Clostridium difficile - PDF Free Download

Clostridium difficile Alex Aspinall MD, PhD, FRCPC Clinical Assistant Professor, University of Calgary Division of Gastroenterology and Hepatology, South Health Campus www.seacourses.com 1

Learning Points C. difficile is the leading cause of antibiotic associated diarrhea Fecal-oral transmission (spores) Disruption of the normal intestinal flora (antimicrobials) allows colonization Production of exotoxins that bind to intestinal epithelium Inflammation Diarrhea www.seacourses.com 2

Learning Points Patients can: Be asymptomatic carriers Have infection with colitis (CDAC) Have fulminant colitis/ileus/toxic megacolon Therapy Stop predisposing antibiotics ASAP Mild Disease: Metronidazole 500mg po tid Severe Disease: Vancomycin 125mg po qid ( to 500mg qid if no response) Infection Control Wash hands with soap and water Spores are alcohol resistant www.seacourses.com 3

Introduction Therapy of Recurrence: First: same therapy as before Second: tapering course of Vancomycin Consider Fidaxomicin 200 mg po bid for 10 days Subsequent: Fecal transplant Vancomycin 125 mg po qid for 7-14 days 125 mg po tid for 7 days 125 mg po od for 7 days 125 mg po eod for 7 days 125 mg po q3 days for 14 days www.seacourses.com 4

Epidemiology USA, 2011 ~453,000 cases 83,000 first recurrences 29,300 patients died Risk Factors Women>Men White>non-White Age 65 159,700 Community Acquired 293,000 Healthcare Associated Lessa FC et al. N Engl J Med 2015;372:825-834 www.seacourses.com 5

Adjusted U.S. National Estimates of Burden and Incidence of CDI, 2011. Lessa FC et al. N Engl J Med 2015;372:825-834 www.seacourses.com 6

Adjusted U.S. National Estimates of Recurrences and Deaths Associated with CDI, According to Epidemiologic Category, 2011. Lessa FC et al. N Engl J Med 2015;372:825-834 www.seacourses.com 7

Epidemiology 1989 1992 J strain highly resistant to clindamycin Implicated in large outbreaks of diarrhea in four hospitals in the United States 2003 2006 New strain BI, NAP1, or ribotype 027 More frequent, severe, refractory to standard therapy, and likely to relapse than previously described Increased endotoxin production Fluoroquinolone use has strongly correlated with the emergence Johnson et al. N Engl J Med 1999; 341:1645 Bartlett, Ann Intern Med 2006; 145:758 He et al, Nat Genet 2013; 45:109 www.seacourses.com 8

Transmission Patients who carry C. difficile reservoir for environmental contamination presence or absence of clinical infection C difficile is highly transmissible Fecal oral route by ingestion of spores Dramatic increases in the incidence and severity of healthcare associated C. difficile infection have occurred since 2000, particularly in patients over age 65 Readily cultured from the hospital environment Items in patient rooms Hands, clothing, stethoscopes of healthcare workers Infection is also transmitted readily between hospital roommates Receipt of antibiotics by prior bed occupants associated with increased risk for C. difficile infection in subsequent patients www.seacourses.com 9

Nosocomial Infections C. difficile carriers 20-50% of adults in hospitals and longterm care facilities carrier rate among healthy adults is about 3% ~20% of patients with negative admission stool cultures become infected during hospitalization Although asymptomatic, these individuals are capable of shedding spores of C. difficile serve as a reservoir for environmental contamination to other hospitalized patients New exposure and colonization more likely to lead to CDAD Patients previously colonized more likely to remain asymptomatic during their hospitalization McFarland et al. N Engl J Med 1989; 320:204 Zacharioudakis et al, Am J Gastroenterol 2015; 110:381 Riggs et al, Clin Infect Dis 2007; 45:992 www.seacourses.com 10

Community-Acquired Infections On the rise Minnesota county (1991-2005) incidence of both communityacquired and hospital-acquired infection increased dramatically 385 cases, 41 percent were community acquired Patients with community-acquired younger (median age 50 versus 72) Healthier female > male (76 vs 60%) Less likely to have antibiotic exposure (78 vs 94%) acid suppressants (22 vs 47%) to have cancer (17 vs 32%) to have severe infection (20 vs 31%) Risk for recurrence did not differ between the two groups (28 vs 30%) www.seacourses.com 11

