Clostridium difficile coli%s. John K. Midturi January 2013

Transcription

1 Clostridium difficile coli%s John K. Midturi January 2013

2 Objec%ves Describe pathogenesis of C. Diff coli%s Review methods of diagnosis of C. Diff coli%s Discuss treatment op%ons first episode refractory Review new pharmaceu%cals in the management of this disease Iden%fy complica%ons of C. Diff coli%s Review preventa%ve measures of infec%on Discuss pa%ent educa%on for eradica%on of C. Diff when discharged from the hospital

3 What are risk factors for Clostridium difficile? 1. Prolonged an%bio%c exposure 2. Advanced Age 3. Use of Proton Pump inhibitors 4. All of the above 0 of Countdown

4 Clostridium difficile coli%s 250,000 hospitalized cases annually in USA 1 2.5% mortality Annual cost: $433 $797 million Risk factors: Aging popula%on Increased healthcare exposure Increase in hospital procedures Environmental exposure

5 C. Diff clinical presenta%on Asymptoma%c Diarrhea Pseudomembranous coli%s Fulminant coli%s Recurrence: ~20% Persistence of intraluminal spores a^er treatment completed If two episodes of C. diff then recurrence >65% Lab: Leukocytosis, rising crea%nine

6 Pathogenesis An%bio%c Disrup%on of colonic flora Toxin producing C. difficile exposure Toxin release Mucosal injury & Inflamma%on

7 Pathogenesis Dependent on host and pathogen Host factors Toxin A an%body produc%on Asymptoma%c carriers demonstrate high levels of IgG an%body against toxin A compared to symptoma%c pa%ents Moun%ng a serum an%body response to toxin A during infec%on was associated with reduced recurrence rates Interleukin 8 levels Elevated IL 8 levels correlated with impaired humoral immune response to Clostridium difficile toxin A Frequency of IL 8 allele (associated with increase in IL8) with single nucleo%de polymorphism genotype AA significantly associated with development of CDI Intes%nal toxin receptors Absence of intes%nal receptors for C. difficile toxins in animal neonate models associated with asymptoma%c state. Coloniza%on with nontoxigenic strains Protec%ve factor against toxin producing strains

8 Other factors associated with pathogenesis An%bio%cs Disrupt normal colonic flora Clostridium difficile an%bio%c resistance to clindamycin(j strain) or quinolones Increased dura%on of an%bio%c therapy Advanced age Tenfold higher rates of infec%on if age>65yrs Diminished immune response Comorbid illnesses placing him at cumula%ve risk of infec%on (greater likelihood for hospitaliza%on or an%bio%c) Gastric acid suppression %mes higher risk of CDI amongst pa%ents exposed to PPI hkp:// Community associated infec%on Increased incidence of community acquired and hospital acquired infec%ons from Community acquired infec%ons less likely to have an%bio%c exposure, less PPI use, less frequency of cancer Retail food products and domes%c animals have been postulated is emerging sources

9 Who is at risk for recurrence? 2043 pa%ents with first posi%ve EIA Sept 2006 December (13%) died within 2 weeks 1678 (82%) followed up a^er 14 days 363 (22%) recurrence Predictors of CDI Recurrence CID 2012: 55:s77 s87

10 Who is at risk for recurrence? Inpa%ent (71%), median admission days 8 Older median age 77yrs 86% prior hospitaliza%on Emergency hospitaliza%on Higher CRP Higher neutrophil count h/o MRSA infec%on

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12 When do they get recurrence?

13 C. Difficle diagnosis ELISA toxin A&B assay presence of toxin Inexpensive 24 hours Sn 60 95%, sp 99% CID 2007; 45: Tissue culture cytotoxicity for toxin B presence of organism, Gold standard (sn %, sp 99%) JID1984;149:781 Culture PCR Two step approach: Glutamate dehydrogenase an%gen (GDH) if posi%ve, followed by ELISA Toxin A/B

14 Alternative: Fidaxomicin 200mg BID x 10days Alternative: Fidaxomicin 200mg BID x 10days n engl j med 359;18 october 30, 2008

15 Treatment Ini%al Episode Mild Moderate Severe Metronidazole 500mg PO TIDx 10 14d Vancomycin 125mg PO QID x 10 14d n engl j med 359;18 october 30, 2008

