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      Significance of Clostridium difficile in community-acquired diarrhea in a tertiary care center in Lebanon

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          Abstract

          Clostridium difficile infection (CDI) is becoming a cause of community-acquired diarrhea. The aim is to describe (CDI) as a cause of acute diarrhea in patients presenting from the community to the Emergency Department (ED) of a tertiary care center in Lebanon. A retrospective study conducted in the ED at the American University of Beirut Medical Center (AUBMC). Adult patients presenting with the chief complaint of diarrhea and having positive CDI by stool laboratory testing (toxins A and B), during a three-year period were included. 125 patients with CDI were included. Average age was 61.43 (±20.42) with roughly equal sex prevalence. 30% (n = 36) of patients had neither antibiotic exposure nor recent hospitalization prior to current CDI. Mortality was 9.6% (n = 12), CDI was attributed as the cause in 16.7% (n = 2) and a contributing factor in 41.6% (n = 5). Recurrence within 3 months occurred in 9.6% (n = 11) in mainly those taking Proton Pump Inhibitors (PPIs) and having multiple co-morbidities. There is a high rate of community acquired CDI in Lebanon. Review of patients’ medications (PPIs and antibiotics) is crucial. More studies are needed to assess mortality associated with CDI and the outcome of coinfection with other enteric pathogens.

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          Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA)

          A panel of experts was convened by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) to update the 2010 clinical practice guideline on Clostridium difficile infection (CDI) in adults. The update, which has incorporated recommendations for children (following the adult recommendations for epidemiology, diagnosis, and treatment), includes significant changes in the management of this infection and reflects the evolving controversy over best methods for diagnosis. Clostridium difficile remains the most important cause of healthcare-associated diarrhea and has become the most commonly identified cause of healthcare-associated infection in adults in the United States. Moreover, C. difficile has established itself as an important community pathogen. Although the prevalence of the epidemic and virulent ribotype 027 strain has declined markedly along with overall CDI rates in parts of Europe, it remains one of the most commonly identified strains in the United States where it causes a sizable minority of CDIs, especially healthcare-associated CDIs. This guideline updates recommendations regarding epidemiology, diagnosis, treatment, infection prevention, and environmental management.
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            Community-acquired Clostridium difficile infection: an increasing public health threat

            Introduction Clostridium difficile is the major cause of infectious diarrhea in hospitalized patients1 and the primary infectious cause of pseudomembranous colitis.2 Recent studies have shown increasing incidence, severity, and recurrence rates of C. difficile infection (CDI).3–9 It has recently surpassed methicillin-resistant Staphylococcus aureus as the most common hospital-acquired infection in the USA.10,11 However, in contrast with prior epidemiological studies, CDI is now being increasingly recognized as a cause of diarrhea in the community, especially in younger individuals and in populations lacking the traditional risk factors for CDI, such as hospitalization and antibiotic exposure.3,4,12–14 This review focuses on the epidemiology, increasing importance, novel risk factors, and outcomes for community-acquired CDI. Epidemiology of community-acquired CDI In 2007, the Infectious Diseases Society of America proposed guidelines for the classification of CDI to overcome the issue of multiple surveillance definitions.15 CDI is defined as: community-acquired if symptom onset occurs in the community or within 48 hours of admission to a hospital, after no hospitalization in the past 12 weeks; hospital-acquired if onset of symptoms occurs more than 48 hours after admission to or less than 4 weeks after discharge from a health care facility; or indeterminate if symptom onset occurs in the community between 4 and 12 weeks after discharge from a hospital.15,16 A study from the Cleveland Clinic (Cleveland, OH, USA) compared two different definitions of community-acquired CDI and showed concordance in only 71% of cases.17 Using different definitions, the percentage of community-acquired CDI varied from 10% to 37% of the total cases in another study.18 These studies have highlighted the need to use a standard definition to distinguish between hospital-acquired CDI and community-acquired CDI. The incidence of CDI was relatively stable until the mid-to-late 1990s, after which its epidemiology changed dramatically. Since 2000, there have been several reports of an increase in the incidence and severity of CDI,5,7,11,19–23 with CDI being increasingly recognized in the community.3,13,24–28 Community-acquired CDI was likely previously underdiagnosed owing to a lack of awareness of CDI outside the hospital setting. Data from North America and Europe suggest that 20%–27% of all CDI cases are community-associated, with an incidence of 20–30 per 100,000 population.3,13,29,30 In a population-based US study, 41% of the 385 definite CDI cases were community-acquired; the overall incidence of community-acquired and hospital-acquired CDI increased by 5.3-fold and 19.3-fold, respectively, over the study period.12 In both this and another study,31 patients with community-acquired infection were younger compared with those with hospital-acquired infection (median age 50 years versus 72 years), more likely to be female (76% versus 60%), had lower comorbidity scores, and were less likely to have severe infection (20% versus 31%).12 Traditional risk factors may be absent in community-acquired CDI Community-acquired CDI has been described in populations previously considered to be at low risk, including healthy peripartum women, children and young adults, antibiotic-naïve patients, and those with no recent health care exposure.3,13,32,33 Antibiotic exposure Exposure to antimicrobial agents is recognized as the most important risk factor for CDI.34 A recent study by Dial et al determined that as many as 45.7% of patients with CDI had no prior exposure to antibiotics in the 90-day period before the onset of CDI.35 In another case-control study, 52% of patients had no antibiotic exposure in the 4-week time period prior to CDI onset.13 