C. difficile Stanley Shapiro, MD Department of Infectious Diseases Kaiser Permanente Panorama City Medical Center Novem

1. C. difficileStanley Shapiro, MDDepartment of Infectious DiseasesKaiser Permanente Panorama City Medical CenterNovember, 2005

2. Historical Background • Pseudomembranous colitis was first described in pre-antibiotic era • Later, presumed role of Staph aureus • After 1977, C. difficile proved to be major cause of antibiotic associated diarrhea

3. History-cont’d • In the later 1970’s, toxigenic C. difficile was established as the cause of pseudomembranous colitis • Cytopathic effects on cells in tissue culture could be demonstrated

4. Figure 92-2 A, Toxic cytopathic effect of fecal suspension in human embryonic lung fibroblasts (MRC 5 cells) from 12-year-old girl with pseudomembranous colitis. B, Uninoculated tissue cultures. These figures accompanied one of the first reports to implicate a bacterial toxin in pseudomembranous colitis; 7 months later, the same investigators reported that this effect was neutralized by Clostridium sordellii antitoxin. (From Larson HE, Perry JV, Price AB, et al. Undescribed toxin in pseudomembranous colitis. BMJ. 1977;1:1246-1248.) Downloaded from: Principles and Practice of Infectious Diseases (on 17 June 2005 12:07 AM) © 2005 Elsevier

5. Microbiology • 1935, organism was isolated from infant stools • obligate anaerobe, spore forming, gram positive rod • It is present in the soil and environment • 20 -40 % of hospitalized patients become reservoirs of these bacteria • Antimicrobial exposure is a major risk factor for the disease ( leads to suppression of the normal flora & promotes the growth of C.difficile) • It is highly resistant to fluoroquinolones, 100 % to moxi & gati and 96% to levofloxacin • Toxigenic • Not related to C. perfringens, C. botulinum or C. tetani

6. Epidemiology • Rates vary greatly depending on setting • In 2002 the epidemic with C.difficile infections started with several outbreaks in Canada & Eastern United States. • It was both community acquired and hospital acquired infection leading to significant economic burden for the hospitals. • recently, increase in severity and rate of disease noted, first reported from Quebec • all classes of antibiotics implicated although clindamycin and respiratory fluoroquinolones have been implicated frequently • anti-neoplastic agents (MTX, 5-FU, cyclophosphamide) are also guilty • Transmission: fecal oral route through contaminated environment and hands of health care personnel. C.diff spores have been recovered from hospital toilet seats, commodes, metal bed rails, bed pans, thermometers and floors. These spores can exist on these surfaces for months. • The incidence increased in those> 65 yrs from 106 ( 91- 92)to 866 in 2003

7. Epi – cont’d • The epidemic strains produce high amount of toxins ( 16 times more of toxin A and 23 times more of toxin B). • Some of these isolates also produce a toxin called binary toxin similar to C.perfringens. • Most commonly the isolates that don’t produce toxins are not pathogenic so there is no need to do surveillance cultures.

8. Contributing factors • advanced age • severity of underlying illness • use of agents that alter normal GI motility (enemas, gastrointestinal stimulants, stool softeners) • on the other hand, HIV does not appear to predispose to C. diff colonization or disease, except when these patients have above risk factors • It causes diarrhea, pseudomembranous colitis, toxic megacolon ( require colectomy) sepsis & death

9. Figure 93-2 Proctoscopic view of pseudomembranous colitis in a patient who received clindamycin. Note the 4- to 8-mm raised, white plaques overlying an erythematous mucosa. (From Tedesco FJ, Barton RW, Alpers DH: Clindamycin-associated colitis. Ann Intern Med 1974;81:429.) Downloaded from: Principles and Practice of Infectious Diseases (on 17 June 2005 12:07 AM) © 2005 Elsevier

10. Figure 92-4 Endoscopic view of multiple scattered, yellowish plaques consistent with pseudomembranous colitis. (From Iseman DT, Hamza SH, Eloubeidi MA. Pseudomembranous [Clostridium difficile] colitis. Gastrointest Endosc. 2002;56:907.) Downloaded from: Principles and Practice of Infectious Diseases (on 17 June 2005 12:08 AM) © 2005 Elsevier

