CASE 15

A 65-year-old nursing home resident comes to your clinic complaining of watery

nonbloody diarrhea for 2 weeks. She denies abdominal pain, nausea, or vomiting. She
denies any recent travel or sick contacts. Three weeks ago she was treated for an ear
infection with a course of oral antibiotics, but she does not remember the name of the
antibiotic. She denies any fevers or chills, but states that she does feel overall more
weak and tired. Her stools have been watery, brown, foul-smelling, and profuse. The
patient denies any other health problems. She is able to maintain oral intake. On
examination, the patient is thin and pale. Her mucous membranes are dry. Her
temperature is 98°F, heart rate is 100 bpm, and blood pressure is 117/75 mm Hg. The
skin has no lesions or jaundice. Examination of the heart and lungs is unremarkable
except for mild tachycardia. The abdominal examination reveals hyperactive bowel
sounds, with mild, diffuse tenderness. No masses, guarding, or rebound tenderness is
noted. Rectal examination demonstrates no tenderness or masses, and stool is guaiac
negative. The CBC reveals a leukocyte count of 8,000 cells/mm 3. Hemoglobin and
complete metabolic panel are normal with the exception of mild hypokalemia (potassium
3.1 mEq/L).

What is your most likely diagnosis?

What is your next diagnostic step?

What is the next step in therapy?

ANSWERS TO CASE 15:

Clostridium Difficile Diarrhea
Summary: A 65-year-old nursing home resident has a 2-week history of watery
diarrhea, which began 1 week after taking antibiotics. On examination, the patient is
afebrile, has mild volume depletion, and is without jaundice. The abdominal examination
reveals hyperactive bowel sounds, with mild diffuse tenderness and without peritoneal
signs. The leukocyte count is normal.

Most likely diagnosis: Clostridium difficile diarrhea.

Next diagnostic step: Test stool for C. difficile antigen and fecal leukocytes to rule
out any other infectious cause of diarrhea.
Next step in therapy: Assure adequate hydration and start oral metronidazole.

ANALYSIS
Objectives
1. To know the common risk factors for C. difficile diarrhea, including antibiotic use.
2. To understand that volume replacement and correction of electrolyte
abnormalities are the first priorities in any case of diarrhea.
3. To be familiar with the treatment modalities for initial C. difficile diarrhea and
treatment options for recurrent C. difficile infection.
4. To understand the diagnostic approach for C. difficile diarrhea.
Considerations
This 65-year-old nursing home resident presents with a 2-week episode of watery
diarrhea. The first priority in any patient with diarrhea is assessing volume status. This
is a clinical assessment and includes reviewing the vital signs, including pulse and
blood pressure, mental status, and skin turgor. Though slightly tachycardic, she seems
to be stable and is able to keep up with her fluid losses. If volume status is stable, the
next step is to determine the likelihood of this being C. difficile diarrhea. She has
multiple risk factors, including advanced age, nursing home residence, and recent
antibiotic use. In addition, she complains of profuse, nonbloody, watery diarrhea that is
typical for C. difficile. The diagnosis of C. difficile infection (CDI) is made by performing
a C. difficile antigen test on a stool sample. This patient does not have a history
consistent with inflammatory bowel disease. Another acute infectious cause of diarrhea
can still be a possibility, but it is more likely due to C. difficile diarrhea. She does not
have grossly bloody stools which would usually mandate an evaluation and suggest
invasive bacterial infection such as hemorrhagic or enteroinvasive Escherichia coli
species, Yersinia species, Shigella, and Entamoeba histolytica. Additionally, the stool
test for occult blood is negative. Fecal leukocytes are an inexpensive and useful test to
differentiate between the various types of infectious diarrhea. If fecal leukocytes are
present in the stool, the physician may have a higher clinical suspicion for Salmonella,
Shigella, Campylobacter, C. difficile, Yersinia, enterohemorrhagic and enteroinvasive E.
coli, and E. histolytica. Stool cultures may also be helpful. In general, ova and parasite
evaluation is unhelpful unless the history strongly points toward a parasitic source or the
diarrhea is prolonged. Though most diarrheal illnesses are self-limited, C. difficile
diarrhea needs to be treated. The first-line treatment is oral metronidazole.

