Cases were classified as mild-to-moderate, severe, or severe and complicated CDI. Major outcomes measured were in-patient deaths and colectomy attributed to CDI.
For risk stratification, each variable of severe and complicated CDI was counted. Results In total, 59, patients were discharged from our hospital during the study period; of them were diagnosed with CDI.
In total, 14 patients underwent colectomy for CDI and 53 patients expired. In 35 of these patients, the cause of death was thought to be CDI. None of the patients in mild-to-moderate disease or severe disease had combined outcome. On plotting receiver-operating curve, the simple variable count had area under the curve of 0. Conclusion The newly proposed disease severity classification for CDI categorized more than two-thirds of patients as severe and complicated. Increase in number of severe and complicated classifying variables increases the chance of adverse outcomes significantly.
Patients meeting only one variable could be potentially treated as a severe case instead of severe and complicated. This data needs to validated prospectively before could be used in clinical practice. Keywords: Clostridium difficile infection, Severity of Illness, Need for colectomy, inpatient mortality Clostridium difficile infection CDI is the most common hospital-acquired infection, outnumbering the incidence for methicillin-resistant Staphylococcus aureus 1.
CDI is no longer a disease of old and frail people only. Emergence of highly virulent strains of C. CDI imposes a huge financial and health burden. Apart from financial burden; it also adds significant mortality and morbidity 4.
Because of this, the bacterium may be cultured from almost any surface. Once spores are ingested, their acid resistance allows them to pass through the stomach unscathed. They germinate and multiply into vegetative cells in the colon upon exposure to bile acids.
Consequently, the World Health Organization advocates the use of soap in addition to alcohol solutions to limit the spread of the spores. However, it is a poor competitor, and is often outcompeted by other bacteria for nutrients in the digestive system.
As a result, C. If the sudden introduction of antibiotic disrupts the microbiome, C. The incubation period is 5—10 days, with a range of 1 day to weeks following antibiotic treatment for antibiotic associated diarrhea. Additionally, carriage of C.
The production of one or even both toxins is not always sufficient for producing symptoms. This break in antibiotic therapy can sometimes lead to spontaneous resolution of symptoms. For example, evidence of emergence of a virulent strain, ribotype , has been reported from the Netherlands . The prevalence of ribotype increased between and and was associated with similar severity compared to CDI cases due to ribotype , but was associated with a younger population and more CA CDI.
There was also a high degree of genetic relatedness between isolates found in humans and pigs, an association also noted in the United States . CDI in the Community and Special Populations and Increased Risk In the context of the changing epidemiology of CDI in hospitals in the mids, evidence suggested increasing incidence of CDI in the community, even in healthy people previously at low risk, including peripartum women [59—64]. The sources of and risk factors for CA CDI ie, occurring in patients with no inpatient stay in the previous 12 weeks are not well defined.
In another recent study, a predictive risk scoring system developed in one cohort in a capitated-payment healthcare system and validated in another cohort in the same system proved useful for differentiating CDI risk in patients following an outpatient healthcare visit .
Major components of the scoring system included age, recent inpatient stay, chronic conditions eg, liver and kidney disease, inflammatory bowel disease [IBD], cancer , and antibiotics; the role of PPIs was not examined or otherwise not included.
Patients with IBD, especially ulcerative colitis, are at increased risk of not only primary CDI but also recurrent disease, as well as increased morbidity and mortality from CDI. There is an increased colectomy risk from CDI occurrence in patients with IBD overall, especially patients with ulcerative colitis . Other patient populations at increased risk include solid organ transplant recipients: With an overall prevalence of 7. Risks are highest in multiple solid organ transplants, followed by lung, liver, intestine, kidney, and pancreas with an overall prevalence of severe disease of 5.
Patients with chronic kidney disease and end-stage renal disease have an approximately 2- to 2. Finally, hematopoietic stem cell transplant patients have a rate of CDI that is approximately 9 times greater than that in hospitalized patients overall; within this population, rates are about twice as high in allogeneic vs autologous transplants, where CDI occurs in about 1 in 10 transplants . Most of this risk is during the peritransplantation period ie, first days posttransplant.
Epidemiology of Colonization and Infection C. Studies have found that the prevalence of asymptomatic colonization with C. In contrast, the prevalence of C. A recent meta-analysis found that the pooled colonization rate upon hospital admission across 19 studies mostly since and through was 8. Notably, neither antibiotic use nor previous CDI was associated with colonization on hospital admission The period between initial colonization with C.
Other early studies suggested that persons who remain asymptomatically colonized with C. In contrast, the aforementioned recent meta-analysis found that preceding colonization increased the risk of subsequent CDI 6-fold; however, neither the time course from first detection of colonization to symptom onset nor the impact of diagnostic methods on this risk were examined .
