A Closer Look at Clostridium difficile Infections

1. A Closer Look at Clostridium difficileInfections Richard Allan Bettis, Fourth-Year Pharm.D. Candidate Preceptor: Dr. Ali Rahimi University of Georgia College of Pharmacy

2. Background • Clostridium species • >190 species identified • Gram-positive • Anaerobic • Spore forming bacilli • Releases exotoxins which are associated with major diseases in humans C. difficile colitis results from the ingestion of spores that vegetate, multiply, and secrete toxins

3. Background • Clostridium tetani • Causes tetanus through spread of potent neurotoxin • Clostridium botulinum • Causes botulism through spread of potent neurotoxins • Clostridium perfringens • Causes gas gangrene through spread of necrotizing, hemolytic exotoxin • Clostridium difficile • Causes pseudomembranous colitis through production of cytotoxin and enterotoxin • Relatively resistant to most commonly used antibiotics • Found in normal gut flora of 2-10% of humans

4. Pathophysiology • Toxin A, the enterotoxin, causes: • Damage to intestinal mucosa • Intestinal fluid secretion • Inflammation via actin disaggregation • Intracellular calcium release • Damage to neurons in the gut • Toxin B, the cytotoxin, causes: • Depolymerization of filamentous actin • More effective damage to colonic mucosa

5. Pathogenesis • Pseudomembranous plaques formation resulting in inflammation of mucosa • Enlargement and spread of plaques through gut results in clinical presentation • Mild to severe diarrhea • Mucosal necrosis • Accumulation of inflammatory cells and fibrin Raised, yellowish-white pseudomembranous plaques

6. Background • Clostridium difficileinfection (CDI) is the most common cause of infectious diarrhea in hospitalized patients • Once antibiotics disrupt normal gut flora: • C. difficilecolonization occurs • Toxins production results in manifestation of CDI • Diarrhea and colitis results • CDI should be suspected in any patients with diarrhea with recent history of antibiotic use

7. CDI Risk Factors • Clostridium difficileinfections occur most often in high risk groups: • Elderly (>65 years old) • Debilitated • Immunocompromised • Surgical patients • Nasogastric tubes • Frequent laxative use • History of antibiotic use

8. CDI Risks • CDI can occur during, shortly after, or several months after the use of broad spectrum antimicrobial treatment • CDI should be suspect in any patients with diarrhea with recent history of antibiotic use within the past THREE MONTHS • Patients whose diarrhea began 72 HOURS after hospitalization

9. CDI-Associated Antimicrobials • Broad spectrum antimicrobials associated with CDIs: • Clindamycin • Ampicillin • Flouroquinolones • Ciprofloxacin, levofloxacin, moxifloxacin • Cephalosporins(2nd & 3rd generation) • Cefotaxime, ceftriaxone, cefuroxime, ceftazidime • Aminoglycosides • Erythromycin • TMP-SMX • Metronidazole • Vancomycin Used to treat CDI!

10. Clinical Presentation • Patients with CDI often present with: • Watery or perfuse diarrhea (as many as 20 bowel movements per day) • Leukocytosis (50%) • Fever (28%) • Abdominal pain (22%) • Ileus (~20%) • Pseudomembraneformation • Malaise • Nausea • Anorexia

11. Clinical Presentation • Clinical diagnosis based upon diarrhea onset during or after antimicrobial use • Delay in diagnosis can result in complications : • Life-threatening toxic megacolon • Pseudomembranous enterocolitis

12. Diagnosis • Pathogens most often responsible for infectious diarrhea or enteritis: • Shigellaspecies • Salmonella species • Escherichia coli • Yersinia species • Vibrio species • Clostridium difficile • Other etiologies less commonly seen or in extreme cases of immunodeficiency • Parasites (Entamoebahistolytica, Giardia lamlia) • Viruses (Cytomegalovirus)

13. Differential Diagnosis • Stool cultures are crucial to making an organism-specific diagnoses and determining antimicrobial sensitivity • Recommended in patients with inflammatory diarrhea • Poor yield of positive cultures • If negative, then a 2nd analysis is recommended

