Clostridium difficile infection (CDI)- what s new in diagnosis and treatment; target of antibiotic stewardship

Transcription

1 Clostridium difficile infection (CDI)- what s new in diagnosis and treatment; target of antibiotic stewardship Thomas J. Louie, MD, FRCPC Medical Director, IP&C, Calgary Health Region; Professor of Medicine, Dept. Medicine and Microbiology, Univ. of Calgary Changing strains; selection for more virulent strains, aging population = higher cost for health care. The cause of transmissible nosocomial diarrhea, due 99% to antibiotic induction Changingepidemiology ~700,000 cases in USA/year, in Canada, Ontario Today Worldwide,? Asia?

2 Disclosures. Tom Louie, Dept.Medicine and Microbiology-Immunol-Infect Dis, Univ Calgary Investigator for Cubist [CB 183,315], Actelion [Cadazolid], Optimer [Fidaxomicin]. Advisory panels: MicrobEX [fecal transplant], Merck: Monoclonal Antibodies; Pfizer [vaccines].

3 C. difficile infection.. update Local epidemiology National epidemiology Strain type 027 is important, we are not up to speed. Current therapy: metro and vanco: strengths and weaknesses testing What is the microbiome? And C. difficile as the arch type model of disturbed microbiome. Narrow agents: better but need formulary decision for Alberta Infection control bundle for C.difficile infection.

4 Emergence of multiple C. difficile infection (CDI)treatment modalities standard antibiotics metronidazole vancomycin [bacitracin, teichoplanin, fucidin] nitazoxanide narrow spectrum antimicrobials Fidaxomicin (OPT-80) Rifaximin CB-183,315 (Cubist) Cadazolid (Actelion) CDI Passive AB humanized mouse monoclonal AB. Merck, phase 3 NEJM Jan.2010 Fecal Microbiome Transplantation Prebiotics Probiotics Non-toxigenic C. difficile Lactobacillus Bifidobacterium S. boulardii Vaccines to induce antibodies to toxins Sanofi-Aventis

5 C. difficile cytotoxin B titers 0-32,000-1 mean Clostridium difficile counts of CFU/ml diarrheal effluent. Spores 1/10 4 to 1/10

6 Death within 30 days: 1.5% % 2008 Toxic Megacolon Colitis Pseudomembranous Colitis Fever, Leucocytosis Creatinine, Albumin Diarrhea : mean 8 movements/day range (4-15) in clinical trials C. difficile cytotoxin B titers 0-32,000-1 mean Clostridium difficile counts of CFU/ml diarrheal effluent. Spores 1/10 4 to 1/10

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10 Canadian Nosocomial Infection Surveillance Program. Health Canada and hospitals across Canada. Surveillance of CDI rates per 1,000 admissions Mark Miller et al

11 C.Difficile incidence by AGE. AHRQ HCUP data 2009

12 Gerding, icaac 2009 NAP 1/ ribo027/rea:bi strains from trials , 50% NAP1 in west Canada 13% 52% 46% 39% 57% 10% 48% 3 fold increase of CDI rates in USA over decade

13 Our plan in AB: CDI bundle 1600 primary cases/year 400 est recurrent disease in hospital, causing multiple encounters with health care cases in the community, not HA or HCA 5% death rate, 30 day mortality 2012 Better diagnositics Better infection control environmental sanitation,hh, isolation Rate/disease/outcomes Medical control: better primary therapies, Arrest recurrent disease,ua/uc N/S clinic Save on est M budgetary impact on AHS

14 Ribotype 027/NAP1/BI strain type: importance Quinolone resistant Hypertoxin producer Hyper spore producer Cause of death rate increase from 1.5% to 5-15% over last 10 yrs Hyper-spreader? Dominates in hospitals; 80% of strains ONT,PQ 2 clades antibiotic resistant clades developed in PQ and pittsburgh circa 2002, spread UK,Europe,Au based on SNP analysis of 400 strains [Nature Genetics, in press] 10% less response, doubles recurrence rate

