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Vancomycin vs Metronidazole in C.Diff

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Vancomycin vs Metronidazole in C.Diff

  1. 1. C. DIFF DIARRHEA: VANCOMYCIN VS. METRONIDAZOLE OVMC LANDMARK TRIALS SERIES Zar FA, et al. "A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile- associated diarrhea, stratified by disease severity". Clinical Infectious Diseases. 2007. 45(3):302-7.
  2. 2. BACKGROUND  C. diff diarrhea is most common infectious entity in nosocomial diarrhea, accounting for 15-25% of all cases  Metronidazole is first line, but more treatment failures evolving  Therefore, C.diff has been increasing in incidence and severity  It is known that Vancomycin orally can treat C.diff; however, it is unclear when Vanc should be used  Prior to this study, no studies have been published on vancomycin versus metronidazole for treating C.diff, stratifying patients in terms of severity
  3. 3. CLINICAL QUESTION In patients with varying disease severity with Clostridium difficile-associated diarrhea, how does metronidazole compare with vancomycin in regards to effecting a cure and preventing relapse?
  4. 4. DESIGN  Analysis: Intention-to-treat  Single center, double-blinded, parallel-group, placebo, randomized controlled trial  N=150  Metronidazole (n=79)  Vancomycin (n=71)  Setting: Affiliate of University of Illinois at Chicago  Enrollment: 1994-2002  Follow-up: 21 days  Primary outcomes:  Cure  Relapse
  5. 5. POPULATION Inclusion Criteria  Diarrhea (>3 nonformed stools/24h), and  Clostridium difficile toxin A in stool within 48h of study entry, or  Pseudomembranes on endoscopy  Ability to receive oral medications Exclusion Criteria  Suspected or proven life-threatening intraabdominal complications (eg, perforated viscus, bowel obstruction)  Pregnancy  History of allergy to either study drug  Prior treatment with metronidazole PO/IV or oral vancomycin in 14 days prior to trial  Patients not allowed to receive antidiarrheal medications or drugs with potential activity against Clostridium difficile
  6. 6. INTERVENTIONS  Randomization to a group:  Metronidazole 250mg PO QID x 10 days, or  Vancomycin 125mg PO QID x 10 days  Stool assays performed on days 6 and 10 of therapy, and again on day 21 if diarrhea was present.  Interviews conducted on days 5, 11, and 21 after completion of therapy.  Thirteen patients (6 vs. 7) with severe disease were lost to follow-up or withdrawn due to death or noncompliance.
  7. 7. RESULTS  Enrolled patients: 172  Patients successfully completing trial: 150  Multiple reasons: non-adherence, lost to follow-up, 8 patients died before therapy completion  Among patients with MILD CDAD, metronidazole led to 90% cure, while vancomycin led to 98% cure (P=0.36)  In patients with SEVERE CDAD, metronidazole led to 76% cure, while vancomycin led to 97% cure (P=0.02)  Cure is defined as resolution of diarrhea within 6 days and sustained through day 10 of treatment NOTE: The authors in the study theorize that it was not resistance to metronidazole that led to treatment failure in severe cases because resistance should have caused failure in patients with mild disease also. They believe that metronidazole is more poorly delivered through the bloodstream in the inflamed colonic mucosa
  8. 8. CRITICISMS  Unclear why dose of medication used in study was Metronidazole 250mg PO QID as opposed to traditional dosing of 500mg PO TID for C.Diff  Performed before the highly virulent NAP1/BI/027 strain emerged in the US  The study showed statistically significant SEVERE risk factors are albumin <2.5, presence of pseudomembranous colitis, ICU stay. WBC> 150K and renal failure were NOT a statistically significant risk factor. However, definition of severe disease has changed.  Study did not perform culture of C.diff strains to identify sensitivities to metronidazole and/or Vancomycin  Unclear of resistance played a role in Metronidazole failure
