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C. Difficile : Accurate Testing & Diagnosing New Treatments on the Horizon. October 2, 2014 For the Georgia Hospital Association(GHA)/ Georgia Advanced Practice Program (GAPP ) Bruce Kalmin, M.D. Board Certified Gastroenterologist. Clostridium difficile infection (CDI). Objectives: - PowerPoint PPT Presentation
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October 2, 2014
For the Georgia Hospital Association(GHA)/Georgia Advanced Practice Program (GAPP)
Bruce Kalmin, M.D.Board Certified Gastroenterologist
C. Difficile: Accurate Testing & DiagnosingNew Treatments on the Horizon
Clostridium difficile infection (CDI)
Objectives: Participant will be able to identify most accurate C.
difficile infection testing and diagnosing recommendations
Participant will become aware of new treatments for C. difficile on the horizon including Fecal Microbial Therapy
What’s so important about Clostridium difficile?
Annual hospitalizations in U.S. with CDI as a diagnosis (Agency for Healthcare Research & Quality) 1993: 85,700 hospitalizations 2010: 346,800 hospitalizations
Category # Cases Excess Costs Deaths
Hospital-onset 165,000 $1.3B 9,000
Community-onset, HCF-associated
50,000 $0.3B 3,000
Nursing home-onset
263,000 $2.2B 16,500
Kelly & Lamont. N Engl J Med 2008;359:1932-40. Bauer et al. Clin Microbiol 2009;15:1067-79. Cohen et al. Infect Control Hosp Epidemiol 2010;31:431-55.
What’s so important about Clostridium difficile?
Clostridium difficile-related deaths
Figure. Yearly Clostridium difficile–related mortality rates per million population, United States, 1999–2004.
Redelings MD, Sorvillo F, Mascola L. Increase in Clostridium difficile–related mortality rates, United States, 1999–2004. Emerg Infect Dis [serial on the Internet]. 2007 Sep [date cited].Available from: http://wwwnc.cdc.gov/eid/article/13/9/06-1116
What is Clostridium difficile?
• C. difficile is a spore-forming, gram-positive anaerobic bacillus that produces two exotoxins: toxin A and toxin B
• Common cause of antibiotic-associated diarrhea (AAD) Accounts for 15-25% of all episodes of AAD
What is Clostridium difficile?
• First identified in 1935 (Hall and O’Toole) 60-70% of newborns colonized (Bacillus difficilis) Possible lack of toxin receptor -> no symptoms
• C. difficile identified as pathogen in 1978 (Tedesco et al. and Bartlett et al.)
Causes pseudomembranous colitis in patients receiving clindamycin
Hall EC, E OT. Intestinal flora in new-born infants with a description of a new pathogenic anaerobe, Bacillus difficilis. Am J Dis Child 1935; 49: 12.Bolton RP, Tait SK, Dear PR, Losowsky MS. Asymptomatic neonatal colonisation by Clostridium difficile. Arch Dis Child 1984; 59: 466–472. Bartlett JG, Chang TW, Moon N, Onderdonk AB. Antibiotic-induced lethal enterocolitis in hamsters: studies with eleven agents and evidence to support the pathogenic role of toxin-producing Clostridia. Am J Vet Res 1978; 39: 1525–1530.Tedesco FJ, Alpers DH. Editorial: pseudomembranous colitis. West J Med 1974; 121: 499–500.Bartlett JG, Moon N, Chang TW, Taylor N, Onderdonk AB. Role of Clostridium difficile in antibiotic-associated pseudomembranous colitis. Gastroenterology 1978; 75: 778–782.
Pseudomembranous Colitis
Colonization vs. Infection
C. difficile colonizationo Patient exhibits NO clinic symptomso Patient tests positive for C. difficile organism and/or
its toxino More common than C. difficile infection
C. difficile infection Patient exhibits clinical symptomso Patient tests positive for C. difficile organism and/or
its toxin
Can Colonization be Protective?
Gerding at al. 2013 Two different strains of non-toxigenic C. difficile
provided protection against both historic and epidemic (BI/NAP1/O27) strain
Can colonization be protective against CDI? ViraPharma is conducting Phase I/II trials
Gerding at al. Non-toxigenic Clostridium difficile vs. BI/NAP1/O27. Antimicrobial Agents and Chemotherapy, October 2013.
