Clostridium difficile infection

For the bacterium, see Clostridium difficile (bacteria).
Clostridium difficile infection
Synonyms pseudomembranous colitis, C. difficile associated diarrhea (CDAD), Clostridium difficile colitis
Pathological specimen showing pseudomembranous colitis
Classification and external resources
Specialty Infectious disease
ICD-10 A04.7
ICD-9-CM 008.45
MedlinePlus 000259
eMedicine med/1942
MeSH D004761

Clostridium difficile infection (CDI) is a symptomatic infection due to the spore-forming bacterium, Clostridium difficile.[1] Symptoms include watery diarrhea, fever, nausea, and abdominal pain. It makes up about 20% of cases of antibiotic-associated diarrhea. Complications may include pseudomembranous colitis, toxic megacolon, perforation of the colon, and sepsis.[2]

Clostridium difficile infection is spread by bacterial spores found within feces. Surfaces may become contaminated with the spores with further spread occurring via the hands of healthcare workers. Risk factors for infection include antibiotic or proton pump inhibitors use, hospitalization, other health problems, and older age. Diagnosis is by stool culture or testing for the bacteria's DNA or toxins. If a person tests positive but has no symptoms it is known as C. difficile colonization rather than an infection.[2]

Prevention is by limiting antibiotic use, hand washing, and terminal room cleaning in hospital.[1] Discontinuation of antibiotics may result in resolution of symptoms within three days in about 20% of those infected. Often the antibiotics metronidazole, vancomycin or fidaxomicin will cure the infection. Retesting after treatment, as long as the symptoms have resolved, is not recommended as the person may remain colonized.[2] Recurrence have been reported in up to 25% of people.[3] There is tentative evidence that fecal microbiota transplantation and probiotics may decrease the risk of recurrence.[1]

C. difficile infections occur in all areas of the world.[4] About 453,000 cases occurred in the United States in 2011 resulting in 29,000 deaths.[1][5] Rates of disease globally have increased between 2001 and 2016.[1][4] Women are more often affected than men.[1] The bacteria was discovered in 1935 and found to be disease causing in 1978.[4] In the United States healthcare acquired infections increase cost of care by 1.5 billion USD each year.[6]

Signs and symptoms

Signs and symptoms of CDI range from mild diarrhea to severe life-threatening inflammation of the colon.[7]

In adults, a clinical prediction rule found the best signs to be significant diarrhea ("new onset of more than three partially formed or watery stools per 24-hour period"), recent antibiotic exposure, abdominal pain, fever (up to 40.5 °C or 105 °F), and a distinctive foul odor to the stool resembling horse manure.[8] In a population of hospitalized patients, prior antibiotic treatment plus diarrhea or abdominal pain had a sensitivity of 86% and a specificity of 45%.[9] In this study with a prevalence of positive cytotoxin assays of 14%, the positive predictive value was 18% and the negative predictive value was 94%.

In children, the most prevalent symptom of a CDI is watery diarrhea with at least three bowel movements a day for two or more days, which may be accompanied by fever, loss of appetite, nausea, and/or abdominal pain.[10] Those with a severe infection also may develop serious inflammation of the colon and have little or no diarrhea.

Cause

How C. difficile spreads

Infection with C. difficile bacteria is responsible for C. difficile diarrhea.

C. difficile

Individual, drumstick-shaped C. difficile bacilli seen through scanning electron microscopy
C. difficile colonies on a blood agar plate

Clostridia are anaerobic motile bacteria, ubiquitous in nature, and especially prevalent in soil. Under the microscope, they appear as long, irregular (often drumstick- or spindle-shaped) cells with a bulge at their terminal ends. Under Gram staining, C. difficile cells are Gram-positive and show optimum growth on blood agar at human body temperatures in the absence of oxygen. When stressed, the bacteria produce spores that are able to tolerate extreme conditions that the active bacteria cannot tolerate.[11]

