The nurse is caring for a patient experiencing diarrhea caused by clostridium difficile

Practice Essentials

Clostridioides difficile (formerly Clostridium difficile) colitis results from a disturbance of the normal bacterial flora of the colon, colonization by C difficile, and the release of toxins that cause mucosal inflammation and damage. Antibiotic therapy is the key factor that alters the colonic flora. C difficile infection (CDI) occurs primarily in hospitalized patients.

Signs and symptoms

Symptoms of C difficile colitis often include the following:

• Mild to moderate watery diarrhea that is rarely bloody

• Cramping abdominal pain

• Anorexia

• Malaise

Physical examination may reveal the following in patients with the disorder:

• Fever: Especially in more severe cases

• Dehydration

• Lower abdominal tenderness

See Clinical Presentation for more detail.

Diagnosis

The diagnosis of C difficile colitis should be suspected in any patient with diarrhea who has received antibiotics within the previous 3 months, has been recently hospitalized, and/or has an occurrence of diarrhea within 48 hours or more after hospitalization. [1] In addition, C difficile can be a cause of diarrhea in community dwellers without previous hospitalization or antibiotic exposure. [2]

Laboratory studies

Laboratory testing for evaluating patients with CDI includes the following:

• Complete blood count: Leukocytosis may be present (the levels can be very high in severe infection)

• Electrolyte levels, including serum creatinine: Dehydration, anasarca, and electrolyte imbalance may accompany severe disease

• Albumin levels: Hypoalbuminemia may accompany severe disease

• Serum lactate level: Lactate levels are generally elevated (≥5 mmol/L) in severe disease

• Stool examination: Stool may be positive for blood in severe colitis, but grossly bloody stools are unusual; fecal leukocytes are present in about half of cases

Stool assays for C difficile, from the most to the least sensitive, include the following:

• Stool culture: The most sensitive test (sensitivity, 90-100%; specificity, 84-100%), but the results are slow and may lead to a delay in the diagnosis if used alone

• Glutamate dehydrogenase enzyme immunoassay (EIA): This is a very sensitive test (sensitivity, 85-100%; specificity, 87-98%); it detects the presence of glutamate dehydrogenase produced by C difficile

• Real-time polymerase chain reaction (PCR) assay: This test is an alternative gold standard to stool culture (sensitivity, 86%; specificity, 97% [3] ); it may be used to detect the C difficile gene toxin

• Stool cytotoxin test: A positive test result is the demonstration of a cytopathic effect that is neutralized by a specific antiserum (sensitivity, 70-100%; specificity, 90-100%)

• EIA for detecting toxins A and B: This test is used in most laboratories (moderate sensitivity, 79-80%; excellent specificity, 98%)

• Latex agglutination technique: Another means of detecting glutamate dehydrogenase; however, the sensitivity of this test is poor (48-59%), although the specificity is 95-96%

Imaging studies and procedures

Abdominal computed tomography (CT) scanning is the imaging modality of choice for C difficile colitis when pseudomembranous colitis (see the image below), complications of CDI, or other intra-abdominal pathology is suspected. [4] In patients with sepsis due to suspected megacolon, abdominal radiography may be performed instead of CT scanning to establish the presence of megacolon in a timely manner.

Endoscopy is less sensitive for diagnosing C difficile than are stool assays. Endoscopy may demonstrate the presence of raised, yellowish white, 2- to 10-mm plaques overlying an erythematous and edematous mucosa. These plaques are termed pseudomembranes. Endoscopic findings may be normal in patients with mild disease or may demonstrate nonspecific colitis in moderate cases.

See Workup for more detail.

Management

Treatment for CDI varies according to its severity. Interventions include the following:

• Asymptomatic carriers: No treatment is necessary

• Mild, antibiotic-associated diarrhea without fever, abdominal pain, or leukocytosis: Cessation of antibiotic(s) may be the only treatment necessary

• Mild to moderate diarrhea or colitis: Metronidazole (oral or intravenous) or vancomycin (oral) for 10 days

• Severe or complicated disease: Vancomycin is considered to produce faster symptom resolution and fewer treatment failures than metronidazole; in fulminant cases, combined therapy with intravenous metronidazole and oral (or per rectum) vancomycin may be considered [5]

Relapse

Relapse occurs in 20-27% of patients. Once a patient has 1 relapse, the risk for a second relapse is 45%. Relapses should be treated as follows:

• First relapse: The choice of antibiotic should be based on the severity of C difficile diarrhea/colitis

• Subsequent relapses: For every relapse after the first, vancomycin (prolonged taper/pulsed regimen) or fidaxomicin with or without probiotics is recommended

Among various investigational therapies, fecal microbiota transplantation (fecal enemas or infusion of donor feces through a nasoduodenal tube) has been reported to repopulate the colonic flora and treat recurrent CDI. [6, 7, 8]

See Treatment and Medication for more detail.

Background

C difficile is a gram-positive, anaerobic, spore-forming bacillus that is responsible for the development of antibiotic-associated diarrhea and colitis. C difficile infection (CDI) commonly manifests as mild to moderate diarrhea, occasionally with abdominal cramping. Pseudomembranes (adherent, yellowish white plaques on the intestinal mucosa) are occasionally observed (see the images below). In rare cases, patients with C difficile infection can present with an acute abdomen and fulminant, life-threatening colitis. (See Presentation.)

Approximately 20% of individuals who are hospitalized become colonized with C difficile during hospitalization, and more than 30% of these patients develop diarrhea. Thus, C difficile colitis is currently one of the most common nosocomial infections. (See Pathophysiology and Etiology.)

The diagnosis of C difficile colitis should be suspected in any patient with diarrhea who has received antibiotics within the previous 3 months, has been recently hospitalized, and/or has an occurrence of diarrhea 48 hours or more after hospitalization. [1] However, more recent studies have shown that C difficile can be the cause of diarrhea in community dwellers without previous hospitalization or antibiotic exposure [2] ; therefore, the diagnosis should be suspected in this population as well. (See Presentation and Workup.)