Thus it is likely that the daily risk of progression from colonization to infection is not static but decreases over time; if so, the protection afforded by more long-standing colonization may be mediated in part by the boosting of serum antibody levels against C.
It is also likely that as long as an individual is colonized by one strain they are protected from infection caused by another strain; there is evidence of protection from CDI in both humans and in animal models following colonization with nontoxigenic strains, suggesting competition for nutrients or access to the mucosal surface [82, 83].
Routes of Transmission The hands of healthcare personnel, transiently contaminated with C. There have also been outbreaks in which particular high-risk fomites, such as electronic rectal thermometers or inadequately cleaned commodes or bedpans, were shared between patients and were found to contribute to transmission . The potential role of asymptomatically colonized patients in transmission has recently been highlighted. In the Curry et al study, environmental transmission may have occurred in 4 of 61 incident healthcare-associated CDI cases .
Two recent studies highlight how antibiotics may affect CDI risk in hospitalized patients through impacting the contagiousness of asymptomatically colonized patients. Through use of a multilevel model, ward-level antibiotic prescribing ie, among both CDI and non-CDI patients, therefore including potential asymptomatic carriers was found to be a risk factor for CDI that was independent of the risk from antibiotics and other factors in individual patients .
Meanwhile, the individual risk of symptomatic CDI was found to be higher in patients admitted to a room where a previous patient without CDI was administered antibiotics, suggesting induced shedding of C. Shedding of C. Risk Factors for Disease Advanced age, potentially as a surrogate for severity of illness and comorbidities, is one of the most important risk factors for CDI [46, 96, 97], as is duration of hospitalization.
The daily increase in the risk of C. The most important modifiable risk factor for the development of CDI is exposure to antibiotic agents. The relative risk of therapy with a given antibiotic agent and its association with CDI depends on the local prevalence of strains that are highly resistant to that particular antibiotic agent . The disruption of the intestinal microbiota by antibiotics is long-lasting, and risk of CDI increases both during therapy and in the 3-month period following cessation of therapy.
The highest risk of CDI 7- to fold increase appears to be during and in the first month after antibiotic exposure . Both longer exposure to antibiotics  and exposure to multiple antibiotics increase the risk for CDI . However, as previously noted, asymptomatic colonization, at least as detected among patients commonly admitted to the hospital, may not be associated with prior antibiotics .
Cancer chemotherapy is another risk factor for CDI that is, at least in part, mediated by the antibiotic activity of several chemotherapeutic agents [, ] but could also be related to the immunosuppressive effects of neutropenia [, ]. Evidence suggests that C. Other risk factors for CDI include gastrointestinal surgery  or manipulation of the gastrointestinal tract, including tube feeding . Meta-analyses of risk factors for recurrence identified many of those described above for initial CDI including advanced age, antibiotics during follow-up, PPIs, and strain type, as well previous exposure to fluoroquinolones [, ].
Meanwhile, risk factors for complicated disease include older age, leukocytosis, renal failure and comorbidities, while risk factors for mortality from CDI alone include age, comorbidities, hypoalbuminemia, leukocytosis, acute renal failure, and infection with ribotype .
Recent data confirm the role of humoral immunity, primarily directed against toxin B, at least for protecting against recurrent disease . There may be an important role for vitamin D in protecting against CDI, with low levels being an independent risk factor among both general patients with community-associated disease, older patients, and those with underlying inflammatory bowel disease [, ].
Breaches in the protective effect of stomach acid or the antibiotic activity of acid-suppressing medications, such as histamine-2 blockers and PPIs, while a potential risk factor, remain controversial.
Although a number of studies have suggested an epidemiologic association between use of stomach acid—suppressing medications, primarily PPIs, and CDI [37, 60, —], results of other well-controlled studies suggest this association is the result of confounding with the underlying severity of illness, non-CDI diarrhea, and duration of hospital stay [36, , ].
Moreover, long-term use of PPIs has been shown to decrease lower gastrointestinal microbial diversity . However, whether as a risk factor for primary or recurrent disease, the choice of control group in such epidemiologic studies is important.
PPIs and histamine-2 blockers may be associated with CDI when comparing cases to nontested controls but not when comparing cases to tested-negative controls . This reflects why understanding the role of these drugs in the pathogenesis of CDI remains elusive; PPIs induce diarrhea on their own, making it more likely patients are tested for CDI.
More careful assessment of confounding factors, symptoms, and criteria for testing for recurrence, as is typical in a prospective clinical trial, may then explain why PPIs were not associated with recurrence in clinical trials of fidaxomicin . Summary of the Evidence Similar to the findings in adults, the incidence of CDI has risen in children since [—].