11. Figure 92-3 Abdominal radiograph demonstrating markedly dilated colon, wall edema, and loss of haustration in a patient with Clostridium difficile-associated pseudomembranous colitis complicated by toxic megacolon. (From Agnifili A, Gola P, Manno M, et al. The role and timing of surgery in the treatment of pseudomembranous colitis: A case complicated by toxic megacolon. Hepatogastroenterology. 1994;41:394-396.) Downloaded from: Principles and Practice of Infectious Diseases (on 17 June 2005 12:08 AM) © 2005 Elsevier

12. Diagnosis • most widely used method is detection of toxins in stool specimens (diarrhea only –NO TURDS FOR TOXIN) • toxins are detected using Elisa kits • rapid, inexpensive and specific • lack sensitivity of cytotoxin assay

13. Toxins and the Gut • Disrupt signal transduction • Leads to cell rounding and retraction • Causes intestinal fluid secretion (is as potent as cholera toxin) • Intense inflammatory response occurs with cytolysis and separation of the apical epithelial cells • Severe diarrhea caused by these toxigenic strains leads to dissemination of spores in the hospital particularly when a patient is incontinent • These strains are highly virulent and easily transmissible among health care workers.

14. Management • d/c abx if possible • Avoid antiperistaltic agents • Start p.o. flagyl : IV if a patient can’t take it orally – dose 250 to 500 mg every 6 – 8hrs for 10 – 14 days • Cheap ( $ 20 per therapy) , most common side effects are metallic taste, Antabuse type of reaction with ETOH and peripheral neuropathy • Vanco orally 125 – 500 mg every 6 hrs for 10 – 14 days, , very expensive and prolonged therapy leads to encourages nosocomial vancomycin resistant organisms ( VRE) • Recurrent episodes : use the initial drug if patient responded if not use the other drug. • Tapering or intermittent therapy might help in some cases • Other meds : Probiotics, rifampin, bacitracin, etc • IVIG/Colonic enemas/ colectomy in extremes of cases

15. Clinical Implication • Standard order sheets are coming… • d/c peri-op prophylaxis after a MAXIMUM of 24 hours • Degerm hands frequently • Use soap and water after seeing patient with C diff

16. Case Study • 77 year old female with unresectable lung cancer receives a course of chemotherapy and then is seen by her dentist. Because of a presumed oral infection, the patient is begun on clindamycin. Shortly thereafter, she is admitted to the hospital with a surgical abdomen and undergoes a partial colectomy. During this hospitalization, she is found to have C. diff toxin in her stool. She is placed on long term metronidazole.

17. Case Study - 2 • Therapy with improvement in diarrhea. However, after several months of therapy, painful peripheral neuropathy develops, requiring a change in therapy. Multiple attempts to taper her medication result in recurrence of symptoms, necessitating at least 2 readmissions to the hospital. At the present time, the patient is improved on oral bacitracin, an orphan drug that requires weekly compounding by the pharmacy.

18. Complications • Complications are high in the following groups: • Age >65 • Hospital acquired infection • Immunosuppression • WBC >20,000 and Creatinine >2 ( complication rate is 60% compared to 10.6% when WBC < 20,000 and creatinine is <2 • Patients admitted to ICU with toxic megacolon and septic shock have high mortality

19. C.difficile diarrhea Control & Prevention Bhavani Rao, MD Department of Infectious Diseases Kaiser Permanente Panorama City Medical Center November 2005

20. C.difficile diarrhea Our hospital data: • From January to September 2005 there were a total of 204 patients with C.difficile diarrhea seen at our medical center. • In-patients : 88 Out-patients : 103 both In & out patients : 13 • Majority of out patients received fluoroquinolones (Cipro (ciprofloxacin), Avelox (moxifloxacin) or Levaquin (levofloxacin) prior to the onset of C.difficile diarrhea. • For In patients, the most common diagnosis was Community Acquired Pneumonia (CAP) where a combination of cephalosporins + Zithromax were given as part of the treatment. • The drug at the time of discharge was Avelox in several cases. • Many patients who developed the C.difficile diarrhea had several problems related to the infection and required several courses of therapy for control of diarrhea. Some of them continued to have diarrhea even after several months. • 2002 – 190 patients; 2003 – 306 patients; 2004 – 304 patients