Once infected with C difficile, the rate of disease recurrence is 20-40%, especially when first-line agents such as metronidazole and vancomycin are not successful. [9] In patients with CDI who develop fulminant colitis, early surgical intervention is crucial. Note that although intravenous immunoglobulin (IVIG) and tigecycline have been used in patients with severe refractory disease, delaying surgery may lead to worse outcomes. (See Treatment and Medication.) [9] In addition, the use of tigecycline in oncology patients with CDI has been reported with breakthrough CDIs in those who received it for non-CDI indications. [10]

Pathophysiology

C difficile colitis results from a disturbance of the normal bacterial flora of the colon, colonization with C difficile, and release of toxins that cause mucosal inflammation and damage. Colonization occurs by the fecal-oral route. Hospitalized patients are the primary targets of C difficile infection (CDI), although C difficile is present as a colonizer in 2-3% of healthy adults and in as many as 70% of healthy infants. [11] (Treatment of asymptomatic carriers is not recommended.)

C difficile forms heat-resistant spores that can persist in the environment for several months to years. Outbreaks of C difficile diarrhea may occur in hospitals and outpatient facilities where contamination with spores is prevalent. Although the normal gut flora resists colonization and overgrowth with C difficile, the use of antibiotics, which alter and suppress the normal flora, allows proliferation of C difficile, toxin production, and diarrhea.

Pathogenic strains of C difficile produce 2 distinct toxins. Toxin A is an enterotoxin, and toxin B is a cytotoxin; both are high–molecular weight proteins capable of binding to specific receptors on the intestinal mucosal cells. Receptor-bound toxins gain intracellular entry by catalyzing a specific alteration of Rho proteins—small glutamyl transpeptidase (GTP)–binding proteins that assist in actin polymerization, cytoskeletal architecture, and cell movement. Both toxin A and toxin B appear to play a role in the pathogenesis of C difficile colitis in humans.

More recently, rat studies suggest that C difficile toxin B induces senescence in enteric glial cells (ECGs); investigators hypothesize that EGCs that survive toxin B and acquire senescence potentially cause the development of irritable bowel syndrome and inflammatory bowel disease via persistent inflammation, transfer of senescence status, and stimulation of preneoplastic cells. [12]

The NAP1 hypervirulent strain of C difficile is associated with the most serious sequelae of CDI, causing severe and fulminant colitis that is characterized by leukocytosis, renal failure, and toxic megacolon. [13] The widespread use of fluoroquinolone antibiotics may have played a role in the proliferation of the NAP1 strain. Once rising white blood cell count or hemodynamic instability occurs and fulminant colitis is imminent, subtotal colectomy with end ileostomy is often necessary. Fecal bacteriotherapy and immunotherapy are investigative treatment strategies that have potential for managing patients with severe CDI. [13]

Etiology

C difficile colitis results from a disruption of the normal bacterial flora of the colon, colonization with C difficile, and release of toxins that cause mucosal inflammation, mucosal damage, and diarrhea.

Risk factors

Antibiotic exposure

The primary risk factor for C difficile colitis is previous exposure to antibiotics; the most commonly implicated agents include the cephalosporins (especially second and third generation), the fluoroquinolones, ampicillin/amoxicillin, and clindamycin. Less commonly implicated antibiotics are the macrolides (ie, erythromycin, clarithromycin, azithromycin) and other penicillins. Agents occasionally reported to cause the disease include aminoglycosides, trimethoprim-sulfamethoxazole, metronidazole, chloramphenicol, tetracycline, imipenem, and meropenem.

Even brief exposure to any single antibiotic can cause C difficile colitis. A prolonged antibiotic course or the use of 2 or more antibiotics increases the risk of disease. Moreover, antibiotics traditionally used to treat C difficile, vancomycin and metronidazole, have also been shown to cause disease. [14]

Hospitalized patients who occupy a bed whose previous occupant received antibiotics appear to have an increased risk of C difficile infection (CDI). [15] A multicenter retrospective (2010-2015) study of 100,615 pairs of patients who sequentially occupied a given hospital bed found that less than 1% (576 pairs; 0.57%) of subsequent patients developed CDI, regardless of whether they themselves received antibiotics or not. [15] The association was statistically significant (log-rank P< 0.01).

Proton pump inhibitors

A US Food and Drug Administration (FDA) safety communication on February 8, 2012, described a possible association between the use of proton pump inhibitors (PPIs) and the development of Clostridium difficile –associated diarrhea (CDAD). [16] Data were collected from the US Food and Drug Administration’s (FDA's) Adverse Event Reporting System (AERS) and the medical literature for cases of CDAD in patients undergoing treatment with PPIs.

Many of the adverse event reports involved patients who were elderly, had chronic and/or concomitant underlying medical conditions, or were taking broad-spectrum antibiotics that could have predisposed them to developing CDAD. [16] The FDA also reviewed a total of 28 observational studies described in 26 publications. Of these studies, 23 showed a higher risk of C difficile infection or disease, including CDAD, associated with PPI exposure, compared with no PPI exposure.

Antidepressants

Two related studies documented an increased risk of CDI in adults taking the antidepressants mirtazapine and fluoxetine. [17, 18] In a longitudinal study of 16,781 older adults (mean age, 67.9 y), 404 of whom had been diagnosed with CDI at least once, major depression was associated with a 36% increase in the odds of developing an infection with C difficile.

In the second study, in which 4047 adult patients had their stools tested for C difficile while they were hospitalized, the odds of testing positive for the bacterium were twice as high in patients who received mirtazapine or fluoxetine as in those who did not. [17, 18] None of the other 10 antidepressants that were tested in the study increased the risk of CDI.

Other risk factors

Advanced age (>60 y) and hospitalization (particularly sharing a hospital room with an infected patient, intensive care unit stays, and prolonged hospital stays) are known risk factors for infection with C difficile. Severe illnesses, immune suppression, and gastric acid suppression [19] (or bypassing gastric acid via enteral feeds) are also well-established risk factors. In addition, in recent years, inflammatory bowel disease (IBD) has been implicated as a strong risk factor for C difficile infection (CDI). [9, 20]  Early emergency general surgery has also been associated with a high incidence of CDI, particularly in patients who receive 3 or more postoperative antibiotics and those who undergo bowel resections. [21]

Rarer associations include the following:

• Antineoplastic agents, principally methotrexate

• Malignancies

• Intestinal ischemia

• Nonsurgical gastrointestinal procedures, including placement of nasogastric tubes