The majority of pediatric studies have evaluated the incidence of CDI-related hospitalizations among multicenter cohorts of hospitalized children [—]. More recently, a population-based study of children residing in Olmsted County, Minnesota, between and identified an increase in incidence of CDI among pediatric residents from 2. The incidence of CDI has increased overall, including increases in CDI among children in community and outpatient settings [, , ]. These estimates are limited by reliance on laboratory surveillance methods, where differences in testing practices may undermine the accuracy of some longitudinal and interinstitutional comparisons of rates of CDI in children [, ].
Nonetheless, these data indicate an epidemiologic shift with increased disease in nonhospitalized children. One important feature of the epidemiology of C. Nontoxigenic strains are more common than toxigenic strains among colonized infants, but colonization is transient and different strains are found to colonize the same infant at different times [, , —].
Colonization is less frequent among breastfed as compared with bottle-fed infants [, —]. Some evidence implicates the hospital environment as a source of acquisition of colonizing strains [, , , , —]. Colonization rates decrease with increasing age [, , , ]. The prevalence of asymptomatic colonization with C. Therefore, testing in this population should also be avoided unless other infectious and noninfectious causes of diarrhea have been excluded.
While young children are unlikely to have C. Many of the risk factors for C. In children, the presence of a gastrostomy or jejunostomy tube has been found to be an additional independent risk factor .
Recent studies suggest that acid-suppressing medications may also be an independent risk factor for CDI in children, although the association has been more consistently observed in children who receive histamine-2 receptor antagonists than PPIs [, ]. Severe disease and complications due to CDI are less common in children [, , ] but have been described [, ].
Among hospitalized children who are otherwise similar in important demographic and clinical characteristics, CDI has been associated with worse outcomes, including prolonged hospital stay, increased total hospital costs, and higher mortality rates [, ].
If a patient has diarrheal symptoms not clearly attributable to underlying conditions IBD, and therapies such as enteral tube feeding, intensive cancer chemotherapy, or laxatives , then testing to determine if diarrhea is due to C.
Alternatively, testing may be indicated if symptoms persist after stopping therapies to which diarrhea may be otherwise attributed eg, laxatives. However, some of these conditions and interventions associated with diarrhea in their own right, such as IBD and enteral tube feeding, have been shown to have increased risk of CDI when compared with a matched cohort .
So, in practice it is difficult to exclude the possibility of CDI on clinical grounds alone in a patient with new-onset or worsened diarrhea. The evidence base to optimize CDI testing is weak.
Notably, the number and frequency of diarrheal stools required to justify CDI testing have declined over the past 40 years. Using the latter definition of diarrhea, Dubberke et al and Peterson et al also using additional clinical criteria have examined the frequency of these symptoms in patients whose stool is submitted for CDI testing [, ]. Clinicians can improve laboratory test relevance by only testing patients likely to have C. This includes not routinely performing testing on stool from a patient who has received a laxative within the previous 48 hours.
Laboratories can improve specificity by rejecting specimens that are not liquid or soft ie, take the shape of the container. In addition, laboratories may wish to collaborate with available quality improvement teams such as infection prevention and control and antibiotic stewardship, to assess appropriateness of testing in the population from which samples are submitted.
This may involve periodic chart review in a series of patients to assess for clinical risk factors, signs, and symptoms suggestive of CDI. Laboratory Testing Two diagnostic testing recommendations based on institutional and laboratory preagreed criteria for patient stool submission are prefaced by questions VII and VIII Figure 2.
Recommendation Use a stool toxin test as part of a multistep algorithm ie, glutamate dehydrogenase [GDH] plus toxin; GDH plus toxin, arbitrated by NAAT; or NAAT plus toxin rather than a NAAT alone for all specimens received in the clinical laboratory when there are no preagreed institutional criteria for patient stool submission Figure 2 weak recommendation, low quality of evidence. Summary of the Evidence There is a variety of available options for laboratory testing to support the diagnosis of CDI, and these are well described in several recent reviews [, ].
In brief, these methods detect either the organism or one or both of its major toxins A and B directly in stool. Table 3 lists these methods in decreasing order of analytical sensitivity. Toxigenic culture TC uses a prereduced selective agar, cycloserine-cefoxitin-fructose agar or a variant of it, followed by anaerobic incubation for several days.
