Update on C.difficile: the end of metronidazole, FMT, and other revelations Rocky Mountain APIC 9/26/2014 Sean Pawlowski, MD Colorado Infectious Disease Associates, LLP Medical Director: Infection Control.
Download ReportTranscript Update on C.difficile: the end of metronidazole, FMT, and other revelations Rocky Mountain APIC 9/26/2014 Sean Pawlowski, MD Colorado Infectious Disease Associates, LLP Medical Director: Infection Control.
Update on C.difficile: the end of metronidazole, FMT, and other revelations Rocky Mountain APIC 9/26/2014 Sean Pawlowski, MD Colorado Infectious Disease Associates, LLP Medical Director: Infection Control and Antimicrobial Stewardship, Porter Adventist Hospital No disclosures Case • 72 yo female, who underwent a dental cleaning. Given peri-cleaning Ampicillin • 2 wks later- profuse diarrhea and diagnosed with C.difficile- Metro x 10d • Developed 4 recurrences, given 2 week courses of vanco, and then was given a vanco taper • During her taper she was evaluated by ID (Cost of oral pill taper- For 110, 125mg caps=$3415) • Pt informed that if she recurred then FMT…she recurred Case • Husband’s stool was checked for C.difficileadditional tests were not performed • “Will I develop my husband’s metabolism?” • Pt stopped Vanco on a Thurs & started on cultured yogurt • Monday-25g of donor stool mixed with 750cc of NS, agitated and strained through a filter- then given 500cc stool solution by retention enema – Cost of stool=$0…..at minimum a $3415 cost savings as compared to vanco taper • She is now diarrhea free for > 3 yrs Questions arising from case 1. How would you define the C.difficile presentation? 2. What are the risk factors for acquisition? 3. Which C.difficile treatment would have been the best to use from the beginning? 4. Why not use FMT sooner? How to get approval. Objectives • Identify the new CDI surveillance definitions • Identify strategies to reduce the risk of acquisition • Identify changes in treatment options • Identify barriers to implementation of FMT and faults with those barriers Background • Gram positive anaerobic spore forming bacillus. – Spores are extremely resistant (can live up to 60 days in hospital • Most common cause of antibiotic associated colitis. C. difficile isolated from TCCFA plates – Most common HAI- +/- CA-UTI • CDI pathogenesis –due to toxins A & B-leads to loss of barrier function, cell death, apoptosis, & release of numerous inflammatory molecules Pseudomembranous colitis Jank T, et al 2007. Pawlowski, 2014 Redelings et al 2007 Lucado et al 2012 Epidemic strain-It’s in the genes • Epidemic strain BI/NAP1 has been present since the 1980’s • It hyperproduces toxins, hypersporulates, increased transmissibility, enhanced sporulation, binary toxin, & increased resistance to disinfectants • Only difference is that it is now resistant to all FQs Loss of (-) regulation McDonald et al 2005 Warny et al 2005 Does epidemic strain lead to worse disease? • Some observational studies yes and some no • In vivo models-no difference in mortality with the epidemic strain • Previous studies showed that in germ-free mice and hamsters-higher toxins in vitro correlated with higher death rates • Most human studies show no correlation to toxin levels and disease severity, but…… Razaq et al 2007 McDonald et al 2005, Cloud et al 2009, Morgan et al 2008 Vernet et al 1989 Akerlund et al 2007 Epidemic strain associated with decreased clinical cure and recurrence Clinical Cure Recurrence 100 Epidemic Strain 80 Non Epidemic 94.3 90 86.6 70 Percent BI: Reduced cure: (OR 0.48, P=0.03) 60 BI: Recurrence risk: (OR 1.57, p=0.046) 50 40 30 20 10 27.4 16.6 0 Petrella et al. 2012 Epidemic strain associated