Genetics/genomics

Two genome-wide association studies (GWAS) found an association between a common polymorphism in the upstream promoter of the interleukin (IL)-8 gene and an increased risk for both the initial occurrence and the recurrence of CDI. [22, 23] Neutrophil recruitment to the intestine is thought to be coordinated by IL-8, and the polymorphism in the IL-8 promoter is thought to influence the manner in which neutrophils are recruited to the intestines when CDI is present. [22, 23]

An additional study looked more specifically at the regulation of the regenerating islet-derived genes (REG) in IBD. Interestingly, the study found that the activities of all REG genes were upregulated not only in IBD but also in patients with pseudomembranous colitis. [24] The implication from this study is that the function of the REG family of genes is more generalized in response to inflammation. These proteins are involved in injury, repair, and growth in the intestine. Also of interest is that REG proteins in the gut appear to be antimicrobial, with a function similar to lectin. [24]

Toxin A is an enterotoxin that is responsible for the major manifestations of colitis in humans. In a murine model deficient in the neurokinin-1 receptor, protection against inflammation from toxin A was demonstrated. [25] This protein, which is encoded by the NK1R gene, functions as the receptor for substance P. Downstream effects from this protective effect included decreased intestinal levels of tumor necrosis factor (TNF)-alpha and leukocyte myeloperoxidase. The overall suggestion from this study is that the substance P receptor is very important in the pathogenesis of inflammatory diarrhea. [25]

Further insight into the genetics of C difficile toxin A reveals that the main binding protein is gp96. [26] In addition, it has been found that C difficile has potent stimulatory activity for the Nod1 gene, and mice who were homozygous knockouts for Nod1 had increased lethality to CDI despite similar levels of intestinal damage relative to control the mice. [27] Those mice also had impaired clearance of bacteria and increased translocation of the bacteria. The implication of this study is that Nod1 regulates the susceptibility to C difficile. [27]

Ultimately, many of the genetic influences on CDI and the clinical course of C difficile colitis likely remain unknown. At this point, it is understood that subtle differences in the immune system may significantly influence the natural history of C difficile disease.

Epidemiology

Occurrence in the United States

In the United States, C difficile infection (CDI) occurs primarily in hospitalized patients, causing as many as 3 million cases of diarrhea and colitis per year. Cancer patients are significantly affected by CDI healthcare-associated diarrhea. [28] Diarrhea caused by C difficile is also linked to 14,000 American deaths annually. [29]  

The incidence of reported CDI infection continues to increase. In the 1980s, McFarland et al reported that 7% of patients admitted to a hospital and 28% of patients who were hospitalized had positive cultures for the organism. By the 1990s, the incidence of C difficile in hospitalized patients had risen to 30-40 per 100,000 population, and by 2005, to 84 per 100,000 population.

Indeed, in contrast to the incidence rates of other nosocomial infections, which declined from 2000 to 2009, the number of hospitalized patients with any CDI as a discharge diagnosis more than doubled in the same period, from approximately 139,000 to 336,600. Furthermore, the number of patients with a primary diagnosis of CDI more than tripled, from 33,000 to 111,000. [30]

New CDI populations have emerged, and studies have challenged the notion that C difficile is primarily a hospital infection, as more cases are being seen in the community. [2, 31, 32] These cases include patients with community-acquired infection and no previous antibiotic exposure, pregnant women, and patients with inflammatory bowel disease (IBD). [9, 20]  

A population-based study from Olmsted County, Minnesota, demonstrated that 41% of the cases of C difficile infection were community acquired and that the incidence of both community- and hospital-acquired C difficile increased significantly from 1991 to 2005. [2]

International occurrence

The incidence of CDI, as well as deaths attributable to C difficile, has also risen in Europe and Canada. In Canada's Estrie region of Quebec, the incidence quadrupled in 2003 to 92.2 cases per 100,000 population. In a survey of 97 hospitals across 34 European countries, the incidence of C difficile in hospitalized patients was 41 per 100,000 patient-days. [33]

The worldwide increased incidence of CDI has been attributed to a variety of risk factors, including more elderly patients in the population, treatment resistance to fluoroquinolones, and the emergence of a newly discovered, more virulent strain of C difficile (BI/NAP1/027). [34] Additional risk factors toward increasing CDIs include the use of penicillins and clindamycin, as well as an increased use in the total number of antibiotics in the community. [34]

Age-related demographics

CDI is more common in elderly people, and old age may promote susceptibility to colonization and disease. Cross-infection by C difficile is common in neonatal units, but neonates do not seem to develop C difficile –associated diarrhea. More recently, there have been specific populations affected by C difficile that were previously believed to be at low risk, such as young, healthy persons not exposed to a hospital environment or antimicrobial therapy and young women in a peripartum setting.

A study by Nylund et al suggested an increase in CDI among hospitalized children, especially in those with medical conditions such as IBD and immunosuppression. [35] Also at risk are individuals hospitalized with conditions that require antibiotic administration.

Prognosis

Some patients with C difficile colitis with mild disease may recover without specific therapy; however, persistent diarrhea may be debilitating and can last for several weeks; therefore, treatment is recommended even in mild disease

The use of oral metronidazole or vancomycin produces response rates of greater than 95% in mild to moderate cases, with symptomatic improvement (diarrhea) in as little as 3-4 days and complete resolution in 7-10 days

Approximately 20-27% of patients treated for a first episode of C difficile colitis relapse after successfully completing therapy, typically 3 days to 3 weeks after treatment has ended.

Patients who relapse once are at an even greater risk for further relapses; the relapse rate for patients with 2 or more relapses is 65%. [36]

Adverse outcomes from C difficile infection (CDI) include treatment failure, development of severe or severe-complicated infection, sepsis and the need for admission to the intensive care unit, need for colectomy, increased length of hospital stay, need for hospital admission in patients with community-acquired CDI, and mortality. [37] (Mortality rates from C difficile –associated diarrhea as high as 4.2-6.9% were found in several centers in North America; in a multicenter study from Quebec, mortality rates increased with age. [38] )

However, there is evidence that reliance primarily on hospital-based studies of CDI, with relatively few studies having been made of community-acquired cases, may have led researchers to underestimate the burden, but overestimate the severity, of the condition. [2] Patients with community-acquired CDI are generally younger, with less severe infection relative to hospitalized patients with CDI. [2]

Severe strains

Several outbreaks have been caused by the North American Pulsed Field type 1 and polymerase chain reaction (PCR) ribotype 027 (NAP1/027) strain. This virulent strain has been associated with increased production of toxins A and B, fluoroquinolone resistance, and the production of a binary toxin. The role of the binary toxin is not clear, but it may synergistically increase the virulence of toxins A and B.