A population-based cohort study from the Mayo Clinic, Rochester, MN, USA, showed that patients with community-acquired CDI were less likely to have been exposed to antibiotics when compared with those having hospital-acquired CDI (78% versus 94%).12 A case-control study demonstrated that, although patients with community-acquired CDI were more likely to have had antibiotic exposure compared with healthy controls, 27% of cases did not receive antibiotics in the 6 months prior to infection.36 A recent large epidemiological study using active surveillance showed that more than a third of patients with community-acquired CDI did not receive antibiotics in the 12 weeks prior to infection.37 These results indicate that although antimicrobial use remains a risk factor for CDI in the community, it may not be as important for hospital-acquired CDI. The risk of developing community-acquired CDI may also be affected by the antimicrobial agent administered, with two recent meta-analyses indicating that exposure to clindamycin, fluoroquinolones, and beta lactams/beta lactamase inhibitors conferred much greater risk of community-acquired CDI compared with macrolides, sulfonamides, and penicillins.38,39 Age Although increasing age is a well recognized risk factor for CDI, studies have consistently shown that case patients with community-acquired CDI were younger than those with hospital-acquired CDI.12,40 In a population-based study from Olmsted County, MN, USA, patients with community-acquired CDI were younger than those with hospital-acquired CDI (median age 50 years versus 72 years) and more likely to be female (76% versus 60%).12 A recent, large, population-based study with active surveillance for community-acquired CDI revealed a median patient age of 51 years.37 An epidemiological study from the UK showed that almost all community-acquired CDI cases occurred in patients younger than 65 years of age.41 In contrast, almost one third of patients with community-acquired CDI in another cohort were elderly (aged <65 years), similar to findings in another investigation where almost a half of patients with community-acquired CDI were elderly.31 These findings suggest that although patients with community-acquired CDI are younger than those with hospital-acquired CDI, community-acquired CDI occurs among all age groups in the community. There has been increasing evidence of community-acquired CDI affecting the pediatric population, traditionally thought to be at low risk for CDI, with a population-based cohort study from the Mayo Clinic, showing a striking increase in CDI in the pediatric population over the last 20 years, especially in the community setting and in infants,42 while other studies have reported an increase in pediatric CDI presenting to the outpatient setting43 and the emergency room.44 The role of asymptomatically colonized infants in the spread of community-acquired CDI is discussed below. Gastric acid suppression The role of gastric acid suppression in CDI remains controversial. There is conflicting evidence as to whether stomach acid kills C. difficile spores.45,46 Proton pump inhibitors (PPIs) may also affect the microbiota of the stomach and the large intestine.47 Recent data have suggested that circumventing the potentially protective effect of stomach acid, for example through the use of post-pyloric enteral feeding or the use of PPIs or histamine-2 receptor blockers, may lead to a two to three-fold increased risk of acquisition of CDI.25,48 Two recent meta-analyses concluded that PPI use is associated with 1.69–1.74 times the odds of CDI relative to no PPI use.49,50 Some other studies have shown that after controlling for important confounders, use of PPIs and histamine-2 receptor blockers was not associated with the risk of CDI,51 or adverse outcomes from CDI.52 Thus, it is not clear whether use of acid-suppressing drugs is an independent risk factor for CDI, although the US Food and Drug Administration has recently issued a warning that PPIs are associated with an increased risk of CDI. Hospital-acquired CDI and community-acquired CDI may differ in their relationship to PPI use owing to differences in circulating Clostridial strains and the differential antibiotic exposure in the two settings.53 There was a trend toward higher PPI use in antibiotic-naïve patients with community-acquired CDI when compared with patients with community-acquired CDI and antibiotic exposure.37 A retrospective review demonstrated a clinically relevant interaction between antibiotic and PPI use in hospitalized patients with CDI, with patients receiving a single antibiotic being more than five times more likely to be exposed to PPIs when compared to patients receiving five or more antibiotics.54 Comorbid conditions Additional potential risk factors for CDI that have been identified include a higher number of comorbid conditions, ie, chronic kidney disease, inflammatory bowel disease, immunodeficiency including human immunodeficiency virus (HIV) infection, hypoalbuminemia, malignant lesions, solid organ transplant, and use of chemotherapeutic agents.55–58 These patients are at increased risk of CDI not only due to their underlying disease, but also their frequent prolonged hospitalizations and broad-spectrum antimicrobial use. As care shifts closer to the home and these patients experience more outpatient health care, it will not be surprising if we observe increasing community-acquired CDI in these patient populations. Reduced microbial diversity in the gut is a common pathogenic pathway for inflammatory bowel disease and CDI.59 Patients with inflammatory bowel disease, especially those with colonic involvement, have long been known to have increased CDI rates and disproportionately higher morbidity and mortality compared with CDI patients without inflammatory bowel disease.55,57,60,61 Multiple reasons probably account for this, including older age, medications (immunosuppressives/antibiotics), and hospitalization. In retrospective population studies of both adults and children, patients with inflammatory bowel disease and CDI were younger and more often had acquired infections as outpatients compared with patients without inflammatory bowel disease and with CDI.60,62,63 Chronic kidney disease has been associated with increased risk of CDI in several studies,64,65 although some found increased risk only in patients undergoing dialysis.66 Concomitant acute kidney injury predicts a worse outcome in CDI,67 which is in line with the Infectious Diseases Society of America guidelines that the presence of acute kidney injury is a marker of CDI disease severity.16 Steroid initiation has been shown to increase CDI risk three times over other immunomodulator agents in patients