Treatments, Tapers, and Transplants: Guidelines and Options for Complicated C. diff Patients MIA A. TAORMINA, DO, FACOI

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1 Treatments, Tapers, and Transplants: Guidelines and Options for Complicated C. diff Patients MIA A. TAORMINA, DO, FACOI DUPAGE MEDICAL GROUP INFECTIOUS DISEASE

2 Objectives To discuss the epidemiology and available testing for C.diff in our institutions To discuss the available treatments for C.diff and how we are using them To discuss the role of probiotics in the treatment/prevention of C.diff To discuss the methods of tapering therapies for C.diff To discuss fecal transplant for refractory/severe C.diff

3 Consult Hey do you have time for a quick consult? 74yo man from an ECF with fever, leukocytosis, decreased O2 they think he aspirated. They gave him doses of zosyn, clindamycin, vancomycin, and Levaquin in the ER. Right now all 4 drugs are still going. Can you please see him before we give him C.diff?!

4 Clostridium difficile how bad is it? ~500,000 cases annually in the U.S. as of ,000 deaths 1/11 age 65 or older die within 1 month of diagnosis! 293,000 cases are healthcare associated, acquired Almost 20% will relapse, with 60% who relapse having additional relapses The major cause of diarrhea in patients hospitalized over 3 days Up to 20% of all hospitalized patients receiving antibiotics Affects 22 patients in every 1000 Estimated $1 billion per year in management costs BRANDT. LJ ET. AL. AM J GASTROENTEROL. 2012

5 LEFFLER DA, LAMONT JT. N ENGL J MED 2015;372:

6 C.diff continued Incidence greater in women, Caucasians, those over age 65yo This anaerobic bacterium colonizes 2-3% of healthy adults Increases to 26% with exposure to healthcare settings Acquired by fecal-oral transmission Poor hand washing among healthcare workers Although all antibiotics have been implicated, infection more common with: Clindamycin, quinolones, 3 rd generation cephalosporins, ampicillin Greater risk in patients on PPIs, those with enteral tube feedings, chemotherapy patients, those with inflammatory bowel disease, and those taking chronic NSAIDs

7 Complications can be severe

8 C.diff toxins 3 Toxins TcdA (enterotoxin), TcdB (enterotoxin), and binary toxin of unclear significance Toxins cause both inflammation and infection Incidence and severity of C. diff appears to be worsening due to more virulent strains NAP1/027 strain contains an 18 base-pair deletion of an inhibitory gene which causes higher toxin A and B production Up to 7% mortality with these highly virulent strains

9 Diagnosis Test only liquid, diarrheal stools Pathogenic strains of C. diff produce either/both toxin A and toxin B Rapid enzyme immunoassays (EIAs) for toxin A/toxin B 75-90% sensitivity on a single stool, 90-95% with 2 stools Nucleic acid amplification testing (PCR) 97% sensitive, now the preferred testing modality Glutamate dehydrogenase assay 95% negative predictive value Mixed results require PCR for confirmation

10 Treatment for Mild to Moderate C. diff If possible, discontinue or streamline all antibiotics Treatment regimens generally include metronidazole, vancomycin, and fidaxomicin For MILD disease Initiate metronidazole 500mg p.o. TID x 14 days For MODERATE disease Initiate vancomycin 125mg p.o. QID x 14 days or fidaxomicin 200mg p.o. BID x 10 days If patients are responding appropriately, no need for test of cure

11 Treatment of Severe C.diff WBC > 15K-30K, serum albumin < 3g/dL, rise in serum crea to > 1.5x baseline Vancomycin 500mg p.o. QID +/- metronidazole 500mg IV q6-8h x 14 days Vancomycin retention enemas 500mg in 100 ML every 6 hours Efficacy of fidaxomicin for severe disease with little data Consideration for fecal transplantation Consideration for colectomy

12 Cost comparison Metronidazole 500mg p.o. TID x 14 days ~$30.00 Vancomycin slurry (compounded IV vancomycin) x 14 days ~$ $40.00 Vancomycin capsules x 14 days ~$ Fidaxomycin x 10 day treatment course ~$ Drug company may offset some of the cost

13 Relapsed, Recurrent C.diff 25% of those who have a relapse of symptomatic diarrhea do so in the 1-2 weeks after discontinuation of therapy If in a healthcare setting (ECF, etc.) could be due to re-exposure Could also be due to incomplete eradication of the organism Protocol for a FIRST recurrence is to repeat the same therapy x 14 days?need to retest A trial in 2011 demonstrated that fidaxomicin had a lower relapse rate (7.8%) vs. those treated with vancomycin (23.6%) Non NAP1/BI/027 strains Relapse rates similar with NAP1/BI/027 Suggests fidaxomicin may be an appropriate initial therapy in patients at high risk for relapse (chemotherapy, immunocompromised, ESRD, etc.) MCCOLLUM DL ET. AL CLIN GASTROENTEROL HEPATOL 2012

14 The Taper Tapering doses of oral vancomycin given over a period of weeks-to-months Often loosely judged practitioner-to-practitioner based on number of relapses, duration of symptomatic disease, comorbidities Suggested tapering strategy: Vancomycin 125mg p.o. QID x 14 days, then Vancomycin 125mg p.o. BID x 7 days, then Vancomycin 125mg p.o. QD x 7 days, then Vancomycin 125mg p.o. q3d x 2-8 weeks Tapering strategies usually suggested in patients with a second relapse after 2 treatment courses have failed or yielded only short-term improvement in symptoms