Risk Factors Antibiotic use most widely recognized modifiable risk factor for CDAD Other RF Hospitalization advanced age severe illness gastric acid suppression enteral feeding gastrointestinal surgery Obesity cancer chemotherapy hematopoietic stem cell transplantation For recurrent C. difficile infection include age 75 years 10 unformed stools per 24 hour period, serum creatinine 1.2 mg/dl For Complications perforation, toxic megacolon, colectomy, admission to intensive care unit, death Older age ( 80 years) abnormal blood tests white blood cell count <4 or 20 albumin <25 g/l blood urea nitrogen >7 mmol/l CRP 150 mg/l abnormal vital signs heart rate >90/minute, respiratory rate >20/minute www.seacourses.com 12

Antibiotics and CDAC Frequently associated Occasionally associated Rarely associated Fluoroquinolones Macrolides Aminoglycosides Clindamycin Cephalosporins (broad spectrum) Penicillins Trimethoprimsulfamethoxazole Tetracyclines Metronidazole Vancomycin www.seacourses.com 13

Pathophysiology C. difficile diarrhea genes for toxin A (tcda) and toxin B (tcdb) inactivate members of the Rho family of guanosine triphosphatases (Rho GTPases) leading to colonocyte death, loss of intestinal barrier function, and neutrophilic colitis Serum antitoxin antibodies are the best described host factor protecting against C. difficile pathogenesis Recurrent CDI recurrence following initial infection not fully understood persistent spores from the initial infection C. difficile spores in colonic diverticula may escape mechanical clearance by peristalsis Antibiotic resistance does not appear to be a factor in recurrence www.seacourses.com 14

Clinical Manifestations Watery diarrhea is the cardinal symptom of C. difficile associated diarrhea 3 loose stools in 24 hours Lower abdominal pain and cramping Low grade fever, nausea, anorexia, and leukocytosis Diarrhea may be associated with mucus or occult blood Melena or hematochezia are rare Fever in 15% of cases Temperature >38.5 C is a sign of severe CDAD. Leukocytosis, elevated creatinine, and elevated lactate in the setting of CDAD are common; CDAD is routinely associated with an average white blood cell count of 15,000/microL www.seacourses.com 15

Symptoms Symptoms of CDI antibiotic therapy During antibiotic therapy 5 to 10 days following antibiotic therapy Rarely, 10 weeks after cessation of antibiotic Unexplained leukocytosis in hospitalized patients even in the absence of diarrhea positive stool C. difficile toxin was observed in 58% of cases (vs 12% in controls) When unexplained leukocytosis is due to CDI, diarrhea typically develops one to two days later. www.seacourses.com 16

Clinical Manifestations Type of infection Diarrhea Other symptoms Diarrhea with colitis Fulminant colitis Asymptomatic carriage Multiple loose bowel movements per day Occult bleeding may be seen Hematochezia rare Diarrhea may be severe OR diminished (due to paralytic ileus and colonic dilatation) Surgical consult required; colectomy can be life saving Nausea, anorexia, fever, malaise, dehydration, leukocytosis with left shift Lethargy, fever, tachycardia, abdominal pain; dilated colon/paralytic ileus may be demonstrated on plain abdominal film Physical examination Abdominal distention, tenderness May present as acute abdomen; peritoneal signs suggest perforation Absent Absent Normal Normal Sigmoidoscopic examination Diffuse or patchy nonspecific colitis Sigmoidoscopy and colonoscopy contraindicated; flexible proctoscopy with minimal air insufflation may be diagnostic www.seacourses.com 17

Fulminant Colitis Clinical manifestations diarrhea lower quadrant/diffuse abdominal pain abdominal distention fever hypovolemia lactic acidosis hypoalbuminemia elevated creatinine marked leukocytosis ( 40,000 white blood cells/µl) www.seacourses.com 18

Recurrent Disease Recurrent C. difficile complete abatement of CDI symptoms while on appropriate therapy subsequent reappearance of symptoms after treatment has been stopped 25 percent of patients experience recurrent C. difficile within 30 days of treatment Less commonly, recurrent CDI can occur as late as two to three months after discontinuation of treatment Once patients have experienced one recurrence, they are at significantly increased risk for further recurrences www.seacourses.com 19

Unusual Presentations Protein losing enteropathy Hypoalbuminemia in the absence of fulminant colitis Inflammation of the bowel leakage of albumin into the lumenserum albumin levels may drop below 20 g/l Ascites and peripheral edema may be observed The protein losing enteropathy responds to appropriate medical therapy of the infection Extracolonic involvement Appendicitis Small bowel involvement - older adults and/or patients with multiple comorbidities prior colectomy with ileostomy manifestations may include increased ileostomy output pseudomembranes Increased risk for fulminant disease with a high mortality rate Rare cases of cellulitis, soft tissue infection, bacteremia, and reactive arthritis www.seacourses.com 20