with severe disease and increased mortality • Severe outcome (colectomy, ICU, death) • OR: 2.12, P=0.008 • Death at 14d • OR: 1.66, P=0.02 • HCA disease also associated with severe outcome and 14d mortality – OR: 2.9, P: 0.0003 & OR: 2.33, P: 0.005 -See et al, 2014 Case definition • Presence of symptoms (diarrhea) with a positive test. (Toxin assay or PCR) – Or pseudomembranes – Same criteria also needed for recurrent disease. • • • • Healthcare facility (HCF) onset Community onset (CO), HCF associated Community associated CDI If you suspect CDI-place in isolation and test Case definition Why are the definitions important? • HO-CDI is reported to National Health Safety Network (NHSN) • In 2015 Medicare will use the #s to judge which hospitals to penalize and #s are made public. -Cohen et al. 2010 Diagnosis-Appropriate testing Test Sensitivity Specificity Advantage Disadvantage Toxin Assay EIA 50-90% 84-95% Cheap Not sensitivenumerous false negatives GDH antigen 90-100% 80-100% Sensitive for presence of C.difficile False positivesdoes not distinguish toxin+ or toxin- 2 step algorithmGDH + EIA ,cytotoxin neutralization, or PCR 94% 99% Cheaper than screening all stools with PCR Time intensive Toxin B PCR 90-100% 94-97% Sensitive. Quick Expensive Cepheid Xpert PCR 95% 95% Sensitive. Distinguishes “epidemic strain” Expensive. • Only send stool that is loose • No advantage to sending more than 1 stool- No test of cure! Risk factors for acquisition • Exposure to antibiotics-1980’s clindamycin, 1990’s ceftriaxone, 2000’s FQ’s. • The elderly-at greater risk for recurrence and severe disease Inadequate immune response to infection Older mice infected with C.difficile have increased & prolonged weight loss McDonald et al 2005. Kyne et al 2001 Pawlowski et al 2010 Risk factors • Exposure to healthcare facilities • C.difficile pressure • Prolonged LOS associated with recurrence • Acid reducing medications!!-1.3-2.36X risk • FDA issued warning (02/2012) • Multiple co-morbidities • Prior CDI episodes • Immunocompromised • New case reports emerging of patients without risk factors with CDI MMWR 2005 McFarland 2009 McDonald et al 2005. Dubberke et al 2010 Pawlowski et al 2013 Price et al 2007 Linsky et al 2010 Howelll et al 2011 Infection control is not enough!! Targeted abx consumption & nosocomial CDI incidence/1000 patient-days of hospitalization. -Valiquette L et al. 2007 20-50% of abx use in the hospital is thought to be inappropriate 250 Days of therapy 200 150 100 50 0 Noninfectious sequelae Treatment of colonization Duration of therapy deemed too long Redundant therapy Hecker et al, J2003 “I think my patient needs antibiotics for the E.coli in his urine.” “It’s asymptomatic bacteriuria and he’s colonized!!!!” Seasonal variation in antimicrobial prescribing and E.coli resistance -Sun et al 2012 How to reduce risk Table I: Risk Factor for acquisition of CDI and strategies to decrease risk Risk factors for acquisition of CDI Strategies to decrease risk Antimicrobial exposure Development of an ASP Exposure to C.difficile Active IP program Environmental cleaning with effective sporicidal agents Advanced age Identification that age is a risk factor and avoid antibiotics and other medications associated with an increased risk of CDI ?Vaccination (in Phase 3 trial) PPI use Education and auditing by pharmacy to ensure appropriate use Prolonged LOS Early identification of patients safe to discharge Note: See Muto (17), Dellit (25), and Zilberberg (44) Abbreviation: CDI: C. difficile infection, ASP: Antimicrobial Stewardship Program, PPI: Proton Pump Inhibitor, LOS: Length of stay Pawlowski 2014 UV light reduces room colonization -Anderson et al 2013 -Levin et al 2013 H2O2 after routine disinfection reduces C.difficile recovery -Best et al 2014 IDSA/SHEA severity definitions • Mild to Moderate Disease 1. White blood cell (WBC) less than 15,000 cells/uL 2. Cr of less than 1.5-fold the premorbid state. • Severe disease 1. WBC greater than 15,000 cells/uL 2. Cr of greater than 1.5-fold the premorbid state • Severe disease with complications 1. Presence of severe disease 2. Ileus 3. Toxic megacolon 4. Shock Fulminant Disease • Others also include: comorbid state, immunosuppression, bandemia, vasopressors, hypoalbuminemia, age, and elevated lactate level IDSA/SHEA treatment guidelines Treatment of CDI: Metro vs Vanco Rates of Cure % of pts cured Severity Metro Vanco Mild 90 98 Severe 76 97 All 84 97 P=.02 Rates of Relapse % relapsed Severity Metro Vanco Mild 8 5 Severe 21 10 All 14 7 P=.30 -Zar et al. 2007 Treatment of CDI: Metro vs Vanco • Study of tolevemar, vancomycin, and metronidazole – Tolevemar was inferior to both – Mild dz: 75% vs 82 % cure P= NS – Severe dz: 66% vs 78% cure P=0.06 – Why a decreased overall cure rate (as compared to Zar study)?-- due to presence of BI strain – OVERALL cure rate: 73% vs 81% P=0.02 Johnson et al. 2014 Fulminant C.difficile • Mortality:~35-50% (colectomy) vs ~60-80% (medical) • Predictors of mortality: WBC>50,000, lactate>5, age >75, immunosuppressed, pressors.. Admission to medical service (time to surgery is greater), 10% bandemia, resp failure • Colectomy more beneficial: aged >65, immunocompetent, WBC >20,000 <50,000, or lactate of 2.2 -4.9 mmol/L. -LaMontagne et al 2007 -Perrera et al. 2010 -Sailhamer et al. 2009 Fulminant C.difficileColectomy vs Loop ileostomy • Method: 1. Lap ileostomy 2. Flush colon antegrade with 8 L polyethylene glycol 3. Post-op Vanco 500 q 8h via malecot catheter x 10d 4. Metro 500 IV TID • No pts were denied sx due to concern for operative risk • 30 day Mortality: 50% vs 19% • 1 recurrence (mean f/u=11mo) • Get surgery involved early in fulminant cases! Neal et al. 2011 CDI recurrence • 5-30% of patients recur after 1st episode of C.difficile •LOS associated with increased risk of recurrence • Risk of recurrence increases with each recurrent episode 40 yo male 5 days after vanco-did not fill script because it was too $$ Vancomycin taper Pts with recurrent CDI had less recurrence when given a Vanco taper (30% recurrence, N=29) or pulsed dose Vanco (14% recurrence, N=7)…BBIS Vanco med. dose Vanco low dose Vanco high dose Vanco taper Vanco pulse McFarland et al 2002 Fidaxomicin • Fidaxomicin (Dificid) – Macrocyclic non absorbable antibiotic with narrow spectrum as opposed to vanco – Non-inferior to Vanco with rates of cure – Lower rate of recurrence: 15% vs 23%, p=0.005-no difference with the BI strain – Lower recurrence after first recurrence: 20% vs 36%, p=0.045, p = 0.045. – It preserves the microbiota: never use in combination with vanco or metronidazole – It’s use is often restricted: but, 2 cost analysis has shown it may be more cost effective than vancomycin (under certain conditions) Louie et al 2011 Cornerly et al 2012 Stranges et al. 2013 Nathwani et al 2014 Additional Treatments • Toxin A & B Monoclonal antibodies – Lower recurrence rate with antibiotics + antibodies vs antibiotics alone (8% vs 32%) • Non toxigenic C.difficile • Surotomycin, anti-C. difficile lipopeptide (Phase 3) – comparable cure rates to vanco and improved recurrence rates (17 vs 36 %, p=0.035) -Lowy et al 2009 -Surotomycin Fact Sheet. Cubist Pharmaceuticals. www.cubist..com/products/cdad. Fecal microbiota transplantation: FMT • For recurrent , fulminant, or persistent disease – Not for IBD, IBS, or other conditions • Methods: By NGT, colonoscopy, enema • Success: 90-100% Fecal transplant: Published studies (N=122) Author Year Cases Method Success Eiseman 1958 4 Enema 100 Bowden 1981 16 Enema 81 Schwan 1984 1 Enema 100 Tvede 1989 6 Enema 100 Flotterod 1991 1 NG 100 Patterson 1994 6 Enema 100 Lund-Tonnesen 1998 18 Enema 100 Persky 2000 1 Colonoscopy 100 Faust 2002 6 ? 