Treatment of Clostridium Difficile Infec5on Gunter Schleicher Director, Wits DGMC ICU

Transcription

1 Treatment of Clostridium Difficile Infec5on 2017 Gunter Schleicher Director, Wits DGMC ICU

2 Community vs hospital acquired CDI Community acquired 1. Younger 2. Exposure to ancbioccs 3. Acid-suppression medicacon 4. Environmental and food contaminacon 5. Contact with infected persons Hospital acquired 1. Risk factors 2. Severity

3 Hospital acquired CDI risk factors Age 65 y Previous hospitalizacon and prolonged length of hospital stay Nursing home or long-term care facility residence Contact with accve carriers An&bio&c exposure (fluoroquinolones) Increased risk with prolonged use or mulcple ancbioccs ConsumpCon of processed meat Previous gastrointescnal surgery or endoscopic procedure Presence of comorbid condi&ons Malignancy and chemotherapy CysCc fibrosis Diabetes mellitus Liver cirrhosis Chronic kidney disease Inflammatory bowel disease Immunosuppression, immunodeficiency, or human immunodeficiency virus MalnutriCon Hypoalbuminemia Use of proton pump inhibitors Solid organ or hematopoiecc stem cell transplantacon Presence of gastrostomy or jejunostomy tube

4 Non-severe disease 1. IniCal therapy 2. Recurrent disease Severe disease 1. AnCbioCcs 2. Surgery Alterna&ve therapies 1. ProbioCcs 2. Faecal microbiota transplant 3. AlternaCve ancbioccs 4. Anion-binding resins 5. Intravenous immune globulin Treatment outline

5 General principles Treat only symptoma&c pacents Early recogni&on of high risk pacents and prompt diagnosis Stop or modify incicng an&bio&cs If ancbioccs are scll necessary try to use aminoglycosides, macrolides, vancomycin, Cgecycline Strict infec&on control (isolacon, wash hands with soap and water) Avoid ancmoclity agents e.g. loperamide, opiods Suppor&ve care, fluid resuscitacon, correct electrolyte imbalances, nutriconal support Surgery

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7 How to wash your hands properly 1. Wet your hands under running water 2. Lather with soap 3. Cover all parts of your hands 4. Rinse well under running water 5. Dry thoroughly

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9 Non-severe CDI Metronidazole mg tds PO x 10 days Cheap Up to 25% failure rate Change to Vancomycin if 1. No clinical improvement or deterioracon within 48 hours 2. Side effects (nausea, rash, neuropathy, alcohol) 3. Pregnant 4. Children

10 Indicators: 1. DehydraCon (stage 1 AKIN AKI) 2. Abdominal tenderness 3. WCC>15, albumin<25 4. Age>60, 5. Pyrexial 6. Pseudomembranous colics Treatment: Moderate CDI 1. SupporCve 2. Vancomycin mg PO qid x 14 days

11 Severe CDI risk factors Age > 65 y AnCperistalCc or narcocc medicacon use Underlying comorbid condi&ons Immunosuppressive medica&on use Acute kidney injury or chronic kidney disease Chronic obstruccve pulmonary disease Altered mental status Fever Hypotension Severe abdominal pain and/or distencon Ten or more bowel movements per day Leukocytosis (WCC>20) Hypoalbuminemia Ileus Presence of pseudomembranes

12 SupporCve Severe CDI - Treatment 1. ICU/High care 2. Goal directed fluid resuscitacon 3. Vasopressors, inotropes, corccosteroids, NGT 4. Consider TPN 5. Monitor IAP 6. Surgical consult 7. Consider broad spectrum ancbioccs in shocked pacents Specific 1. Metronidazole 500mg IV tds 2. Vancomycin 500mg PO/NGT/enema 3. Fidaxomicin 200mg PO bd

13 Complicated CDI Toxic megacolon PeritoniCs Abdominal compartment syndrome Suspected bowel perforacon or necrosis Refractory shock Worsening MOF (AKI, ARDS, delirium, etc)