APPROACH TO:
Suspected C. difficile Infection

DEFINITIONS
CLOSTRIDIUM DIFFICILE INFECTION (CDI): It is defined by the presence of
symptoms (typically diarrhea) and a stool test positive for C. difficile toxins or toxigenic
C. difficile, or colonoscopic or histopathologic findings of pseudomembranous colitis
PSEUDOMEMBRANOUS COLITIS: A serious colonic disease that occurs as a result of
a severe inflammatory response to C. difficile toxins. The classic finding is C. difficile–
associated pseudomembranes with adherent yellow plaques
TOXIC MEGACOLON: A life-threatening complication of fulminant colitis in which the
colon becomes markedly dilated with risk of perforation. Most cases of toxic megacolon
require surgery

CLINICAL APPROACH
Etiology
Clostridium difficile is a gram-positive, spore-forming rod that is responsible for a
significant amount of antibiotic-associated diarrhea and most cases of
pseudomembranous colitis. Due to the frequent use of antibiotics, the incidence of C.
difficile diarrhea has increased tremendously. In addition, infection with C. difficile costs
up to $1.1 billion in health-care expenditures in the United States, and each year CDI
affects up to 3 million people. A common risk factor for acquiring this pathogen is
hospitalization. Admission to an acute care facility is associated with development of
CDI, and C. difficile has been cultured from hospital bed railings, floors, toilets, and
even in the hands of health-care workers; hence, hand washing is important. The
organism is a hardy bug that can persist in hospital rooms for up to 40 days after the
infected patient has left, and commonly used alcohol foams and gels are not effective in
killing C. difficile spores. Other common risk factors associated with CDI include
admission to the intensive care unit, advanced age, antibiotic therapy,
immunosuppression, prolonged hospital stay, residence in a nursing home or other
chronic care facility, and sharing a hospital room with a C. difficile–infected patient.
Pathogenesis
The instigating event is usually antibiotic exposure. Antibiotic use disrupts the
normal colonic microflora, and in this environment, C. difficile spores germinate. These
spores are then converted into a vegetative form within the colon, and the vegetative
cells multiply. Clostridium difficile adheres to the mucus layer and subsequently adheres
to enterocytes to colonize the gut. Once the mucosal lining is interrupted, it provides a
fertile feeding ground for the C. difficile spores. From there, the host can become an
asymptomatic carrier or a symptomatic patient. Symptoms in patients colonized with C.
difficile can range from carrier state, to diarrhea, to life-threatening colitis, and to toxic
megacolon. These symptoms can be present even after discontinuing the antibiotics,
even weeks after stopping the medication.
The symptoms in C. difficile–colonized patients depends on the host response. If the
host can respond adequately and does not have pertinent risk factors, then the patient
will continue to be a carrier of the spores indefinitely. If, on the other hand, the patient
has risk factors (ie, advanced age, antibiotic use) and cannot mount an adequate
immune response, the symptoms will be more attenuated.
Clinical Presentation
Diarrhea in the geriatric population is a common symptom and complaint. Most acute
diarrheas are self-limited and do not require a significant workup. History is critical in
helping to narrow the differential diagnosis for acute diarrhea. The clinician should
determine the onset, course, and character of the diarrhea. Medication use (including
laxatives and stool softeners) and foods, travel history, antibiotic use, and whether other
friends or family members have similar symptoms are important to know. The clinician
should determine if the patient can tolerate oral hydration and is able to maintain
adequate volume status.
The physical examination should focus on the vital signs, clinical impression of
volume status, presence of signs of sepsis, mental status, and abdominal examination.
Volume status is determined by blood pressure, pulse, skin turgor, and examination of
the mucous membranes. A rectal examination to assess blood is important in the
differential diagnosis workup.
Clostridium difficile–associated diarrhea is typically nonbloody and foul smelling. Most
patients will complain of an increased amount and/or frequency of stool. This should
prompt further evaluation in a geriatric patient who complains of a change in the bowel
habits, especially if they are living in a nursing home.
Differential Diagnosis
Up to 90% of acute diarrhea is infectious in etiology. Elderly patients can also acquire
the same infectious diarrheal pathogens as younger patients, including E. coli,
Campylobacter, Shigella, Salmonella, Giardia, Yersinia species, Entamoeba histolytica,
Staphylococcus aureus, Vibrio, Clostridium perfringens, or viruses (including rotavirus
or hepatitis viruses). Noninfectious diarrheas warrant assessment for inflammatory
bowel disease or for bloody, colonic ischemia (especially in the frail or very elderly).
Diagnosis
The diagnosis can be made with a careful history and physical examination, with an
emphasis on use of antibiotics within the past 3 months. Any antibiotics can be
associated with the infection, but the most notorious ones include clindamycin,
cephalosporins, and broad-spectrum penicillins. Care must be taken to elicit a
detailed description of the patient’s diarrhea, including color, consistency, and
frequency, which is important in differentiating other causes of diarrhea from C. difficile–
associated diarrhea.
The most common laboratory test for diagnosing C. difficile–mediated disease is an
enzyme immunoassay that detects toxins A and B. This assay has a specificity of
93% to 100% but a sensitivity of 63% to 99%, which means that false-negative results
can occur. This assay will remain positive for an extended period of time, and should
not be used as an indicator of response; the clinical picture will best determine if a
patient is responsive to treatment.
The gold standard for the diagnosis of C. difficile–mediated disease is a cytotoxic
assay. Although this test is highly sensitive and specific, it is difficult to perform, and
results are not available for 24 to 48 hours. Clostridium difficile can also be cultured.
Lastly, endoscopy can be used. The classic endoscopic finding is the characteristic
pseudomembranes. Endoscopy is indicated in more severe disease and is not routinely
done in mildly symptomatic patients. The finding of pseudomembranes is pathognomic
for C. difficile infection.
Treatment
Treatment of C. difficile depends on the severity of the symptoms. For otherwise healthy
adults, the first step is to stop the offending antibiotics and assure adequate
hydration and fluid balance. Electrolytes must also be carefully monitored to ensure
there is not an imbalance. Metronidazole is first-line therapy in mild to moderate CDI.
(See Table 15-1 for guidelines of treatment.)

