Clostridioides difficile infection explained

Clostridioides difficile infection
Synonyms:C. difficile associated diarrhea (CDAD), Clostridium difficile infection, C. difficile colitis
Field:Infectious disease
Symptoms:Diarrhea, fever, nausea, abdominal pain
Complications:Pseudomembranous colitis, toxic megacolon, perforation of the colon, sepsis
Causes:Clostridioides difficile spread by the fecal-oral route
Risks:Antibiotics, proton pump inhibitors, hospitalization, other health problems, older age
Diagnosis:Stool culture, testing for the bacteria's DNA or toxins
Prevention:Hand washing, terminal room cleaning in hospital
Treatment:Metronidazole, vancomycin, fidaxomicin, fecal microbiota transplantation
Frequency:453,000 (US 2011)
Deaths:29,000 (US)

Clostridioides difficile infection[1] (CDI or C-diff), also known as Clostridium difficile infection, is a symptomatic infection due to the spore-forming bacterium Clostridioides difficile.[2] Symptoms include watery diarrhea, fever, nausea, and abdominal pain. It makes up about 20% of cases of antibiotic-associated diarrhea. Antibiotics can contribute to detrimental changes in gut microbiota; specifically, they decrease short-chain fatty acid absorption which results in osmotic, or watery, diarrhea.[3] Complications may include pseudomembranous colitis, toxic megacolon, perforation of the colon, and sepsis.

Clostridioides 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 inhibitor use, hospitalization, hypoalbuminemia,[4] 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, the condition is known as C. difficile colonization rather than an infection.[5]

Prevention efforts include terminal room cleaning in hospitals, limiting antibiotic use, and handwashing campaigns in hospitals.[6] Alcohol based hand sanitizer does not appear effective.[6] Discontinuation of antibiotics may result in resolution of symptoms within three days in about 20% of those infected.[5]

The antibiotics metronidazole, vancomycin, or fidaxomicin, will cure the infection.[5] [7] Retesting after treatment, as long as the symptoms have resolved, is not recommended, as a person may often remain colonized.[5] Recurrences have been reported in up to 25% of people.[8] Some tentative evidence indicates fecal microbiota transplantation and probiotics may decrease the risk of recurrence.[6] [9]

C. difficile infections occur in all areas of the world. About 453,000 cases occurred in the United States in 2011, resulting in 29,000 deaths.[6] [10] Global rates of disease increased between 2001 and 2016.[6] C. difficile infections occur more often in women than men.[6] The bacterium was discovered in 1935 and found to be disease-causing in 1978.[11] Attributable costs for Clostridioides difficile infection in hospitalized adults range from$4500 to $15,000.[12] In the United States, healthcare-associated infections increase the cost of care by US$1.5 billion each year.[13] Although C. difficile is a common healthcare-associated infection, at most 30% of infections are transmitted within hospitals.[14] The majority of infections are acquired outside of hospitals, where medications and a recent history of diarrheal illnesses (e.g. laxative abuse or food poisoning due to Salmonellosis) are thought to drive the risk of colonization.[15]

Signs and symptoms

Signs and symptoms of CDI range from mild diarrhea to severe life-threatening inflammation of the colon.[16]

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.[17] In a hospital population, prior antibiotic treatment plus diarrhea or abdominal pain had a sensitivity of 86% and a specificity of 45%.[18] 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.[19] Those with a severe infection also may develop serious inflammation of the colon and have little or no diarrhea.

Cause

See main article: Clostridioides difficile. Infection with C. difficile bacteria is responsible for C. difficile diarrhea.

C. difficile

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.

C. difficile may colonize the human colon without symptom; approximately 2–5% of the adult population are carriers, although it varies considerably with demographics. The risk of colonization has been linked to a history of unrelated diarrheal illnesses (e.g. laxative abuse and food poisoning due to Salmonellosis or Vibrio cholerae infection).

Pathogenic C. difficile strains produce multiple toxins.[20] 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 people, although their relative contributions have been debated. 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.[21] Another toxin, binary toxin, also has been described, but its role in disease is not fully understood.[22]

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). 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.[23] 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.[24]

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. People without a history of gastrointestinal disturbances due to antibiotic use or diarrheal illness are less likely to become colonized by C. difficile.

