We also recommend the maintenance of an oral or enteral diet (but not an elemental diet) in patients who have normal bowel function as fermentable carbohydrates are crucial for microbial health and may contribute to normalizing the microbiota (61,62,63,64).
There are limited data on alternate antibiotic regimens for severely ill CDI patients. Fidaxomicin, as mentioned previously, was not inferior to vancomycin for initial cure for CDI, but no data are available on the efficacy of this drug in severe or complicated disease. Tigecycline is a novel analog of minocycline that exhibits broad antimicrobial activity against Gram-negative and Gram-positive organisms. Several published case reports suggest open-label benefit of intravenously administered tigecycline as a rescue strategy for the treatment of patients with severe CDI, in whom therapy with vancomycin and metronidazole has failed. However, further RCTs are required before we can make definitive recommendations regarding the use of tigecycline or fidaxomicin for the treatment of complicated CDI (68).
It has become evident that surgery is of benefit to patients at the advanced extreme of CDI, and early surgical consultation has been associated with improved survival. Data reviewed in several series suggest that earlier colectomy (time from presentation to surgery) was associated with a significantly decreased mortality (40,73,74). In an analysis of the literature from January 1989 to May 2009, earlier diagnosis and treatment with subtotal colectomy and end-ileostomy reduced mortality associated with fulminant CDI (75). One study demonstrated a trend toward decreased mortality rates in patients with fulminant disease who underwent colectomy compared with those who did not (42). These investigators further showed that admission of patients with complicated CDI to a surgical service was associated with a decreased mortality and a shorter mean interval from admission to operation compared with admission to a non-surgical service.
Independent risk factors for mortality in patients who underwent colectomy that have been found consistently among multiple studies include the development of shock, as determined by the need for vasopressors, and increased lactate (≥5 mmol/l), mental status changes, end organ failure, renal failure, and the need for preoperative intubation and ventilation (39,43,65,74).
The above findings suggest that early operative management before the development of shock and organ failure leads to improved survival. Currently, there is no scoring system that creates a threshold for operative management. However, the more negative prognostic signs a patient has, the earlier surgical consultation and operative management should be considered.
The established operative management of severe, complicated CDI has been subtotal colectomy with end-ileostomy. Survival of patients treated with segmental colectomy were worse than those treated with subtotal colectomy (41,76,77), likely because CDI usually involves the entire colon. Intraoperative assessment of the extent of disease is difficult based upon the external appearance of the colon from the serosal surface. Although some series have reported perforation or infarction of the colon to be common findings at the time of surgery, colonic necrosis and perforation are not inherent to the disease process (69); they likely result from the development of shock with secondary non-occlusive ischemia and the use of vasopressors or when abdominal compartment syndrome develops and compromises colonic perfusion.
Interest has developed in early operative management other than colon resection given that the colon is most often viable at this stage without perforation (78,79). A recent case-controlled series demonstrated that loop ileostomy with intraoperative colon lavage with polyethylene glycol 3350/balanced electrolyte solution and post-operative antegrade colonic vancomycin flushes via the ileostomy led to colon preservation in over 90% of patients and had significantly improved survival compared with historical controls who had undergone colectomy (19% vs. 50% mortality) (78). Over 80% of cases were performed using a minimally invasive surgical approach, and a majority of patients who were followed long term had restoration of gastrointestinal continuity. Advantages of this approach are the potential willingness to utilize this treatment earlier in the course of disease based upon potential preservation of the colon and fewer long-term adverse consequences. Further validation of this approach is required.
RCDI is a therapeutic challenge because there is no uniformly effective therapy. After treatment of an initial episode of C. difficile, the chance of RCDI within 8 weeks is 10–20%, but when a patient has had one recurrence, rates of further recurrences increase to 40–65% (80). Recurrence can be due to the same strain or to a different strain (81). Recurrences may be due to an impaired immune response and/or alteration of the colonic microbiota. Evidence for an impaired immune response comes from small studies. In one study of hospitalized patients with CDI, those who developed RCDI had lower levels of immunoglobulin G (IgG) antibody to toxin A (82). In another, three patients who were given a vaccine to clear C. difficile developed an IgG response to toxin A (83).