Based on the data from the Centers of Disease Control and Prevention (CDC), the virulent strain NAP1/027 has been reported in most US states and in several countries in Europe.

PCR ribotypes 018 and 056, identified in Europe, have been associated with more severe Cdifficile colitis. [33]

Predictors of severe outcomes in IBD and ulcerative colitis

Patients with IBD are well known to be at an increased risk for CDI. A study identified 3 independent predictors for severe outcomes in hospitalized IBD patients with CDI: (1) serum albumin less than 3 g/dL, (2) hemoglobin level below 9 g/dL, and (3) elevated serum creatinine above 1.5 mg/dL. [39]

In another study, investigators found that CDI is associated with a worse long-term outcome in patients with ulcerative colitis. [40] In the year following treatment for CDI in these patients, an escalation in medical management was noted. In addition, independent predictors for colectomy within 1 year were infection with C difficile and endoscopically proven severe disease. [40]

Complications

Fulminant colitis

Fulminant colitis is a rare form of CDI, occurring in only 3% of patients but accounting for most of the serious complications. These include toxic megacolon, colonic perforation, and death. Surgical intervention is usually required in patients who develop fulminant colitis.

Sailhamer et al conducted a retrospective review of 4796 patients with C difficile colitis, 199 (4.1%) of whom had the fulminant form, as defined by the need for colectomy or admission to the intensive care unit. [41] The in-hospital mortality rate for fulminant C difficile colitis was 34.7%. The investigators determined that independent predictors of mortality included the following:

• Age of 70 years or older

• Severe leukocytosis or leukopenia or bandemia

• Cardiorespiratory failure

The presence of all 3 factors resulted in a 57.1% mortality rate; in the absence of all 3, the mortality rate was 0%. [41] The investigators concluded that despite awareness and treatment of fulminant C difficile colitis, this condition remains highly lethal. Thus, reliable predictors of mortality should be used to prompt aggressive surgical intervention. [41]

To determine the long-term survival rate, rate of gastrointestinal continuity restoration, and rate of recurrence following an attack of fulminant C difficile colitis, Miller et al searched a pathologic database for patients with this condition, defined as those who had a bout of C difficile colitis and whose disease required surgical intervention after failure of medical therapy. [42]

Of the 49 patients who fit the criteria, the investigators found a 30-day mortality rate of 57% (28/49), with an in-hospital mortality rate of 49%. Moreover, the 5-year survival rate for the long-term survival group was poor, at 38% (16.3% for all patients). Twenty percent of patients had restored gastrointestinal continuity. One case of recurrence of C difficile colitis was reported. [42]

Toxic megacolon

Toxic megacolon is an acute toxic colitis with dilatation of the colon. This condition is diagnosed clinically in a patient with signs and symptoms of severe toxicity, the presence of a tender abdomen, and a dilated colon on plain radiograph of the abdomen.

Colonic perforation

Colonic perforation is usually accompanied by abdominal rigidity, involuntary guarding, rebound tenderness, and absent bowel sounds. Free air may be revealed on abdominal radiographs. Any suspicion of perforation in this setting should prompt immediate surgical consultation.

1. McDonald LC, Coignard B, Dubberke E, Song X, Horan T, Kutty PK. Recommendations for surveillance of Clostridium difficile-associated disease. Infect Control Hosp Epidemiol. 2007 Feb. 28(2):140-5. [QxMD MEDLINE Link].

2. Khanna S, Pardi DS, Aronson SL, et al. The epidemiology of community-acquired Clostridium difficile infection: a population-based study. Am J Gastroenterol. 2012 Jan. 107(1):89-95. [QxMD MEDLINE Link]. [Full Text].

3. Sloan LM, Duresko BJ, Gustafson DR, Rosenblatt JE. Comparison of real-time PCR for detection of the tcdC gene with four toxin immunoassays and culture in diagnosis of Clostridium difficile infection. J Clin Microbiol. 2008 Jun. 46(6):1996-2001. [QxMD MEDLINE Link]. [Full Text].

4. Grant TH, Rosen MP, Fidler JL, et al, for the Expert Panel on Gastrointestinal Imaging. ACR Appropriateness Criteria: acute abdominal pain and fever or suspected abdominal abscess. [online publication]. Reston, Va: American College of Radiology (ACR); 2008.

5. Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol. 2010 May. 31(5):431-55. [QxMD MEDLINE Link].

6. Brandt LJ, Aroniadis OC, Mellow M, et al. Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection. Am J Gastroenterol. 2012 Jul. 107(7):1079-87. [QxMD MEDLINE Link].

7. Laidman J. Fecal transfer proves potent clostridium difficile treatment. [serial online]. Medscape Medical News. January 16, 2013. Available at http://www.medscape.com/viewarticle/777772. Accessed: July 23, 2013.

8. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013 Jan 31. 368(5):407-15. [QxMD MEDLINE Link].

9. Ananthakrishnan AN. Clostridium difficile infection: epidemiology, risk factors and management. Nat Rev Gastroenterol Hepatol. 2011 Jan. 8(1):17-26. [QxMD MEDLINE Link].

10. Brinda BJ, Pasikhova Y, Quilitz RE, Thai CM, Greene JN. Use of tigecycline for the management of Clostridium difficile colitis in oncology patients and case series of breakthrough infections. J Hosp Infect. 2017 Apr. 95(4):426-32. [QxMD MEDLINE Link].

11. Carroll KC, Bartlett JG. Biology of Clostridium difficile: implications for epidemiology and diagnosis. Annu Rev Microbiol. 2011. 65:501-21. [QxMD MEDLINE Link].

12. Fettucciari K, Macchioni L, Davidescu M, et al. Clostridium difficile toxin B induces senescence in enteric glial cells: a potential new mechanism of Clostridium difficile pathogenesis. Biochim Biophys Acta Mol Cell Res. 2018 Oct 5. [QxMD MEDLINE Link].

13. Pant C, Sferra TJ, Deshpande A, Minocha A. Clinical approach to severe Clostridium difficile infection: update for the hospital practitioner. Eur J Intern Med. 2011 Dec. 22(6):561-8. [QxMD MEDLINE Link].