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.[25]

Risk factors

Antibiotics

C. difficile colitis is associated most strongly with the use of these antibiotics: fluoroquinolones, cephalosporins, and clindamycin.[26]

Some research suggests the routine use of antibiotics in the raising of livestock is contributing to outbreaks of bacterial infections such as C. difficile.[27]

Healthcare environment

People are most often infected in hospitals, nursing homes,[28] or other medical institutions, although infection outside medical settings is increasing. Individuals can develop the infection if they touch objects or surfaces that are contaminated with feces and then touch their mouth or mucous membranes. Healthcare workers could possibly spread the bacteria or contaminate surfaces through hand contact.[29] The rate of C. difficile acquisition is estimated to be 13% in those with hospital stays of up to two weeks, and 50% with stays longer than four weeks.[30]

Long-term hospitalization or residence in a nursing home within the previous year are independent risk factors for increased colonization.[31]

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.[32] [33] Increased risk in recurrent CDI is also found with gastric acid repression use in observational studies, with a rate of 22.1%, compared to patients without gastric acid repression has a rate of 17.3% of recurrent CDI.[34]

Diarrheal illnesses

People with a recent history of diarrheal illness are at increased risk of becoming colonized by C. difficile when exposed to spores, including laxative abuse and gastrointestinal pathogens. Disturbances that increase intestinal motility are thought to transiently elevate the concentration of available dietary sugars, allowing C. difficile to proliferate and gain a foothold in the gut.[35] Although not all colonization events lead to disease, asymptomatic carriers remain colonized for years at a time. During this time, the abundance of C. difficile varies considerably day-to-day, causing periods of increased shedding that could substantially contribute to community-acquired infection rates.

Other

As a result of suppression of healthy bacteria, via a loss of bacterial food source, prolonged use of an elemental diet increases the risk of developing C. difficile infection.[36] Low serum albumin levels is a risk factor for the development of C. difficile infection and when infected for severe disease.[37] The protective effects of serum albumin may be related to the capability of this protein to bind C. difficile toxin A and toxin B, thus impairing entry into enterocytes.[38]

Chronic kidney disease (CKD) has been identified as a risk factor in the development of a C. difficile infection.[39] [40] Patients with CKD have a higher risk of both initial and recurring infection, as well as a higher chance of severe infection, than those without CKD.[41] Patients with Inflammatory Bowel Disease are also at higher risk for infection and a recent study suggests they may have intermittent C. difficile infection masked by IBD symptoms, and testing should be considered in patients with changes in disease activity.[42]

Pathophysiology

The use of systemic antibiotics, including broad-spectrum penicillins/cephalosporins, fluoroquinolones, and clindamycin, causes the normal microbiota 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. C. 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.[43] 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.[44]

Diagnosis

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.[45] 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.[46]

Classification

CDI may be classified in non-severe CDI, severe CDI and fulminant CDI depending on creatinine and white blood count parameters.

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. 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.[47]

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%, depending on detection assays.

Previously, experts recommended sending as many as three stool samples to rule out disease if initial tests are negative, but evidence suggests repeated testing during the same episode of diarrhea is of limited value and should be discouraged.[48] C. difficile toxin should clear from the stool of somebody previously infected 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.[49] [50] 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.[51]

Polymerase chain reaction (PCR)

Testing of stool samples by real-time polymerase chain reaction is able to detect C. difficile about 93% of the time and when positive is incorrectly positive about 3% of the time.[52] This is more accurate than cytotoxigenic culture or cell cytotoxicity assay.[52] Another benefit is that the result can be achieved within three hours.[52] Drawbacks include a higher cost and the fact that the test only looks for the gene for the toxin and not the toxin itself.[52] The latter means that if the test is used without confirmation, overdiagnosis may occur.[52] Repeat testing may be misleading, and testing specimens more than once every seven days in people without new symptoms is highly unlikely to yield useful information.[53] The screening specificity is relatively low because of the high number of false positive cases from asymptomatic infection.

Prevention

Self containment by housing people in private rooms is important to prevent the spread of C. difficile.[54] Contact precautions are an important part of preventing the spread of  C. difficile. C. difficile does not often occur in people who are not taking antibiotics so limiting use of antibiotics decreases the risk.[55]

Antibiotics

The most effective method for preventing CDI is proper antibiotic prescribing. In the hospital setting, where CDI is most common, most people who develop CDI are exposed to antibiotics. Although proper antibiotic prescribing is highly recommended, about 50% 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 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.[56] In some regions of the UK, reduced used of fluoroquinolone antibiotics seems to lead to reduced rates of CDI.[57]

Probiotics

Some evidence indicates probiotics may be useful to prevent infection and recurrence.[58] [59] Treatment with Saccharomyces boulardii in those who are not immunocompromised with C. difficile also may be useful.[60] [61] Initially, in 2010, the Infectious Diseases Society of America recommended against their use due to the risk of complications. Subsequent reviews, however, did not find an increase in adverse effects with treatment, and overall treatment appears safe and moderately effective in preventing C. difficile-associated diarrhea.[62]

One study in particular found that there does appear to be a "protective effect" of probiotics, specifically reducing the risk of antibiotic-associated diarrhea (AAD) by 51% in 3,631 outpatients, but it is important to note that the types of infections in the subjects were not specified.[63] Yogurt, tablets, dietary supplements are just a few examples of probiotics available for people.