C. difficile may become established in the human colon; it is present in 2–5% of the adult population.[11]

Pathogenic C. difficile strains produce multiple toxins.[12] The most well-characterized are enterotoxin (Clostridium difficile toxin A) and cytotoxin (Clostridium difficile toxin B), both of which may produce diarrhea and inflammation in infected patients, although their relative contributions have been debated.[11] Toxins A and B are glucosyltransferases that target and inactivate the Rho family of GTPases. Toxin B (cytotoxin) induces actin depolymerization by a mechanism correlated with a decrease in the ADP-ribosylation of the low molecular mass GTP-binding Rho proteins.[13] Another toxin, binary toxin, also has been described, but its role in disease is not fully understood.[14]

Antibiotic treatment of CDIs may be difficult, due both to antibiotic resistance and physiological factors of the bacteria (spore formation, protective effects of the pseudomembrane).[11] The emergence of a new and highly toxic strain of C. difficile that is resistant to fluoroquinolone antibiotics such as ciprofloxacin and levofloxacin, said to be causing geographically dispersed outbreaks in North America, was reported in 2005.[15] The U.S. Centers for Disease Control and Prevention in Atlanta warned of the emergence of an epidemic strain with increased virulence, antibiotic resistance, or both.[16]

C. difficile is transmitted from person to person by the fecal-oral route. The organism forms heat-resistant spores that are not killed by alcohol-based hand cleansers or routine surface cleaning. Thus, these spores survive in clinical environments for long periods. Because of this, the bacteria may be cultured from almost any surface. Once spores are ingested, their acid-resistance allows them to pass through the stomach unscathed. Upon exposure to bile acids, they germinate and multiply into vegetative cells in the colon.

In 2005, molecular analysis led to the identification of the C. difficile strain type characterized as group BI by restriction endonuclease analysis, as North American pulse-field-type NAP1 by pulsed-field gel electrophoresis and as ribotype 027; the differing terminology reflects the predominant techniques used for epidemiological typing. This strain is referred to as C. difficile BI/NAP1/027.[17]

Risk factors

Antibiotics

C. difficile colitis is associated most strongly with the use of the following antibiotics: fluoroquinolones, cephalosporins, and clindamycin.[18]

Some research suggests the routine use of antibiotics in the raising of livestock is contributing to outbreaks of bacterial infections such as C. difficile.[19]

Healthcare environment

People are most often infected in hospitals, nursing homes, or other medical institutions, although infection outside medical settings is increasing. The rate of C. difficile acquisition is estimated to be 13% in patients with hospital stays of up to two weeks, and 50% with stays longer than four weeks.[20]

Long-term hospitalization or residence in a nursing home within the previous year are independent risk factors for increased colonization.[21]

Acid suppression medication

Increasing rates of community-acquired CDI are associated with the use of medication to suppress gastric acid production: H2-receptor antagonists increased the risk 1.5-fold, and proton pump inhibitors by 1.7 with once-daily use and 2.4 with more than once-daily use.[22][23]

Pathophysiology

The use of systemic antibiotics, including (but not limited to) any penicillin-based antibiotic such as ampicillin, cephalosporins, and clindamycin, causes the normal bacterial flora of the bowel to be altered. In particular, when the antibiotic kills off other competing bacteria in the intestine, any bacteria remaining will have less competition for space and nutrients. The net effect is to permit more extensive growth than normal of certain bacteria. Clostridium difficile is one such type of bacterium. In addition to proliferating in the bowel, C. difficile also produces toxins. Without either toxin A or toxin B, C. difficile may colonize the gut, but is unlikely to cause pseudomembranous colitis.[24] The colitis associated with severe infection is part of an inflammatory reaction, with the "pseudomembrane" formed by a viscous collection of inflammatory cells, fibrin, and necrotic cells.[11]

Diagnosis

Micrograph of a colonic pseudomembrane in C. difficile colitis, a type of pseudomembranous colitis, H&E stain
Endoscopic image of pseudomembranous colitis, with yellow pseudomembranes seen on the wall of the sigmoid colon
Pseudomembranous colitis on computed tomography