with inflammatory bowel disease independent of dose and treatment duration,68 and steroid use has been shown to increase short-term mortality in hospitalized patients with CDI.69 High-dose corticosteroid use has also been associated with an increased risk of CDI relapse in solid organ transplant patients.70 Data on risk of CDI with other immunomodulatory medications is more controversial, with some studies failing to find an association68,71 and others showing increased risk.60,72 C. difficile has been recognized as the most common cause of bacterial diarrhea in HIV patients, although rates of CDI have reduced in the HIV population after initiation of antiretroviral therapy, so not mirroring the global trend of increased CDI burden.73 Several early studies have shown an increased risk of CDI in the transplant population, although infection did not seem to have a worse outcome in hematopoietic stem cell transplant patients, and most patients responded well to standard CDI therapy.74–77 No significant difference was found with regard to disease severity in solid organ transplant recipients and controls.70 A recent, nested, retrospective, case-control study demonstrated a high rate of CDI in hematopoietic stem cell transplant recipients, with prior chemotherapy, broad-spectrum antimicrobial use, and vancomycin-resistant enterococci colonization recognized as risk factors.78 Similar risk factors were observed in a retrospective study in kidney transplant recipients.79 The onset to CDI in autologous hematopoietic stem cell transplant recipients and kidney transplant recipients has been found to be less than a week.74,78,79 This supports the hypothesis that CDI is not always nosocomially acquired, even when it presents in the hospital setting, and patients may have been colonized earlier, even in the community setting. Sources and transmission of community-acquired CDI The primary means of transmission of CDI is believed to be from environment-to-person or person-to-person via the fecal-oral route. The organism is ingested either as the vegetative form or as spores (which survive for longer periods in the environment and are able to endure acidic stomach pH). Antimicrobial drugs alter the protective gut microbiome by decreasing bacterial diversity and create a favorable microenvironment for C. difficile to colonize and proliferate. Patients with diarrhea secondary to CDI shed spores into the environment and may be considered as a primary source of spreading infection.80 Infection control guidelines strongly recommend strict isolation of these patients when inpatients, in order to limit person-to-person transmission via health care personnel or the environment.81–83 Despite implementation of infection control practices, there is an increasing incidence of community-acquired CDI, which suggests alternate sources of infection and modes of transmission in the community. Assorted sources may be playing a role in C. difficile transmission alongside symptomatic patients. Using whole genome sequencing of more than 1,200 C. difficile isolates from the health care and community setting, a study based in Oxfordshire, UK, demonstrated that 45% of all isolates were genetically distinct from all previously tested isolates.84 The genetically diverse nature of these isolates suggests the existence of other important sources of infection apart from symptomatic patients. These possible novel factors are discussed below. Novel and established risk factors The factors responsible for the emergence of CDI in the community include increasing outpatient antibiotic prescriptions, greater use of acid-suppression medications, an increase in the proportion of asymptomatic carriers in the community leading to an increase in person-to-person transmission, novel risk factors like food and water contamination, and the epidemic C. difficile strain.3,85–87 Higher clinician awareness of CDI as a possible explanation of diarrhea in the community probably also contributes to the increased incidence via an increase in the number of stool tests for C. difficile performed in patients with diarrhea. Role of asymptomatic carriers Colonization of healthy nonhospitalized adults is uncommon, but colonization rates among hospitalized patients are much higher, ranging from 25% to 55%.88,89 In the context of a C. difficile infection outbreak in a long-term care facility, a study from Cleveland, OH, USA, found that more than half of asymptomatic residents were fecal carriers of toxigenic C. difficile strains, more than a third of which were epidemic North American pulse-field type 1 (NAP1) strains. Asymptomatic carriers outnumbered CDI patients seven to one during this study. Previous CDI and recent antibiotic use were found to predict asymptomatic carriage. Skin and environmental surface contamination in asymptomatic carriers was nearly as high as in CDI patients, and spores were also recovered from the study investigators’ hands. These findings suggest that asymptomatic carriers contribute significantly to CDI transmission in long-term care facilities, and may have a role in dissemination of C. difficile in the community as well.88 High rates of internally acquired C. difficile colonization and CDI have been reported inside long-term care facilities,90 and a recent study from Scotland showed increased CDI rates among care home residents older than 65 years of age when compared with controls residing at home.91 A case-control study identified close contact with infants under the age of 2 years as a potential risk factor for community-acquired CDI.13 A plausible role for infants and young children acting as reservoirs and vectors for C. difficile is supported by data showing that several toxigenic and nontoxigenic strains are carried by infants, although none were found to carry the hypervirulent 027 or 078 strains.92,93 Regular diaper changing of babies carrying C. difficile by mothers has been hypothesized to explain the female predilection of community-acquired CDI.94 Role of outpatient health care exposure Exposure to C. difficile in outpatient settings may provide a possible link in the chain between nosocomial CDI and community-acquired CDI. More than 80% of CDI patients discharged from hospital had an outpatient clinic visit within 12 weeks of discharge in one study,95 and CDI patients have been known to shed spores even after completion of therapy.96 Health care exposure in outpatient settings (physicians’ offices, emergency departments, dialysis facilities) is a potential risk factor for community-acquired CDI, with a recent large study showing that more than two thirds of patients with community-acquired CDI without inpatient hospital exposure had low-level exposure in the preceding 12 weeks.37 