2. SUBHAJIT SARKAR ASSISTANT PROFESSOR UNM DEPARTMENT OF MEDICINE SECTION OF HOSPITAL MEDICINE AUGUST 2010 Clostridium difficile update Recent Treatment Guidelines

3. Why Review? Increasing virulence and incidence  More prominent virulent strain of c.diff  Higher incidence in hospitals and community  Now most common nosocomial infection New clinical trials affecting antibiotic choice New therapies for relapse New guidelines issued within past year by IDSA and by ESCMID

4. Case 68 year old woman with no significant comorbidities admitted for gallstone pancreatitis. Was started on meropenem for WBC of 15 and obstructive pattern of LFTs Subsequently had spontaneous resolution of LFTs and leucocytosis Completed 5 days of meropenem; ERCP normal Had cholecystectomy on hosp day 6 On hosp day 7 developed diarrhea WBC rose to 20 K, Cr 1.2 (baseline 0.7), Albumin 3.5 Mild central abdominal pain, no peritonitis Nausea, vomiting and ileus C. diff positive stool How would you treat her c. diff infection?

5. Background Gram-positive Anaerobic Drumstick-shaped Motile Spore-forming Bacillus

6. First described in 1935  By Hall and O’Toole  Named bacillus difficilis (renamed in 1970) Commensal in 2-5 % of adults and 70% of healthy infants < 1 year Discovered as causative agent for antibiotic- associated diarrhea in 1978  Bartlett et al 1978 and others  Staph aureus implicated before this

7. Pathogenesis Spore-forming bacteria – heat resistant, survive months to years Fecal-oral transmission Endogenous vs exogenous infection (symptoms develop 2-3 days after colonization) Toxins  Toxin A  Toxin B  relative contributions have been debated.  glucosyltransferases that target and inactivate the Rho family of GTPases-> actin condensation and cell rounding->followed by death of the cell  TcdA ->intestinal epithelium,  TcdB -> broader cell tropism  Binary toxin Mucosal inflammation and damage Pseudomembrane formation

9. Risk Factors Antibiotics  2/2 to disturbance of normal bacterial flora  Abx in 96% within 14 days and 100% within 3 mo (Olsen et al)  25-40% of patients may not become symptomatic for as many as 10 weeks  Clindamycin and Amoxicillin/ampicillin in 1970s and cephalosporins (2 nd and 3 rd gen) in 1980s; macrolides, other penicillins, aminoglycosides, fluoroquinolones, trimethoprim- sulfamethoxazole, metronidazole, chloramphenicol, tetracycline, imipenem, and meropenem.  A prolonged antibiotic course or the use of 2 or more antibiotics increases the risk of disease Hospitalization  Likely 2/2 to high rates of colonization  20-40% in hospital compared to 2-3% in healthy adults  Risks = sharing a hospital room with an infected patient, intensive care unit stays, prolonged hospital stays, nursing home resident Age > 65  In 1998 Swedish study: age > 65 yrs incidence = 20 x higher than age < 20

10. Rarer Associations Gastric acid suppressive therapy Anti-neoplastic agents Hemolytic-uremic syndrome Malignancies Intestinal ischemia Renal failure Necrotizing enterocolitis Hirschsprung disease Inflammatory bowel disease Nonsurgical gastrointestinal procedures, including nasogastic tubes GI surgery

11. Clinical Features and Diagnosis Diagnosis of CDI  Generally = signs and symptoms of CDI + positive stool test or endoscopic appearance of pseudomembrane Tests  Tissue culture assay – 24-48hrs, high cost, highest sp/sn  Enzyme immunoassay for toxin A or A and B  PCR (but 10-50% of all hospitalized patients are colonized) Asymptomatic carrier state -> “Mild to Moderate” -> “Severe”  Diarrhea (> 3 unformed stool / 24 hours), mucus, rare blood -> ileus -> toxic megacolon-> death  Leukamoid reaction  Cramping abdominal pain, anorexia, malaise, fever, dehydration, lower abdominal tenderness

12. Clinical Features and Diagnosis Important to differentiate “severe” from “mild”  Definition of “severe” varies between studies  Now accepted severity changes antibiotic choices and delivery Same criteria should used to diagnose recurrent CDAD History of antibiotics often found Response to specific therapy is suggestive Initial episode vs relapsing episodes  50-65 % chance of additional episodes if at least one episode