Evidence that an altered colonic microbiota is the main factor in the pathophysiology of RCDI is growing. A study of the colonic microbiota in normal controls, individuals with one episode of CDI and patients with RCDI, showed that those with RCDI had a marked decrease in the diversity of the flora compared with the other two groups (84). Moreover, therapy that puts healthy donor stool into the stomach, small intestine, or colon of patients with RCDI (fecal microbiota transplant (FMT)) has the highest rate of success (≥90%) compared with results of other therapies (85).
The first documented use of FMT in the English language was a case series of four patients with pseudomembranous enterocolitis, three of whom were critically ill; fecal enemas (donated by the residents caring for the patients) were administered as an adjunct to antibiotic treatment; all four patients had resolution of symptoms within hours of FMT (93). The first documented case of confirmed RCDI treated with FMT was reported in 1983 in a 65-year-old woman who had “prompt and complete normalization of bowel function” (94). Up until 1989, retention enemas had been the most common technique for FMT; however, alternative methods subsequently were used, including fecal infusion via nasogastric duodenal tube in 1991 (95), colonoscopy in 2000 (96), and self-administered enemas in 2010 (97). By 2011, approximately 325 cases of FMT had been reported worldwide, including approximately 75% by colonoscopy or retention enema, and 25% by nasogastric or nasoduodenal tube, or by esophagogastroduodenoscopy (98,99). Overall, mean cure rates to date are approximately 91% (99). In a recent series of 70 patients with RCDI, FMT was effective even in patients with the C. difficile NAP1/BI/027 strain (100). A retrospective multicenter follow-up study of RCDI patients treated with FMT demonstrated a 91% primary cure rate and a 98% secondary cure rate (101).
FMT appears to be safe, with no adverse effects or complications directly attributed to the procedure yet described in the existing literature (85,102). The potential for transmission of infectious agents is a concern, however, and a recent publication outlines rigorous screening of stool donors’ blood and stool for common bacterial and viral enteropathogens (85). In one series, a standardized filtered, frozen, and then thawed preparation of stool from pre-screened universal donors showed cure rates equal to or better than those from patient-identified donors (103).
Long-term follow-up of FMT is limited. In the only such follow-up study to date, 77 patients had FMT and were followed for >3 months (3 months to >10 years). Of these 77 subjects, four developed an autoimmune disease (rheumatoid arthritis, Sjögren's syndrome, idiopathic thrombocytopenic purpura, and peripheral neuropathy) at some time after the FMT, although a clear relationship between the new disease and the FMT was not evident (101). RCTs are necessary to prove the efficacy of FMT and to determine the optimal route of administration among other variables and safety in immunosuppressed patients needs to be established. An RCT of donor feces administered by duodenal infusion with gut lavage showed significant efficacy compared to vancomycin or vancomycin with gut lavage without donor feces (104). The study was terminated early because it was deemed unethical to continue as the cure rate was 81% compared to 23% with vancomycin alone and 31% with vancomycin and gut lavage. An NIH-funded blinded RCT is underway, using FMT via colonoscopy with donor or recipient stool for transplant (Colleen Kelly, Lawrence Brandt, personal communication).
A meta-analysis of probiotics for the prevention of antibiotic-associated diarrhea and for the treatment of CDI concluded that S. boulardii was only effective for C. difficile disease (110); however, a Cochrane analysis concluded that there was insufficient evidence to recommend probiotics, in general, as an adjunct to antibiotics in the treatment of C. difficile diarrhea (111). The most recent systematic review and meta-analysis of S. boulardii concluded that although there is strong evidence from numerous large RCTs for efficacy in prevention of antibiotic-associated diarrhea, the evidence for efficacy in the treatment of C. difficile as an adjunct to antibiotics is weak and more RCTs are needed (112).
Thus, there are no strong data to support the use of probiotics for RCDI treatment, and only weak evidence of therapeutic efficacy for S. boulardii. There is no evidence for the use of probiotics in the treatment of initial or severe disease. Moreover, these are live organisms and they should be used cautiously, if at all, in individuals with significant immune suppression because of the possible risk of bacteremia or fungemia. There are cases of S. boulardii fungemia reported in patients with central venous catheters, and thus its use in an ICU or in immunocompromised patients is not recommended (113,114). There are also numerous case reports of invasive lactobacillus infections in non-immunosuppressed (mostly elderly) patients (115,116,117). Finally, the use of probiotics is not regulated by the Food and Drug Administration, there is no good quality control for most probiotics, and studies have shown that some probiotics contain no live organisms, or alternatively, contain organisms not on the product label (118,119). In view of the lack of efficacy data, abundant data on potential harm, high costs, and lack of biological plausibility for these non-human micro-organisms to confer colonization resistance, their use cannot be recommended.