Infection control

Rigorous infection protocols are required to minimize this risk of transmission.[64] Infection control measures, such as wearing gloves and noncritical medical devices used for a single person with CDI, are effective at prevention.[65] This works by limiting the spread of C. difficile in the hospital setting. In addition, washing with soap and water will wash away the spores from contaminated hands, but alcohol-based hand rubs are ineffective.[66] These precautions should remain in place among those in hospital for at least 2 days after the diarrhea has stopped.[67]

Bleach wipes containing 0.55% sodium hypochlorite have been shown to kill the spores and prevent transmission.[68] Installing lidded toilets and closing the lid prior to flushing also reduces the risk of contamination.[69]

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

Common hospital disinfectants are ineffective against C. difficile spores, and may promote spore formation, but various oxidants (e.g 1% sodium hypochlorite solution) rapidly destroy spores.[70] Hydrogen peroxide vapor (HPV) systems used to sterilize a room after treatment is completed have been shown to reduce infection rates and to reduce risk of infection to others. The incidence of CDI was reduced by 53%[71] or 42%[72] through use of HPV. Ultraviolet cleaning devices, and housekeeping staff especially dedicated to disinfecting the rooms of people with C. difficile after discharge may be effective.[73]

Treatment

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

Medications

Several different antibiotics are used for C. difficile, with the available agents being more or less equally effective.[74]

Vancomycin or fidaxomicin by mouth are the typically recommended for mild, moderate, and severe infections.[75] They are also the first-line treatment for pregnant women, especially since metronidazole may cause birth defects.[76] Typical vancomycin 125mg is taken four times a day by mouth for 10 days. Fidaxomicin is taken at 200 mg twice daily for 10 days. It may also be given rectally if the person develops an ileus.[75]

Fidaxomicin is tolerated as well as vancomycin,[77] and may have a lower risk of recurrence.[74] Fidaxomicin has been found to be as effective as vancomycin in those with mild to moderate disease, and it may be better than vancomycin in those with severe disease.[78] Fidaxomicin may be used in those who have recurrent infections and have not responded to other antibiotics.[78] Metronidazole (500 mg 3 times daily for 10 days) by mouth is recommended as an alternative treatment only for C. difficile infections when the affected person is allergic to first-line treatments, is unable to tolerate them, or has financial difficulties preventing them from accessing them.[75] [79] In fulminant disease vancomycin by mouth and intravenous metronidazole are commonly used together.[75]

Medications used to slow or stop diarrhea, such as loperamide, may only be used after initiating the treatment.[80]

Cholestyramine, an ion-exchange resin, is effective in binding both toxin A and B, slowing bowel motility, and helping prevent dehydration.[81] Cholestyramine is recommended with vancomycin. A last-resort treatment in those who are immunosuppressed is intravenous immunoglobulin. Monoclonal antibodies against C. difficile toxin A and C. difficile toxin B are approved to prevent recurrence of C. difficile infection including bezlotoxumab.[82]

Probiotics

Evidence to support the use of probiotics in the treatment of active disease is insufficient.[83] [84] [85] Researchers have recently begun taking a mechanical approach to fecal-derived products. It is known that certain microbes with 7α-dehydroxylase activity can metabolize primary to secondary bile acids, which inhibit C. difficile. Thus, incorporating such microbes into therapeutic products such as probiotics may be protective, although more pre-clinical investigations are needed.[86]

Fecal microbiota transplantation

Fecal microbiota transplant, also known as a stool transplant, is roughly 85% to 90% effective in those for whom antibiotics have not worked.[87] [88] [89] It involves infusion of the microbiota acquired from the feces of a healthy donor to reverse the bacterial imbalance responsible for the recurring nature of the infection.[90] The procedure replenishes the normal colonic microbiota that had been wiped out by antibiotics, and re-establishes resistance to colonization by Clostridioides difficile.[91] Side effects, at least initially, are few.