Symptoms of CDI
Watery diarrheaFeverLoss of appetiteNauseaAbdominal
pain/tenderness
At-Risk Populations
Patients with: Antibiotic exposure Proton pump inhibitors Gastrointestinal
surgery/manipulation Long length of stay in healthcare
settings Serious underlying illness Immunocompromising conditions Advanced age
Laboratory Testing
Stool culture Most sensitive but most often associated with false-
positive results due to presence of non-toxigenic strains
False positivity can be overcome by testing isolates for toxin production
Labor intensive Slow turn-around time (48-96 hours)
Laboratory Testing
Molecular Tests FDA-approved PCR assays
Test for gene encoding toxin B Highly sensitive and specific
Antigen detection (latex agglutination or immunochromatographic assay) Rapid test (<1 hour) Non-specific but used in combination with toxin
detection, PCR, or toxigenic culture
Laboratory Testing
Toxin testing Tissue culture cytotoxicity assay
Detects toxin B only Costly Slow turn-around time (24-48hrs) Historical gold standard but replaced by PCR or toxigenic
culture Enzyme immunoassay
Detects toxin A, toxin B, or toxin A and B Concerns over A-/B+ strains causing disease Same-day assay Relatively insensitive
Less than tissue culture cytotoxicity and much less than PCR or toxigenic culture
Laboratory Testing
Important Note!!! C. difficile toxin is VERY unstable Degrades at room temperature May be undetectable within 2 hours after
collection of a stool specimen Specimens can be kept refrigerated
When can you repeat PCR Testing for C. difficile?
PCR has high sensitivity (~90%) and specificity (~90%) with high negative predictive value
Summary of literature review (8 studies: 2008-2013)
PCR testing is reliable; no need to repeat when initial results are negative
If C. difficile is suspected (persistent symptoms) but initial negative test, repeat from days 8-14 or after day 10
http://www.stmarysmadison.com/physicianfocus/Documents/Sept.2013/link-C%20Diff%20testing%20summary%20mar%202013.pdf
When can you repeat PCR Testing for C. difficile?
If initial test was positive, may remain positive. May represent asymptomatic colonization or false positives due to PCR sensitivity. If retesting is done, wait for 7 days.
Most studies look at retesting after initial negative test and not if initial test was positive.
“Test of cure” is NOT recommended.
http://www.stmarysmadison.com/physicianfocus/Documents/Sept.2013/link-C%20Diff%20testing%20summary%20mar%202013.pdf
CDI Prevention
Use antibiotics judiciouslyContact Precautions
Private rooms or (if not available) cohorted with other patients with C. difficile infection
Gloves/Gowns Wash hands with SOAP and WATER
Alcohol-based hand rubs are not as effective Removal of C. difficile spores is challenging, even
with soap and water
CDI Prevention
Dedicate or clean any shared equipmentUse EPA-registered disinfectant with
sporicidal claim or hypochlorite (bleach) Standard EPA-registered hospital disinfectants are
NOT effective against C. difficile sporesContinue precautions until diarrhea ceases
Most institutions will routinely continue isolation for either several days beyond symptom resolution or until discharge
The “New” C. difficile Strain
BI/NAP1/O27 Outbreaks
Pittsburgh (2000) Atlanta (2001-2) Montreal (2003)
More virulent Increased production of toxins A and B Additional toxin: binary toxin Resistant to fluoroquinolones
Additional info: Read Bench-to-Bedside review: Clostridium difficile colitis at http://www.cdc.gov/HAI/pdfs/cdiff/Gould_CritCare2008.pdf
The “New” C. difficile Strain
Detection Any of the current tests will detect
BI/NAP1/O27 None of them differentiate between the various
strains of C. difficileTreatment
Same as standard therapy Controversial
Metronidazole first: prevents VRE Vancomycin first: strain may be resistant to
metronidazole
Management of CDI
Stratified by Disease Severity
CDI Severity Treatment
Mild to moderate Metronidazole500 mg 3 times per day PO 10-14 days
Severe Vancomycin125 mg 4 times per day PO 10-14 days
Severe, complicated Vancomycin500 mg 4 times per day PO or by nasogastric tube or enema plus Metronidazole 500 mg q8h IV
Cohen SH, et al. Clinical Practice Guidelines, IDSA & SHEA. ICHE 2010;31(5):431-455.
Management of CDI
Vancomycin is more effective than metronidazole in treating severe CDI1
Severe complicated CDI (refractory/fulminant) Early surgical consultation2
WBC >20K, creatinine >1.5 baseline, lactate >5mmol/L In addition to vancomycin po/enema & metronidazole IV, consider
Tigecycline IV? IVIG 400 mg/kg? Fidaxomicin?
Colectomy vs. loop ileostomy3 93% of colon can be preserved with intraoperative colonic lavage via
ileostomy and post-op antegrade vancomycin installation via ileostomy
1 Zar et al. Clin Infect Dis 2007; 45:302-72 Lamontagne F, et al. Ann Surg 2007; 245:267-272. Pepin J, et al. Can Med J Assoc 2004; 171:466-472. Miller MA. Clin Infect Dis 2007;45:S122-S128.3 Neal MD, et al. Ann Surg 2001;254:423-429.