Publications to date on IVIG to treat RCDI in humans include six case reports and six small case series with varied patient inclusions (severe and recurrent), ages, doses of therapy used, and duration of therapy among other parameters (124,125). Many patients also received concomitant standard therapy, making interpretation of efficacy difficult. Passive immunizations with IVIG have been reported to be successful in several small series, including both children and adults. A recent review concluded that the grade of evidence is weak, given the lack of RCTs (125). One exception may be patients with hypogammaglobulinemia, which is common in patients following solid organ transplants, and may predispose to CDI. In one study, there was a fivefold increased risk of CDI in heart transplant recipients. These patients had decreased immunoglobulins and immunoglobulin therapy reduced the risk of CDI and RCDI recurrence (126). For this group of patients, IVIG may be beneficial, but more studies are needed before this can be stated definitively. IVIG has been associated with drug-induced aseptic meningitis and fluid overload states.
In a phase II clinical trial, a monoclonal antibody to toxins A and B used as an adjunct to antibiotics was shown to decrease recurrence rates in patients with CDI (7% compared with 38%); in patients with a previous episode of CDI, the recurrence rate was 7% compared with 18% in the control group (P=0.07) (127). This product is only available in phase III trials. An oral anti-Clostridium whey protein from cows immunized to C. difficile toxoid was studied in the Netherlands. Early studies of C. difficile showed promise for treatment of patients with RCDI, with no further recurrences (128), but in a later study there was no significant decrease in recurrences (44% vs. 45%) (129). Further development of this product has been halted due to lack of funding.
Several patient groups are newly recognized as either at an elevated risk for acquiring the infection or suffering adverse outcomes from CDI: patients with inflammatory bowel disease (IBD), including those with an ileostomy or an ileo-anal pouch following colectomy (135,136,137,138); patients with chronic liver disease (139,140); organ transplant recipients (solid organ and hematopoietic); patients with ongoing malignancy, particularly those undergoing chemotherapy, patients who chronically use steroids; patients with hypogammaglobulinemia and pregnant women and women in the peripartum period (141,142,143).
Risk factors are pre-existing colonic inflammation, especially in ulcerative colitis, severe underlying IBD, and ongoing immunosuppression (136,149,150,151,152). Among the different therapies, the highest risk appears to be with corticosteroid use, which confer a threefold increase of CDI. Corticosteroid exposure within 2 weeks of the diagnosis of CDI was also associated with a twofold increase in mortality (153). Patients with IBD have a higher rate of colectomy and a greater mortality than either non-CDI IBD or non-IBD CDI controls (135,137,150). The clinical presentation of an IBD flare and CDI often is indistinguishable and requires a high index of suspicion for prompt detection and institution of appropriate therapy. All patients who require hospitalization because of an IBD flare, as well as ambulatory patients with risk factors for CDI (e.g., recent hospitalization, antibiotic use) or unexplained worsening of symptoms in the setting of previously quiescent disease, should be tested for C. difficile.
Patients who have had a colectomy and have an ileostomy or an ileo-anal pouch remain at risk for CDI, with symptoms of increased stool frequency, or ostomy output, bleeding, or systemic features of fever, abdominal pain, and leukocytosis (155,156,157,158). Because some studies have reported high rates of adverse outcomes for CDI in such patients, it is essential to have a high index of suspicion. All patients with persistent or unexplained symptoms should be tested for C. difficile. Treatment of C. difficile pouchitis or enteritis is similar to treatment of other IBD patients.
A previous report describes one institution's comprehensive efforts to control an outbreak of CDI caused by the hypervirulent strain (NAP1/BI/027) using a C. difficile infection control “bundle”, consisting of education, increased and early case finding, expanded infection control measures, development of a C. difficile management team, and antimicrobial stewardship. Hospital rates of C. difficile decreased from 7.2 cases per/1,000 discharges during the year before institution of these measures to 4.8 cases per/1,000 discharges in the subsequent 5 years (168).