13. Relapsing Disease Complete abatement of symptoms followed by subsequent reappearance of diarrhea and other symptoms Impossible clinically to distinguish relapse from reinfection Relapse occurs in 10-25% of cases treated with metronidazole or oral vancomycin Most occur within 1-2 weeks but can occur up to 3 mo later May be due to persistent spores from initial infection Risk related to immune response  asymptomatic carriers have high serum IG levels to toxin A, low levels in patients with multiple relapses Rates higher with age Treatment with abx for c.diff may make things worse by altering colonic flora -> more relapses

14. “Severe” Zar et al. 2007 >= 2 points < 48hrs IDSA-SHEA 2010 Any of the below ESMID 2009 Any of the below WBC >15 WBC > 15 or Bands >20% Albumin < 2.5Cr > 50% baselineCr > 50% above baseline T > 38.3T > 38.5 or rigors Age>60(Age mentioned in text but not specified) (Age>65, serious comorbidity, ICU admission or immune defiency = severe?) Ileus*Ileus Megacolon*Large bowel distension Pseudomembranous colitis*Pseudomembranous colitis OR large bowel thickening or colonic wall thickening or pericolic fat stranding ICU admission*Hypotension/shock*Hemodynamic instability or elevated lactate Ascites *= 2 points*= “complicated” Peritonitis

16. Treatment – Historical Approach C.diff identified as causative agent for antibiotic- associated diarrhea in 1978 Oral Vancomycin was initial treatment of choice  Keighley al 1978 – RCT vs placebo (78% cure vs 14%)  Bartlett et al 1980 – 96% cure, 14% relapse  Silva et al 1981 – 100% cure, 13% relapse Metronidazole introduced in 1980s  Cherry et al 1982 – 100% cure, 13% relapse

17. Treatment – Historical Approach RTCs comparing Metronidazole and Vancomycin (not blinded, small power)  Teasley et al 1983  Vanco 500 mg qid x 10 d vs Metro 250 mg qid x 10d  95 patients (52 vanc, 42 metro)  95% cure metro vs 100% vanco  6% relapse metro vs 19% vanco  No difference in pseudomembranous colitis* (? Severe)  No signficance difference in cure or relapse rates  $387-$520 for vanco vs $11.84 for metro  Wenisch et al 1996  Vanco 500 tid x 10 d vs Metro 500 tid x 10 d vs Teicoplanin 400 bid x 10d vs Fusidic acid 500 td x 10 days  31 vanc, 31 metro, 28 teicoplanin, 29 fusidic acid  No stratification  94% cure metro vs 96% vanco, 93% fusidic acid, 96% teicoplanin  16% relapse metro vs 16% vanco, 28% fusidic acid, 7% teicoplanin

18. SHEA Position Paper 1995

19. American College of Gastroenterologists 1997 Guidelines 1. Antibiotics should be discontinued if possible. 2. Nonspecific supportive therapy should be given, and is often all that is needed in treatment. Specific antibiotics should not be given routinely. 3. When the diagnosis of C. difficile diarrhea is confirmed and specific therapy is indicated, metronidazole given orally is preferred. 4. If the diagnosis of C. difficile diarrhea is highly likely and the patient is seriously ill, metronidazole may be given empirically before the diagnosis is definitely established. 5. Vancomycin given orally is reserved for therapy of C. difficile-associated diarrhea until one or more of the following conditions are present:  (a) The patient has failed to respond to metronidazole.  (b) The patient's organism is resistant to metronidazole.  (c) The patient is unable to tolerate metronidazole, or is allergic to it, or is being treated with ethanol containing solutions.  (d) The patient is either pregnant or a child under the age of 10 years of age.  (e) The patient is critically ill because of C. difficile-associated diarrhea or colitis.  (f) There is evidence suggesting the diarrhea is caused by Staphylococcus aureus.

