clostridioides difficile infection clostridioides difficile infection clostridioides difficile infection (cdi or c-diff), also known as clostridium difficile infection, is a symptomatic infection due to the spore-forming bacterium clostridioides difficile. 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. complications may include pseudomembranous colitis, toxic megacolon, perforation of the colon, and sepsis. clostridioides difficile infectionother namesc. difficile associated diarrhea (cdad), clostridium difficile infection, c. difficile colitispathological specimen showing pseudomembranous colitisspecialtyinfectious diseasesymptomsdiarrhea, fever, nausea, abdominal paincomplicationspseudomembranous colitis, toxic megacolon, perforation of the colon, sepsiscausesclostridioides difficile spread by the fecal-oral routerisk factorsantibiotics, proton pump inhibitors, hospitalization, other health problems, older agediagnostic methodstool culture, testing for the bacteria's dna or toxinspreventionhand washing, terminal room cleaning in hospitaltreatmentmetronidazole, vancomycin, fidaxomicin, fecal microbiota transplantationfrequency453,000 (us 2011)deaths29,000 (us) 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, 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. prevention efforts include terminal room cleaning in hospitals, limiting antibiotic use, and handwashing campaigns in hospitals. alcohol based hand sanitizer does not appear effective. discontinuation of antibiotics may result in resolution of symptoms within three days in about 20% of those infected. the antibiotics metronidazole, vancomycin or fidaxomicin, will cure the infection. retesting after treatment, as long as the symptoms have resolved, is not recommended, as a person may often remain colonized. recurrences have been reported in up to 25% of people. some tentative evidence indicates fecal microbiota transplantation and probiotics may decrease the risk of recurrence. 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. global rates of disease increased between 2001 and 2016. c. difficile infections occur more often in women than men. the bacterium was discovered in 1935 and found to be disease-causing in 1978. in the united states, healthcare-associated infections increase the cost of care by us$1.5 billion each year. although c. difficile is a common healthcare-associated infection, at most 30% of infections are transmitted within hospitals. 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. signs and symptoms signs and symptoms of cdi range from mild diarrhea to severe life-threatening inflammation of the colon. 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. in a hospital population, prior antibiotic treatment plus diarrhea or abdominal pain had a sensitivity of 86% and a specificity of 45%. 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. those with a severe infection also may develop serious inflammation of the colon and have little or no diarrhea. cause main article: clostridioides difficile 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. 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. 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. another toxin, binary toxin, also has been described, but its role in disease is not fully understood. 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. 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. 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. antibiotics c. difficile colitis is associated most strongly with the use of these antibiotics: fluoroquinolones, cephalosporins, and clindamycin. some research suggests the routine use of antibiotics in the raising of livestock is contributing to outbreaks of bacterial infections such as c. difficile. healthcare environment people are most often infected in hospitals, nursing homes, 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. 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. long-term hospitalization or residence in a nursing home within the previous year are independent risk factors for increased colonization. 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. 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. 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. 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. low serum albumin levels is a risk factor for the development of c. difficile infection and when infected for severe disease. 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. chronic kidney disease (ckd) has been identified as a risk factor in the development of a c. difficile infection. 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. 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. 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. 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. 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. 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. 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, but evidence suggests repeated testing during the same episode of diarrhea is of limited value and should be discouraged. 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