15 Pathogenesis Antibiotic therapy Altered colonic flora (loss of colonization resistance) C. difficile exposure and colonization Toxin production Protective immune response No protective immune response Asymptomatic carriage Diarrhea and colitis (Adapted from Kyne GI Clinics N. Am 2001)

16 C. difficile Pathogenicity Locus (PaLoc) tcda codes for toxin A tcdb toxin B tcdc negative regulator of toxin production tcdd positive regulator of toxin production (Geric J Clin Microbiol 2003)

17 Toxin A & B protein structure Toxins A & B are monoglucosyl transferases that target Rho GTPases Toxin A = 308 kda Toxin B = 270 kda 50% amino acid homology Toxin production varies with culture conditions/nutrients Clinical isolates typically produce < 200 ng/ml (McFarland Inf & Immunity 1991) 25% of C. difficile isolates are toxin A-/B- (Fekety JAMA 1993)

18 Tests for C.difficile infection using toxigenic culture i.e growth of C.difficile and proof bug makes toxin as gold standard. J.Clin Micro : , Novak-Weekley et al. Enzyme Immuno assay [EIA] C.difficile common antigen [Glutamic Dehydrogenase = GDH ] plus EIA GDH followed by PCR for cytotoxin B gene [gene xpert] PCR every sample for cytotoxin B gene [gene Xpert] Sensitivity (n=72) 58.3% 83.1% 86.1% 94.4% Specificity (n=360) 94.7% 96.7% 97.8% 96.3%

19 Points on C.difficile testing. Specificity is good for all tests, but EIA used in most places lacks sensitivity, more in 70% range. If negative repeat. Switch over to PCR should be coming. Endoscopy, special requests for PCR should be established. Often, patients on metro or vanco become test negative for varying durations; test before you treat. Do not ask for test for cure. They still have the bug 80% of the time [more likely all the time]

20 Treatment of C.difficile infection Mild -moderate severe disease: [4-10 diarrheal bowel motions (BM)/day, no fever, leucocytosis or abdominal pain] Metronidazole 500 mg TID for days [ not approved by US Food and Drug Administration] Severe disease Unresponsive to metronidazole, fever, leucocytosis, abdominal pain, hypoalbuminemia elevated serum creatinine Vancomycin 125 mg QID for days [ mg QID x days occasionally required for some patients] [vancomycin tapering dosage for recurrent disease] Mild, moderate and severe disease Fidaxomicin 200 mg BID x 10 days

21 Comparison of metronidazole vs vancomycin in 2 trials [Genzyme 301 and 302) S.Johnson et al, IDSA, San Diego, Oct 19, 2012 % Response to treatment 81.1% 210/259 Vanco

22 % recurrence by day 40 Recurrence of CDI as a function of age category, Metronidazole vs Vancomycin Johnson et al, IDSA, Oct 19, 2012

23 Increasing risk of recurrence of CDI after repeated recurrences; by -product of dependence on vancomycin McFarland et al, ICHE 1999; 20: 43, Gerding, Curr Top Microbiol Immunol 2000; 250: 127 Louie, 2011 NEJM Feb 3. Kuijper 2011, personal communication Serial damage to microbiome? VS increased adherence/persistence, biofilm?

24 Impact of Metro, Vanco treatment of Metronidazole C. difficile effect : d Suspected/expected damage to normal microbiota VRE selection, less well quantified Spores, low numbers, persist ~ 7-8 ug/ml peak, via serum. MIC=0.5 (up to 2-4 for ribotype 027). CDI Vancomycin C. difficile effect: < d Proven damage to normal microbiota by 2-4 log 10 CFU/g VRE very strong selection Spores, low numbers persist High gut concentrations ug/ml fecal filtrate, MIC =2

25 Advancing the concept of sustained response for chemotherapy of CDI 2 major endpoints for CDI therapy: resolution of diarrheal illness & absence of recurrent disease = sustained response, global cure treatment cure recurrence Sustained response Vancomycin (003) Metronidazole (Genzyme) Tolevamer (Genzyme) 88% (485/563) 24% 64% 72% (103/143) 20% 52% 47% ( 124/266) 4% 43%