20. Cochrane Review 2007 Reviewed 12 RTCs assessing abx treatment for c.diff 8 antibiotics compared: vancomycin, metronidazole, fusidic acid, nitazoxanide, teicoplanin, rifampin, rifaximin and bacitracin Symptomatic and bacteriological initial response, cure and recurrence In paired comparison, no antibiotic was superior Teicoplanin showed some significant benefit in some outcomes (bacteriologic cure and borderline symptomatic cure) over vancomycin and trend towards benefit over metronidazole No advantage to synergistic metronidazole and rifampin Mild CDI may not need treatment  Johnson et al 1992 – placebo better than vanc or met in eliminating c. diff in asymptomatic carriers “Teicoplanin is best choice” Teicoplanin and Fusidic acid not available in USA 10 day course (Vancomycin $7358, Metronidazole $765, Bacitracin $200, Teicoplanin $1374, Fusidic acid $706) Did not include recent RTCs since 2007

22. Emergence of Hypervirulent C. Diff Increased, incidence, severity and mortality in Canadian studies  1721 cases of CDI in Sherbrooke, Quebec (Pepin 2004)  Incidence increased from 35.6 per 100 000 population in 1991 to 156.3 per 100 000 in 2003  Complicated cases increased from 7.1% to 18.2%  30 day mortality from 4.7% to 13.8% (54/390) in 2003  > 65 years incidence went from 102.0 to 866.5 per 100 000 Increased incidence and virulence in US  Increase in ICD-9 coding from 82000 cases in 1996 to 178000 in 2003  8 hospital outbreaks in 6 states 2001-5: epidemic strain of C. difficile was been associated with these (McDonald 2005)  Cases in previously uncommon populations (CDC 2005): May-Jun 2005: in 4 states: 10 peripartum cases, 23 CA-CDAD cases; 24% had no abx exposure within 3 mo, 9% after < 3 doses of abx

23. Emergence of Hypervirulent C. Diff Increasing rate of relapse and greater with risk or relapse with age (Pepin 2005)  1991-2002, recurrence rates 20.0%, 13.8%, and 28.9% among individuals aged 0- 17, 18-64, and > or = 65 years, respectively  2003-2004, the probabilities were 25.0%, 27.1%, and 58.4%, respectively No significant differences in vanco and metro relapse rates (Pepin 2007)  Vancomycin therapy was associated with a lower probability of developing SC- CDAD in 1991-2002 (AOR 0.21) but not during 2003-2006 (AOR 0.90) : Loss of superiority of vancomycin over metronidazole coincided with the emergence of NAP1/027.  For both metronidazole and vancomycin, risk of recurrence increased in 2003- 2004 but decreased in 2005-2006.  No difference in second relapse rate between vanc and metronidazole B1/NAP1/027 strain responsible for new outbreaks in Quebec (Loo 2005) and US hospital outbreaks  A predominant strain, resistant to fluoroquinolones, was found in 129 of 157 isolates (82.2 percent), and the binary toxin genes and partial deletions in the tcdC gene were present in 132 isolates (84.1 percent)

24. Emergence of Hypervirulent C. Diff B1/NAP1/027 strain.  Increased production of toxins A + B  16-23 times wild type  Toxinotype III  Toxinotype =group of strains with same PaLoc changes (codes for TcdA and TcdB)  At this time 24 toxinotypes are known  Deletion of tcdC protein  Putative negative regulator of TcdA and TcdB  Fluoroquinolone resistance  Excessive fluoroquinolone use appears to be a contributing factor in the recent outbreaks.  Binary toxin  actin-specific ADP-ribosyltransferase; similar to iota toxin  hamsters studies: strains with just binary toxin did not cause diarrhea

25. Emergence of Hypervirulent C. Diff Likely worldwide epidemic May have surpassed MRSA as the most common nosocomial infection  0.28 vs 0.25 per 1000 patient days in recent conference report Clinical features similar to historical disease but more severe  more toxic megacolon, leukamoid reactions, requirement for colectomy and death Are current antibiotic guidelines still optimal given worse rates of relapse, incidence and severity? Necessity to examine “severe” disease as a separate clinical entity….