Role of food and animals Given the genetic diversity in C. difficile isolates, the isolation of C. difficile in food and animals, the similarities in strains isolated from animals and humans, and the absence of traditional risk factors in a large subset of patients with community-acquired CDI, there is mounting concern over food-borne and zoonotic spread of C. difficile in the community.97–99 A recent study showed that C. difficile spores survived the 71°C temperature recommended for cooking ground meats.100 C. difficile carriage has also been reported in many animal species, including cattle and pigs; these may be a potential reservoir for clinically relevant strains eventually causing CDI in humans.101–107 There have been several recent studies identifying C. difficile strains in retail meat products, including beef, chicken, and pork,102,108,109 and similarities between strains isolated from animal feed and those reported to cause CDI in humans.98,99,102,105 C. difficile ribotype 078 was originally identified as the predominant strain in swine and cattle, and is now increasingly identified in human CDI as causing severe disease and increased mortality, especially in the community setting.110 Animal and human strains of ribotype 078 are almost clonal, indicating that isolates had a common ancestry and porcine to human transmission is a possibility.98,111 These findings are also supported by the fact that ribotype 078 was the predominant type found in retail meat as well.109 However, in a recent study, the most common strain isolated was NAP1, while less than 7% of culture-positive isolates from community-acquired CDI patients were NAP7 or NAP8, which are the more common strains found in food and animals.37,108 There is currently no strong objective evidence to classify C. difficile as a food-borne or zoonotic illness. Laboratory contamination of meat samples and circulation of clonal C. difficile isolates among animals may contribute to the identical genotypes often seen, and strict discriminatory typing may be the only way to clarify this issue.112 Emergence of new strains A hypervirulent C. difficile strain belonging to a specific type (ribotype 27/protein profile NAP1) was identified in 2005 in several CDI outbreaks all over the world, including the USA.5,6,113–118 It is identified by polymerase chain reaction (PCR) as ribotype 27, by pulsed-field gel electrophoresis as NAP1 and by restriction-endonuclease analysis as group BI, leading to its nomenclature as BI/NAP1 or NAP1/027.6 It is also classified as toxinotype III by restriction fragment length polymorphism PCR of the toxin genes. The increased virulence of this strain may be related to the production of toxin early in infection and markedly increased toxin production (16–23 times more than other strains).9 Asymptomatic carriage of the hypervirulent strain has been linked to transmission in long-term care facilities.88 Although some regions are starting to see a decrease in the prevalence of this strain,119,120 it is likely that other epidemic strains of C. difficile may emerge. There has also been increased focus on PCR ribotype 078 in the past decade owing to its hypervirulence and clonal presence in pigs and humans. Community-associated disease was more common among ribotype 078-infected cases, and affected patients were younger when compared with those having the 027 strain.110 Recent reports have corroborated the fear that new strains are emerging with non-027 and non-078 “hypervirulent” strains causing severe infection in both the community and hospital settings.121,122 Newer nontypical strains now account for a majority of infections in the community setting.123 The molecular epidemiology of C. difficile is both diverse and dynamic,124 with some strains causing large clusters during certain periods and then becoming endemic. The genetic diversity of this organism likely contributes to it being able to establish infection and cause epidemics. Molecular typing of community-acquired CDI isolates Typing is an essential tool to identify and characterize C. difficile isolates. There are various methods currently adapted globally to type C. difficile isolates, including pulsed-field gel electrophoresis, PCR ribotyping, toxinotyping based on restriction fragment length polymorphism, restriction endonuclease analysis, multilocus variable-number tandem-repeat analysis, multilocus sequence typing, amplified fragment length polymorphism, and surface layer protein A gene sequence typing.125 Different methods are used across the globe, with PCR ribotyping and pulsed-field gel electrophoresis more frequently used in Europe and North America, respectively.126 A uniform worldwide method to type strains would be more ideal. Multilocus variable-number tandem-repeat analysis127 and whole genome sequencing128 both offer increased discrimination over other typing schemes, and have reported very similar findings despite the fact that they analyzed different parts of the bacterial genome.129 Specific C. difficile genotypes have been recognized to predict outcomes in CDI. Walker et al recently demonstrated that strain-specific inflammatory pathways may contribute to increased severity of illness in PCR ribotypes 027 and 078.130 Increased toxin production was primarily thought to be responsible for their “hypervirulent” behavior.9 However, no single factor can fully explain the increased virulence of C. difficile strains, and differences in toxins, sporulation, drug resistance, and cell surface proteins all play a role.131 Typing studies have demonstrated that community-acquired CDI strains have a diverse molecular epidemiology, with similarities to and differences from hospital-acquired CDI strains.26,40,132 Some studies indicate that ribotype 027 is associated with community-acquired CDI more than hospital-acquired CDI and others have reported that ribotype 027 accounts for more cases of hospital-acquired CDI,9,123,133 whereas a large surveillance study showed that similar percentages of community-acquired CDI and hospital-acquired CDI patients were infected with the NAP1 epidemic strain.40 NAP1/toxinotype (TOX) 3 and NAP1/TOX 5 were the most common types isolated from 89 community-acquired CDI samples in one study, whereas TOX 0 strains have historically been most common in nosocomial CDI.134,135 Similarities in strain distribution in the community and hospital settings indicate that C. difficile may move easily from either setting to the other and common reservoirs may exist. Long-term care facilities and outpatient facilities may both be important for transfer of isolates between inpatient health care facilities and the community. Reports have also shown the preponderance of several PCR ribotypes in