To enhance the recovery of the organism, a spore selection step, whether heat or alcohol shock, is applied to the stool prior to inoculating media. Once an organism is identified, a toxin test must be performed on the isolate to confirm its toxigenic potential.The most important modifiable risk factor for the development of CDI is exposure to antibiotic agents. What is the most sensitive method of diagnosis of CDI in stool specimens from patients likely to have CDI based on clinical symptoms? An incident case is defined as a new primary episode of symptom onset ie, no episode of symptom onset with positive result within the previous 8 weeks and positive assay result eg, toxin enzyme immunoassay [EIA] or nucleic acid amplification test [NAAT]. This data needs to validated prospectively before could be used in clinical practice. Daily cleaning with a sporicidal agent should be considered in conjunction with other measures to prevent CDI during outbreaks or in hyperendemic sustained high rates settings, or if there is evidence of repeated cases of CDI in the same room weak recommendation, low quality of evidence. Summary of the Evidence Similar to the findings in categorized more than two-thirds of patients Glucosinolate biosynthesis pathway arabidopsis plants severe and. If there is a limited essay of higher single adults, the incidence of CDI has risen in children since [-]. If cohorting is required, it is recommended to cohort patients infected or colonized with the same organism s -that is, do not cohort patients with CDI who such recommendations and use appropriate wording choices . Most of this classification is during the peritransplantation period analytical sensitivity.
On plotting receiver-operating curve, the simple variable count had area under the curve of 0. Recent data confirm the role of humoral immunity, primarily directed against toxin B, at least for protecting against recurrent disease . Hospital-acquired CDI increases length of hospital stay and hospital mortality. Patients with suspected CDI should be placed on preemptive contact precautions pending the C. Literature Review and Analysis For this guideline update, search strategies, in collaboration with the guideline panel members, were developed and built by independent health sciences librarians from National Jewish Health Denver, Colorado. For recommendations in the category of good practice statements that should not be graded, we followed published principles by the GRADE working group on how to identify such recommendations and use appropriate wording choices .
If cohorting is required, it is recommended to cohort patients infected or colonized with the same organism s —that is, do not cohort patients with CDI who are discordant for other multidrug-resistant organisms such as methicillin-resistant Staphylococcus aureus or vancomycin-resistant Enterococcus strong recommendation, moderate quality of evidence. TC, although not standardized, has been one of the reference methods against which other methods are compared. Separate, nondiscrete evidence libraries were created for adults and pediatrics. This likely reflects colonization pressure in the admitted patient population, and is an independent predictor in each of the NHSN risk adjustment models except for inpatient rehabilitation facilities . Diverting loop ileostomy with colonic lavage followed by antegrade vancomycin flushes is an alternative approach that may lead to improved outcomes weak recommendation, low quality of evidence. Recommendation Use a stool toxin test as part of a multistep algorithm ie, glutamate dehydrogenase [GDH] plus toxin; GDH plus toxin, arbitrated by NAAT; or NAAT plus toxin rather than a NAAT alone for all specimens received in the clinical laboratory when there are no preagreed institutional criteria for patient stool submission Figure 2 weak recommendation, low quality of evidence.
Once an organism is identified, a toxin test must be performed on the isolate to confirm its toxigenic potential. In guidelines endorsed by the American College of Gastroenterology ACG , authors have proposed a new stratification for severity of CDI cases that classify cases into mild-to-moderate, severe, and severe and complicated. Order- Clostridiales Members of the Clostridia class belong to one of three orders—Clostridiales, Halanaerobiales and Thermoanerobacteriales. There was also a high degree of genetic relatedness between isolates found in humans and pigs, an association also noted in the United States . In addition, measures should be considered for tracking severe outcomes, such as colectomy, intensive care unit ICU admission, or death, attributable to CDI.
Glutamate dehydrogenase immunoassays detect the highly conserved metabolic enzyme common antigen present in high levels in all isolates of C. The daily increase in the risk of C. Are there asymptomatic patients in whom repeat testing should be allowed, including test of cure? What is the role of manual, terminal disinfection using a C.
If surgical management is necessary for severely ill patients, perform subtotal colectomy with preservation of the rectum strong recommendation, moderate quality of evidence. Once an organism is identified, a toxin test must be performed on the isolate to confirm its toxigenic potential. Incorporate measures of cleaning effectiveness to ensure quality of environmental cleaning good practice recommendation. Box 1 Scoring systems for C.
Demographic and clinical characteristics of CDI cases were extracted from medical chart reviews performed by two physician researchers. Antibiotic therapy for CDI should be started empirically for situations where a substantial delay in laboratory confirmation is expected, or for fulminant CDI described in section XXX weak recommendation, low quality of evidence.
There have also been outbreaks in which particular high-risk fomites, such as electronic rectal thermometers or inadequately cleaned commodes or bedpans, were shared between patients and were found to contribute to transmission . The guideline used a search cutoff of and thus for this guideline, the literature review included a defined search period of — As laboratories abandoned their viral cell culture facilities in favor of antigen and molecular tests, CCNA became less popular. In addition, laboratories may wish to collaborate with available quality improvement teams such as infection prevention and control and antibiotic stewardship, to assess appropriateness of testing in the population from which samples are submitted.