27. Superiority of Vancomycin in Severe Disease Zar et al 2007  1994-2002  150 patients  Stratified into “mild” (81) and “severe” (69)  Metronidazole po 250 mg qid x 10 days vs Vanco 125 mg po qid x 10 days  Followed up for 21 days to assess cure, failure, relapse  Mild: 90% metro vs 98% vanco (p=0.36)  Severe: 76% metro vs 97% vanco (p=0.02)  Relapse: 15% metro vs 14% vanco  Metronidazole treatment failure in severe disease correlated with  Low albumin, admission to ICU and pseudomembranous colitis Louie et al 2007 and Bouza et al 2008  2 RTCs Phase 3 that investigated the efficacy of tolevamer found oral vanco superior to metronidazole in severe cases

28. Other Therapies IV metronidazole  No RTC: case reports and case series  logical given pharmacokinetics (absorbed then secreted): weakly plasma protein bound, favors good penetration into body tissue  Friedenberg et al 2001: case series of 10: iv met -> “majority” had resolution of symptoms (abdominal pain, vomiting, fever, dehydration, wcc)  Bolton and Culshaw (1986) 9 pts: bactericidal faecal concentrations were present in all patients with acute disease receiving oral or intravenous metronidazole, and all responded to therapy Vancomycin enema  Anecdotal reports – optimal dosage unknown  Apisarnthanarak et al 2002: 8/9 cases of CDAD with megacolon, fulminant colitis or refractory CDAD resolved  Considered “prudent” by IDSA if ileus and no peforation

29. Other Therapies Higher dose po vancomycin in “complicated” severe (ileus, megacolon)  -> 500 mg qid: highe dose as delivery may be impaired -> no direct evidence for this Vancomycin taper and/or pulse dosage  Metronidazole not used for second recurrence -> concern for cumulative neurotoxicity  Hope that normal flora restored and spores turn to vegetative forms between pulses  No RTC but observational studies suggestive of efficacy  McFarland 2002: 163 cases of recurrent disease: 45% recurrence, reduced to 31% with vanco taper and 14% with pulse regimen  E.g. 125 mg qid x 10-14 days then bid for 1 week, qday for 1 week, then q 2-3 days for 2-8 weeks

30. Other Therapies Vancomycin + Rifaximin  Johnson et at 2007: uncontrolled case series: oral rifaximin (400 mg bid x 2 weeks) given after 10 d course of vanco cured 7/8 of patients getting multiple recurrences – > Uptodate recommend this Tigeclycline  Herpers et al 2009: 4 patients with recurrent CDAD cured with no relapses (all were admitted to intensive care units with septic shock) Stool transplant  High degree of success in several uncontrolled case series  Repopulates the colonic flora but is limited by the risk of hepatitis and retrovirus transmission

31. Other Therapies Probiotics (1)  Probiotics are live, nonpathogenic bacteria capable of colonizing the colonic mucosa  Several probiotics are available over the counter and in health food stores  Saccahoromyces boulardii and lactobacillus most studied  Potential role for probiotics to restore a diverse intestinal microflora after disruption by antimicrobial therapy  Saccahoromyces seems to inhibit the effects of toxins A and B on the human colonic mucosa  Clinical role of probiotics for CDAD treatment and prevention is uncertain  Risk of fungemia – avoid in critically ill patients, significant comorbidities, immune supressed

32. Other Therapies Probiotics (2)  Treatment  Limited data may play a useful role for recurrent CDAD  McFarland et al 1994 124 pts ->4 wks of S. boulardii or placebo (+ vanc or metro) -> 19.3 vs 64.7 % recurrence  2008 Cochrane review reviewed probiotics for treatment of CDAD w 4 RTCs -> “insufficient evidence”  McFarland 2006 meta-analysis of 6 RTCS w 354 patients: S. boulardii was tge only effective probiotic for rec. CDAD  Surawicz et al 2000 S. boulardii + vanc 500 mg qid better than vanc 500 mg qid alone (17% vs 50% recurrence) Standard antibiotic for 10 days and then added either S. boulardii (1 g/day for 28 days) or placebo

