CLOSTRidium defficile lecture DR MOKHTAR.pptx

review about clostridium deficile and atypical presentation with unexplained leucocytosis

1. Clostridium defficile Emerging concepts Dr Abd elRahman A MoUkhtar Proffessor of internal medicine Mansoura university Sept- 2019

2. Why this topic

3. Your text here Asking the literature FEATURE Unexplained leukocytosis in a hospitalized patient Publish date: August 10, 2017 By Douglas S. Paauw , MD A 70-year-old man is evaluated for a persistent leukocytosis. He was hospitalized 10 days ago for a severe exacerbation of chronic obstructive pulmonary disease. He was intubated for 3 days, was diagnosed with a left lower lobe pneumonia, and was treated with antibiotics. His white blood cell count on admission was 20,000 per mcL . It dropped as low as 15,000 on day 6 but is now 25,000, with 23,000 polymorphonuclear leukocytes (10% band forms). He is on oral prednisone 15 mg once daily. Chest x-ray shows no infiltrate. Urinalysis without WBCs. What is the most likely cause of his leukocytosis? A) Pulmonary embolus. B) Lung abscess. C) Perinephric abscess. D) Prednisone. E) Clostridium

4. The most likely diagnosis in otherwise unexplained leukocytosis in a hospitalized patient is C.difficile . This isn’t an uncommon scenario, in which your hospitalized patient has a climbing WBC without a clear cause. Often, the patient may well be improving from the condition that they were originally hospitalized for, but the climbing WBC count is concerning and often delays discharge . What should we think of in the patient whose WBC climbs in the hospital, and the cause isn’t readily apparent? Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected] .

5. Almost 60% of the patients with unexplained leukocytosis (35 of 60) had a positive C. difficile toxin, compared with 12% of the controls ( P less than .001 ). More than half of the patients with a positive C. difficile test had the onset of leukocytosis prior to any symptoms of colitis . Leukocytosis responded to treatment with metronidazole in 83% of the patients with a positive C. difficile toxin, and 75% of the patients who had leukocytosis did not have a positive C. difficile toxin. Anna Wanahita , MD <http://www.stjohnhealthsystem.com/clinic/physician-search? drnumber =1993> , of the St. John Clinic in Tulsa, Okla., and her colleagues prospectively studied 60 patients admitted to their hospital who had unexplained leukocytosis. All patients had stool specimens sent for C. difficile toxin; in addition, 26 hospitalized control patients without leukocytosis also had stool sent for C. difficile toxin.

6. Another possibility in this case was WBC elevation because of the patient’s prednisone. Prednisone can increase WBC as early as the first day of therapy. The elevation and rapidity of increase are dose related. The important pearl is that steroid-induced leukocytosis involves an increase of polymorphonuclear white blood cells with a rise in monocytes and a decrease in eosinophils and lymphocytes .

7. Importantly , increased band forms (greater than 6%) and toxic granulation rarely ever occur with steroid-induced leukocytosis, and the presence of these features should strongly suggest a different cause. Pearl: Think of underlying C. difficile infection in your hospitalized patient with unexplained leukocytosis .

8. Can Clostridium DI present without Diarrhoea ?

9. Back to the literature

10. Challenging Case 73 yo female readmitted to the hospital with weakness and syncope 3 weeks after admission for a wound infection following femoral bypass surgery for which she was treated with levofloxacin and augmentin .  On admission: WBC –6,800 cells/mL then increased to 14,000 cells/mL, Creatinine –normal  CT of the C/A/P on admission showed colitis. However, she had no diarrhea, no abdominal cramping or abdominal pain.  Urine analysis showed pyuria so antibiotics were started for presumed UTI. Urine culture subsequently grew Enterococcus and her treatment was narrowed to Ampicillin/ sulbactam CRISTINA BAKER, MD, MPH INFECTIOUS DISEASE ( Sept 2019 ) PARK NICOLLET/HEALTH PARTNERS

