Clostridioides difficile Infection

Antibiotic-associated diarrhea was described in the 1950s. By 1978, Clostridioides difficile (formerly Clostridium difficile) had been established as the most common cause of this type of diarrhea, accounting for 15% to 25% of cases (1). The reported incidence and severity as measured by total mortality and colectomy rates increased steadily between 1993 and 2003 (2). In 2011, there were an estimated 453000 incident C difficile infections in the United States, at 147.2 cases per 100000 persons, and an estimated 29300 associated deaths (3). The increased incidence, severity, and mortality of C difficile infections have been largely attributed to the epidemic strain ribotype 027 (formerly referred to as NAP1/BI/027), which emerged in the early 2000s and has resulted in outbreaks in Canada, the United States, Europe, and Asia (46). This strain has high-level fluoroquinolone resistance, produces a binary toxin that was previously uncommon in C difficile, and produces substantially (15- to 20-fold) more toxin A and B than other strains (5). It has also been linked to community-associated disease in persons with no established risk factors, including peripartum women and children (7). Of note, from 2007 to 2010 the prevalence of ribotype 027 in England decreased significantly from 55% to 21%, likely due to a concomitant reduction in fluoroquinolone use; this decrease seemed to be associated with a significant decrease in C difficile incidence and mortality (8, 9). The emergence of another virulent strain, ribotype 078, which is found predominantly in pigs and calves, has been reported (10). This strain also causes human infection, and an association between human infection and pig farms has been observed in the Netherlands, where the prevalence of ribotype 078 has been increasing since 2005 (11). Infections caused by this strain present with similar severity as ribotype 027 but affect a younger population and are more frequently community-associated (11). Continued surveillance for emerging virulent strains along with judicious antibiotic use and adherence to recommended practices are critical to the prevention of C difficile infection. In 2017, the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) updated their 2010 clinical practice guidelines for C difficile infection (6). Many recommendations in this article are based on these updated guidelines. Prevention Susceptibility to colonization with C difficile occurs through alteration in the intestinal microbiota. Person-to-person transmission occurs through the fecaloral route. Acquisition can result from direct person-to-person contact, exposure to contaminated environmental surfaces and equipment, or contact with the hands of transiently colonized health care personnel (12). Although risk for infection is much higher in hospitalized persons than in those dwelling in the community, C difficile still causes an estimated 51.9 episodes of community-associated infection per 100000 persons (7). Exposure to persons with health careassociated colonization or disease is assumed to be the most common source of community-associated infection. Limited studies suggest that the outpatient health care environment, where contamination of C difficile has been found, might also be a potential source of community acquisition (13, 14). Studies have found that approximately 82% of persons with community-associated C difficile infection had a recent outpatient health care visit (14, 15). Receipt of care in an emergency department in the preceding 12 weeks was found to be significantly associated with community-associated infection, independent of receiving antibiotics. This suggests that the emergency department might be a reservoir for C difficile, although this exposure is only present in 11% to 24% of U.S. community-associated cases (14, 15). Another study found that exposure to infants aged 2 years or younger was significantly associated with community-associated infection, an exposure present in 14% of cases (16). Transmission among households and between humans, pets, and farm animals has been documented (17, 18). Isolation of the organism from retail meats and vegetables has also been reported (19), but none of these products have been found to be a risk factor for community-associated infection (14). Of note, C difficile forms hardy spores that survive the acidic environment of the stomach. Asymptomatic colonization may occur in 3% to 18% of patients in acute care hospitals, and increasing length of stay correlates with a greater likelihood of acquisition (20). From 4% to 20% of long-term care residents carry the organism (21). In an outbreak setting, the rate of asymptomatic colonization in a long-term care facility can be as high as 51% (22). Colonization rates in the community are estimated at 2% to 10% (20). Once colonization is established, certain factors favor development of symptomatic disease. Antibiotic disruption of the microbial balance of the gut is the most common, and longer courses and use of multiple types of antibiotics increase the risk for disease. In addition, resistance can develop through acquisition of mobile genetic elements and other mechanisms. Exposure to certain antibiotics can select for resistant strains and drive the epidemic of C difficile infection. For example, past outbreaks of a clindamycin-resistant strain (J strain) were driven largely by clindamycin use (23), and the emergence of ribotype 027 has been driven primarily by fluoroquinolone use. Other antibiotics that have been associated with C difficile infection include third- and fourth-generation cephalosporins and carbapenems, although almost all antibiotics carry some risk for gut microbial disruption (6). Chemotherapeutic agents may have the same effect (24). Some data suggest that proton-pump inhibitors or H2-receptor blockers play a role in some patients, but reports are contradictory (6, 25, 26). Further, although unnecessary use of any drug should be discouraged, there is no strong evidence that reducing use of these agents in a population prevents C difficile infection. Other physical manipulations of the gastrointestinal tract, such as surgery, enemas, stool softeners, and even tube-feeding, have been identified in some studies as contributing factors (2729). Specific immune defects, such as neutropenia or advanced HIV infection, may play a role in disease development. Finally, factors associated with general debility, such as advanced age or severe underlying disease, have been associated with increased risk, especially when multiple factors coexist (6, 30). What can clinicians do to reduce the likelihood of infection? The primary means of preventing C difficile are to limit the use of antibiotics, particularly those in specific classes believed to carry particularly high risk, and to adhere to infection prevention measures, such as the use of gloves and gowns and hand hygiene. Additional infection prevention measures include appropriate daily environmental cleaning and disinfecting. Physicians should participate in antibiotic stewardship programs that are designed in conjunction with microbiologists, infectious disease specialists, pharmacists, infection preventionists, hospital epidemiologists, and hospital administrators. Many strategies have been used, from restricting the use of high-risk drugs to routinely reviewing antibiotic therapy and giving feedback to the treating clinicians. Stewardship protocols can also focus on improving antibiotic use for specific syndromes or conditions, such as urinary tract infections and respiratory infections. A prospective controlled, interrupted time-series study of the geriatric service of a large teaching hospital evaluated the rates of C difficile infection over 2 periods of 21 months, before and after institution of an antibiotic prescription protocol involving feedback on the appropriate use of narrow-spectrum antibiotics. After institution of the antibiotic policy, C difficile infection decreased significantly (incidence rate ratio, 0.35; P= 0.009) (31). Because of the increasing frequency of community-associated infection, antibiotic use among outpatients may also be an important contributor to C difficile infection and such use may be a target for preventing these infections. Hospitalized patients with C difficile infection should be assigned to a private room or a room with other similarly infected patients until 48 hours after diarrhea has resolved (6, 32). Patients with C difficile infection who are colonized or infected with another multidrug-resistant organism should not room with patients with C difficile infection who have another multidrug-resistant organism that differs from theirs (6). Routine infection prevention practices include strict hand hygiene before and after every patient encounter and contact precautions that include use of disposable gloves and gowns during care of patients with C difficile infection or when there is the possibility of exposure to their body fluids. Although no published trials have been designed specifically to study the protective effect of gowns, C difficile has been cultured from the uniforms of hospital workers and use of disposable gowns is recommended on that basis (6, 33). A prospective controlled trial examined the incidence of C difficile infection on 3 similar hospital wards to evaluate the efficacy of vinyl gloves in preventing health careassociated transmission on 1 of the wards. Use of vinyl gloves was associated with a statistically significant reduction in symptomatic C difficile infection and asymptomatic colonization (34). Several studies have shown that conventional handwashing with soap and water is superior to alcohol-based hand sanitizers for removing C difficile spores, and any remaining spores of C difficile are highly resistant to alcohol (35, 36). Because organic matter interferes with alcohol's ability to i