16 Treatment First Recurrence Mild Moderate Severe Metronidazole 500mg PO TIDx 10 14d Vancomycin 125mg PO QID x 10 14d n engl j med 359;18 october 30, 2008

17 n engl j med 359;18 october 30, 2008

18 n engl j med 359;18 october 30, 2008

19 Treatment Second Recurrence Vancomycin Tapered & Pulsed Vancomycin 125mg QID x 14d BID x 7d QD x 7d QOD x 8d (4 doses) Every 3 days x 15d (5doses) n engl j med 359;18 october 30, 2008

20 Treatment Third Recurrence Vancomycin 125mg QID x 14d Rifaximin 400mg BID x 14d n engl j med 359;18 october 30, 2008

21 Other Op%ons IVIg 400mg/Kg every 3 weeks (total 2 3 doses) Fecal Transplant n engl j med 359;18 october 30, 2008

22 Treatment op%ons Discon%nue implicated an%microbial agent Ins%tute suppor%ve care Hydra%on and electrolyte replacement Avoid an% peristal%c Including narco%cs and loperamide Infec%on control Single room with bathroom Hand hygiene with soap and water Avoidance of rectal thermometers Terminal room cleaning with 1:10 household bleach

23 Complica%ons Inability to take oral medica%ons IV metronidazole 500 mg IV 4 %mes a day plus vancomycin 500 mg by reten%on enema or NG tube every 6 hours Delayed response in cri%cal illness Consider IVIG 400 mg/kg Surgical consulta%on for possible colectomy Prophylac%c metronidazole or oral vancomycin may increase rate of C. difficile carriage Not recommended

24 Treatment Agents

25 Vancomycin Has remained a highly effec%ve treatment agent Not absorbed Highly effec%ve for ini%al cure, recurrence rate of 20% No jus%fica%on for increased dose or extending the length of treatment Neither of these strategies has been tested high concentra%ons of vancomycin achieved by 125 mg dose

26 Vancomycin Pulse taper approach is prac%cal Decrease frequency to twice daily and once daily then every other day to every third day High cost Promo%ng overgrowth or coloniza%on of other pathogens such as enterococcus and Staphylococcus species Intracolonic vancomycin 500mg in 100ml NS q6 hours ileus

27 Metronidazole Uses first line treatment since 1994 Effec%ve for mild to moderate disease Increased failure rates and slower %me to symptom resolu%on Inferior to vancomycin for severe disease Clinical infec%ous diseases 2007; 45: th interscience conference on an%microbial agents and chemotherapy, 17 September Abstract L Severity based on white blood cell count and serum crea%nine level Infec%on control Hospital epidemiology 2010; 31: Highly absorbed Fecal concentra%ons are zero and asymptoma%c carriers Modest levels in pa%ents with diarrhea

28 Nitazoxanide Thiazolide compound that has an%parasi%c ac%vity Similar response rate to vancomycin and metronidazole clinical infec%ous diseases 2006; 43:421 7 Clinical infec%ous diseases 2009; 48: E Small size of these studies does not permit appropriate conclusion about non inferiority or superiority Ten day course of Nitazoxide a^er failing 14 days of metronidazole clinical cure rate 54% Relapse 20% Failure 26% Larger studies comparing the efficacy of Nitazoxanide with that of standard therapies are needed to help define its place in the management of CDI detested non inferiority to current available agents

29 rifaximin Nonabsorbable an%bio%c, somewhat flora sparing Subject to high level resistance cri%cal amino acid subs%tu%on in the beta subunit of the bacterial RNA polymerase Chaser 79% of pa%ents who had rifaxamin chaser had no recurrence Clinical infec%ous diseases 2007; 44:846 8 Anaerobe 2009; 15: Unresponsive to metronidazole 64% who were on rifaximin had stool cultures nega%ve at 56 day followup Therapeu%c advances of gastroenterology 2010; 3:221 5

30 Tigecycline Broad spectrum ac%vity Does not promote growth of C. difficle in human gut model No large compara%ve studies

31 Bacitracin Polypep%de an%bio%c similar to Vancomycin in controlling symptoms Inferior to Vancomycin in clearance from feces High level resistance noted Limited role in current management of CDI