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Definitions of CDI
CDI may be further defined according to the time of symptom onset and history of hospitalization (189,190): Health-care onset health-care facility-associated (HO-HCFA) CDI is defined as onset of symptoms3 days after admission to a health-care facility. Community onset health-care facility-associated (CO-HCFA) CDI is defined as onset of symptoms within 4 weeks after being discharged from a health-care facility. Community-associated (CA) CDI occurs when a person develops CDI outside of a health-care facility or <3 days after admission in someone who has not been discharged from a health-care facility in the previous 12 weeks. If CDI develops after being discharged from a health-care facility 4–12 weeks previously, the case is considered as indeterminate disease (ID). RCDI is defined as an episode of CDI that occurs 8 weeks after the onset of a previous episode, provided the symptoms from the previous episode have resolved. Several studies performed in different geographic areas of the United States document HO-HCFA CDI to be the most frequent (53–89%) followed by CO-HCFA CDI (3–28%), CA (5–27%), and ID (5%) of cases (15,191,192,193). In order to ensure uniformity of data reporting and to allow comparability among studies, we recommend these definitions be used. For surveillance studies, incidence rates should be expressed as cases of CDI per 10,000 patient-days (194).
CDI prevalence/incidence Rates of CDI have been increasing globally since 2000, a national point—prevalence of CDI from a survey in US health-care facility inpatients in 2008 was 13.1/10,000 patients (195). Almost 70% of patients were >60 years of age, and 52.2% were 70 years. Nearly 80% had received antibiotics in the previous 30 days. Overall, 73% of cases were health-care-associated CDI. More recent surveillance data from 2010 from the Emerging Infections Program that includes 111 acute-care hospitals and 310 nursing homes and from the 711 acute-care hospitals reporting to the National Health Care Safety Network found that 97% of cases were health-care related. Of these, 75% had onset of among persons previously hospitalized (196). In a study of US trends from 2000 to 2005, the incidence of CDI in adults increased from 5.5/10,000 to 11.2/10,000 (197). In adults aged 18–44 years, the increase was only 1.3/10,000 to 2.4/10,000, but in those aged 65–84 years, the increase was from 22.4/10,000 to 49/10,000 and in those >85 years CDI it nearly doubled from 52/10,000 to 112/10,000 (197).
Carriage of C. difficile occurs in 5–15% of healthy adults and may be transient (198,199,200). Among newborns and healthy infants, carriage rates may be as high as 84.4% up to age 2 years (199,201,202). Some infants may have non-toxigenic strains. Hospitalized patients have much higher carriage rates; in a prospective study, 26% of 428 patients in a medical ward acquired C. difficile; 62% remained asymptomatic (15). Among the elderly, carriage rates may be higher, especially in those in LTCFs. In one study of an epidemic in a LTCF, 51% of asymptomatic carriers had toxigenic C. difficile (203), indicating that LTCF may be a reservoir for cases of CDI.
CA-CDI has received a great deal of attention as a potential emerging cause of outpatient diarrheal illness, but all of the studies of CDI in non-hospitalized populations have used laboratory surveillance to find cases (204,205,206,207). A recent prospective study of outpatients with diarrheal illnesses presenting to emergency rooms and outpatient clinics in the United States showed only 43/1091 (3.9%) with positive tests for C. difficile, of whom only 7 (0.6%) had no traditional risk factors for CDI and no co-infections (208). Within hospitals, even outbreaks of diarrhea attributed to norovirus have been initially mis-attributed to C. difficile because of the high carriage rate within hospital populations (209). Given these data, the pre-test suspicion for CDI in healthy outpatients without antimicrobial exposures remains low and should remain so even for outpatients with positive C. difficile tests.
Since 2000, an epidemic strain has emerged (NAP1/BI/027), associated with an increase in the endemic incidence and an increase in the mortality of patients in some institutions (210,211,212,213,214). The NAP1/BI/027 strains have a higher rate of fluoroquinolone resistance, produce 16 times more toxin A, and 23 times more toxin B in vitro than other C. difficile strains (215); and produce a binary toxin. Patients infected with this strain are reported to have lower clinical cure rates and higher rates of CDI recurrences than patients with other strains (216). However, several studies have failed to demonstrate an association between NAP1/BI/027 strains and severe disease (217,218,219,220). Moreover, non-027 ribotype strains have been associated with severe clinical outcomes in at least two studies (221,222).