community-acquired CDI not often seen in the hospital epidemic setting.123,136 This argues against the presence of a direct link between nosocomial outbreaks and community onset cases. These results indicate that community-acquired CDI isolates have extremely diverse genomes, and multiple transmission routes and sources for infection probably exist. Outcomes of community-acquired CDI Recent reports indicate a significant increase in severe cases, colectomies, and deaths related to CDI.20 Identifying patients who are at high risk for severe CDI early in the course of infection may direct therapy and help to improve outcomes. Severe disease in the hospital has been associated with increasing age, presence of the hypervirulent strain, elevated white cell count, hypoalbuminemia, and elevated creatinine.5–9,51,137–140 Although community-acquired CDI has generally been characterized as a mild illness, it can be associated with complications and poor outcomes, including hospitalization and severe CDI. In a study of patients with community-acquired CDI at the Mayo Clinic, 40% required hospitalization, 20% had severe infection, 4.4% had severe complicated infection, 20% had treatment failure, and 28% had recurrent CDI.141 Increasing age was a predictor of need for hospitalization, severe infection, severe complicated infection, and treatment failure, but not recurrence. Higher Charlson Comorbidity Index scores predicted the need for hospitalization and severe complicated infection, but not other outcomes. Patients who required hospitalization were older, had higher comorbidity scores, and had a higher incidence of severe infection than those who were treated in the community. The need for hospitalization has a tremendous impact on health care costs and patient outcomes. Hospitalization inadvertently exposes patients to other risks and avoidable complications, including venous thrombosis and other hospital-acquired infections. Therefore, patients with community-acquired CDI who are older or who have higher comorbidities, as well as those who meet the current definition of severe infection (based on white blood cell count or rising creatinine), should be monitored closely and managed more aggressively in the community to prevent poor outcomes. Conclusion The incidence of community-acquired CDI has increased significantly over the past decade. Utilizing only hospital data likely underestimates the burden of CDI. Community-acquired CDI accounts for a significant proportion of total CDI and is increasingly being recognized as an important health threat. Community-acquired CDI can affect younger patients lacking the traditional risk factors like antibiotic exposure, prior hospitalization, or age. The absence of these risk factors is not enough to exclude CDI, and testing for CDI must be considered in all patients with acute diarrhea. Environmental sources like food, water, animals, and pets may play an important role in these infections, apart from the role symptomatic patients and asymptomatic carriers play in spore dispersal. Prospective strain typing is a possible way to explore the suspected diverse sources of CDI in the community and the genetic diversity of this organism. However, strain typing is not widely available, and currently treatment recommendations do not differ according to C. difficile strain. Without belittling the inpatient infection control measures in place, we require additional studies to identify C. difficile sources in the community, and determine measures to control this infection outside the hospital. Patients with community-acquired CDI do not necessarily have a good outcome, with a large proportion requiring hospitalization. Given the additional risks and costs associated with hospitalization, clinicians should be aware of factors that predict a need for hospitalization in these patients, which might lead to more intensive therapy and monitoring.
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              Risk Factors for and Estimated Incidence of Community-associated Clostridium difficile Infection, North Carolina, USA1

              CME ACTIVITY MedscapeCME is pleased to provide online continuing medical education (CME) for this journal article, allowing clinicians the opportunity to earn CME credit. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of MedscapeCME and Emerging Infectious Diseases. MedscapeCME is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. MedscapeCME designates this educational activity for a maximum of 0.75 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test and/or complete the evaluation at http://www.medscape.com/cme/eid ; (4) view/print certificate. Learning Objectives Upon completion of this activity, participants will be able to: Specify the prevalence of community-acquired Clostridium difficile infection Describe demographic trends in community-acquired C. difficile infection Identify case characteristics of C. difficile infection List risk factors for community-acquired C. difficile infection EDITOR Nancy Mannikko, PhD, MS, BS, Copyeditor, Emerging Infectious Diseases. Disclosure: Nancy Mannikko, PhD, MS, BS, has disclosed no relevant financial relationships. CME AUTHOR Charles P. Vega, MD, Associate Professor, Residency Director, Department of Family Medicine, University of California, Irvine, California, USA. Disclosure: Charles P. Vega, MD, has disclosed no relevant financial relationships. AUTHORS Disclosures: Preeta K. Kutty, MD, MPH; Arlene C. Sena, MD, MPH; Stephen R. Benoit, MD, MPH; Susanna Naggie, MD; Joyce Frederick, MSN; Sharon Evans, RN; Jeffery Engel, MD; and L. Clifford McDonald, MD, have disclosed no relevant financial relationships. Christopher W. Woods, MD, MPH, has disclosed the following relevant financial relationships: served as an advisor or consultant for Cepheid Diagnostics, Roche Molecular, and bioMérieux; received grants for clinical research from Cepheid Diagnostics, Roche Molecular, bioMérieux, Cubist Pharmaceuticals, and Theravance Pharmaceuticals. Earning CME Credit To obtain credit, you should first read the journal article. After reading the article, you should be able to answer the following, related, multiple-choice questions. To complete the questions and earn continuing medical education (CME) credit, please go to http://www.medscape.com/cme/eid . Credit cannot be obtained for tests completed on paper, although you may use the worksheet below to keep a record of your answers. You must be a registered user on Medscape.com. If you are not registered on Medscape.com, please click on the New Users: Free Registration link on the left hand side of the website to register. Only one answer is correct for each question. Once you successfully answer all