Clostridium difficile

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1 Clostridium difficile Sarah Doernberg, MD, MAS Assistant professor and Medical Director of Antimicrobial Stewardship Division of Infectious Diseases, UCSF 2.19,2018 Outline Brief background and epidemiology Diagnosis Management mild, uncomplicated disease Management moderate-severe disease Management recurrent/relapsed disease Management fulminant disease Prevention 1

2 One of CDC s 3 Urgent Threats 500, billion CDI Background Anaerobic, spore-forming grampositive bacillus Toxins A + B Multiple strains Epidemic strain ID d strain Fecal-oral spread 12% of all HAIs Carriage of C. difficile < 3% for healthy adults in community 20% in hospitalized pts up to 50% in LTCF Risk factors: Antibiotics Age Hospitalization Acid-suppression IBD Tube feeds Host immune factors Chemotherapy Female gender Domestic animals? Retail food? Magill SS et al., NEJM

3 Epidemiology trends, inpatients Molecular testing era Epidemic strain Duration, number, and intensity of antibiotics affect risk for CDI 6 Stevens V, et al. Clin Infect Dis 2011; 53:

4 Antibiotic use affects the population risk Brown K et al. JAMA Intern Med Apr;175(4): Spread of CDI in the hospital Asymptomatic carriers 30%? Endogenous carriage Symptomatic cases 25-33% Walker AS et al. PLoS Med Feb;9(2):e ; Kamboj M et al. Infect Control Hosp Epidemiol Jan; 37(1): 8 15; Curry SR et al. Clin Infect Dis Oct 15; 57(8): ; McDonald LC, Clin Infect Dis Oct;57(8):

5 Diagnostic testing Glutamate dehydrogenase Ag (GDH) Bacterial detection Sensitive but not specific Polymerase chain reaction (PCR): Toxin-producing gene Sensitivity Enzyme immunoassay (EIA) Protein detection Sensitivity Specificity for disease CDI overdiagnosis 21% +PCR Of these, 44% + toxin Toxin-/PCR+ bacterial load abx diarrhea No CDIcomplications Polange CR et al., JAMA Intern Med Nov;175(11):

6 Case 63 year old F s/p spinal fusion c/b hardware infection. She received a 6 week course of antibiotics for this and is admitted for redo spinal fusion. She has been constipated and has daily orders for senna, colace and miralax. On HD# 8, she develops 2 loose stools and tests positive for C. difficile. She is afebrile with a normal WBC and is started on PO metronidazole. She has no further episodes of loose stools during the remainder of hospitalization. Overdiagnosis case 63 year old F s/p spinal fusion c/b hardware infection. She received a 6 week course of antibiotics and is admitted for redo spinal fusion. She has been constipated and has daily orders for senna, colace and miralax. On HD# 8, she develops 2 loose stools and tests positive for C. difficile. She is afebrile with a normal WBC and is started on PO metronidazole. She has no further episodes of loose stools during the remainder of hospitalization. 6

7 MANAGEMENT Treatment scenario #1. 63 y/o F recently treated for a UTI with levofloxacin, now having watery stools 4x/day, fever to 38.3, WBC 16K, Cr 1.7 (baseline 0.5). PCR positive for C. difficile toxin. With what should you treat her? A. Vancomycin 125 mg po qid B. Vancomycin 500 mg po qid C. Metronidazole 500 mg po tid D. Fidaxomicin 200 mg po bid 7

8 CDI treatment depends on severity Mild to moderate: Does not meet criteria for severe Diarrhea 3 stools/24 hours Severe Not well validated IDSA/SHEA guidelines: Severe disease = Peak WBC > 15K or Cr > 50% above baseline or advanced age (65? 75?) Severe, complicated Severe plus hypotension, shock, ileus, and/or megacolon Zar F A et al. Clin Infect Dis. 2007;45: ; Cohen et al., Infection Control and Hospital Epidemiology, 2010; 31: RCTs metronidazole vs. vancomycin p = NS p = 0.02 NS MTZ Vanco 20 0 Cure, all Cure, mild-mod Cure, severe Recurrence Similar findings for recent study of metronidazole vs vancomycin vs tolevamer Cure not differential with regard to levels of severity Higher recurrence across the board (20%) Only vancomycin is FDA-approved Zar F A et al. Clin Infect Dis. 2007;45: ; Leffler DA and Lamont JT. NEJM 2015; 372: ; Johnson S et al., Clin Infect Dis 2014;59(3):

