3. FDA-approved
microbiota-based products include:
o Fecal
microbiota, live-jslm (Rebyota)
o Fecal
microbiota spores, live-brpk (Vowst)
4. These
products are used to prevent recurrence after completion of
antibacterial treatment for recurrent CDI, not to treat active acute
CDI
5. Microbiota-restoration
therapy may be considered earlier in selected patients at particularly high
risk of further recurrence
7.4 Infection Control
1. Use
contact precautions with gloves and gown in healthcare
settings
2. C.
difficile spores persist in the environment and require appropriate sporicidal
environmental cleaning
3. Alcohol-based
hand rub remains appropriate for routine healthcare hand hygiene unless hands
are visibly soiled
4. Soap-and-water
handwashing is particularly emphasized:
o When
hands are visibly soiled
o After
restroom use
o During
CDI outbreaks
5. Soap
and water physically remove spores, whereas alcohol-based products have poor
activity against C. difficile spores
8. Complications
1. Dehydration
and electrolyte abnormalities
2. Severe
colitis
3. Toxic
megacolon
4. Colonic
perforation
5. Sepsis
and shock
6. Recurrent
CDI
9. Key Clinical Insight
Recent fluoroquinolone exposure followed by new-onset watery
diarrhea, abdominal cramping, leukocytosis, and a positive stool NAAT for
toxigenic Clostridioides difficile is highly
consistent with Clostridioides difficile infection. A positive PCR detects
toxin genes and must be interpreted together with compatible clinical symptoms.
References
1. Fischer
M, Vaughn BP, Peery AF, Kelly CR. AGA Clinical Practice Update on Management of
Clostridioides difficile Infection in Adults: Expert Review. Clin
Gastroenterol Hepatol. 2026;24(9):2359-2369.
doi:10.1016/j.cgh.2026.05.007.
2. Johnson
S, Lavergne V, Skinner AM, et al. Clinical Practice Guideline by the Infectious
Diseases Society of America and Society for Healthcare Epidemiology of America:
2021 Focused Update Guidelines on Management of Clostridioides difficile
Infection in Adults. Clin Infect Dis. 2021;73(5):e1029-e1044.
doi:10.1093/cid/ciab549.
3. Centers for Disease Control and Prevention. Clinical Guidance for C. diff Infection Prevention in Acute Care Facilities. Updated May 13, 2026.
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