14. Bingley PJ, Harding GM. Clostridium difficile colitis following treatment with metronidazole and vancomycin. Postgrad Med J. 1987 Nov. 63(745):993-4. [QxMD MEDLINE Link]. [Full Text].

15. Freedberg DE, Salmasian H, Cohen B, Abrams JA, Larson EL. Receipt of antibiotics in hospitalized patients and risk for Clostridium difficile infection in subsequent patients who occupy the same bed. JAMA Intern Med. 2016 Dec 1. 176(12):1801-8. [QxMD MEDLINE Link].

16. US Food and Drug Administration. FDA Drug Safety Communication: Clostridium difficile-associated diarrhea can be associated with stomach acid drugs known as proton pump inhibitors (PPIs). February 15, 2013. Available at http://www.fda.gov/Drugs/DrugSafety/ucm290510.htm. Accessed: July 23, 2013.

17. Lowry F. Antidepressants linked to doubling of C difficile risk. Medscape Medical News. May 7, 2013. Available at http://www.medscape.com/viewarticle/803712. Accessed: July 23, 2013.

18. Rogers MA, Greene MT, Young VB, et al. Depression, antidepressant medications, and risk of Clostridium difficile infection. BMC Med. 2013 May 7. 11:121. [QxMD MEDLINE Link]. [Full Text].

19. Tariq R, Singh S, Gupta A, Pardi DS, Khanna S. Association of gastric acid suppression with recurrent Clostridium difficile infection: a systematic review and meta-analysis. JAMA Intern Med. 2017 Mar 27. [QxMD MEDLINE Link].

20. Ananthakrishnan AN, Issa M, Binion DG. Clostridium difficile and inflammatory bowel disease. Gastroenterol Clin North Am. 2009 Dec. 38(4):711-28. [QxMD MEDLINE Link].

21. Coleoglou Centeno AA, Horn CB, et al. Early emergency general surgery is associated with a higher incidence of Clostridium difficile infection. Surg Infect (Larchmt). 2018 Oct 9. [QxMD MEDLINE Link].

22. Garey KW, Jiang ZD, Ghantoji S, Tam VH, Arora V, Dupont HL. A common polymorphism in the interleukin-8 gene promoter is associated with an increased risk for recurrent Clostridium difficile infection. Clin Infect Dis. 2010 Dec 15. 51(12):1406-10. [QxMD MEDLINE Link].

23. Jiang ZD, DuPont HL, Garey K, et al. A common polymorphism in the interleukin 8 gene promoter is associated with Clostridium difficile diarrhea. Am J Gastroenterol. 2006 May. 101(5):1112-6. [QxMD MEDLINE Link].

24. Granlund Av, Beisvag V, Torp SH, et al. Activation of REG family proteins in colitis. Scand J Gastroenterol. 2011 Nov. 46(11):1316-23. [QxMD MEDLINE Link]. [Full Text].

25. Castagliuolo I, Riegler M, Pasha A, et al. Neurokinin-1 (NK-1) receptor is required in Clostridium difficile- induced enteritis. J Clin Invest. 1998 Apr 15. 101(8):1547-50. [QxMD MEDLINE Link]. [Full Text].

26. Na X, Kim H, Moyer MP, Pothoulakis C, LaMont JT. gp96 is a human colonocyte plasma membrane binding protein for Clostridium difficile toxin A. Infect Immun. 2008 Jul. 76(7):2862-71. [QxMD MEDLINE Link]. [Full Text].

27. Hasegawa M, Yamazaki T, Kamada N, et al. Nucleotide-binding oligomerization domain 1 mediates recognition of Clostridium difficile and induces neutrophil recruitment and protection against the pathogen. J Immunol. 2011 Apr 15. 186(8):4872-80. [QxMD MEDLINE Link].

28. Hebbard AI, Slavin MA, Reed C, et al. The epidemiology of Clostridium difficile infection in patients with cancer. Expert Rev Anti Infect Ther. 2016 Nov. 14(11):1077-85. [QxMD MEDLINE Link].

29. Centers for Disease Control and Prevention. CDC vital signs: making health care safer. Stopping C. difficile infections. March 6, 2012. Available at http://www.cdc.gov/VitalSigns/Hai/StoppingCdifficile/. Accessed: July 23, 2013.

30. Centers for Disease Control and Prevention. Vital signs: preventing Clostridium difficile infections. MMWR Morb Mortal Wkly Rep. 2012 Mar 9. 61(9):157-62. [QxMD MEDLINE Link].

31. Wilcox MH, Mooney L, Bendall R, Settle CD, Fawley WN. A case-control study of community-associated Clostridium difficile infection. J Antimicrob Chemother. 2008 Aug. 62(2):388-96. [QxMD MEDLINE Link].

32. Dumyati G, Stevens V, Hannett GE, et al. Community-associated Clostridium difficile infections, Monroe County, New York, USA. Emerg Infect Dis. 2012 Mar. 18(3):392-400. [QxMD MEDLINE Link]. [Full Text].

33. Bauer MP, Notermans DW, van Benthem BH, et al. Clostridium difficile infection in Europe: a hospital-based survey. Lancet. 2011 Jan 1. 377(9759):63-73. [QxMD MEDLINE Link].

34. Khanna S, Pardi DS. The growing incidence and severity of Clostridium difficile infection in inpatient and outpatient settings. Expert Rev Gastroenterol Hepatol. 2010 Aug. 4(4):409-16. [QxMD MEDLINE Link].

35. Nylund CM, Goudie A, Garza JM, Fairbrother G, Cohen MB. Clostridium difficile infection in hospitalized children in the United States. Arch Pediatr Adolesc Med. 2011 May. 165(5):451-7. [QxMD MEDLINE Link].

36. Johnson S. Recurrent Clostridium difficile infection: a review of risk factors, treatments, and outcomes. J Infect. 2009 Jun. 58(6):403-10. [QxMD MEDLINE Link].

37. Khanna S, Pardi DS, Aronson SL, Kammer PP, Baddour LM. Outcomes in community-acquired Clostridium difficile infection. Aliment Pharmacol Ther. 2012 Mar. 35(5):613-8. [QxMD MEDLINE Link]. [Full Text].

38. Loo VG, Poirier L, Miller MA, et al. A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med. 2005 Dec 8. 353(23):2442-9. [QxMD MEDLINE Link].