The number of children diagnosed with CDI has also steadily risen in since 2000. A research study conducted between 1991 and 2009 showed a rise in the number of pediatric CDI cases from 2.6 to 32.6 per 100,000 children.
In 2011, CDI caused nearly 29,000 deaths. Most of them occurred in adults over 65 years of age. The overall mortality of CDI is 2-6%. In older adults admitted to intensive care units (ICU) and those with inflammatory bowel disease (IBD) the rate tends to be 15% or more. It has been estimated that healthcare costs related to CDI range from $1.9 to 7 billion USD each year. CDI prolongs hospital stays by 2.8 to 10.4 days. This raises hospital stay costs at over $42,000 per admission.

How does CDI spread?
CDI is most often spread from one person to another from direct exposure to the bacteria. In the environment this is often due to personal hygiene, specifically lack of hand washing. CDI spreads from the stool in one patient and ingested by the mouth of another. This type of spread is termed 'fecal-oral'. Thorough hand washing with soap and water is important as hand sanitizers cannot kill CDI.
The C. difficile infection is able to grow within the gastrointestinal (GI) system. The bacteria and its spores resist heat, acid and antibiotics. For most people infected by CDI, symptoms will begin in 2-3 days. In some cases, CDI may take greater than one week and up to 28 days to become symptomatic. Some patients can have the bug inside and not be aware or have any symptoms. This is referred to as being 'colonized' by the bacteria. CDI secretes several toxins, or poisonous substances in the colon (large intestine). These toxins cause inflammation in the GI tract and diarrhea.