15 But how do YOU taper Always begin with a full treatment course of vancomycin mg p.o. QID x days With very protracted symptoms or those who fall into a severe category (p.o. vancomycin + IV metronidazole initially), QID dosing often prolonged Tapers we use often suggest TID dosing x 14 days, BID dosing x 14 days, QD dosing x We have some patients on QD or BID dosing indefinitely

16 What about Probiotics? Two published trials utilizing Saccharomyces boulardii Did NOT decrease recurrence rates for initial C.diff patients (19% vs. 24% placebo) DID decrease the frequency of relapse in those with recurrent CDI (34.6% vs. 64.7% placebo) Second trial demonstrated no added benefit with standard dosing of metronidazole or vancomycin, only some benefit when used with high dose oral vancomycin in severe cases Recurrence rates found to be somewhat worse with Lactobacillus Overall outcomes have been less than ideal

17 Probiotics continued IDSA guidelines state: Administration of currently available probiotics is not recommended to prevent primary CDI, as there are limited data to support this approach and there is a potential risk of bloodstream infection (C-III). But what do we really do? Do not, as a rule, give probiotics simultaneously with all treatment Do not give probiotics in immunocompromised patients or those with PICC lines Consideration for after treatment course? Consideration for patients with a h/o mild C.diff and a need for antibiotic use

18 Hey, yeah, what if my patient has had C.diff before and now needs antibiotics? If your patient has had mild to moderate c.diff in the past 1-2 years consider giving concurrent probiotics or encouraging daily active culture yogurt intake while on antibiotics If your patient has a h/o severe c.diff, consider narrowest spectrum antibiotics to treat acute infection Also consider concurrent empiric p.o. vancomycin in high risk patients Dosing? When to stop empiric p.o. vancomycin?

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20 Fecal Transplant A 2009 study found that fecal bacteriotherapy was an effective and simple procedure that was more cost-effective than continued antibiotic administration and reduced the incidence of antibiotic resistance A protocol was designed by a team of physicians in 2011 outlining the indications and methods of performing fecal transplant BAKKEN JS (DEC 2009). "FECAL BACTERIOTHERAPY FOR RECURRENT CLOSTRIDIUM DIFFICILE INFECTION"

21 Fecal Transplant continued INDICATIONS: Recurrent or relapsing CDI At least three episodes of mild-to-moderate CDI and failure of a 6-8 week taper with vancomycin with or without an alternative antibiotic (e.g., rifaximin, nitazoxanide). At least two episodes of severe CDI resulting in hospitalization and associated with significant morbidity. Moderate CDI not responding to standard therapy (vancomycin) for at least a week. Severe (and perhaps even fulminant C. difficile colitis) with no response to standard therapy after 48 hours. In all cases, primary consideration must be given to the severity and pace of the patient's CDI when deciding whether early use of FMT is appropriate to prevent further clinical deterioration.

22 Donor selection? Possible theoretical advantage to spouse/significant other Possible theoretical advantage to maternal first-line relatives Exclusion criteria similar to blood donation: Known HIV, Hepatitis B or C infections Known exposure to HIV or viral hepatitis (within the previous 12 months) High-risk sexual behaviors (examples: sexual contact with anyone with HIV/AIDS or hepatitis, men who have sex with men, sex for drugs or money) Use of illicit drugs Tattoo or body piercing within 6 months Incarceration or history of incarceration Known current communicable disease (e.g., upper respiratory tract infection) Risk factors for variant Creutzfeldt-Jakob disease Travel (within the last 6 months) to areas of the world where diarrheal illnesses are endemic or risk of traveler's diarrhea is high

23 Procedure? Donor stool should be used as soon as possible, preferably within 6 hours after it is passed Although the choice of diluents may differ among practitioners, the use of either preservativefree normal saline for intravenous injection or 4% milk is preferred to dilute the stool sample For best results, a conventional household blender (dedicated to this purpose) should be used. The stool should be homogenized, adding more diluent as necessary, until it reaches a liquid slurry consistency The stool should be filtered to remove as much particulate matter as possible. This can be accomplished using a number of methods (e.g., gauze pads, urine stone strainers) The finished stool slurry should be used immediately The ideal volume for instillation has not been established. However, smaller volumes (e.g., ml) should be used for delivery from above; larger volumes (e.g., ml) should be used for delivery from below

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25 Outcomes? >90% clinical cure in patients who successfully complete FMT 20-25% of patients have to have the procedure done twice to induce remission Other options? IVIG therapy has been a consideration Study results for the use of IVIG have been equivocal at best Colectomy in refractory or life threatening cases remains a consideration

26 Take Home Points C.diff is a major healthcare issue and is easily one of the greatest burdens when it comes to nosocomial infections Attention to contact isolation procedures and hand washing is key Treatment considerations include metronidazole, vancomycin, and fidaxomicin Tapering courses of vancomycin are strongly considered in those with a second relapse as well as immunocompromised hosts and those at high risk for further relapse Fecal transplantation is rapidly becoming a strong consideration for refractory and severe cases of C.diff and has a >90% success rate