26 log10 CFU/g Wet Wt Feces Quantitative C.difficile CFUs in patients randomized to Vanco, Metro or Tolevamer, Genzyme 301 (n=43) Van Mtz Tol P= V or M vs T P= V vs M Day 0 Day 4 Day 10 Day 14 Day 21 Day 28 Day 42 P=0.04 V vs T, day 42, Louie TJ, 48th ICAAC/46th IDSA. October 2008; Washington, DC. Abstract K-520.

27 Clindamycin deodorizes stool

28 Fast findings about gut normal flora ~ 1000 species 1/3 cultivable ½ are live, 20% injured, 30% dead C. coccoides, C. leptum, Bacteroides groups most numerous, old folks have less Host genetics govern make up, likely every person has a unique microbial composition genetically linked persons have more similar flora [spouses are different] Few data about which microbes might confer colonization resistance against C. difficile Diagnosis of C.diff with stools, yet disease is mucosal

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30 Ecklund, Bernstein, Relman. Science Multiple colonic biopsies and feces examined by 16S rrna sequencing of 3 patients. Bacteroidetes predominate on the mucosal surface. Firmacutes (major groupings: Clostridium coccoides and Clostridium leptum)

31 HEALTHY CONTROLS /g Antibiotic, C.difficile spore C. difficile CLOSTRIDIUM DIFFICILE INFECTION Proteobacter coliforms CDI occurs in association with a 10-1 to -3 CFU/g reduction of Firmacutes 10-2 to -6 reduction of Bacteroidetes 10 2 to 3 increase in coliforms

32 Clinical predictors of recurrent CDI based on 999 patients, 794 pts with recurrence, in 2 recent RCTs variable comparison OR P-value Age category > 65 years / < Concomitant antibiotic exposure Yes / No Strain type 027 vs non Renal insufficiency Yes / No Treatment group Fidaxo vs Vanco 0.41 <0.001

33 Fidaxomicin (OPT-80) New Class of Antibacterial - New class for CDI: Macrocyclic antibiotic - Targets bacterial RNA polymerase - No cross resistance with known antibacterials - Evidence of low rate of C. difficile resistance development Potent compound against C. difficile, including BI (NAP1/027) - MIC 90 vs. C. difficile, µg/ml - Bactericidal activity against C. difficile - Long post-antibiotic affect (>24h) Narrower spectrum (?) - No activity vs. Gram- - Moderate vs. some Gram+ Low systemic absorption - ng/ml plasma concentrations - High fecal concentrations >10,000 x the MIC 90 33

34 2011; 364: O H O H H O O O O O O O H 3 C O O O O H O O H O C l C l O H H O Lancet Infectious Disease 2012; 12 (4)

35 Log 10 CFU/gm Log10 CFU/gm Log10 CFU/ gm Log 10 CFU/ gm Quantitative reduction of C. difficile counts in the OPT-80 phase 2A study. Louie et al, AAC 2009 OPT mg bid OPT mg bid Day 0 Day 10 0 Day 0 Day 10 OPT mg bid Vanco 125 mg QID Day 0 Day 10 0 Day 0 Day 10

36 Log 10 CFU/gm Bacteroides group organisms by increasing doses of OPT-80 BID or vancomycin 125 mg qid; Phase 2a study (Louie, AAC Jan 09) [ recurrence: 2/41 ] 9 Mean Counts of B. fragilis grp Day 0 Day mg bid 100 mg bid 200 mg bid vancomycin OPT-80 treatment Response: 12/14 13/15 16/16

37 Results of FISH/FLOW study of OPT-80 or Vancomycin treatment of CDI, Phase 2, Tannock et al. Microbiology 2010

38 Cure of CDI by Fidaxomicin or Vancomycin, Two DB- RCTs, involving 999 per protocol patients 003 (NA) study 004 (Int l) study Fidaxomicin (200 mg bid) 92.1% (244/265) 91.7% (198/216) Oral Vancomycin (125 mg qid) 89.8% (254/283) 90.6% (213/235) Per Protocol: Patient group with CDI confirmed by diarrhea with a positive toxin assay, protocol compliant, and received at least 3 days of therapy if failure and at least 8 days of therapy for cure NEJM 2011; 364: (Feb 3, 2011) and Lancet Infect Dis 2012; 12 (4) : (April 4, 2012).