39. Ananthakrishnan AN, Guzman-Perez R, Gainer V, et al. Predictors of severe outcomes associated with Clostridium difficile infection in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2012 Apr. 35(7):789-95. [QxMD MEDLINE Link]. [Full Text].

40. Navaneethan U, Mukewar S, Venkatesh PG, Lopez R, Shen B. Clostridium difficile infection is associated with worse long term outcome in patients with ulcerative colitis. J Crohns Colitis. 2012 Apr. 6(3):330-6. [QxMD MEDLINE Link].

41. Sailhamer EA, Carson K, Chang Y, et al. Fulminant Clostridium difficile colitis: patterns of care and predictors of mortality. Arch Surg. 2009 May. 144(5):433-9; discussion 439-40. [QxMD MEDLINE Link].

42. Miller AT, Tabrizian P, Greenstein AJ, Dikman A, Byrn J, Divino C. Long-term follow-up of patients with fulminant Clostridium difficile colitis. J Gastrointest Surg. 2009 May. 13(5):956-9. [QxMD MEDLINE Link].

43. Martinez-Melendez A, Camacho-Ortiz A, Morfin-Otero R, Maldonado-Garza HJ, Villarreal-Trevino L, Garza-Gonzalez E. Current knowledge on the laboratory diagnosis of Clostridium difficile infection. World J Gastroenterol. 2017 Mar 7. 23(9):1552-67. [QxMD MEDLINE Link].

44. Khanna S, Pardi DS, Rosenblatt JE, Patel R, Kammer PP, Baddour LM. An evaluation of repeat stool testing for Clostridium difficile infection by polymerase chain reaction. J Clin Gastroenterol. 2012 Nov-Dec. 46(10):846-9. [QxMD MEDLINE Link].

45. El Feghaly RE, Stauber JL, Tarr PI, Haslam DB. Intestinal inflammatory biomarkers and outcome in pediatric Clostridium difficile infections. J Pediatr. 2013 Dec. 163(6):1697-1704.e2. [QxMD MEDLINE Link].

46. [Guideline] McDonald LC, Gerding DN, Johnson S, Bakken JS, Carroll KC, Coffin SE, et al. 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). Clin Infect Dis. 2018 Mar 19. 66 (7):987-94. [QxMD MEDLINE Link].

47. Lewis R. C difficile Guidelines Refine Diagnosis, Add FMT. Medscape Medical News. WebMD Inc. Available at https://www.medscape.com/viewarticle/892813. February 16, 2018; Accessed: February 25, 2018.

48. Khan MY, Dirweesh A, Khurshid T, Siddiqui WJ. Comparing fecal microbiota transplantation to standard-of-care treatment for recurrent Clostridium difficile infection: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol. 2018 Nov. 30 (11):1309-17. [QxMD MEDLINE Link].

49. Martin J, Wilcox M. New and emerging therapies for Clostridium difficile infection. Curr Opin Infect Dis. 2016 Dec. 29(6):546-54. [QxMD MEDLINE Link].

50. Debast SB, Bauer MP, Kuijper EJ, European Society of Clinical Microbiology and Infectious Diseases. European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect. 2014 Mar. 20 Suppl 2:1-26. [QxMD MEDLINE Link].

51. Barclay L. Guidelines: Antibiotics for all but very mild C difficile. Medscape Medical News. October 30, 2013. Available at http://www.medscape.com/viewarticle/813521. 2013 Oct 30; Accessed: November 4, 2013.

52. Fridkin S, Baggs J, Fagan R, et al. Vital signs: improving antibiotic use among hospitalized patients. MMWR Morb Mortal Wkly Rep. 2014 Mar 7. 63(9):194-200. [QxMD MEDLINE Link]. [Full Text].

53. Lowes R. CDC urges doctors to improve antibiotic prescribing. Medscape Medical News. March 4, 2014. Available at http://www.medscape.com/viewarticle/821485. Accessed March 12, 2014;

54. Law CC, Tariq R, Khanna S, Murthy S, McCurdy JD. Systematic review with meta-analysis: the impact of Clostridium difficile infection on the short- and long-term risks of colectomy in inflammatory bowel disease. Aliment Pharmacol Ther. 2017 Apr. 45(8):1011-20. [QxMD MEDLINE Link].

55. Lee DY, Chung EL, Guend H, Whelan RL, Wedderburn RV, Rose KM. Predictors of mortality after emergency colectomy for Clostridium difficile colitis: an analysis of ACS-NSQIP. Ann Surg. 2014 Jan. 259(1):148-56. [QxMD MEDLINE Link].

56. Kling J. Low-dose vancomycin effective against C difficile. Medscape Medical News. September 24, 2013. Available at http://www.medscape.com/viewarticle/811555. Accessed: October 21, 2013.

57. Cornely OA, Crook DW, Esposito R, et al. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial. Lancet Infect Dis. 2012 Apr. 12(4):281-9. [QxMD MEDLINE Link].

58. Feher C, Munez Rubio E, Merino Amador P, et al. The efficacy of fidaxomicin in the treatment of Clostridium difficile infection in a real-world clinical setting: a Spanish multi-centre retrospective cohort. Eur J Clin Microbiol Infect Dis. 2017 Feb. 36(2):295-303. [QxMD MEDLINE Link].

59. FDA approves Merck’s ZINPLAVA (bezlotoxumab) to reduce recurrence of Clostridium difficile infection (CDI) in adult patients receiving antibacterial drug treatment for CDI who are at high risk of CDI recurrence [press release]. MerckNewsroom.com. October 21, 2016. Available at http://www.mercknewsroom.com/news-release/corporate-news/fda-approves-mercks-zinplava-bezlotoxumab-reduce-recurrence-clostridium-. Accessed: November 1, 2016.

60. Kelly CP, Gerding DN, Rahav G, et al. 599 The monoclonal antibody, bezlotoxumab targeting C. difficile toxin B shows efficacy in preventing recurrent C. difficile infection (CDI) in patients at high risk of recurrence or of CDI-related adverse outcomes. Gastroenterology. 2016 Apr. 150 (4 suppl 1):S122.

61. Videlock EJ, Cremonini F. Meta-analysis: probiotics in antibiotic-associated diarrhoea. Aliment Pharmacol Ther. 2012 Jun. 35(12):1355-69. [QxMD MEDLINE Link].