post-test questions you will be able to view and/or print your certificate. For questions regarding the content of this activity, contact the accredited provider, CME@medscape.net. For technical assistance, contact CME@webmd.net. American Medical Association’s Physician’s Recognition Award (AMA PRA) credits are accepted in the US as evidence of participation in CME activities. For further information on this award, please refer to http://www.ama-assn.org/ama/pub/category/2922.html. The AMA has determined that physicians not licensed in the US who participate in this CME activity are eligible for AMA PRA Category 1 Credits™. Through agreements that the AMA has made with agencies in some countries, AMA PRA credit is acceptable as evidence of participation in CME activities. If you are not licensed in the US and want to obtain an AMA PRA CME credit, please complete the questions online, print the certificate and present it to your national medical association. Article Title: Risk Factors and Estimated Incidence of Community-associated Clostridium difficile Infection, North Carolina, USA CME Questions What was the approximate percentage of all Clostridium difficile infections (CDIs) that were community associated in the current study? A. 2% B. 7% C. 20% D. 57% Which of the following demographic trends in community-associated (CA) CDI was present in the current study? A. Adults over the age of 64 years had the highest prevalence of CA-CDI B. Adults younger than 44 years had the highest prevalence of CA-CDI C. Physician visits had no impact on the prevalence of CA-CDI D. Women had a higher prevalence of CA-CDI compared with men Which of the following case characteristics of CDI in the current study is most accurate? A. Less than 10% of patients with CDI were admitted to the hospital B. Diarrhea was the most common complaint C. Nearly all patients had been exposed to antimicrobials in the 3 months prior to testing for CDI D. Clindamycin was the antibiotic most frequently implicated in promoting CDI All of the following variables were associated with a higher risk for CA-CDI in the current study, except: A. Recent treatment with antimicrobial drugs B. More outpatient visits at the VA hospital C. Treatment with proton-pump inhibitors D. Cardiac failure Activity Evaluation 1. The activity supported the learning objectives. Strongly Disagree Strongly Agree 1 2 3 4 5 2. The material was organized clearly for learning to occur. Strongly Disagree Strongly Agree 1 2 3 4 5 3. The content learned from this activity will impact my practice. Strongly Disagree Strongly Agree 1 2 3 4 5 4. The activity was presented objectively and free of commercial bias. Strongly Disagree Strongly Agree 1 2 3 4 5 Risk Factors and Estimated Incidence of Community-associated Clostridium difficile Infection, North Carolina, USA Clostridium difficile is an anaerobic spore-forming gram-positive bacillus that produces exotoxins that are pathogenic to humans. C. difficile is known to infect persons receiving antimicrobial drug therapy, older and severely ill patients who are hospitalized, or residents of long-term care facilities. C. difficile infection (CDI) is manifested as diarrhea, pseudomembranous colitis, and, occasionally, toxic megacolon or even death. Recent reports suggest an increasing incidence and severity of CDI ( 1 – 3 ) that may be related to the emergence of a hypervirulent strain ( 4 – 6 ). In addition, reports have been published of CDI emerging in persons previously thought to be at low risk, including otherwise healthy persons in the community ( 7 – 9 ). Community-associated or -acquired CDI (CA-CDI) was first reported in 1984 by Stergachis et al. ( 10 ) who found that the attack rate of CA antimicrobial drug–associated colitis requiring hospitalization was 1.4/100,000 population. In a review by Riley et al. ( 11 ) of 580 C. difficile toxin–positive stool samples submitted from patients with diarrhea and a clear history of recent ( 18 years of age with a nonformed (i.e., taking the shape of the container) stool specimen with positive test results for C. difficile toxin. If the case-patient had a previous C. difficile–positive stool test results within the 8 weeks preceding the collection date, he or she was excluded. All laboratories used the same toxin enzyme immunoassay (C. DIFFICILE TOX A/B II; TECHLAB, Blacksburg, VA, USA). CDI cases were further categorized according to when and where the stool specimen was collected, as community onset, CA, or inpatient healthcare exposure. We defined community onset as occurring 1) in an outpatient setting; 2) 1 overnight stay. We excluded CDI case-patients whose medical records appeared incomplete for determination of disease categorization; these case-patients were classified as unknowns. Community-onset CDI case-patients who were seen at Durham County hospitals but who resided outside the state were excluded because of frequent gaps in data necessary to determine the date of their last discharge from a healthcare facility and because their data could not contribute to the county population incidence. Among CA-CDI case-patients, ambulatory patients with a history of bone marrow transplant (BMT) or end-stage renal disease (ESRD) were excluded because of their intensive outpatient healthcare exposures. In addition, all prisoners were excluded. Although included in the incidence estimation, patients with inflammatory bowel disease and chronic diarrhea were excluded from the case–control study because they are recognized populations at increased risk for CDI and because their disease symptoms are difficult to differentiate from the symptoms of CDI ( 15 – 17 ). We interviewed a subset of case-patients to confirm and expand information available from medical records pertaining to previous inpatient healthcare exposures and medication histories. We also surveyed physicians in Durham County to assess perceptions regarding the frequency and severity of CDI in the community and to determine laboratories used for C. difficile diagnostic testing. This survey included physicians working in emergency departments and in family medicine, internal medicine, obstetrics and gynecology, infectious diseases, gastroenterology, and urgent care practices. We also contacted other academic institutions and laboratories in nearby counties to determine whether our case finding was comprehensive. VA Case–Control Study We conducted an unmatched 1:3 case–control study of VA CA-CDI case-patients using controls chosen from among VA outpatients randomly selected from VA outpatient clinics seen at the 4 facilities on 4 random dates distributed throughout 2005. Exclusion criteria for controls included a documented clinical diagnosis of diarrhea or a stool test result