Diagnosis Clinically significant diarrhea or ileus relevant risk factors (including recent antibiotic use, hospitalization, and advanced age) positive laboratory stool test for C. difficile toxins or C. difficile toxin gene Pseudomembranous colitis highly suggestive of C. difficile infection and should prompt laboratory testing www.seacourses.com 21

Who Should be Tested? Only in patients with clinically significant diarrhea testing cannot distinguish between CDAD and asymptomatic carriers (who do not warrant treatment). For patients with ileus, laboratory diagnosis via perirectal swab for toxin assay or anaerobic culture may be performed www.seacourses.com 22

A Word on When to Test There is no role for repeat laboratory testing or testing for cure There is no role for laboratory testing in asymptomatic patients There is no role for repeat testing in patients receiving treatment for acute C. difficile infection Repeat stool assays are NOT warranted during or following treatment in patients who are recovering or are symptom free 50%of patients have positive stool assays for as long as six weeks after the completion of therapy Stool assays may remain positive during or after clinical recovery www.seacourses.com 23

Endoscopy Lower gastrointestinal endoscopy is not warranted in patients with classic clinical manifestations of C. difficile infection, a positive laboratory test, and/or clinical response to empiric treatment circumstances in which an alternative diagnosis is suspected that requires direct visualization and/or biopsy of the bowel mucosa. It may also be helpful for patients with ileus or fulminant colitis in the absence of diarrhea since it may allow visualization of pseudomembranes not all patients with CDAD have pseudomembranes, particularly patients with mild or partially treated infection www.seacourses.com 24

Differential Diagnoses C. difficile must be distinguished from other infectious and noninfectious causes of diarrhea. Most antibiotic-associated diarrhea is not attributable to C. difficile infection (but rather to osmotic mechanisms), whereas antibiotic-associated diarrhea associated with colitis is nearly always C. difficile associated diarrhea (CDAD) www.seacourses.com 25

Osmotic vs C. difficile Diarrhea www.seacourses.com 26

Other Infectious Diarrhea Staphylococcus aureus Klebsiella oxytoca Clostridium perfringens Possibly Candida albicans Salmonella can present as a pseudomembranous colitis (severe inflammation of the inner lining of the bowel) www.seacourses.com 27

Other Non-infectious Diarrhea Mimics of C. difficile infection: Post-infectious irritable bowel syndrome Inflammatory bowel disease Celiac disease Collagenous colitis. Differentiation of noninfectious antibiotic associated diarrhea from C. difficile infection may be difficult Especially in patients who are asymptomatic C. difficile carriers Most relevant among patients in nursing homes or hospitals where the rate of asymptomatic carriage is 10 to 50 percent in community populations, the rate of asymptomatic carriage is 5 percent Cessation of symptoms with discontinuation of oral intake is a distinguishing feature of osmotic diarrhea www.seacourses.com 28

Post-infectious Irritable Bowel Syndrome Post-infectious irritable bowel syndrome occurs in about 10 percent of patients who have been successfully treated for an initial episode of C. difficile these patients may have up to 10 watery stools per day this must be distinguished from a relapse of the original C. difficile infection www.seacourses.com 29

Association with Inflammatory Bowel Disease Infection with C. difficile may complicate the course of inflammatory bowel disease Enteric infections account for about 10% of symptomatic relapses in patients with IBD C. difficile accounts for about half of these infections www.seacourses.com 30

Treatment Indications for treatment Patients with typical manifestations of C. difficile infection (eg, diarrhea, abdominal pain, or nausea and vomiting) and a positive diagnostic assay should receive antibiotics for treatment for C. difficile infection Empiric therapy is appropriate pending results of diagnostic testing if the clinical suspicion is high Treatment of C. difficile infection is not indicated in patients who have a positive toxin assay but are asymptomatic www.seacourses.com 31

Treatment Stop precipitating antibiotics ASAP Infection Control Use Soap and Water to wash hands C. difficile spores are resistant to alcohol www.seacourses.com 32