Table 15–1 • 2010 ISDA/SHEA GUIDELINES FOR TREATMENT OF Clostridium

difficile INFECTION

First-line therapy consists of metronidazole, 500 mg orally 3 or 4 times a day for 10 to

14 days. Using this drug has a >90% response rate. For a second relapse, the same
treatment regimen is used. Another effective option is vancomycin, again with a
response rate of >90%. This can be used if the patient is pregnant or does not
response to metronidazole treatment. The initial dose used is 125 to 500 mg orally 4
times a day for 10 to 15 days.
Roughly one-quarter of patients will have a recurrence due to persistent germination
of C. difficile spores in the colon, and not due to resistant strains. In addition, patients
can be reinfected due to reingestion if appropriate measures (ie, hand washing) are not
undertaken properly.
Approximately 3% of patients infected with C. difficile will develop serious infections.
The mortality rate in these patients ranges from 30% to 85%. Initial treatment of severe
cases involves intravenous metronidazole and oral vancomycin used in combination. If
medical therapy fails or perforation or toxic megacolon develops, surgical interventions
are necessary. Despite treatment, this still has a high mortality rate.
Prevention is the best way to eliminate the potential for infections. Important
measures include the selective use of antibiotics, hand washing between patient
contacts, rapid detection of C. difficile, and isolation of patients.

CLINICAL CASE CORRELATION

See also Case 14 (Colon Cancer).

COMPREHENSION QUESTIONS

15.1 The patient’s diarrhea from the clinical scenario has not resolved after 8 days
of oral metronidazole therapy. An evaluation includes assays for stool for
various laboratories. The C. difficile assay is negative. Which of the following is
the most accurate statement?
A. Clostridium difficile diarrhea typically takes 3 weeks to resolve and this
patient’s response is not unusual.
B. The presence of fecal leukocytes is consistent with C. difficile infection.
C. Bloody diarrhea is usually seen with C. difficile infection.
D. Clostridium difficile cytotoxic assay is more sensitive than C. difficile toxin
assay.
E. Oral clindamycin is an alternative treatment for C. difficile infection.

15.2 A 67-year-old woman is in your clinic. She has a history of hypertension,

diabetes, and prior C. difficile infection treated 1 month ago. Most of her
symptoms after the C. difficile infection cleared, but she is complaining of
recurrent diarrhea. She describes it as foul-smelling and watery. Stool for C.
difficile antigen is positive. What would be the next step in treatment?
A. Oral cefuroxime
B. Oral metronidazole
C. Oral vancomycin and oral metronidazole
D. Oral metronidazole and intravenous vancomycin
E. Oral sulfamethoxazole and trimethoprim (Bactrim)

ANSWERS

15.1 D. Most diarrhea persists for 7 to 10 days and will resolve on its own. If it
persists, then further workup may be necessary. Fecal leukocytes will help
determine if the bacteria is invasive and speaks against C. difficile. Clostridium
difficile assay is more sensitive than the C. difficile toxin assay, but is more
difficult to perform.
 15.2 B. First-time C. difficile diarrhea should be treated with oral metronidazole.
Recurrent infection should again be treated with oral metronidazole. Another
infection after that is treated with a vancomycin taper. Fulminant C. difficile
colitis is treated with oral vancomycin and intravenous metronidazole.

CLINICAL PEARLS

Clostridium difficile is a common cause of diarrhea in patients using antibiotics.

One should have a high index of suspicious of this disease entity is in the right
clinical setting.

Initial treatment and first-time relapse are treated with metronidazole.

Prevention is a key strategy for avoiding contamination with C. difficile spores.

REFERENCES
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Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium
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