11. Challenging Case Her condition initially was stable and then worsened 7 days into her hospitalization. She was transferred to the ICU with septic shock and need for intubation. Procalcitoninwas >100  Vancomycin and piperacillin / tazobactam were started.  A repeat CT scan of the A/P showed free air in the abdominal cavity. She was evaluated by surgery and it was felt that she would not survive surgical intervention. It became difficult to support her and she was transitioned to comfort cares.  Blood cultures results obtained after her death were positive for Clostridium difficile  TEACHING POINT: The absence of diarrhea does not exclude the diagnosis of CDI CRISTINA BAKER, MD, MPH INFECTIOUS DISEASE ( sept 2019) PARK NICOLLET/HEALTH PARTNERS

12. Back to our patient:

13. Back to Clostridium Defficili

14. Back to Clostridium Defficili What we know about CDI?

15. We know C. difficile ! Antibiotic-resistant, spore-forming, bacterium that colonizes the intestines Produces toxins in the gut that can lead to gastrointestinal illness

16. We KNOW the CD Toxins C . difficile releases two toxins –Toxin A and Toxin B. Toxin A causes inflammation, activates neutrophils and causes mucosal injury Toxin B is 10x more potent than toxin B BI/NAP1/027 strain produces binary toxin (an additional toxin) and more A and B (lacks a gene, tcdC , responsible for downregulation of toxin production)

17. We KNOW the classic presentation Patients may develop associated diseases such as: Pseudomembrane colitis Toxic megacolon Sepsis Perforation of colon

18. We Know Risk Factors! • Antimicrobial exposure • Acquisition of C. difficile • Advanced age • Underlying illness • Immunosupression • Tube feeds • ? Gastric acid suppression Main modifiable risk factors Clostridium difficile (CDI) Infections Toolkit Activity C: ELC Prevention Collaboratives Draft - 12/23/09 --- Disclaimer: The findings and conclusions in this presentation are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Carolyn Gould, MD MSCR , Cliff McDonald, MD, FACP Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention

19. We know who’s at risk! Elderly (80% of patients are over 65) Hospitalized and/or immunocompromised patients Patients undergoing gut surgery Patients undergoing repeated enemas

20. We know who’s at risk! Chronic kidney disease/ESRD (2-2.5x) Obesity Cancer chemotherapy (antimicrobial effect of chemotherapeutic agents) Stem cell transplant (9x) Solid organ transplant (5x) Inflammatory bowel disease Cirrhosis HIV Tube feeding Low vitamin D

21. We Know What makes C. difficile successful! Alcohol scrub gels do not kill C. diff spores Patients/residents with C. diff continue to shed the bacteria for a number of days after diarrhea stops C. diff can continue to live on surfaces for months to years

22. “BUT” do we KNOW how easily C. diff spread? Spores spread via the fecal-oral route and can survive for years outside of gut Common reservoirs for spores include toilets, washrooms, toothbrushes, mugs, utensils, and patient’s own contaminated hands Once ingested, spores pass through stomach and germinate in small intestine C. diff colonizes gut and may cause infection if space is “available” ex. lack of resident flora due to an antibiotic treatment

23. Do We Know about the carriage in the community C. difficile carriage 8-10% of adults in hospitals or long-term care facilities 3% in healthy adults  Newly exposed patients develop CDI much more frequently than colonized patients (4.5 vs 1.1%)  Persons who remain asymptomatically colonized over longer periods of time are at decreased risk for CDI, likely due to increased antibody levels against toxins A and B  Duration of hospitalization is proxy for duration and degree of exposure so longer hospitalization = increased risk of CDI McFarland LV et al. Nosocominalacquisition of Clostridium difficile infection. N EnglJ Med 1989;320:204 ZachariousdakisIM et al. Colonization with toxogenic C . difficile upon hospital admission and risk of infection: a systematic review and meta-analysis. Am J Gastroenterology 2015;110:381

24. “BUT” do we KNOW how easily C. diff Kills ? Infection reoccurs in about 20% of patients C. diff is linked to around 15,000 American deaths each year (2011)