33. Other Therapies Probiotics (3)  Prevention  Useful role for prevention of CDAD, particularly among older patients  Hickson et al 2007 135 pts (mean age 74) -> probiotic preparation = casei immunitas, Lactobacillus bulgaricus, and Streptococcus thermophilus during and following completion of antibiotic therapy (one week) Less likely to develop CDAD than those receiving placebo (0 versus 17 %)  Plummer et al 2004 150 elderly hospitalized patients -> probiotic preparation of Lactobacillus acidophilus and Bifidobacterium bifidum had a lower incidence of CDAD (2.9 versus 7.25 %)  May be considered in elderly patients without significant comorbidities receiving antibiotic therapy

34. Other Therapies Nitazoxanide  Thiazolide antiparasitic  As effective as metronidazole (Musher et al 2006) and vancomycin (Musher et al 2009) Teicoplanin, Fusidic acid  Fusidic acid: lipophilic steroid antibioitic, the product of Fusidium coccineum -> mainly active against gram-positive bacteria  Teicoplanin: glycopeptide antiobiotic extracted from Actinoplanes teichomyceticus -> similar spectrum of activity to vancomycin  Both may be at least as effective as vancomycin or metronidazole OPT-80 (difimicin/fidaxomicin)  RNA polymerase inhibitor  Phase 3 RTC suggests is effective for the treatment of mild-to- moderate C. difficile infection at a dose of 200 mg orally every 12 hours.  Favorable outcomes for fidaxomicin when compared to oral vancomycin

35. Other Therapies Ramoplanin  Glycolipodepsipeptide– only effective orally  Freeman 2005:  Hamster and gut CDAD model: ramoplanin and vancomycin were similarly effective at reducing cytotoxin production and in resolving symptoms  Ramoplanin may be more effective than vancomycin at killing spores and preventing spore recrudescence  In phase 3 trials IVIG  Some case reports of usefulness as an adjunct to abx in refractory CDAD, but no signficant effect in 2007 case control study (Juang 2007) Monoclonal antibodies  Lowy 2010  200 patients: monoclonal ab to toxin A and B (101) vs placebo (99) as an adjunct metro or vanco reduced recurrence rates from 25 to 7% overall  Recurrence rates among patients with BI/NAP1/027 strain were 8% for the antibody group and 32% for the placebo group  Among patients with more than one previous episode of C. difficile infection, recurrence rates were 7% and 38%, respectively

36. Other Therapies Toxin-binding resins and polymers  Do not alter flora.  No RTC. Mixed results.  Colestipol and cholestyramine  Not effective as primary therapy but may help in relapse  Small case series of 11 pts with relapsing CDI, resolved after use of colestipol with vanco taper (Tedesco 1982)  No trial evidence for cholestyramine: it can be used in desperate situations such as numerous relapses  Tolavemer  Novel c. diff toxin binding resin.  2 phase 3 studies (see earlier) showed was inferior to met and vanco but had much lower recurrence rates (3-6% compared to 23-18% w vanco and 27-19% w metro).  Use in the future as an adjunct? C. difficile vaccination  Investigational toxoid vaccine to provide immunity against toxins A and B  Phase 1 trials in UK; now in phase 2 trial.

37. Clinical Microbiology and Infection Vol 15 (12) Dec 2009 1067-1079

38. Infection Control and Hospital Epidemiology Vol 32 (5) May 2010 431-455

40. Initial Mild or Moderate Episode ESCMID (< 4 BM/day no signs of severe colitis) IDSA-SHEA (WCC < 15, Cr < 1.5 x baseline) Avoid antiperistaltic agents (B-II) If possible avoid use of antiperistaltic agents (C-III) Use antibiotics covering necessary spectrum only (B-III) If the stool toxin assay result is negative, the decision to initiate, stop, or continue treatment must be individualised (C-III) When severe or complicated CDI suspected initiate empiric treatment as soon as diagnosis is suspected (C-III) Stop inducing antibiotic and observe closely (B-III) Discontinue therapy with inciting antimicrobials as soon as possible (A-II) Metronidazole po 500 mg tid 10 days (AI) Or 500 mg iv tid 10 days if cannot take po (A-III) Metronidazole po 500 mg tid x 10-14 days (A-I)