Prior to the advent of tests to detect C. difficile toxins, the diagnosis most often was made by colonoscopy or sigmoidoscopy. The appearance of "pseudomembranes" on the mucosa of the colon or rectum is highly suggestive, but not diagnostic of the condition.[25] The pseudomembranes are composed of an exudate made of inflammatory debris, white blood cells. Although colonoscopy and sigmoidoscopy are still employed, now stool testing for the presence of C. difficile toxins is frequently the first-line diagnostic approach. Usually, only two toxins are tested for—toxin A and toxin B—but the organism produces several others. This test is not 100% accurate, with a considerable false-negative rate even with repeat testing.

Cytotoxicity assay

C. difficile toxins have a cytopathic effect in cell culture, and neutralization of any effect observed with specific antisera is the practical gold standard for studies investigating new CDI diagnostic techniques.[11] Toxigenic culture, in which organisms are cultured on selective media and tested for toxin production, remains the gold standard and is the most sensitive and specific test, although it is slow and labor-intensive.[26]

Toxin ELISA

Assessment of the A and B toxins by enzyme-linked immunosorbent assay (ELISA) for toxin A or B (or both) has a sensitivity of 63–99% and a specificity of 93–100%.

Previously, experts recommended sending as many as three stool samples to rule out disease if initial tests are negative, however, evidence suggests repeated testing during the same episode of diarrhea is of limited value and should be discouraged.[27] C. difficile toxin should clear from the stool of previously infected patients if treatment is effective. Many hospitals only test for the prevalent toxin A. Strains that express only the B toxin are now present in many hospitals, however, so testing for both toxins should occur.[28][29] Not testing for both may contribute to a delay in obtaining laboratory results, which is often the cause of prolonged illness and poor outcomes.

Other stool tests

Stool leukocyte measurements and stool lactoferrin levels also have been proposed as diagnostic tests, but may have limited diagnostic accuracy.[30]

PCR

Testing of stool samples by real-time polymerase chain reaction is able to pick up the disease about 90% of the time and when positive is incorrectly positive about 4% of the time.[31] Multistep PCR testing algorithms can improve overall performance. Repeat testing may be misleading, and testing specimens more than once every seven days in patients without new symptoms is highly unlikely to yield useful information.[32]

Prevention

Antibiotics

The most effective method for preventing CDI is proper antimicrobial prescribing. In the hospital setting, where CDI is most common, nearly all patients who develop CDI are exposed to antimicrobials. Although proper antimicrobial prescribing sounds easy to do, about 50% of antimicrobial use is considered inappropriate. This is consistent whether in the hospital, clinic, community, or academic setting. A decrease in CDI by limiting antibiotics or by limiting unnecessary antimicrobial prescriptions in general, both in an outbreak and non-outbreak setting has been demonstrated to be most strongly associated with reduced CDI. Further, reactions to medication may be severe: CDI infections were the most common contributor to adverse drug events seen in U.S. hospitals in 2011.[33]

Probiotics

Some evidence indicates probiotics may be useful to prevent infection and recurrence.[34][35] Treatment with Saccharomyces boulardii in those who are not immunocompromised with C. difficile also may be useful.[36][37] Initially, in 2010, the Infectious Diseases Society of America recommended against their use due to the risk of complications.[34][36] Subsequent reviews, however, did not find an increase in adverse effects with treatment,[35] and overall treatment appears safe.[38]

Infection control

Rigorous infection protocols are required to minimize this risk of transmission.[39] Infection control measures, such as wearing gloves and noncritical medical devices used for a single person with CDI, are effective at prevention.[40] This works by limiting the spread of C. difficile in the hospital setting. In addition, washing with soap and water will eliminate the spores from contaminated hands, but alcohol-based hand rubs are ineffective.[41]

Bleach wipes containing 0.55% sodium hypochlorite have been shown to kill the spores and prevent transmission between patients.[42] Installing lidded toilets and closing the lid prior to flushing also reduces the risk of contamination.[43]