62. Paknikar R, Pekow J. Fecal microbiota transplantation for the management of Clostridium difficile infection. Surg Infect (Larchmt). 2018 Oct 9. [QxMD MEDLINE Link].

63. Bakken JS, Borody T, Brandt LJ, et al. Treating Clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol. 2011 Dec. 9(12):1044-9. [QxMD MEDLINE Link]. [Full Text].

64. Hamilton MJ, Weingarden AR, Sadowsky MJ, Khoruts A. Standardized frozen preparation for transplantation of fecal microbiota for recurrent Clostridium difficile infection. Am J Gastroenterol. 2012 May. 107(5):761-7. [QxMD MEDLINE Link].

65. Kassam Z, Hundal R, Marshall JK, Lee CH. Fecal transplant via retention enema for refractory or recurrent Clostridium difficile infection. Arch Intern Med. 2012 Jan 23. 172(2):191-3. [QxMD MEDLINE Link].

66. Kronman MP, Nielson HJ, Adler AL, et al. Fecal microbiota transplantation via nasogastric tube for recurrent clostridium difficile infection in pediatric patients. J Pediatr Gastroenterol Nutr. 2015 Jan. 60(1):23-6. [QxMD MEDLINE Link].

67. Kling J. Fecal transplant an option even in the immunocompromised. Medscape Medical News. October 16, 2013. Available at http://www.medscape.com/viewarticle/812685. Accessed: October 21, 2013.

68. Gough E, Shaikh H, Manges AR. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Clin Infect Dis. 2011 Nov. 53(10):994-1002. [QxMD MEDLINE Link].

69. [Guideline] Sartelli M, Di Bella S, McFarland LV, et al. 2019 update of the WSES guidelines for management of Clostridioides (Clostridium) difficile infection in surgical patients. World J Emerg Surg. 2019. 14:8. [QxMD MEDLINE Link]. [Full Text].

70. [Guideline] Mullish BH, Quraishi MN, Segal JP, et al. The use of faecal microbiota transplant as treatment for recurrent or refractory Clostridium difficile infection and other potential indications: joint British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS) guidelines. J Hosp Infect. 2018 Sep. 100 suppl 1:S1-31. [QxMD MEDLINE Link].

71. Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011 Feb 3. 364(5):422-31. [QxMD MEDLINE Link].

72. Drekonja DM, Butler M, MacDonald R, et al. Comparative effectiveness of Clostridium difficile treatments: a systematic review. Ann Intern Med. 2011 Dec 20. 155(12):839-47. [QxMD MEDLINE Link].

73. Reuters Health. Fidaxomicin effective for C. difficile in cancer patients. Medscape Medical News. May 30, 2013. Available at http://www.medscape.com/viewarticle/805062. Accessed: July 23, 2013.

74. Cornely OA, Miller MA, Fantin B, Mullane K, Kean Y, Gorbach S. Resolution of Clostridium difficile-associated diarrhea in patients with cancer treated with fidaxomicin or vancomycin. J Clin Oncol. 2013 Jul 1. 31(19):2493-9. [QxMD MEDLINE Link].

75. Venuto C, Butler M, Ashley ED, Brown J. Alternative therapies for Clostridium difficile infections. Pharmacotherapy. 2010 Dec. 30(12):1266-78. [QxMD MEDLINE Link].

76. Abougergi MS, Broor A, Cui W, Jaar BG. Intravenous immunoglobulin for the treatment of severe Clostridium difficile colitis: an observational study and review of the literature. J Hosp Med. 2010 Jan. 5(1):E1-9. [QxMD MEDLINE Link].

77. Bartlett JG. Pseudomembranous enterocolitis and antibiotic-associated colitis. Feldman M, Scharschmidt BF, Sleisenger MH, eds. Sleisenger and Fordtran's Gastrointestinal and Liver Disease. 6th ed. Philadelphia, Pa: WB Saunders Co; 1998. 1633-47.

78. Cleary RK. Clostridium difficile-associated diarrhea and colitis: clinical manifestations, diagnosis, and treatment. Dis Colon Rectum. 1998 Nov. 41(11):1435-49. [QxMD MEDLINE Link].

79. Fekety R. Guidelines for the diagnosis and management of Clostridium difficile-associated diarrhea and colitis. American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 1997 May. 92(5):739-50. [QxMD MEDLINE Link].

80. Gilbert DN, Moellering RC, Sande MA. Antimicrobial Therapy. The Sanford Guide to Antimicrobial Therapy. 30th ed. Hyde Park, Vt: 2000. 12.

81. Guerrero DM, Chou C, Jury LA, Nerandzic MM, Cadnum JC, Donskey CJ. Clinical and infection control implications of Clostridium difficile infection with negative enzyme immunoassay for toxin. Clin Infect Dis. 2011 Aug 1. 53(3):287-90. [QxMD MEDLINE Link].

82. Johnson S, Gerding DN. Clostridium difficile--associated diarrhea. Clin Infect Dis. 1998 May. 26(5):1027-34; quiz 1035-6. [QxMD MEDLINE Link].

83. Jones EM, Kirkpatrick BL, Feeney R, Reeves DS, MacGowan AP. Hospital-acquired Clostridium difficile diarrhoea. Lancet. 1997 Apr 19. 349(9059):1176-7. [QxMD MEDLINE Link].

84. Kelly CP, LaMont JT. Clostridium difficile infection. Annu Rev Med. 1998. 49:375-90. [QxMD MEDLINE Link].

85. Kelly CP, LaMont JT. Clostridium difficile--more difficult than ever. N Engl J Med. 2008 Oct 30. 359(18):1932-40. [QxMD MEDLINE Link].

86. Kelly CP, Pothoulakis C, LaMont JT. Clostridium difficile colitis. N Engl J Med. 1994 Jan 27. 330(4):257-62. [QxMD MEDLINE Link].

87. Kolling GL, Wu M, Warren CA, et al. Lactic acid production by Streptococcus thermophilus alters Clostridium difficile infection and in vitro Toxin A production. Gut Microbes. 2012 Nov-Dec. 3(6):523-9. [QxMD MEDLINE Link]. [Full Text].