25. Although C. difficile is not currently significantly resistant to antibiotics used to treat it, it was included in the threat assessment because of its unique relationship with resistance issues, antibiotic use, and its high morbidity and mortality. Do we know that the Centers for Disease Control in the states designate it as an urgent antibiotic resistance threat in 2015, 1 of only 3 pathogens to earn this attribute

26. “ Clostridium difficile is on the rise, and if you are not seeing an increase in your hospital, your hospital needs to evaluate its testing methods.” (Dr. B. Miller, 5 th Decennial International Conference on Healthcare Associated Infections, March 2010) Do we Know that

27. Better antibiotic prescription Better identification Better contact precautions Better Environmental Cleaning Better Communication What to Do

28. What is the New CDI Bundle

29. Do We Know what is the preferred test for Diagnosis? “Patients with unexplained and new-onset ≥3 unformed stools in 24 hours are the preferred target population for testing for CDI (weak recommendation, very low quality of evidence ).”

30. Further, the quality of the stool should be faithfully scrutinized prior to laboratory assessment; the stool should take the form of the container in which it is sent – in other words – Bristol Stool Type 6 and 7 .

31. If Institutional Criteria for Stool Submission Absent e.g . laboratories have no clinical data and accept all unformed stools for testing – then the guidelines recommend that both a sensitive and specific test be implemented [a ‘multi-step’ approach ]. The guidelines characterize the following as sensitive but less specific in an institution with relatively indiscriminant testing: - GDH [glutamate dehydrogenase] which is a highly-conserved enzyme present in high levels in all isolates of C. difficile – in both toxigenic and nontoxigenic strains . - NAATs [nucleic acid amplification tests] note that there at least a dozen of these tests of varying diagnostic accuracy directed against several genetic foci including the genes for toxin A and B; nevertheless, in the setting of relatively indiscriminant stool testing, the NAATs should be viewed as less specific, . To the above should be added the less sensitive, but more specific stool toxin A and B assays; these tests use monoclonal or polyclonal antibodies to detect C. difficile toxins – there are also numerous commercial assays available.

32. By contrast, if an institution appropriates prerequisite clinical criteria for stool testing [ideally , this avoids patients with a lower pre-test probability of CDI], then a NAAT alone , or a multi-step approach, as above, is preferable to a toxin test alone.

33. Management A key take away for CDI management in the 2018 guidelines is that metronidazole should only be used: 1. As an intravenous adjunct for fulminant CDI . 2. If there are absolute contraindications to vancomycin or fidaxomicin or 3. If vancomycin and fidaxomicin are not available. Thus, therapy for all CDI severities should now begin with oral vancomycin or fidaxomicin .

34. Back to Our patients

35. IBD patients Liver Cirrhosis patients

36. IBD patients Increasing rates of C difficile infection among hospitalized IBD patients compared with non-IBD gastrointestinal (GI) patients, and a representative sample of all hospital discharges. Published with permission from Elsevier Clinical Gastroenterology and Hepatology 2017;15:166–174

37. Differences in the pathogenesis of C difficile infection in patients with and without inflammatory bowel disease.

38. Atypical Features of C dif fi cile Infection Complicating In fl ammatory Bowel Disease May develop without antimicrobial use Younger age More often community-onset Lack typical colonoscopic features Simple colonization without infection also is more common Symptom presence or resolution is an unreliable marker Clinical Gastroenterology and Hepatology 2017;15:166–174

39. Adverse Outcomes of C dif fi cile Infection Complicating In fl ammatory Bowel Disease Subsequent IBD flares More likely to fail medical therapy More frequent need to escalate IBD therapy Higher surgery rates Higher mortality rate than for IBD alone More frequent CDI recurrences Increased emergency room visits Longer hospital stay Increased health care costs Clinical Gastroenterology and Hepatology 2017;15:166–174

40. The biggest challenge in the management of CDI in IBD remains distinguishing symptoms of an IBD flare from those of superimposed CDI.