  9. 9. BOTTOM LINE Although oral metronidazole is first-line therapy for mild Clostridium difficile-associated diarrhea, Vancomycin is superior in treating patients with severe C. diff associated diarrhea (CDAD). *** ***Significant risk factors for severity leading to treatment failure in the study was albumin <2.5, presence of pseudomembranous colitis via endoscopy, ICU study (p<0.05). See next page for recommendations by the 2010 IDSA/SHEA
  10. 10. 2010 IDSA/SHEA C. DIFF GUIDELINES Severity Clinical Picture Treatment First episode (Mild/Moderate) WBC <15000 or Creatinine <1.5 baseline Metronidazole 500mg PO TID For 10-15 days First episode (Severe) WBC > 15000 or Creatinine >1.5 baseline Vancomycin 125mg PO QID 10-14 days First episode (Complicated) Hypotension, shock, ileus, megacolon Vancomycin 500mg PO/NG QID PLUS Metronidazole 500mg IV q8Hour First Recurrence … Same as first episode Second Recurrence … Vancomycin in tapered or pulsed regimen Infection Control Hospital Epidemiology 2010
  11. 11. DISCUSSION QUESTIONS  Is resistance the reason for treatment failure of metronidazole in severe C.diff cases?  According to the IDSA/SHEA, what defines mild, severe, complicated C.diff?  According the this trial, what were statistically significant risk factors for severe C.diff?  In patients with severe CDAD in this trial, how many patients were cured of disease with Metronidazole? Vancomycin?
  12. 12. DISCUSSION ANSWERS  Is resistance the reason for treatment failure of metronidazole in severe C.diff cases?  ANSWER: Unknown, but unlikely because resistance should have caused metronidazole failure in patients with mild disease also  According to the IDSA/SHEA, what defines mild, severe, complicated C.diff?  MILD: WBC <15000, Creatinine <1.5 baseline  SEVERE: WBC >15000, Creatinine >1.5 baseline  COMPLICATED: Hypotension, shock, ileus, megacolon  According the this trial, what were statistically significant risk factors for severe C.diff?  ANSWER: albumin <2.5, presence of pseudomembranous colitis via endoscopy, ICU study (p<0.05).  In patients with severe CDAD in this trial, how many patients were cured of disease with Metronidazole? Vancomycin?  ANSWER: Metronidazole led to 76% cure, while vancomycin led to 97% cure (P=0.02)
  13. 13. BOARD-LIKE QUESTION A 67yo male develops 5 days of diarrhea after completing a course of Clindamycin. He has 4-7 liquid bowel movements per day. He reports mild fever, abdominal pain, nausea, or vomiting. Physical exam: Febrile 38.3, HR 110, BP 150/82, RR 18 Abdomen: soft, B+, NTND Labs: WBC 8.8, Creatinine 2.8 (baseline 0.7) Stool polymerase chain reaction assay is positive for C. difficile toxin. Which of the following is the most appropriate oral treatment? A. Metronidazole x 14 days B. Vancomycin x 14 days C. Metronidazole x 6 weeks D. Vancomycin x 6 weeks E. Rifaximin x 14 days
  14. 14. BOARD-LIKE QUESTION ANSWER Which of the following is the most appropriate oral treatment? A. Metronidazole x 14 days B. Vancomycin x 14 days C. Metronidazole x 6 weeks D. Vancomycin x 6 weeks E. Rifaximin x 14 days Educational Objective: Treat a patient with a severe C.diff infection (Creatinine >1.5 baseline OR WBC>15000) Key Point: - Metronidazole is first line for mild/moderate C.diff. - 20% of patients with C.diff can experience relapse - Rifaximin is not recommended as a stand- alone drug for C.diff
  15. 15. REFERENCES  Zar FA, et al. "A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity". Clinical Infectious Diseases. 2007. 45(3):302-7.  Vancomycin vs. Metronidazole in C. difficile Diarrhea LLC Brain - https://www.wikijournalclub.org/wiki/Vancomycin_vs._ Metronidazole_in_C._difficile_Diarrhea

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