positive for C. difficile toxin in 2005, a history of inpatient healthcare exposure in the prior 8 weeks, or a history of ESRD. Similar data were collected for the controls as for case-patients, except for prior hospitalization within 8 weeks. We attempted phone interviews of all the VA CA-CDI case-patients, but not the controls, regarding their admission, symptoms, and medications. To overcome the limitation of recall bias, we reviewed electronic records after asking case-patients if they received their medications only from the VA (where electronic records were then reviewed) or whether they ever (also) obtained prescriptions from non-VA providers. All case-patient interviews were completed by the first quarter of 2006. Durham County Case–Control Study We conducted a case–control study at the 2 major hospitals serving Durham County residents. Controls were randomly selected from the county voter registration list; we made 3 attempts to reach residents by phone and elicit their participation. Exclusion criteria for controls included a history of inpatient healthcare exposure or diarrhea in the year 2005, ESRD, or BMT. We also performed phone interviews on a convenience sample of case-patients. All interviews were completed by December 2006. Data Analysis Data for the case characterization and case–control study were entered into Microsoft Office Access 2003 (Microsoft Corp., Redmond, WA, USA). Data checks were performed and double entries were removed. Incidence was estimated for the North Carolina VA hospital catchments by dividing the number of CA-CDI case-patients by all veterans registered for outpatient services at the 4 VA facilities in 2005 per 100,000 person-years. An estimate of the Durham County population-based rate was determined by dividing the number of CA-CDI case-patients from Durham County (including VA case-patients who resided in the county) by the 2005 adult (>18 years of age) population census per 100,000 person-years. Multivariable analysis was performed by using SAS version 9.1 (SAS Institute Inc., Cary, NC, USA) and stepwise logistic regression. Significant variables based on the univariate analysis (p 64 years of age combined (p 65 VA M 14.7 28.5† 15.9 20.8 Durham County M 11.0 56.6† 57.5 28.4 F 21.9 70.4 204.6 61.9‡ Overall 16.5 63.9 146.4 46.0 *VA, Veterans Affairs.
†p 65 y combined.
‡p 8 weeks prior to symptom onset; medians were 33 weeks (range 10–84) and 34 weeks (range 9–92), respectively. The remaining case-patients had no recorded history of previous hospitalization. Median time from symptom onset to testing was 1 week (range 1 day–9 weeks). Overall, 58% of case-patients in each population were admitted around the time of their CDI diagnosis, for a median duration of 1 week (maximum 3 and 5 weeks, Durham County and VA catchments, respectively). Diarrhea was the most common sign or symptom, followed by abdominal pain and vomiting. Among potential exposures, >50% of case-patients in each population had >1 outpatient visit in the 3 months before the test date. Overall, 53 case-patients (49%) did not have exposure to antimicrobial drugs in the 3 months prior to the test date. Among those who had recently received antimicrobial drug therapy, pencillins and quinolones were most commonly reported. Case-patient Interview We interviewed 22 VA and 31 county (non-VA hospital) resident CA-CDI case-patients. Only 2 (4%) of the 53 patients interviewed were reclassified as other than CA-CDI on the basis of interview findings: 1 had a history of CDI 2 months before the index episode, and 1 was newly identified as an ESRD patient. Of the remaining interviewees, 25 were able to provide information on whether they had been exposed to antimicrobial drugs. Of the 11 interviewees whose medical records suggested no exposure to antimicrobial drugs within the past 3 months, 5 (45%) reported taking antimicrobial drugs during this time. These included 3 from the VA who indicated that they received all their medications from the VA; however, their electronic medical records did not have documentation of recent antimicrobial drug prescriptions. Case–Control Study at VA Case-patients and controls were similar with regard to age, sex, and race (Table 2). Over the 3 months before CDI onset, exposure to antimicrobial drugs (OR 19.6, 95% CI 7.6–51, p 65 years is a risk factor for hospital-onset CDI ( 2 , 26 , 27 ). In comparison, the median age of the case-patients in this community appeared to be younger, 61 years in Durham County and 63 years in VA. In addition, the proportion and severity of fever, leukocytosis, and renal insufficiency for our case-patients were lower ( 26 , 28 , 29 ). No case-patients were admitted to the intensive care unit for CA-CDI, and none underwent colectomy. One case-patient in each population died within 10 days of diagnosis, and the death was attributable to CDI. Nonetheless, 15% had disease severe enough to require a visit to the emergency department, and another 59% required hospital admission for CDI management. Antimicrobial drug exposure has long been known as a risk factor for healthcare-associated CDI. However, among CA cases in our study, 49% were not exposed to antimicrobial drugs. This percentage was slightly higher than the recent findings from Philadelphia ( 13 ) and Connecticut ( 19 ), where 24% and 36%, respectively, were not exposed to antimicrobial drugs. In contrast, Dial et al. found the absence of antimicrobial drug exposure >90 days to range from 60% to 70% ( 30 ). However, their analysis was limited to a clinical research database in which some hospitalization and antimicrobial drug exposures may not have been included. Two prospective studies have recently been conducted in the community. Bauer et al. ( 31 ) found that 42% of CA-CDI case-patients had not been exposed to antimicrobial drugs during the prior 6 months, and Wilcox et al. ( 20 ) found that 84% case-patients had not received antimicrobial drugs during the month before C. difficile detection. One hypothesis to explain the absence of antimicrobial drug exposure is that there are unmeasured factors affecting the epidemiology of CDI. For example, remote antimicrobial drug exposure, or exposure to other medications with antimicrobial activity, may be increasing the risk of disease; alternatively, increased awareness of CDI may be leading to increased testing and documentation of C. difficile in patients not previously tested. Another possibility is that strains with new virulence properties (e.g., binary toxin) that enable disease in the absence of prior antimicrobial drug use have emerged. Despite antimicrobial drug exposure being absent in many patients, we found that this exposure remained the most important modifiable risk factor for