What are Risk Factors to getting CDI?
The main risk factor for CDI is exposure to the bacteria and use of antibiotics. Exposure most often occurs in a hospital setting. Antibiotics are given to treat a specific infection in a person. In addition to this, these drugs also suppress the normal gut bacteria. A healthy and diverse number of gut bacteria is necessary for health. Suppressing healthy bacteria allows C. difficile to grow and colonize the large intestine. Even after stopping antibiotics, the risk for CDI remains for up to one month. There is even a risk of CDI with a single dose of any antibiotic. Long-term treatment or taking multiple antibiotics at a time can further increase the risk for CDI. Age is also an important factor in CDI risk. This may be related to a higher chance of having other medical conditions and longer hospital stays.
Risk Factors which can lead to worse outcomes associated with CDI may include: • • IBD Recurrence CDI recurrence is the reappearance of symptoms within eight weeks after treatment ends after initial improvement. It is estimated that between 13 and 50% of patients with CDI will have at least one recurrence. This is often the result of a failure to kill all the spores, rather than a new infection. Clinical Features of CDI CDI has a wide range of clinical features, from asymptomatic colonization to life-threatening infection. According to the Infectious Diseases Society of America (IDSA) along with the Society for Healthcare Epidemiology of America (SHEA) the first case of CDI should be classified as non-severe, severe, or fulminant CDI. Non-Severe CDI -The most common form of CDI seen is either mild colitis, or simple diarrhea. This diarrhea is watery and contains mucus but generally not blood. A sigmoidoscopy usually shows normal tissue in the colon. This test involves placing an endoscope through the anus and into the last part of the colon. An endoscope is a long flexible tube with a camera and light on the end. The camera allows your healthcare provider to see inside your GI tract during the test. With non-severe CDI, diarrhea may resolve by simply stopping the antibiotics. In others, a healthcare provider will prescribe antibiotic pills. Severe CDI -Severe colitis is often present with a case of severe CDI or full-blown C. difficile-associated colitis. Severe CDI occurs when the patient has very bad diarrhea and possible dehydration as well as abnormal lab tests and/or Xrays. Sometimes, 'plaques' (pseudomembranes) can be seen with a camera during sigmoidoscopy in the lower colon. These plaques can also imply a severe case of CDI. Fulminant CDI -This is the most serious type of CDI and is often seen with very serious complications. This can be lifethreatening and occurs in 3% of patients. Most of those affected by this type are elderly and/or debilitated from other diseases. Patients with this form of the disease feel severe lower abdominal pain, diarrhea, high fever with chills, and rapid heartbeat. They usually have markedly abnormal blood tests and can have low blood pressure.

Diagnosis in Adults
Generally, testing for CDI should be done in any patient who has new unexplained diarrhea. This is defined as three or more unformed bowel movements a day without the use of laxatives. Currently there are many laboratory testing options for detecting the presence of C. difficile in a patient's stool. These tests usually check for presence of toxin or genes from the bacteria, rather than culturing the bacteria itself. In fact, the name 'difficile' was applied as the bacteria is quite difficult to culture.

Diagnosis in Children
For children, diagnostic testing recommendations are based on age.
• Children younger than 12 months of age should not be tested. C diff can be a normal finding in newborns and not cause illness • Children older than 12 months may be tested if they have prolonged diarrhea, have other risk factors (e.g. IBD, cystic fibrosis, malignancy) and other causes of diarrhea have been ruled out. • Children older than 3 years, diagnostic recommendations are the same as adults. It is recommended to test for other possible causes of the diarrhea at the same time. This includes viral infections or other conditions. Treatment The primary treatment for C. difficile is an antibiotic that kills the bacteria itself. The choice of antibiotics depends on the severity and recurrence status of the infection. Sometimes, if symptoms are severe, antibiotic use before test results are available. Supportive care, and close monitoring in a hospital setting is necessary for severe cases. In some cases of recurrent disease, Fecal Microbiota Transplant (FMT) may be recommended. With FMT, stool from a healthy donor is placed in the patient in an effort to add more of the 'good' bacteria. This can be highly effective in difficult cases. Surgery may be needed in a small subset of patients with toxic megacolon, colonic perforation, or necrotizing colitis. Prevention Prevention strategies should be used in every suspected case, not only in confirmed patients. These include proper use of personal protective equipment (PPE). Gloves and disposable gowns should be used by anyone in contact with the patient during the duration of symptoms.
• Proper hand washing by the patient and anyone in contact with him/her. (Note: alcohol-based hand sanitizer does not kill C. difficile well, but soap and water work very well on our hands, and bleach works well in the environment) • Patients with CDI should be isolated in single rooms.
These rooms should be cleaned with chlorine-based solutions.
• In the community, patients with CDI should wash their hands with water and soap often. This includes after using the bathroom, before eating or preparing food, and when hands are visibly dirty. • Patients with CDI should avoid sharing toilets with other family members when possible. • Bathrooms should be sanitized with bleach-containing cleaners. Note: All of these measures seek to prevent spreading the infection. The best prevention of all is to avoid getting the infection, largely by 'antibiotic restraint' (ie only using when clearly required).