41. A proposed management algorithm for CDI in patients with inflammatory bowel disease. *Severe-complicated CDI is defined by the intensive care unit admission, hypotension, temperature higher than 38.5C, ileus/ megacolon, mental status changes, leukocyte count greater than 35,000/mL or less than 2000/mL, or lactate level greater than 2.2 mmol/L.

42. Patients with cirrhosis may be at particular risk of developing CDI for three reasons : First, antibiotic use is common in cirrhosis patients. Prophylactic use of broad-spectrum quinolone or beta-lactam antibiotics is standard practice to prevent infections and reduce mortality in cirrhotic patients . Second , cirrhotic patients also commonly receive proton pump inhibitor (PPI), both for established indications, such as symptomatic gastro esophageal reflux, and prior peptic ulcer disease, as well as for unproven indications such as healing of esophageal ulcers after endoscopic band ligation . Finally , there is frequently a need for hospitalization to treat complications of cirrhosis , such as variceal bleeding, ascites, or encephalopathy, which places patients in an environment in which there is a high likelihood of exposure to C. difficile . Patients with cirrhosis have an impaired local gut immune response, increased bowel wall edema , and poor intestinal motility, all of which can promote perturbations of the intestinal microflora and bacterial overgrowth. 2019 Meyyur Aravamudan et al. Cureus 11(8): e5463. DOI 10.7759/cureus.5463

43. Background. Patients with cirrhosis are at high risk of Clostridium difficile infection (CDI). Rifaximin is commonly used in cirrhotic patients as prophylaxis for hepatic encephalopathy (HE). Several studies have demonstrated the efficacy of rifaximin in the treatment of CDI; however, resistance to rifaximin has also been reported. Few studies have assessed the risk of developing CDI in cirrhotic patients receiving rifaximin . Our objective was to assess the incidence and characteristics of CDI in patients with cirrhosis, especially in those who received rifaximin . Methods. We assessed the incidence and clinical characteristics of CDI in cirrhotic patients over a 6-year period in our hospital. Medical charts were retrospectively reviewed. Ribotyping and antimicrobial susceptibility testing of all strains against rifaximin were performed. Results. A total of 388 cirrhotic patients were included, of whom 127 patients had at least 1 episode of diarrhea in which a sample was sent to the laboratory. CDI was detected in 46 patients. Fourteen patients (30.4%) were receiving rifaximin as prophylaxis for HE. The main ribotypes detected were 001 (30.4%), followed by 014 (19.6%). Resistance to rifaximin was 34.1% overall, and 84.6% in patients who had received rifaximin . Multivariate analysis showed that rifamycin therapy and ribotype 001 were significant risk factors for having a rifaximin -resistant C. difficile strain. Conclusions. A high percentage of CDI cases were detected in cirrhotic patients receiving rifaximin , mostly owing to selection of rifaximin -resistant C. difficile strains. Clinicians should be aware of the risk of CDI in cirrhotic patients, even in those receiving rifaximin Breakthrough Clostridium difficile Infection in Cirrhotic Patients Receiving Rifaximin Elena Reigadas, 1 , 2 , 3 Luis Alcal ل, 1 , 3 , 4 Javier Gَmez, 1 Mercedes Mar ي n, 1 , 2 , 3 , 4 Adoraciَn Martin, 1 , 3 Raffaella Onori, 1 Patricia Muٌoz, 1 , 2 , 3 , 4 and Emilio Bouza 1 , 2 , 3 , 4 1 Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón , 2 Medicine Department, School of Medicine, Universidad Complutense de Madrid, 3 Instituto de Investigación Sanitaria Gregorio Marañón , and 4 CIBER de Enfermedades Respiratorias (CIBERES CB06/06/0058), Madrid, Spain. Rifaximin -Resistant C. difficile Clinical Isolates • CID 2018:66 (1 April)

44. Take home messages : The absence of diarrhea does not exclude the diagnosis of CDI. Awareness and multidisciplinary team actions are urgently needed. Hospital and National programs for proper infection control are urgently needed. IBD patients and those with liver cirrhosis are at high risk for CDI and in need for further studies. Antibiotic prescription should consider the local microbiologic reports .