39 Recurrence within 4 weeks post treatment Fidaxomicin had a 47% lower recurrence rate Fidaxomicin (200 mg bid) Vancomycin (125 mg qid) P value (95% CI) 003 (NA) study 13.3% (28/211) 24.0% (53/221) ( 17.9, 3.3) 004 (Int l) study 12.8% (23/180) 25.3% (46/182) (-20.3, -4.4) Louie T et al. Presented at: 19th ECCMID. May 17, 2009; Helsinki, Finland. Abstract. Miller M et al. Gastroenterology. 2009;136 (Suppl 1):Abstract 751a. Golan Y et al. Presented at: 49th ICAAC. Sept. 14, 2009; San Francisco, CA. Abstract L Crook, D et al, LB2401, ECCMID 2010, Vienna, Austria, April 2010

40 Proportion of Patients Without Recurrence Time to Recurrence (003 trial) 1.0 Vancomycin Fidaxomicin n=221 n=211 Recurrence within 10d 30/221 (14%) 7/211 (3%) Recurrence within 20d 45/221 (20%) 18/211 (9%) Log rank: P value <0.01 Generalized Wilcoxon: P value <0.01 Vancomycin Fidaxomicin Number of Days From Treatment Completion Louie T et al. Presented at: 19th ECCMID. May 17, 2009; Helsinki, Finland. Abstract. Miller M et al. Gastroenterology. 2009;136 (Suppl 1):Abstract 751a. Golan Y et al. Presented at: 49th ICAAC. Sept. 14, 2009; San Francisco, CA. Abstract L

41 Log CFU Log CFU qpcr: Vancomycin kills major components of the normal flora thought to prevent C. difficile disease. CID 2012 Vanco Bacteroides CFU's over 7 time points in 10 patients on Vancomycin Day Day 42 Mean Day 42 Vanco Mean Day 42 Fidaxomicin Mean Normal Control Mean (N=10) Bacteroides CFU's over 7 time points in 10 patients on Fidaxomicin Fidaxo Day 42 Mean Day 42 Vanco Mean Day 42 Fidaxomicin Mean Normal Control Mean (N=10) Day

42 Log CFU Log CFU C.coccoides group CFU's over 7 time points in 10 patients on Vancomycin Vanco Day 42 Mean Day 42 Vanco Mean 4.00 Day 42 Fidaxomicin Mean Normal Control Mean Day C.coccoides group CFU's over 7 time points in 10 patients on Fidaxomicin Fidaxo Day 42 Mean 4.00 Day 42 Vanco Mean Day 42 Fidaxomicin Mean 3.00 Normal Control Mean Day

43 Log CFU Log CFU C.leptum group CFU's over 7 time points in 10 patients on Vancomycin Vanco Day 42 Mean Day 42 Vanco Mean 2.00 Day 42 Fidaxomicin Mean Normal Control Mean Day C.leptum group CFU's over 7 time points in 10 patients on Fidaxomicin Fidaxo Day 42 Mean Day 42 Vanco Mean Day 42 Fidaxomicin Mean Normal Control Mean Day

44 Log CFU Log CFU Prevotella CFU's over 7 time points in 10 patients on Vancomycin Vanco Day 42 Mean Day 42 Vanco Mean 4.00 Day 42 Fidaxomicin Mean Normal Control Mean Day Prevotella CFU's over 7 time points in 10 patients on Fidaxomicin Fidaxo Day 42 Mean Day 42 Vanco Mean 4.00 Day 42 Fidaxomicin Mean Normal Control Mean Day