9 New evidence to support vancomycin arr death vanco vs metronidazole Any severity: 0.86; (0.74 to 0.98) Severe: 0.79 (0.65 to 0.97) NNT to prevent 1 death, severe CDI: 25 Stevens VW et al. JAMA Intern Med Feb 6. doi: /jamainternmed What about fidaxomicin? Bottom line vs. vanco: Similar cure (~88%), lower recurrence (13-15% vs % ) Unclear role in multiply recurrent or severe disease Cure Relapse Strain Epidemic Same Same Non-epidemic Same Concomitant abx Prior CDI Same =/ Fidaxomicin Vancomycin Metronidazole $2800 $ $22 Louie TJ, et al. NEJM 2011;364: ; Cornely et al, Lancet Infect Dis 2012;12:281-8 ; Petrella LA, et al. Clin Infect Dis 2012;55(3):351-7; Mullane et al., CID 2011;53(5):440-7; Corneley et al., CID 2012;55:s154-s161.; Bartsch SM et al., CID 2013; 57(4): ; Konijeti GG et al., CID 2014; 58:

10 Real-world fidaxomicin experience UK Trust Hospitals analyzed preand postinformation s/p introduction of fidaxomicin Each hospital had a different approach to rx with fidaxomicin (e.g. all patients vs. selected populations) A and B: Fidaxomicin used first-line for all C, E, F, G: Selected episodes D: Recurrences only Goldenberg SD et al. Euro J Clin Microbiol and Infect Dis 2016; 35L UCSF guidelines Clinical definition Criteria Treatment Initial, mild mod, Outpatient Not meeting criteria for severe Metronidazole 500 mg po q8h x days If no 5 days, switch to vancomycin 125 mg po q6h x days Initial, mild mod, Inpatient Not meeting criteria for severe Initial, severe WBC 15 OR Cr 1.5x baseline without hypotension, shock, ileus, and/or megacolon Vancomycin 125 mg po q6h x days If unable to obtain upon discharge, okay to complete the course with metronidazole 500 mg po q8h Vancomycin 125 mg po q6h x days 10

11 Additional considerations Stop unnecessary antibiotics Shorten antibiotic courses Narrow antibiotic spectrum Stop acid-suppressive medications when possible Esp PPI Do not use anti-peristaltic agents until acute symptoms of CDI improve Take-home For mild-moderate disease, can choose metronidazole, more movement towards PO vancomycin in recent years For severe disease, choose vancomycin Higher cure, but same relapse Role of fidaxomicin unclear Consider if high risk of relapse or need CA? Use in multiply recurrent disease? Role in severe disease 11

12 Treatment scenario #2: You are seeing a 62 y/o F who has takes chronic amoxicillin/clavulanic acid for suppression of Enterococcal osteomyelitis and has developed her second bout of C. difficile colitis. Her WBC count is 9 and Cr is 0.3. What should you treat her with? A. Metronidazole 500 mg po TID B. Vancomycin 125 mg PO QID C. Vancomycin taper Risk for recurrent CDI 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 1st episode 2nd episode 3rd episode No recurrence Recurrence Johnson S. J Infect 2009;58(6):403-10; Pepin J et al. Clin Infect Dis Jun 1;40(11):

13 Treatment scenario #3. This patient returns one month after you have treated her with a 14-day course of PO metronidazole complaining of ongoing diarrhea. A repeat stool toxin is positive. What do you do? A. Metronidazole 500 mg po TID x 14 days B. Vancomycin 125 mg PO QID x 14 days C. Vancomycin taper D. Fidaxomicin 200 mg PO BID x 10 days E. Other Vancomycin taper 125 mg po 4x daily x 14 days 125 mg po 2x daily x 7 days 125 mg po 1x daily x 7 days 125 mg po every other day x 8 days (4 doses) 125 mg po every 3 days x 15 days (5 doses) Kelly and LaMont, N Engl J Med. 2008;359(18):