15. Diagnosis • Detection of toxins • C. difficiletoxins A or B • Enzyme assays for • Glutamate dehydrogenase (GDH) • Endoscopy • Reserved when rapid diagnosis is needed • Used when ileus is present • Stool samples are unavailable • Differential diagnoses with concurrent colonic diseases Raised, yellowish-white pseudomembranous plaques characteristic of CDI

17. Prevention • Clostridium difficilecan be cultured in rooms of infected individuals UP TO 40 DAYS after discharge • Strict hand washing • Contact precautions • Vaccines?

18. Clostridium difficilecan be cultured in rooms of infected individuals UP TO 40 DAYS after discharge

19. Is There A Problem? • Most frequently acquired exogenously from: • Hospital • Nursing home • Long-term care facility • >20% fecal colonization among patients hospitalized for >1 week • C. difficilespores can persist for months on most surfaces • Risk of colonization increases with length of stay • Other risk factors: • Poor hand hygiene of hospital personnel • Use of electronic rectal thermometers • Enteral tube feeding

21. Why So Serious? • Both the incidence and severity of Clostridium difficileinfections have increased significantlyin the past decade • Clostridium difficileinfection rates in U.S. hospitals tripledbetween 2000 and 2005 • CDI rates in Canada have quadrupledsince 1997 • Increased rates directly attributed to an increase in mortality from 1.7% to 6.9%

22. Why So Serious? • Causality attributed to emergence of specific strain-types of outbreaks known synonymously as: • North American pulsed-field type (NAP-1) • Toxinotype III • REA type BI • PCRribotype 027 • Emergence may be explained in part by patterns of antibiotic use in hospitals

23. CDI Epidemic • North American pulsed-field type (NAP-1) • Highly resistant to fluoroquinolones • Carries deletion mutations in toxin regulatory gene • Results in higher levels of toxin production • 16 to 23 times more toxin A and B! • Results in significantly more serious disease • More resistant to standard therapy

24. Fluoroquinolones • Most recent drug class implicated in hospital outbreaks of C. difficileinfections • Increasing fluoroquinolone resistance seen in: • Campylobacter, Salmonella, Clostridium difficile

25. Treatment

26. Treatment • Discontinue offending agent • Diarrhea may resolve in up to 25% of patients within 48 hours of discontinuation • Fluid and electrolyte replacement as necessary • Most patients will require antibiotics • Vancomycin • Metronidazole

27. Treatment • Vancomycin(Oral) • IV does not achieve high enough gut concentrations • Contraindications, intolerance, or poor response to metronidazole • Retention enema delivery if ileus or inability to reach infection site • Concerns of vancomycin resistant enterococci (VRE) • Metronidazole • Drug of choice for mild to moderate CDI • Less expensive

28. CDI Treatment Guidelines • Published by IDSA in 2010 • Metronidazole 500mg PO TID for 10-14 days • For mild to moderate CDI • Vancomycin125mg PO QID for 10-14 days • For initial episode of severe CDI • Vancomycin +/- 500mg metronidazole IV • For severe, complicated CDI • Vancomycin dose is 500mg PO QID + 500mg IV in 100mL NS rectally

29. Treatment

30. Contraindicated Regimens • Drugs that inhibit peristalsis or slow gut transit time should NOT be used in patients with fever or bloody stool • Diphenoxylate • Loperamide • Evidence to support an increase risk for development of hemolytic-uremic syndrome due to delayed intestinal clearance and increased toxin absorption

31. Recurrence • Treatments similar in diarrhea resolution, incidence of side effects, and relapse rates • Relapse occurs in approximately 20% of patients • Relapse usually occurs within 1 to 2 weeks but can be delayed for up to 12 weeks • Frequency increases with subsequent recurrences • One prior episode: >40% recurrence risk • >2 prior episodes: >60% recurrence risk

32. Recurrence • Risk factors for recurrence: • History of recurrence • Advancing age • Additional antimicrobials • Inadequate immune response to C. difficile toxins

33. Recurrence & Treatment • Optimal management of multiple relapses is unclear • Alternative regimens: • Fecal transplantation • Vancomycin + rifampin • Vancomycin followed by rifaximin • Nitazoxanide • IVIG • Poor regimens • Bacitracin, cholestyramine, colestipol, fusidic acid, probiotics

34. Recurrence • There is more than just C. difficileamidst normal gut flora • Further disruption of gut flora only causes susceptibility to other infections Where is the selective agent?