45 Log 10 CFU/gm Feces of Major Cultivable and Noncultivable Genera of the Normal Fecal Microbiota; n=20 (Fidaxomicin phase 3 [003] protocol) C. coccoides group Bacteroides/Prevotella group P= P=0.001 P< Day 0 Day 10 Day 14 Day 21 Day 28 FDX VAN Day 0 Day 0 Day 10 Day 14 Day 21 Day 28 C. leptum group P<0.03 Day 10 Day 14 Day 21 Day 28 T. Louie, ECCMID 2010, Vienna, Austria April 2010, IDSA Vancouver Oct 2010 and in press, Clin Infect Dis April 2012.

46 Vancomycin vs Fidaxomicin: C. Difficile colony forming units (CFU) and [toxin] in 89 pts at FMC log 10 CFU/g + SD Van Treatment period Day 0 Day 4 Day Day Day Day Day Toxin B titer + SEM (pos/total) Fdx Van neg neg 7/30 15/30 3/22 1/12 (26/94) Fdx neg neg 1/23 6/27 5/20 1/21 (13/91) , one value 16,000 No difference in C. diff effect, toxin re-expression halved, recurrence 10 Vanco vs 5 Fidaxomicin

47 Ribotype 027/ NAP1/BI: 10% reduced response and higher recurrence. Strain type vancomycin fidaxomicin cure BI/NAP1 84.7% (61/72) 86.2% (56/65) Other 94.4% (119/126) 96.6% (115/119) recurrence BI/NAP1 23.6% (13/55) 24.4% (11/45) Other 25.5% (27/106) 7.8% (8/103)

48 Lawley et al, Plos Pathogens, October Ribotype 027 persists post infection in C57BL mice, whereas ribotype 012 [630], and 017 [toxaneg] clear spontaneously. 027 is a special strain type. All strains were clindamycin R/ermB pos.

49 LOG (CFU/g wet stool) GC, 46yo Female: Fecal Transplant Gut Microflora Profile Pre Post Donor Comparison of microbial group changes pre- and post fecal microflora transplantation, by enema. Fecal transplantation appears better accepted today. IDSA and AmerGastroenterolAssociation working group 2012.

50 LOG (CFU/g wet stool) BL, 83yo Female: Oral Transplant Gut Microflora Profile Pre Post 5 days Post 1 week Post 1 month Donor Group This patient failed enema x2 and was successfully treated with concentrated fecal microbes by serial high speed centrifugation; 5 cc daily x 4 consecutive days.

51 Microbe groups that appear to restore colonization resistance against recurrent C. difficile infection: analysis of 25 patient-donor pairs by qpcr (T. Louie, unpublished). Bacteroidetes Prevotella spp. Firmacutes : C. coccoides and C. leptum groups Bifidobacteria spp Desulfovibrio spp Achieved by FMT or by narrower spectrum therapy

52 My parting shots on CDI Stop excess antibiotic use Culprits selecting for C diff: cephs, quinolones. Only SXT, aminoglycosides, aztreonam safe Monitor daily..can turn on you toxic megacolon Colonization by week 3 is 20%, 30% by week 4. Allow up to a week for response, but if worsens change therapy C.diff clinic North/South being entertained Reduce recurrent disease will reduce hospital transmission. We need to be like the netherlands, rates 0.4/10000 pt days. Hands!!!

53 Some departing concepts today: Interplay of host, gut microbiota, pathogen & therapeutics How damaged is the normal gut flora in CDI patients? What do metro & vanco do to C. diff and to normal flora? Which microbial groups break the cycle of CDI recurrence? Lessons learned from antimicrobial agent effects during treatment of CDI and from fecal microbiota transplantation* * The ultimate probiotic?

54 Wash your hands! NOTE: The hand print on the left was touched to a sheep blood agar plate after performing patient care and before hand hygiene; the yellow spots are bacterial colonies. The hand print on the right was touched to a sheep blood agar plate after patient care and after hand hygiene with chlorhexidine soap or alcohol-based hand rub.