14 Complicated CDI - Treatment SupporCve Specific 1. IV Metronidazole + Vancomycin (PO/NGT/colonic irrigacon) 2. Consider Fidaxomicin 200mg PO/NGT bd 3. Consider Tigecycline 100mg IV bd 4. Consider IVIG Surgical 1. Consider if worsening MOF or peritonics 2. Subtotal colectomy with ileostomy (mortality up to 50%) 3. DiverCng loop ileostomy with Vancomycin colonic lavage

15 Recurrent CDI Inability of CDI treatment to clear spores Survive in acidic environments and colonic diverccula Resistant to ancbioccs Can persist due to disrupcon of proteccve microbiota Inadequate produccon of anc-toxin ancbodies Spores germinate and convert to vegetacve form, produce toxin

16 Recurrent CDI risk factors Age 65 y Previous episodes of C difficile infeccon History of severe C difficile infeccon Increasing peripheral leukocyte count Hypoalbuminemia Fever Presence of comorbid condicons Inflammatory bowel disease Ongoing or recurrent ancbiocc exposure Decreased serum anc toxin A IgG Use of acid suppression medicacons (controversial)

17 First recurrence Recurrent CDI 1. Vancomycin mg PO qid x 14 days 2. Fidaxomicin 200mg PO bd x 10 days Second and further recurrence 1. Tapered/pulsed oral Vancomycin with ProbioCcs 2. Fidaxomicin 200mg PO bd x 10 days 3. Fecal microbiota transplant 4. Rifaximin chaser 400mg PO bd x 14 days aler Vancomycin 125mg PO qid x 14 days 5. IVIG 400mg/kg repeated up to 3 Cmes (3 week intervals)

18 Fidaxomicin Not yet registered in SA Macrolide ancbiocc with no systemic absorpcon AcCvity against gram posicve aerobic and anaerobic bacteria, including C. Difficile Clinical efficacy similar to vancomycin in mild-moderate CDI Lower recurrence rates among pacents with non-nap1 strains (19% vs 35%) Appropriate therapy in pacents with recurrent CDI, or as inical therapy in pacents at high risk of developing recurrent disease

19 Comparison of fidaxomicin with vancomycin on clinical cure of CDI, prevencon of recurrence, and sustained cure Subjects achieving endpoint (%) ( 3.1, 7.8) [P=NS] / / 309 Clinical cure 9.9 ( 16.6, 2.9) [P=0.005] / / 265 Recurrence 10.5 (3.1, 17.7) [P=0.0006] / 287 Sustained clinical cure 1. European Public Assessment Report, 22 September 2011 (EMA/857570/2011); 2. Louie TJ, et al. N Engl J Med 2011;364:422 31; 3. Cornely OA, et al. Lancet Infect Dis 2012;12: / ( 4.9, 6.7) [P=NS] / / 257 Clinical cure 14.2 ( 21.4, 6.8) [P=0.0002] / / 223 Recurrence 003 1, (5.2, 20.9) [P=0.001] / / 257 Sustained clinical cure Difference (confidence interval) [P value] Fidaxomicin Vancomycin Data from modified intent-to-treat populacon NS, not significant; Study 003: USA, Canada; Study 004: Belgium, Canada, France, Germany, Italy, Spain, Sweden, UK, USA From The New England Journal of Medicine, TJ Louie, MA Miller, KM Mullane, K Weiss, A Lentnek, Y Golan, S Gorbach, P Sears, Y-K Shue, for the OPT Clinical Study Group, Fidaxomicin versus Vancomycin for Clostridium difficile InfecCon, 364, Copyright 2011 Massachusevs Medical Society. Reprinted with permission from Massachusevs Medical Society. Copyright 2011, Massachusevs Medical Society Reprinted from Lancet Infect Dis, 12, OA Cornely, DW Crook, R Esposito, A Poirier, MS Somero, K Weiss, P Sears, S Gorbach, for the OPT Clinical Study Group, Fidaxomicin versus vancomycin for infeccon with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial, , Copyright (2012), with permission from Elsevier. hvp://