88. Lyerly DM, Wilkins TD. Clostridium difficile. Infections of the Gastrointestinal Tract. Raven Press; 1995. 867-891.

89. McDonald CL, Gerding DN, Johnson S. "Clostridium difficile: Changing Diagnosis, Epidemiology, and Treatment" The content of this virtual lecture is derived from a satellite symposium presented on April 7, 2008, during the 18th Annual SHEA Scientific Meeting. Philadelphia, Pa:. Available at http://www.rmei.com/CDI010/.

90. McFarland LV, Mulligan ME, Kwok RY, Stamm WE. Nosocomial acquisition of Clostridium difficile infection. N Engl J Med. 1989 Jan 26. 320(4):204-10. [QxMD MEDLINE Link].

91. Schneeweiss S, Korzenik J, Solomon DH, Canning C, Lee J, Bressler B. Infliximab and other immunomodulating drugs in patients with inflammatory bowel disease and the risk of serious bacterial infections. Aliment Pharmacol Ther. 2009 Aug. 30(3):253-64. [QxMD MEDLINE Link].

92. Sonnenberg A. Similar geographic variations of mortality and hospitalization associated with IBD and Clostridium difficile colitis. Inflamm Bowel Dis. 2010 Mar. 16(3):487-93. [QxMD MEDLINE Link].

93. Starr J. Clostridium difficile associated diarrhoea: diagnosis and treatment. BMJ. 2005 Sep 3. 331(7515):498-501. [QxMD MEDLINE Link]. [Full Text].

94. Dzunkova M, D'Auria G, Xu H, et al. The monoclonal antitoxin antibodies (actoxumab-bezlotoxumab) treatment facilitates normalization of the gut microbiota of mice with Clostridium difficile infection. Front Cell Infect Microbiol. 2016 Oct 4. 6:119. [QxMD MEDLINE Link].

95. Wang Q, Euler CW, Delaune A, Fischetti VA. Using a novel lysin to help control Clostridium difficile infections. Antimicrob Agents Chemother. 2015 Dec. 59(12):7447-57. [QxMD MEDLINE Link].

96. Buxey KN, Sia C, Bell S, Wale R, Wein D, Warrier SK. Clostridium colitis: challenges in diagnosis and treatment. ANZ J Surg. 2017 Apr. 87(4):227-31. [QxMD MEDLINE Link].

97. Khan MY, Dirweesh A, Khurshid T, Siddiqui WJ. Comparing fecal microbiota transplantation to standard-of-care treatment for recurrent Clostridium difficile infection: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol. 2018 Nov. 30 (11):1309-17. [QxMD MEDLINE Link].

Author

Faten N Aberra, MD, MSCE Assistant Professor of Medicine, Division of Gastroenterology, Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine

Faten N Aberra, MD, MSCE is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, Crohn's and Colitis Foundation of America, Sigma Xi, The Scientific Research Honor Society

Disclosure: Nothing to disclose.

Coauthor(s)

Jennifer A Curry, MD, MPH Attending Physician, Infectious Disease Clinic, Naval Medical Center Portsmouth; Assistant Professor of Medicine, Uniformed Services University of the Health Sciences

Jennifer A Curry, MD, MPH is a member of the following medical societies: American College of Physicians, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Chief Editor

Acknowledgements

Acknowledgments

The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the US government.

LCDR Jennifer Curry is a military service member. This work was prepared as part of official duties. Title 17 U.S.C. §105 provides that ‘Copyright protection under this title is not available for any work of the United States Government.’ Title 17 U.S.C. §101 defines a U.S. Government work as a work prepared by a military service member or employee of the US Government as part of that person’s official duties.

Additional Contributors

Burke A Cunha, MD Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital

Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Gary L Gorby, MD Associate Professor, Departments of Internal Medicine and Medical Microbiology and Immunology, Division of Infectious Diseases, Creighton University School of Medicine; Associate Professor of Medicine, University of Nebraska Medical Center; Associate Chair, Omaha Veterans Affairs Medical Center

Gary L Gorby, MD is a member of the following medical societies: Alpha Omega Alpha, American Medical Association, American Society for Microbiology, Infectious Diseases Society of America, and New York Academy of Sciences

Disclosure: Nothing to disclose.

Craig A Gronczewski, MD Clinical Assistant Professor, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey; Consulting Staff, Princeton Medical Center; Consulting Staff, Robert Wood Johnson University Hospital

Craig A Gronczewski, MD is a member of the following medical societies: Alpha Omega Alpha and American College of Emergency Physicians

Disclosure: Nothing to disclose.

Braden R Hale, MD, MPH Assistant Clinical Professor, Department of Internal Medicine, University of California at San Diego; Consulting Staff, Department of Internal Medicine, Division of Infectious Diseases, Naval Medical Center at San Diego

Disclosure: Nothing to disclose.

Duane R Hospenthal, MD, PhD, FACP, FIDSA Adjunct Professor of Medicine, Department of Medicine, University of Texas Health Science Center at San Antonio

Duane R Hospenthal, MD, PhD, FACP, FIDSA is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Medical Association, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Armed Forces Infectious Diseases Society, Association of Military Surgeons of the US, Infectious Diseases Society of America, International Society for Human and Animal Mycology, International Society for Infectious Diseases,International Society of Travel Medicine, and Medical Mycology Society of the Americas

Disclosure: Nothing to disclose.

Joseph F John Jr, MD, FACP, FIDSA, FSHEA Clinical Professor of Medicine, Molecular Genetics and Microbiology, Medical University of South Carolina College of Medicine; Associate Chief of Staff for Education, Ralph H Johnson Veterans Affairs Medical Center

Disclosure: Nothing to disclose.

Jonathan P Katz, MD Assistant Professor of Medicine, Department of Medicine, University of Pennsylvania School of Medicine

Jonathan P Katz, MD is a member of the following medical societies: American Gastroenterological Association and American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Joseph Lee, MD Staff Physician, Department of Medicine, Walter Reed Army Medical Center

Disclosure: Nothing to disclose.

Waqar A Qureshi, MD Associate Professor of Medicine, Chief of Endoscopy, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine and Veterans Affairs Medical Center

Waqar A Qureshi, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, and American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

When an older patient experiences diarrhea the nurse identifies that the patient is at risk of which complication?

Which gastrointestinal manifestations is the result of bacterial fermentation?

Which gastrointestinal manifestation is the result of bacterial fermentation of an absorbed carbohydrates?

Which condition is a common manifestation associated with protein deficiency?