14 Fecal diversity with rcdi FMT basics Colonization resistance Related donors or banked stool Need to screen for transmissible diseases Multiple RCTs have now been done Guidance document available (Bakken et al) Chang JY et al. JID 2008; 197: 435-8; Kassam et al., Arch Intern Med. 2012;172(2): Gough et al., CID 2011;53(10): ; Bakken JS et al Clin Gastroenterol Hepatol 2011; 9: FMT trial trends 6 published 3 vs. abx management 3 vs. FMT refinements Over time, efficacy in RCTs response to comparator abx Might matter whether active recurrence vs. prior recurrence? Might need multiple FMTs Vanco taper might be better than we thought? Commercially-prepared FMT in development Johnson S and Gerding DN. Clin Infect Dis (2016) 64 (3): ; van Nood E et al. N Engl J Med 2013; 368: ; Orenstein R et al. Clin Infect Dis (2015) 62 (5):

15 The latest on FMT Multiple previous trials supported FMT But comparator group not standard of care Phase 2/3 open-label RCT Stopped early for futility FMT by enema Recurrence: 9/16 (56%) FMT vs. 5/12 (42%) taper group 95% CI for CDI with FMT = -2.8% to +47.3% Hota SS et al. Clin Infect Dis (2016) 64 (3): FMT meta-analysis Overall response: Multiple infusions: 92% (89-94%) Single infusion: 84% (79-89%) Just RCTs: Multiple: 91% (88-94%) Single: 77% (56-93%) Quarashi MN et al. Aliment Pharmacol Ther Sep;46(5): doi: /apt Epub 2017 Jul

16 FMT leads to better cure rates RCT of rcdi treated with autologous vs donor FMT 3 episodes Via colonoscopy Note regional differences 1 donor had a 9.1 KG wt gain Good results for RCT of FMT via NGT vs colo (N = 20) Kelly CR et al. Ann Int Med 2016; Van Nood E, et al. NEJM 2013; 368: ; Cammarota et al, Alim Pharm Ther 2015:41:835; Youngster I et al., CID 2014;58: FMT for abx resistance? Millan B et al. Clin Infect Dis 2016;62:

17 FMT via pill? Unblinded noninferiority (15%) multicenter RCT of 117 adults with 3 episodes of CDI Stratified by age (65) and immunosuppressed status (15%) Median duration of rcdi rx prior to transplant: mths Absence of 12 weeks: 51/53 (96%) in capsule group versus 50/52 (96%) colonoscopy group (per-protocol) Difference: 0% (95% CI, -6.1% to infinity) Pts with recurrence were retreated with same modality Sensitivity analyses including LTFU as recurrences still met noninferiority Both groups had increased microbial diversity post-transplant Kao D et al. JAMA. 2017;318(20): doi: /jama FMT adverse events Common Diarrhea Cramping Belching Nausea Bloating Rare/serious Procedure-related harms Perforation Aspiration Norovirus Bacteremia IBD flare Unknown long-term effects Weight changes Chronic disease exacerbation Drekonja D et al. Ann Intern Med 2015;162(9):

18 FMT durability Single-center retrospective f/u of all patients receiving FMT 137/191 (72%) response rate (additional 26 deceased and 15 without contact information) 2/26 (7.7%) of deceased died of rcdi Median time to f/u: 22 months (range, 3-51) Most (97%) got PO vancomycin, 53 (39%) also fidaxomicin 24/137 (18%) had rcdi post-fmt 61/137 (45%) got additional antibiotics 43/113 (38%) w/o rcdi vs. 18/24 (75%) w/ rcdi (p < 0.01) Mamo Y et al. Clin Infect Dis Dec 19. doi: /cid/cix1097. [Epub ahead of print] UCSF guidelines Clinical definition Criteria Treatment 1 st recurrence Except special populations below 1 st recurrence, special population Hematologic cancer with neutropenia expected > 30 days Recent bone-marrow transplant or treatment for GVHD Solid-organ transplant < 3 mths Otherwise not an FMT candidate Same as for initial therapy, stratified by illness severity Fidaxomicin 200 mg po q12h x 10 days (be sure to check insurance coverage before prescribing for outpatients; if insurance does not cover can try the MERCK pt assistance program at www. merckhelps.com) 2 nd recurrence Vancomycin tapered and/or pulsed PLUS Evaluate for FMT Consult ID, GI 18