20 Faecal microbiota transplant Indicated for mild or complicated disease, recurrent CDI Oral or rectal transplantacon of faeces from a healthy, pretested donor and the simultaneous cessacon of all ancbiocc use in the recipient are successful in treacng more than 90% of pacents with recurrent C. difficile infeccon Risk of transmission of infeccous agents can be minimised by obtaining stool from healthy donors with normal bowel funccon and by tescng both stool and blood for common viral and bacterial pathogens and parasites Donor tescng: 1. Blood: CMV, EBV, HAV, HBV, HCV, HEV, Syphilis, HIV, Entamoeba histolytica, FBC, CRP, Albumin, U&E, LFT 2. Stool: Clostridium difficile, Salmonella, Shigella, Campylobacter, Escherichia coli O157 H7, Yersinia, VRE, MRSA, MDR-GNB, Norovirus, Giardia lamblia and Criptosporidium parvum, Protozoa and helminths, Faecal occult blood testing

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22 Faecal microbiota transplant - Protocol Stool preparacon: use fresh stool within 6 hours/frozen Treat pacents with vancomycin or fidaxomicin at least for 3 days before FMT. AnCbioCcs should be stopped hours before faecal infusion PPI used if stool delivered by NGT Donor stool can be delivered by C-scope, enema, G-scope, NGT, NJT/ capsule Frozen FMT non-inferior to fresh FMT FMT appears to be safe even in immunocompromised and criccally ill pacents regardless the route of delivery - faecal infusion by enema(s) preferred

23 Probio5cs ProbioCcs may be indicated for pacents receiving ancbioccs who are felt to be at increased risk for CDI There is currently no data to support administering adjunccve probioccs for roucne treatment of CDI No data supporcng a role for probioccs in treatment of severe CDI ProbioCcs may be a useful adjunccve therapy to ancmicrobial therapy for CDI in pacents with non-severe recurrent disease

24 Alterna5ve an5bio5cs Nitazoxanide: equivalent to metronidazole and vancomycin, the cost is significantly more, further studies are needed to assess this medicacon as an alternate in the treatment of severe disease Tigecycline: may be an opcon for severe, complicated disease in criccally ill pacents in combinacon with other CDI therapies Rifaximin: sequencal therapy with vancomycin followed by rifaximin may be effeccve for the treatment of recurrent CDI

25 Anion-binding resins Coles&pol (5 g every 12 hours) or Cholestyramine (4 g 3-4 x daily) for 1-2 weeks Not effeccve as primary therapy for CDI, although they may be beneficial as adjunccve therapy for relapsing infeccon Anion-exchange resins bind Vancomycin as well as C. difficile toxins Tolevamer is a C. difficile toxin-binding resin developed specifically for CDI, inferior to both Vancomycin and Metronidazole as primary therapy

26 Immunotherapy Pooled IVIG 1. Contains C. difficile anctoxin (IgG anc-toxin A Abs) 2. May have a role in relapsing, severe or fulminant CDI in addicon to ancbiocc therapy Bezlotoxumab 1. Human monoclonal ancbodies against C. difficile toxin B 2. In pacents receiving ancbiocc treatment for primary or recurrent C. difficile infeccon bezlotoxumab was associated with a substancally lower rate of recurrent infeccon (clinical cure without recurrent infeccon in 12 weeks 64% vs 54%) 3. Expensive

27 Thank you! Ques5ons?

28 Cost Vancomycin 1gram vial 14 vials (R176.85) R Metronidazole 400mg tablets 3 x 14 = 42 tablets (R5.09) R Tigecycline 50mg vials x 14 = 30 vials (R891.77) R IVIG 30g x 5 = 150g (R ) R Cholestyramine 4 gram sachet 4 x 14 = 56 (R7.47) R Fidaxomycin 200mg tablets 10 x 2 = 20 R? Bezlotoxumab 10 mg/kg x 1 USD17000 (R238000)