41. Initial Severe Episode ESCMID ( signs of severe colitis, ?age ?comorbidity) IDSA-SHEA (WCC >15, Cr >1.5 x baseline,?age) Vancomycin 125 mg po qid x 10 days (Teicoplanin 100 mg po bid if available) (A-I) Vancomycin 125 mg po qid x 10-14 days (B-I) Or if cannot take po: Metronidazole mg 500 mg iv tid 10 days (A-III) + intracolonic vancomycin 500 mg q 4-12 hours (C-III) +/- vancomycin 500 mg qid by nasogastric tube (C-III) Severe, complicated (Hypotension/shock,ileus megacolon): Metronidazole mg 500 mg iv tid +/- vancomycin 500 mg qid by mouth or nasogastric tube +/- rectal vancomycin if complete ileus (C- III) Recommendation for surgical treatment (colectomy) For perforation, megacolon, shock. Attempt to operate before lactate reaches 5.0 (assoc. with 75% mortality) or WCC > 50 K – monitor these

42. Recurrence ESCMIDIDSA-SHEAUptodate First recurrence: As for initial episode First recurrence: As for initial episode (A-II) First recurrence: As for initial episode or if symptoms mild, conservative management Second recurrence: Vancomycin 125 po mg qid (or Teicoplanin 100 mg po bid if available) for at least 10 days (B-II) + consider a taper/pulse strategy (B-II) Or if cannot take po: Metronidazole mg 500 mg iv tid 10 days (A- III) + intracolonic vancomycin 500 mg q 4- 12 hours (C-III) +/- vancomycin 500 mg qid by nasogastric tube (C-III) Second recurrence: Vancomycin po in a tapered and/or pulsed regimen (B-III) [metronidazole not rec’d for prolonged duration] Second recurrence: Vancomycin po in a tapered and/or pulsed regimen (125 mg qid x 7 days, then bid x 7 days, then qday x 7 days, then qod x 7 days then q 3 days for 14 days). 3 wks of Saccharomyces boulardii 500mg bid may be used (overlapped with the final week of the taper and continued for two additional weeks) Subsequent relapse: Vancomycin 125 mg qid x 14 days then Rifaximin 400 mg bid x 14 days

43. Proposed UNM Guideline Stop offending antibiotic if feasible Use metronidazole po 500 mg tid (or iv if cannot take po) 10-14 days in all cases except in the following situations. Use vancomycin po (125 mg po qid 10-14 days) if:  WCC > 15, Cr > 1.5 x baseline Consider vancomycin po first line if:  Age > 60, significant comorbidity/ fever or chills/ Albumin < 2.5 / SIRS/periotoneal signs/pseudomembrane on endoscopy/ICU admission Use vancomycin po (500 mg qid) with metronidazole iv (500 mg iv tid) (+/- vancomycin enema) while they have any of the following:  Shock/hypotension, ileus, megacolon If prolonged duration of antibiotics needed for underlying disease continue CDAD treatment throughout the antibiotic course plus one additional week after its completion (*use vancomycin) Do not repeat stool toxin assay (upto 50 % positive after six weeks)

44. Proposed UNM guideline For first recurrence assess severity and give treatment as as for first episode For subsequent recurrences use taper and/or pulse vancomycin dosing Consider adding overlapping (by 1 week) 3 week course of saccharomyces (500 mg bid) to 6 wk vanco taper in second recurrence Consider vancomycin 125 mg po qid x 14 days then rifaximin 400 mg x 14 days in third recurrence Consult surgery early: if any signs of peritonitis, perforation, megacolon, SIRS/sepsis/shock not responding to medical treatment (consider surgery before lactate > 5) Consult ID if no improvement with above treatment plans or if relapses > 2 times to consider alternative therapies

45. Back to the Case 68 year old woman with no significant comorbidities admitted for gallstone pancreatitis. Was started on meropenem for WBC of 15 and obstructive pattern of LFTs Subsequently had spontaneous resolution of LFTs and leucocytosis Completed 5 days of meropenem Had cholecystectomy on hosp day 6 On hosp day 7 developed diarrhea WBC rose to 20 K, Cr 1.2 (baseline 0.7), Albumin 3.5 Mild central abdominal pain, no peritonitis Mild nausea and ileus C. diff positive stool How would you treat her c. diff infection? = Vancomycin 500 mg po qid and metronidazole 500 mg iv tid -> if resolution of ileus -> vancomycin 125 po qid

46. Questions?