CA-CDI. Additional risk factors included markers of chronic disease such as outpatient visits in the VA population and GERD and cardiac failure in the county population. In the VA population, frequent outpatient visits could reflect transmission in ambulatory care settings and could be a marker of a more severe underlying disease. Unlike other recent studies ( 9 ), we did not find proton pump inhibitors or H2 blockers were a major risk factor for CA-CDI. However, the finding of GERD as a risk factor suggests the possibility that undocumented use of over-the-counter proton pump inhibitors could have increased risk in these patients. Alternatively, there may be factors in the pathogenesis of GERD that increases the risk for CDI. Our study has several limitations. First, it is likely that there was incomplete case ascertainment, especially in those who underwent testing by outside laboratories so that, as high as these population incidence estimates are, they are likely underestimates of the true incidence. However the degree of underestimate is less likely in the VA system as there is financial incentive for patients to undergo testing within the system. The community physician survey conducted in Durham County indicated that there were 2 commercial laboratories other than Durham hospital laboratories used for testing. Although we were unable to determine the number of C. difficile tests performed at 1 laboratory, only 14 case-patients were identified from the other. It is also possible that patients received empiric therapy for CDI without a test being performed. However, the same survey of Durham County physicians indicated this was not a common practice. Some potential case-patients were categorized as unknowns when little or no medical records were available. We did not collect data on laboratory testing performed for any other enteric pathogens besides C. difficile nor did we perform cultures for C. difficile, and therefore no isolates were available. Instead, case confirmation was limited to toxin immunoassay testing using the C. DIFFICILE TOX A/B II TECHLAB test. In an independent review ( 32 ), the sensitivity of this test was 83.3% and the specificity was 98.7%. To address the concern of inadequate sensitivity in the toxin immunoassay and to avoid any misclassification bias in our case–control studies, we excluded controls who had diarrhea. Despite the high specificity of this test, there are valid concerns that if a low-prevalence population, such as relatively asymptomatic persons without prior antimicrobial drug exposures, is tested, the likelihood of a false-positive result may be unacceptably high. Although this is an insurmountable obstacle to a retrospective analysis of current clinical testing practice for CDI, the fact that all study laboratories had rejection criteria to prevent testing formed stool, near uniform medical record documentation of diarrhea (i.e., patients with documented absence of diarrhea were excluded), and a median duration of diarrhea symptoms of 1 week suggests a reasonable pretest likelihood of CDI among these patients. Another limitation was that few interviews were performed with case-patients. However, the adequacy of records indicating exposure to inpatient healthcare or antimicrobial drugs was verified among 53 case-patients who were interviewed by telephone. Only 1 case-patient was reclassified on the basis of an undocumented healthcare exposure, which was discovered during the interview process. Five of the 11 case-patients for whom antimicrobial drug exposure was not identified in their available medical records reported antimicrobial drug use. However, 3 of these were VA case-patients for whom medical records did not document such use, which suggests that some patients may have been mistaken about their antimicrobial drug exposure. Another limitation is that our use of outpatient controls for the VA case–control study may have resulted in bias toward the null with regard to outpatient healthcare-related risk factors. Although we attempted to contact >400 candidate controls from the voter registration list for the Durham County case–control study, we encountered difficulty in reaching persons by phone and eliciting their participation. This resulted in only 48 controls being available and limited the power of this analysis. In summary, CA-CDI is a relatively common clinical diagnosis. Although we did not determine the incidence in children, we found that CA-CDI in Durham County has a spectrum of disease that involves predominantly middle and older-aged women with underlying illness. As previously documented in other recent studies, this disease may, and commonly does, occur in patients without recent antimicrobial drug exposure. Nonetheless, antimicrobial drug exposure use remains the most important modifiable risk factor, suggesting prudent antimicrobial use remains a prominent public health prevention strategy. Further research into the incidence, sources, and risk factors for CA-CDI should be an ongoing public health priority. Supplementary Material Appendix Table Characteristics of case-patieints with community-associated Clostridium difficile infection, North Carolina, USA, 2005
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                Contributors
                ab00@aub.edu.lb
                melsayed@aub.edu.lb
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                30 March 2020
                30 March 2020
                2020
                : 10
                : 5678
                Affiliations
                [1 ]ISNI 0000 0004 0581 3406, GRID grid.411654.3, Department of Emergency Medicine, , American University of Beirut Medical Center, ; Beirut, Lebanon
                [2 ]ISNI 0000 0004 0581 3406, GRID grid.411654.3, Department of Internal Medicine, Division of Infectious Diseases, , American University of Beirut Medical Center, ; Beirut, Lebanon
                [3 ]ISNI 0000 0004 0581 3406, GRID grid.411654.3, Emergency Medical Services and Pre-hospital Care Program, , American University of Beirut Medical Center, ; Beirut, Lebanon
                Author information
                http://orcid.org/0000-0003-2031-8465
                http://orcid.org/0000-0001-9679-1131
                Article
                62418
                10.1038/s41598-020-62418-9
                7105455
                32231237
                1122038e-7b3e-42a7-8b6a-9c8578961364
                © The Author(s) 2020

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                : 2 October 2019
                : 11 March 2020
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                gastroenteritis,clostridium difficile
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