35. Treatment Failure & Recurrence • Resistance to antimicrobials is rarely the cause of relapse • Relapse occurs because treatment: • Fails to eliminate C. difficilespores • Makes patients vulnerable to another infection by impairing normal flora

36. CDI Treatment Guidelines • Fidaxomicin?

37. Fidaxomicin (Dificid) • Narrow spectrum, macrocyclic antibiotic active against gram-positive aerobes and anarobes • Lacks activity against gram-negative bacteria • Poor activity against normal gut flora • Relatively selective activity against C. difficile • Inhibits bacterial protein synthesis by binding to sigma subunit of RNA polymerase • Negligible systemic absorption with oral administration • High fecal concentrations

38. Fidaxomicin (Dificid) • As effective as vancomycin and may be associated with lower rates of relapse • 1st antimicrobial FDA approved by the FDA forCDI treatment in over 25 years • Orphan drug designation to all formulations for treatment of CDI in pediatric patients <16 years and younger • Administered 200mg PO BID

39. Fidaxomicin versus Vancomycin for Clostridium difficileInfection Published in February 2011!

40. Study Design • Prospective, multi-centered, double-blind, randomized, parallel-group trial • Non-inferiority study • All patients were enrolled at 52 sites in the United States and 15 sites in Canada • Conducted from May 2006 to August 2008

41. Grading Recommendations

42. Eligibility Criteria • > 16 years of age • Diagnosis of CDI • Presence of diarrhea defined as >3 unformed bowel movements in a 24-hour period • Presence of C. difficiletoxin A, B, or both in stool sample obtained within 48 hours of randomization • Could not be recipient of any potentially effective concurrent CDI treatments • Oral bacitracin, fusidic acid, rifaximin

43. Exclusion Criteria • Patients receiving any potentially effective concurrent CDI treatments • Oral bacitracin, fusidic acid, rifaximin • Patients with: • Life-threatening or fulminant CDI • Toxic megacolon • Previous exposure to fidaxomicin • History of ulcerative colitis or Crohn’s disease • >1 occurrence of CDI within 3 months before study start

44. Efficacy Outcomes • Primary endpoint • Rate of clinical cure in the modified intention-to-treat and per-protocol populations at the end of therapy or at the time of early withdrawal • Secondary endpoints • Recurrence of CDI during 28-day period after the end of the course of therapy • Global cure in the modified intention-to-treat and per-protocol populations

45. Treatment • Randomized into two groups • Vancomycin125mg every 6 hours • Fidaxomicin200mg every 12 hours • Dosing scheduled with placebo for q6h dosing • Both medications were over-encapsulated to conceal identities • Oral dosing for 10 days

46. Definitions • Modified intention-to-treat (MITT) population • Patients with documented CDI who underwent randomization and received at least one dose of study medication • Per-protocol population • Patients who received >1 dose of fidaxomicinwho received treatment for >3 days (treatment failure) or >8 days (clinical cure) • Documented adherence to protocol • Underwent end-of-therapy evaluation

47. Study Enrollment • 629 patients enrolled and randomized • 596 included in modified intention-to-treat analysis (received > 1 dose of Dificid) • 548 included in per-protocol analysis

48. Randomization

49. Follow-up

50. Follow-up • Assessed daily for clinical cure or clinical failure • Assessed weekly for 28 days after last dose for recurrence • Only patients who remained in the study and had a follow-up assessment between days 36 and 40 after randomization