Fecal microbiota, live (Rebyota) was approved for medical use in the United States in November 2022.[92]

Fecal microbiota spores, live (Vowst) was approved for medical use in the United States in April 2023.[93] [94] It is the first fecal microbiota product that is taken by mouth. A 2023 review article discusses the beneficial effects of fecal microbiota transplantation in recurrent Clostridioides difficile infection [95]

Surgery

In those with severe C. difficile colitis, colectomy may improve the outcomes.[96] Specific criteria may be used to determine who will benefit most from surgery.[97]

Recurrent infection

Recurrent CDI occurs in 20 to 30% of the patients, with increasing rates of recurrence with each subsequent episode.[98] In clinical settings, it is virtually impossible to distinguish a recurrence that develops as a relapse of CDI with the same strain of C. difficile versus reinfection that is the result of a new strain. However, in laboratory settings paired isolates can be differentiated using Whole-Genome Sequencing or Multilocus Variable-Number Tandem-Repeat Analysis.[99]

Several treatment options exist for recurrent C difficile infection. For the first episode of recurrent C difficile infection, the 2017 IDSA guidelines recommend oral vancomycin at a dose of 125 mg four times daily for 10 days if metronidazole was used for the initial episode. If oral vancomycin was used for the initial episode, then a prolonged oral vancomycin pulse dose of 125 mg four times daily for 10-14 days followed by a taper (twice daily for one week, then every two to three days for 2-8 weeks) or fidaxomicin 200 mg twice daily for 10 days. For a second recurrent episode, the IDSA recommends options including the aforementioned oral vancomycin pulse dose followed by the prolonged taper; oral vancomycin 125 mg four times daily for 10 days followed by rifaximin 400 mg three times daily for 20 days; fidaxomicin 200 mg twice daily for 10 days, or a fecal microbiota transplant.[79]

For patients with C. diff infections that fail to be resolved with traditional antibiotic regimens, fecal microbiome transplants boasts an average cure rate of >90%.[100] In a review of 317 patients, it was shown to lead to resolution in 92% of the persistent and recurrent disease cases.[101] It is clear that restoration of gut flora is paramount in the struggle against recurrent CDI. With effective antibiotic therapy, C. difficile can be reduced and natural colonization resistance can develop over time as the natural microbial community recovers. Reinfection or recurrence may occur before this process is complete. Fecal microbiota transplant may expedite this recovery by directly replacing the missing microbial community members.[102] However, human-derived fecal matter is difficult to standardize and has multiple potential risks, including the transfer of infectious material and long-term consequences of inoculating the gut with a foreign fecal material. As a result, further research is necessary to study the long term effective outcomes of FMT.

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.[103]

Epidemiology

C. difficile diarrhea is estimated to occur in eight of 100,000 people each year. Among those who are admitted to hospital, it occurs in between four and eight people per 1,000.[104] In 2011, it resulted in about half a million infections and 29,000 deaths in the United States.[10]

Due in part to the emergence of a fluoroquinolone-resistant strain, C. difficile-related deaths increased 400% between 2000 and 2007 in the United States.[105] According to the CDC, "C. difficile has become the most common microbial cause of healthcare-associated infections in U.S. hospitals and costs up to $4.8 billion each year in excess health care costs for acute care facilities alone."[106]

History

Ivan C. Hall and Elizabeth O'Toole first named the bacterium Bacillus difficilis in 1935, choosing its specific epithet because it was resistant to early attempts at isolation and grew very slowly in culture.[107] André Romain Prévot subsequently transferred it to Clostridium, binomen Clostridium difficile.[108] [109] Its combination was later changed to Clostridioides difficile after being transferred to the new genus Clostridioides.[110]

Pseudomembranous colitis first was described as a complication of C. difficile infection in 1978,[111] when a toxin was isolated from people with pseudomembranous colitis and Koch's postulates were met.

Notable outbreaks

Etymology and pronunciation

The genus name is from the Greek klōstēr (Greek, Ancient (to 1453);: κλωστήρ), "spindle",[129] and the specific name is from Latin difficile, neuter singular form of difficilis "difficult, obstinate",[130] chosen in reference to fastidiousness upon culturing.

Regarding the pronunciation of the current and former genus assignments, Clostridioides is and Clostridium is . Both genera still have species assigned to them, but this species is now classified in the former. Via the norms of binomial nomenclature, it is understood that the former binomial name of this species is now an alias.

Regarding the specific name, is the traditional norm, reflecting how medical English usually pronounces naturalized New Latin words (which in turn largely reflects traditional English pronunciation of Latin), although a restored pronunciation of is also sometimes used (the classical Latin pronunciation is reconstructed as pronounced as /la/). The specific name is also commonly pronounced, as though it were French, which from a prescriptive viewpoint is a "mispronunciation" but from a linguistically descriptive viewpoint cannot be described as erroneous because it is so widely used among health care professionals; it can be described as "the non-preferred variant" from the viewpoint of sticking most regularly to New Latin in binomial nomenclature, which is also a valid viewpoint, although New Latin specific names contain such a wide array of extra-Latin roots (including surnames and jocular references) that extra-Latin pronunciation is involved anyway (as seen, for example, with Ba humbugi, Spongiforma squarepantsii, and hundreds of others).

Research

Other animals

External links

Notes and References

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