19 Take-home Recurrent CDI is a challenge Treat first episode with same agent, adjust for severity Subsequently, use vanco taper Primary FMT indications Recurrent or relapsing FMT (usu > 2 episodes) Moderate CDI not responding to Rx Possibly severe/complicated Treatment scenario #4: 63 y/o F recently treated for a UTI with levofloxacin, now with profuse diarrhea, T 38.7, BP 79/50, HR 140, WBC 30K, Cr 3.2, and lactate 3.7. What do you treat her with? A. Vancomycin 125 mg po qid B. Vancomycin 500 mg po qid C. Vancomycin 500 mg PR qid D. Metronidazole 500 mg iv tid E. Fidaxomicin 200 mg po bid F. A+C+D G. B+C+D 19

20 Total colectomy with end ileostomy Retrospective cohort pts in ICU for CDI N = 161 (38 surgery, 123 medical rx) Indications: Shock (40%), megacolon (29%), no response to med rx (26%), perforation (5%) aor death 0.2 ( ) colectomy vs. medical rx WBC > 50K and lactate > 5 conferred very poor prognosis More beneficial in age 65, immunocompetent, WBC 20, lactate % died (58% medical rx, 34% surgical) Selection bias likely Lamontagne et al., Ann Surg 2007;245(2): Diverting loop ileostomy + colonic lavage 3/42 (7%) converted to total colectomy (2 for abd compartment sx) 79% had ileostomy reverted VS historical colectomy controls, OR for death = 0.24 ( ) 19% died w/i 30 days 14% more died afterwards, all deemed due to underlying illness RCT recruiting (projected end date 2018) Neal et al. Ann Surg Sep;254(3):423-7; discussion

21 Multicenter loop ileostomy study 10 centers, 98 patients 21% LI patients ; trend towards lower APACHE, less vasopressor use, later surgery Overall mortality 32% (unadjusted, 34% TC vs 24% LI, p = 0.4) Mortality adjusted for confounders, LI 17% vs TC 40%; p = Less blood loss for the LI group LI group did worse if reoperation needed Ferrada P et al. J Trauma Acute Care Surg Jul;83(1):36-40 FMT for severe disease Study Population Intervention Outcome Cammarota et al, Aliment Pharmacol Ther 2015 Fischer et al, Aliment Pharmacol Ther 2015 Subgroup of RCT w/ recurrent CDI, N = 7 w/ pseudomembranes Single-center Cohort, N = 29 Severe (10) +/- complicated (19) Single-center RCT FMT via colo vs vanco Initial 2 pts 1 FMT via colo; remainder FMT q3 days prn FMT via colo ~qwk with intermittent vanco Mortality: 29% (1 FMT) Cure: 71% ( 2 FMT) Mortality: 7% (both severe/comp) Success: 93% ( 2 FMT in 55%) Zainah H et al. Dig Dis Sci 2015 Aroniadis et al. J Clin Gastroenterol 2015 Cohort, N = 14 with severe, refractory CDI (43% in ICU) Single-center Multicenter cohort N = 17 76% severe/complicated FMT via NGT, rpt at 48-72hr if not response FMT mostly via colo Mortality: None d/t CDI (29% at 100 dd 2/2 underlying dz) Success: 79% ( 2 FMT in 21%) Success: 94% ( 2 FMT in 6%) 21

22 FMT for severe disease Single center retrospective cohort analysis of 111 patients FMT group treated with vanco 2-4 days pre- & 4 days post-fmt Clinician discretion whether to offer FMT 66 (59%) underwent FMT; 45 (41%) did not (incl 26 due to clinical improvement on medical rx and 13 due to instability) 3 month mortality: 12.1% (8/66) in the transplant group vs 42.2% (19/45) in the antibiotic group (OR 0.19 [95% CI, ]) Multivariable analysis: FMT OR, 0.13 (95% CI,.04.44) However, risk of confounding by indication high No control for systemic antibiotic receipt Hocquart M et al. Clin Infect Dis Aug 24. doi: /cid/cix762. [Epub ahead of print] Take-home for severe, complicated CDI Use high-dose oral +/- rectal vancomycin Use IV metronidazole Consider surgical intervention early Consider diverting loop ileostomy FMT is promising but need more data, multiple FMTs may be needed Make sure medical therapy has been optimized Additional therapies (IVIG, other antibiotics) lack data 22