Management of CDI
Fidaxomicin vs. Vancomycin No significant difference in initial response
88.2% fidaxomicin vs. 85.8% vancomycin (modified ITT)
92.1% fidaxomicin vs. 89.8% vancomycin (per protocol) Fidaxomicin is superior in preventing recurrence
15.4% fidaxomicin vs. 25.3% vancomycin (modified ITT) P=0.005
13.3% fidaxomicin vs. 24.0% vancomycin (per protocol) P=0.004
Louie TJ, et al. New Engl J Med 2011; 364:422-431.
Management of CDI
Fidaxomicin (Dificid) vs. Vancomycin Fidaxomicin superior to vancomycin for preventing
a first recurrence of CDI but not long-lasting
Group Fidaxomicin200mg BID
x10d
Vancomycin125mg QID
x10d
P=
N=128 66 62
Total Recurrences
19.7% (13/66) 35.5% (22/62) 0.045
Recurrences to 14 days post therapy
7.6% (5/66) 27.4% (17/62) 0.003
Recurrences 15-28 days post therapy
13.1% (8/61) 11.1% (5/45) NSComely, OA et al. CID 2012;55 (Suppl 2); 154-61.
Management of CDI
Taper & pulsed dosing of oral vancomycin 125mg QID x10-14d 125mg BID x7d 125mg daily x7d 125mg every 2nd day x8d 125mg every 3rd day x15d
Recurrence rates were lower Vancomycin ≤ 1g 54.2% Vancomycin > 1g 54.3% Vancomycin taper 31.0% (P=0.01) Vancomycin pulsed 14.3% (P=0.02) Metronidazole ≤ 1g 44.6% Metronidazole > 1g 40.0%
Tedesco et al. Am J Gastroenterol 1985;80:867-868. McFarland et al. Am J Gastroenterol 2002;97:1769-1775.
Management of CDI
Rifaximin “chaser” in recurrent CDI Standard therapy (metronidazole 82% or vancomycin
18%) PLUS placebo vs. rifaximin 400mg po TID x20d Standard therapy + placebo = 31% recurrence within 6
months Standard therapy + rifaximin = 15% recurrence within 6
months Recurrence = proportion not experiencing recurrent
diarrhea
Garey, et al. J Antimicrob Chemother, 2011;66:2850-5.
Management of CDI
SummaryEpisode of CDI Treatment
First recurrence • Treat as first episode according to disease severity
• Fidaxomicin?
Second recurrence • Prolonged oral vancomycin (tapering and pulse-dosed)
• Fidaxomicin?
Third recurrence • Prolonged oral vancomycin (tapering and pulse-dosed)
• Fidaxomicin?• Rifaximin “chaser”• Fecal microbial
transplant (FMT aka “stool transplant”)
• IVIG?Cohen SH, et al. IDSA & SHEA Guidelines, ICHE 2010;31(5):431-455. Surawicz, et al. ACG Guidelines. Am J Gastroenterol, 2013. Kelly & LaMont. “Uptodate” accessed Apr 24, 2013.
Fecal Microbial Therapy
Concept originated in China millennia ago 'Yellow soup' was made of fecal matter and water,
which was drunk by the patient.The first description of FMT was published in 1958
by Ben Eiseman and colleagues, a team of surgeons from Colorado, who treated four critically ill patients with fulminant pseudomembranous colitis (before C. difficile was the known cause) using fecal enemas, which resulted in a rapid return to health.
At the Centre for Digestive Diseases in Sydney, Australia, FMT has been offered as a treatment option for more than 20 years.
Eiseman B, et al. (1958). "Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis". Surgery 44 (5): 854–859.
Fecal Microbial Therapy
Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile infection First infusion of donor feces resulted in 81.3% cure rate
without relapse (N=16) Vancomycin resulted in 30.2% cure rate without relapse
(N=13) Vancomycin with bowel lavage resulted in 25.1% cure
rate without relapse (N=13)Conclusion: The infusion of donor feces was
significantly more effective for the treatment of recurrent C. difficile infection than the use of vancomycin
van Nood et al. N Engl J Med, 2013;368(5):407-413.
Fecal Microbial Therapy
Multiple methods of administration From below: ~75% by colonoscopy or retention
enema From above: ~25% by nasogastric tube or upper GI
endoscopy Reported efficacy: From below >90%, from above
~80%
Bakken et al. Clin Gastroenterol & Hepatol 2001;9:1044-9. Hamilton et al. Am J Gastroenterol, 2012;107:761-7. Kelly CP, N Engl J Med 2013;368:474-5.
Fecal Microbial Therapy
The Future of FMT Stool banking? “Poop pill”? Isolation of “protective” microbes
Bacteroidetes and Firmicutes Treatment of other disorders
Ulcerative colitis? Crohn’s disease?
Summary
Test early with PCRStop all non-C. difficile antibiotics ASAPGive oral vancomycin as first line in severe
diseaseFor recurrent disease, consider
Fidaxomicin? Vancomycin taper/pulse? Rifaximin “chaser”? FMT?
Questions?