Transmission Transmission within health-care facilities largely results from horizontal transmission via environmental surface contamination, hand carriage by hospital personnel, and infected roommates (15,217,218,219,220,221,222,223,224,225). In a cohort of 2,859 patients, a multivariate analysis found that physical proximity to a patient with CDI significantly increased the risk of CDI (relative risk=1.86, 95% confidence interval 1.06–3.28) (224). In addition to health-care facility sources, C. difficile is found in soil, a variety of animals and pets (e.g., cats, dogs, horses, cattle, swine), and food products, including various meats and ready-to-eat salads (226,227,228,229,230,231). In animals, some strains are species specific but others affect humans as well. The epidemic strain NAP1/BI/027 has been isolated from food and from domestic pets; however, there are no documented studies that this route of transmission has caused human illness (230,231).
Risk factors The two biggest risk factors for CDI are exposure to antibiotics, especially broad-spectrum antibiotics and exposure to the organism, usually through admission to a health-care facility. Other factors in epidemiological studies that increase the risk of CDI include older age, gastrointestinal surgery, nasogastric tube feeding, reduced gastric acid, and concurrent disease, including inflammatory bowel disease (144,145,232,233,234,235,236). An impaired immune response has been implicated; a small series showed that patients with C. difficile in their stools who developed diarrhea had lower levels of IgG to toxin A than those who remained asymptomatic (237). Serious underlying illness and the presence of other concurrent diseases place the patient at increased risk of CDI, especially if the patient is receiving additional antibiotics for concurrent infections and has a longer hospital stay. As many risk factors for CDI are correlated, multivariate analysis provides independent risk estimates for variables that occur at the same time. Most multivariate models find advanced age, antibiotic use, co-morbidities, and longer hospital stays are independently predictive of CDI (211,214,232). Although several studies have not shown an association with proton pump inhibitors (PPIs) and CDI, many other studies have found an association (235,236). A meta-analysis of 29 studies of patients with CDI found that PPI increased the risk of CDI (pooled odds ratio=2.15, 95% confidence interval (CI) 1.81–2.55) (234). Two recent meta-analyses confirm association and strengthen the evidence that PPI use is associated with an increased risk of CDI (7,8).
The risk factors for recurrent CDI are slightly different from those for initial CDI. In a prospective study of 209 patients with recurrent CDI, logistic regression revealed only two significant independent risk factors for CDI recurrence: increased age and a lower quality of health at enrollment (238). One meta-analysis of 12 studies totaling 1,382 patients with recurrent CDI and found risk factors for recurrent CDI that included continued use of non-C. difficile antibiotics (odds ratio (OR)=4.23, 95% CI 2.1–8.5), antacids (OR=2.1, 95% CI 1.1–4.1), and older age (OR=1.6, 95% CI 1.1–2.4) (239). Another group developed a prediction rule with a 77% accuracy based on three risk factors: age >65 years, severe or fulminant illness, and additional antibiotic use after CDI therapy was completed (240).
There are several FDA-approved NAAT's, including PCR assay and loop-mediated isothermal amplification (LAMP). PCR is an excellent confirmatory test, but data for LAMP testing is not yet sufficient to recommend it. Currently, there are six FDA-approved NAATs available: four PCR assays, a LAMP method, and a ribonuclease-mediated isothermal amplification and chip-based detection method (83,84,85,86,87,88,89,90,91,92,93,241,242,243,244,245,246,247,248,249,250,251). Because there are few published data on the performance of one of the PCR tests, Simplexa-C. difficile Universal Direct Test (Quest Diagnostics, Madison, NJ), and the ribonuclease-mediated isothermal amplification and chip-based detection method test (Great Basin Corporation, Salt Lake City, UT), it is not possible to comment on their performance at this time. Meta-analysis of three commercial PCR assays, GeneOhm Cdiff Assay BD Diagnostics GeneOhm, San Diego, CA; Xpert C. difficile Test Cepheid, Sunnyvale, CA; and ProGastro Cd Assay Gen-Probe, San Diego, CA indicate that they have similar sensitivities of and specificities of ∼90% and ∼95%, respectively, compared with TC (214). A recent large study comparing widely used commercially available tests showed that PCR for toxigenic C. difficile and GDH testing were the most sensitive tests for detection of C. difficile in stool specimens compared with a composite reference method of TC or a negative culture in patients with multiple positive tests and a clinical course consistent with CDI. Additionally, the PCR test studied was more specific than GDH. Importantly, both methods were statistically more sensitive than CCNA and various toxin A+B EIAs (245).
PCR is an excellent confirmatory test for GDH compared with TC; no such data currently exist for LAMP testing (25,249,251). Amplification methods, however, do have superior sensitivity compared with GDH, toxin A + B EIA, and CCNA tests (245,248,249,250,251).