23 Treatment scenario #5. You are starting your 70 y/o M patient on 4 weeks of ciprofloxacin for prostatitis. He asks you whether he should take probiotics. How do you counsel him? A. Probiotics will prevent antibiotic-associated diarrhea, including CDI B. Probiotics will prevent antibiotic-associated diarrhea but not CDI C. Probiotics are useless RCT of probiotics for CDI Diarrhea class Probiotic Placebo OR AAD 159/1470 (11%) 153/1471 (10%) 1.04 ( ) CDI 12/1470 (0.9%) 17/1471 (1.2%) 0.70 ( ) No benefit for probiotic Very low rates of CDI in this population Majority of patients were receiving amoxicillin/ampicillin or second-generation cephalosoporins (UK study) Likely underpowered for the CDI outcome Allen SJ et al., Lancet 2013 Oct 12;382(9900):

24 Meta-analysis Very rigorous NNT: 43 (95% CI, 36 58) Remained significant even when missing data was excluded Studies limiting people to initiation within first 1-2 days on abx had stronger effect size Limits UK study (Allen) Shen NT et al. Gastroenterology Jun;152(8): Approaches to prevent CDI Gerding D N, Johnson S. CID 2010;51:

25 Infection control Gloves + gowns for duration of diarrhea Wash with soap and water Private rooms Dedicated commode Bleach cleaning Antimicrobial stewardship Cohen et al., Infection Control and Hospital Epidemiology, 2010; 31: Identification and isolation of carriers Longtin Y et al. JAMA Intern Med. 2016;176(6):

26 Non-toxigenic C. diff for secondary prevention 173 patients with 1 st or 2 nd episode of CDI w/i 28 days (phase II) 1-2 days after stopping CDI treatment randomized to nontoxigenic C diff (NTCD-M3) vs. placebo Recurrence: OR 0.3; 95% CI, Of NTCD-M3 group, 2% for those colonized vs. 31% if not colonized Gerding DN et al., JAMA 2015; 313(17): Secondary prophylaxis? 1. Retrospective cohort at two hospitals in Quebec ahr 0.59 ( ) Adult w/ CDI Rx d non-cdi abx within 90 d (in or outpt) Recurrence w/i 6 mo ahr 1 st CDI 0.91 ( ) ahr recurrence 0.47 ( ) 2. Retrospective cohort St. Louis Adult w/ CDI Rx d non-cdi abx within 90 d (inpt) Recurrence w/i 4 weeks OR 0.12 ( ) No multivariate analysis Carignan A et al. Am J Gastroenterol Dec;111(12): Van Hise NW et al. CID 2016; 63 (5):

27 Host protection Actoxumab Bezlotoxumab Kyne et al., NEJM 2000;342(6): Lowy et al. NEJM 2010 Jan 21;362(3): Monoclonal Abs for secondary prevention MODIFY I and II trials NNT = 10 No clear subgroup benefited Cost may be an issue sustained cure Bezlotux vs. SOC: 9.7% ( ) Wilcox MH et al. N Engl J Med 2017; 376:

28 C diff vaccine? CDI prevention summary Remember infection control basics Role of isolation of carriers evolving Unclear role for probiotics, unlikely to be a game-changer Non-toxigenic C. diff is promising Passive immunity is effective but costly There may be a role for vaccine in the future Do not forget good infection control and antimicrobial stewardship practices! 28

29 CDI take-home Vancomycin preferred, metronidazole okay for mild-moderate disease Vancomycin for severe disease Fidaxomicin may be appropriate for those at high risk for relapse and/or those requiring CA But, might not be cost effective Fulminant disease: PO/PR vancomycin and IV metronidazole Consider surgery Maybe FMT 1 st recurrence same agent (or fidaxomicin) 2 nd and beyond vancomycin pulse and taper FMT may be the best option for recurrent CDI Prevention is important THANK YOU! 29

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