Treatment Initial episode Mild disease: metronidazole 500 mg orally three times daily or 250 mg four times daily for 10 to 14 days Severe disease: vancomycin 125 mg orally four times daily for 10 to 14 days First relapse Confirm diagnosis If symptoms are mild, conservative management may be appropriate If antibiotics are needed, repeat treatment as in initial episode above. Alternative: fidaxomicin 200 mg orally twice daily for 10 days. www.seacourses.com 33

Treatment Second relapse Confirm diagnosis Tapering and pulsed oral vancomycin (below), with or without probiotics (for example, Saccharomyces boulardii 500 mg orally twice daily). The probiotics may be overlapped with the final week of the taper and continued for two additional weeks in the absence of antibiotics. 125 mg orally four times daily for 7 to 14 days 125 mg orally twice daily for 7 days 125 mg orally once daily for 7 days 125 mg orally every other day for 7 days 125 mg orally every 3 days for 14 days Alternative: fidaxomicin 200 mg orally twice daily for 10 days www.seacourses.com 34

Treatment Subsequent relapse Confirm diagnosis Fidaxomicin 200 mg orally twice daily for 10 days if not used previously Fecal bacteriotherapy (fecal microbiota transplant) www.seacourses.com 35

Severe Disease Initial Treatment Oral vancomycin (125 mg four times daily) (consider an increase to 500mg four times daily if not improving) If ileus, ADD metronidazole 500 mg iv every eight hours If not improving, consider fidaxomicin 200 mg orally twice daily Consider Surgery Toxic megacolon, Ileus, Peritoneal signs Immunocompetent, age 65 years, WBC 20,000/ µl, plasma lactate 2.2-4.9 meq/l www.seacourses.com 36

What about Probiotics? Probiotics are live, nonpathogenic bacteria capable of colonizing the colonic mucosa The alteration of gut microflora in the setting of CDAD has raised interest in a potential role for use of probiotics to restore a diverse intestinal microflora after disruption by antimicrobial therapy and CDAD Johnston, Ann Intern Med 2012; 157:878 www.seacourses.com 37

Probiotics and CDAD Prevention In patients receiving antibiotics who are at increased risk for CDAD, coadministration might decrease the chance of developing CDAD Meta-analysis including 20 randomized trials and 3818 patients, probiotics reduced the incidence of CDAD by 66 percent Relative risk of 0.34 (95% CI 0.240.49) Large RCT 2941 older adults with antibiotic exposure Probiotics multistrain preparation of Lactobacillus acidophilus and Bifidobacterium bifidum No risk reduction for CDAD (RR 0.71; 95% CI 0.341.47) Another large RCT 2444 hospitalized patients Stopped early for futility Johnston, Ann Intern Med 2012; 157:878 Allen, Lancet 2013; 382:1249 Erhardt, Open Forum Infect Dis 2016; 3 www.seacourses.com 38

Probiotics and CDAD Treatment Two meta-analyses Treatment of antibiotic-associated diarrhea Suggested a possible benefit of probiotics for treatment of CDAD Routine use not usually recommended Patients with recurrent disease that is not severe No significant comorbidities Hempel, JAMA 2012; 307:1959 Ritchie, PLoS One 2012; 7 www.seacourses.com 39

Probiotics Regimens Publication date Probiotic regimen studied Study population Study findings Similar (commercially available) product* Studies in adults Beausoleil et al (2007) L. acidophilus and L. casei (25 x 109 CFU/day for 2 days, then 50 x 109 CFU/day for duration of the antibiotic course) 89 adults (inpatients) Antibiotic associated diarrhea occurred in 16% of treated patients and 36% of patients in placebo group (OR 0.34; 95% CI 0.12 to 0.94; p = 0.05) BioK Hickson et al (2007) L. casei (19 x 109 CFU/day), L. bulgaris (1.9 x 109 CFU/day), and S. thermophiles (19 x 109 CFU/day) within 48 hours of starting antibiotic therapy until 7 days after discontinuation 135 adults (inpatients) Antibiotic associated diarrhea occurred in 12% of treated patients and 34% of patients in placebo group (p = 0.007; arr 0.17 [0.07 0.27]). Actimel (also known as Danactive in United States and Canada) www.seacourses.com 40

Probiotics and Risks A small number of case reports Bacteremia or fungemia attributed to probiotics Saccharomyces boulardii and Lactobacillus rhamnosus GG Severe comorbidities, immunosuppressive medication, recent surgical intervention, recent prolonged hospitalization www.seacourses.com 41

On the Horizon. www.seacourses.com 42

Decreased Recurrent C. difficile infection www.seacourses.com 43

Questions? www.seacourses.com 46