32 Fusidic Acid CDI cure rates 83 93% Recurrence rate 28% High rates of resistance Not available in USA Limited role in current management of CDI

33 Teicoplanin Glycopep%de an%bio%c similar to Vancomycin Cure rates and recurrence rates similar Not available in USA

34 Anion binding resins Advantage Bowel flora is not altered, as occurs with vancomycin or metronidazole. More rapid recons%tu%on of the normal colonic flora. Disadvantage Bind vancomycin as well as toxins; thus, the resin must be taken at least two or three hours apart from the vancomycin. Coles%pol and cholestyramine are not effec%ve as primary therapy for CDI may be beneficial as adjunc%ve therapy for relapsing infec%on. Coles%pol (5 g every 12 hours) or cholestyramine (4 g three or four %mes daily) for one to two weeks, usually with vancomycin. Tolevamer is a C. difficile toxin binding resin developed specifically for CDI inferior to both vancomycin and metronidazole as primary therapy for CDI

35 Fidaxomicin Macrocylic an%bio%c bacteriocidal against Clostridium difficile (metronidazole and vancomycin her bacteriosta%c) More narrow an%microbial spectrum less disrup%on of normal colonic anaerobic microflora. Clinical cure rates similar to vancomycin, but less relapses Cost ~$3000/course

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39 Other op%ons Nitazoxanide 500mg BID x 10 days Useful if intolerance to 1 st line Abdominal pain, nausea Rifaximin 200mg TID x 10days Useful as chaser Nausea, dizziness, fa%gue Tigecycline 100mg IV then 50mg IV BID IV op%on Nausea, vomi%ng Fecal Transplant 95% cure rates

40 Factors for severe disease Presence of 2 or more Age >60 Fever >100.9 Albumin <2.5mg/dL WBC >15,000 Pseudomembranous coli%s >10 BM/day WBC>20,000 Severe abdominal pain Crea%nine >1.5 %mes baseline

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42 So how do we prevent transmission of Clostridium difficile? Contact precau%ons Gloves for all pa%ent contact Placement in single room with associated bathroom Pa%ent cohort in may be reasonable Wash hands with soap and water Environmental cleaning 1 10 dilu%on of household bleach Caus%c to environmental surfaces An%bio%c streamlining

43 How about Probio%cs? Microorganisms to counteract disturbances and intes%nal flora and thereby reduce risk of coloniza%on by pathogenic bacteria Low cost in low incidence of associated adverse events Akrac%ve choice for preven%on of CDAD

44 Ann Intern Med. 2012;157(12): From: Probiotics for the Prevention of Clostridium difficile Associated Diarrhea: A Systematic Review and Meta-analysis Randomize, controlled trials an adult and pediatric pa%ents treated with an%bio%cs comparing the effect of any dose of specific probio%c with placebo or no treatment

45 Ann Intern Med. 2012;157(12): From: Probiotics for the Prevention of Clostridium difficile Associated Diarrhea: A Systematic Review and Meta-analysis Figure Legend: Summary of evidence search and selection. AMED = Allied and Complementary Medicine Database; CD = Clostridium difficile; CDAD = Clostridium difficile associated diarrhea; CENTRAL = Cochrane Central Register of Controlled Trials; RCT = randomized, controlled trial. * Sources were BIOSIS Previews, Canadian Agency for Drugs and Technology in Health, Dissertation Abstracts, Google Scholar, British Society of Gastroenterology Annual General Meeting, McGill University Technology Assessment Unit, Inflammatory Bowel Disease/Functional Bowel Disease register, Copyright the Turning The Research American Into Practice College of database, Physicians. HighWire, clinical trial registries industry contact, and bibliographies. All rights reserved.

46 Ann Intern Med. 2012;157(12): From: Probiotics for the Prevention of Clostridium difficile Associated Diarrhea: A Systematic Review and Meta-analysis Copyright The American College of Physicians. All rights reserved.

47 Ann Intern Med. 2012;157(12): From: Probiotics for the Prevention of Clostridium difficile Associated Diarrhea: A Systematic Review and Meta-analysis Copyright The American College of Physicians. All rights reserved.

48 Ann Intern Med. 2012;157(12): From: Probiotics for the Prevention of Clostridium difficile Associated Diarrhea: A Systematic Review and Meta-analysis Copyright The American College of Physicians. All rights reserved.