100 Aas 2003 16 NG 94 Jorup-Ronstrom 2006 5 Enema 100 Surawicz 2010 19 Colonoscopy 100 Yoon 2010 16 Colonoscopy 100 Silverman 2010 7 Self-admin enema 100 Adapted from Bakken IDSA 2007, updated 2011 FMT performs better than vancomycin in recurrent disease -FMT: 6% recurrence -Vanco: 62% recurrence -Vanco + lavage: 54% -Els van nood et al 2013 Loss of microbiota diversity prevalent in recurrent disease -Chang et al 2008 FMT restores diversity and richness -els van nood et a l2013 -Alexander et al 2010 FMT safe to use in immunocompromised patients • Condition: HIV/AIDS (3), SOT(19), oncologic condition (7), immunosuppressants for IBD (36), & other • 89% cure rate (12 of the patients required a second transplant) • No secondary infections related to the transplants • 1 death due to aspiration during colonoscopy -Kelly et al 2014 Protocol • Recipient: should be off treatment for about 48h • Mix 25-30 g stool in 500-1000 ml NS (one guideline recommends milk) • Stool can be mixed in blender or other method • Solution then filtered through cheesecloth, gauze, or stone strainer • For NGT: use 25-30ml, Colonoscopy: 200-250ml, Retention enema: 5001000ml Other Studies on FMT • Frozen fecal inocula by colonoscopy or NGT (N=20)---90% success (5 required 2 procedures) • Concentrated “stool bacteria” pillsrequired taking 24-34 pills (N=37)--100% success • Multiple studies now touting the use of universal donors -Youngster et al. 2014 -Louie et al 2013 (IDSA abstract -Hamilton et al 2012 Commercial companies now in the FMT business Fecal transplant complications • Potential complications: – Complication from colonoscopy – Electrolyte disturbance from purging solution – Translocation of normal flora across a disturbed epithelium – Enteric pathogen infection – Don’t know the long term effects Barriers to implementation • FDA: To have an IND or to not have an IND or to maybe have an IND – “Intend to exercise enforcement discretion as long as..” 1. Need adequate informed consent- the use of FMT products to treat C. difficile is investigational and a discussion of its potential risks. 2.The FMT product is obtained from a donor known to either the patient or the treating licensed health care provider 3. The stool donor and stool are qualified by screening and testing performed under the direction of the licensed health care provider for the purpose of providing the FMT product to treat his or her patient http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/ucm387023.htm Barriers to implementation • Facilities unwilling to allow it- a lot of work to approve – IC/IP fear • Lack of ancillary staff willing to participate • Insurances do not cover it-How to charge? • OOP costs to recipient: >$1000 for lab tests • Lack of physicians willing to participate • One study has shown it is the most cost effective strategy for recurrent disease Donor testing -Numerous opinion pieces recommend forgoing these tests with intimate partners. -Bakken et al. 2011 How to implement • Administrative support • Use sample from commercial site-cheaper than performing donor screening • Set a systems wide algorithm on who to treat, how to test, and how to administer • Have a dedicated team willing to perform • Ensure payment to those providing the service • Document outcomes Thanks The End Questions? 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