Those who have CDIs should be in rooms with other people with CDIs or by themselves when in hospital.[40]

Common hospital disinfectants are ineffective against C. difficile spores and, in fact, may promote spore formation, however, disinfectants containing a 10:1 ratio of water to bleach effectively kill the spores.[44] Hydrogen peroxide vapor (HPV) systems used to sterilize a patient room post-discharge have been shown to reduce infection rates and to reduce risk of infection to subsequent patients. The incidence of CDI was reduced by 53%[45] or 42%[46] through use of HPV. Ultraviolet cleaning devices and housekeeping staff especially dedicated to disinfecting the rooms of patients infected with C. difficile after discharge may be effective.[47]

Treatment

Carrying C. difficile without symptoms is common. Treatment in those without symptoms is controversial. In general, mild cases do not require specific treatment.[11][48] Oral rehydration therapy is useful in treating dehydration associated with the diarrhea.

Medications

A number of different antibiotics are used for C. difficile, with the available agents being more or less equally effective.[49]

Drugs used to slow or stop diarrhea such as loperamide may worsen C. difficile disease, so are not recommended.[54] Cholestyramine, an ion exchange resin, is effective in binding both toxin A and B, slowing bowel motility, and helping prevent dehydration.[55] Cholestyramine is recommended with vancomycin. A last-resort treatment in those who are immunosuppressed is intravenous immunoglobulin (IVIG).[55]

Probiotics

Evidence to support the use of probiotics in the treatment of active disease is insufficient.[36][56] Thus in this situation, they are recommended neither as an add-on to standard therapy nor for use alone.[57]

Stool transplant

Fecal bacteriotherapy, also known as a stool transplant, is approximately 85% to 90% effective in those for whom antibiotics have not worked.[58][59] It involves infusion of bacterial flora acquired from the feces of a healthy donor to reverse the bacterial imbalance responsible for the recurring nature of the infection.[60] The procedure replaces normal, healthy colonic flora that had been wiped out by antibiotics, and reestablishes resistance to colonization by Clostridium difficile.[61] Side effects, at least initially, are few.[59]

There is evidence that looks hopeful that fecal transplant can be delivered in the form of a pill.[62] They are available in the United States but are not FDA-approved as of 2015.[63]

Surgery

In those with severe C. difficile colitis, colectomy may improve the outcomes.[64] Specific criteria may be used to determine who will benefit most from surgery.[65]

Prognosis

After a first treatment with metronidazole or vancomycin, C. difficile recurs in about 20% of people. This increases to 40% and 60% with subsequent recurrences.[66]

Epidemiology

C. difficile diarrhea is estimated to occur in 8 out of 100,000 people each year.[67] Among those who are admitted to hospital, it occurs in between 4 and 8 people per 1,000.[67] In 2011 it resulted in about half a million infections and 29,000 deaths in the United States.[5] Due in part to the emergence of a fluoroquinolone resistant strain, C. difficile-related deaths increased 400% between the years 2000 and 2007 in the United States.[68]

History

Initially named Bacillus difficilis by Hall and O'Toole in 1935 because it was resistant to early attempts at isolation and grew very slowly in culture, it was renamed in 1970.[66][69]

Pseudomembranous colitis first was described as a complication of C. difficile infection in 1978,[70] when a toxin was isolated from patients suffering from pseudomembranous colitis and Koch's postulates were met.

Notable outbreaks

Pronunciation

The anglicized pronunciation /klɒsˈtrɪdiəm dᵻˈfɪsᵻliː/ is common, though a more classical /dᵻˈfɪkᵻleɪ/ is also used. The classical Latin sound is /dɨˈffɪkɨle/. Difficile commonly is mispronounced /diːfiˈsiːl/, as though it were French. The word is from the Greek kloster (κλωστήρ), "spindle",[89] and Latin difficile, "difficult, obstinate".[90]

Research

Other animals

References

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