21. Moxifloxacin Total RX from Jan 01 to Sept05 First Peak occurred in December 2003 – with 79 prescriptions

22. Levofloxacin Total RX from Jan 01 to Sept 05 Peak about 12/03 with 72 RX

23. C.difficile diarrhea • It is a preventable illness. • Major risk factor : antibiotics / antibiotics/ antibiotics • What you can do to prevent this diarrhea: • Limit the use of antibiotics. For CAP follow these guidelines. • When IV cephalosporins are given change to PO meds sooner. • Add coverage for Atypical infections only when indicated. • Avoid routine use of cephalosporins & Zithromax combination . • Reserve moxifloxacin for patients who can’t take any other meds. • Don’t give moxifloxacin for UTI or Ciprofloxacin for gonorrhea • Limit the duration of antibiotics to 7 days particularly when all cultures are negative • Order appropriate serologies – Cocci, crypto, mycoplasma, legionella • UTI : - TMP/SMX, cephalosporins, nitrofurantion. ciprofloxacin as the last choice • Surgical prophylaxis : • choose the appropriate agent / dose/ just for the recommended duration, don’t continue for a prolonged period.

24. Prevention strategies What we will be doing : • We formed a multidisciplinary group to address the C.difficile problem at our medical center. Our goal is to prevent the occurrence of C.difficile diarrhea. Therefore we will address the use of various abx at our medical center. • C.diff S.W.A.T team : Infection control :Leslie Budrick & Breda Mulvihill Nursing : Cecily Byron & Shirin Farman EVS : Irene Essayan In-patient Pharmacy : Patrick Kerrigan DUAT & OP pharmacy : Annet Arakelian ID physicians : Rao & Shapiro

25. C.difficile prevention team Nursing: • Identify a patient with C.diff diarrhea (first episode/ recurrent episode/presumed C.difficile diarrhea) prior to admission to the floor • Make sure that all these patients are admitted to private rooms or cohort patients with the same diagnosis • Transfer patients to private rooms when the patients have diarrhea. • Place a sign in the room & in front of the room for hand washing • Use appropriate precautions while taking care of the patient ( gloves, gowns etc) • Remind the providers to wash their hands prior to and after leaving the room. • When a patient has diarrhea they will get an order for C.diff testing from patient’s MD or MOD. Order the test & send the specimen to the lab. • Inform EVS to clean the room with bleach when the patient is moved to a different room or discharged. • Limit movements of the patients from place to place for various tests • Keep dedicated transportation – wheel chair in the room. Commode, portable stethoscopes etc for use in the room

28. C.difficile prevention • EVS: • Follow the protocol for cleaning the rooms properly and in an expedited manner • Use Bleach solution for cleaning • Maintain enough supplies of soap and alcohol degermer available on the floors

29. C.difficile prevention • Infection control: - will get a daily update of all positive C.difficile tests from the lab. • check to see if the patient is already in a private room if not they will inform the staff to move the patient to a private room. • will inform EVS about the patient’s location and remind about cleaning the rooms with bleach after the patients are moved. - will provide proper signs for hand washing etc. - Educate all the staff ( nursing , EVS, transportation etc) - Make regular rounds in the hospital to check on cleaning procedures - Get a monthly update on all the C.diff patients and compile the data for review by our group on a regular basis

30. C.difficile prevention • In-Patient Pharmacy : • Target CAP patient’s abx therapy. • Recommend D/C abx if there is no definite pneumonia. • Limit the duration of abx to 7 days when cultures are negative. • Change to PO abx when ever possible. • Avoid routine use Avelox, limit it to patients who can’t tolerate other meds or those that have positive cultures requiring avelox • Monitor dual therapy for CAP ( consider narrowing the spectrum when not indicated). Remind physicians to order serologies for atypicals when needed. • Recommend private room for any patient with suspected C.difficile diarrhea.

31. C.difficile prevention • DUAT & OP Pharmacy : • Target therapy of CAP for OP: • drugs of choice - EES/Azithro/doxy • COPD/DM etc - Cefpodoxime / augmentin + doxy • Last choice - moxifloxacin for 7 days • Monitor usage of Avelox/LevaquinNF: encourage providers to write the indication on the prescription pad when Avelox or Levaquin are given • Educate Per Diem/ Lancaster/ SCL clinic physicians. • Prepare educational material for pharmacy newsletters

32. C.difficile team • Physicians : • Educate all the providers about limiting abx use. • Attend the nursing staff/ nursing manager’s dept meetings and educate all the nursing staff about C.difficile infection, management and prevention • Inform all the hospitalists, OTU physicians and others about the management of CAP and limiting the use of moxifloxacin. • Intervene when ever our help is required.