Treating Clostridium difficile infection (CDI) the second time around

Transcription

1 Treating Clostridium difficile infection (CDI) the second time around Ciarán P. Kelly, MD Professor of Medicine Harvard Medical School. Beth Israel Deaconess Medical Center, Boston

2 The difficult Clostridium Objectives: CDI - More difficult than ever Who gets recurrent CDI? How do we manage recurrent CDI? What s new in CDI therapy? Spore

3 Difficulties with CDI Increasing disease incidence Increasing disease severity Low cure rate (<70%) 10% of patients don t respond to days of treatment 4% of patients die from CDI 25% have recurrence Overall cure rate < 70%

4 Pathogenesis of Clostridium difficile infection (CDI) Antibiotic therapy Disturbed colonic microflora (loss of colonization resistance) C. difficile exposure & colonization Toxin A & Toxin B Diarrhea & colitis Kelly & LaMont N Engl J Med 2008

5 C. difficile toxin-induced Pseudomembranous colitis C. difficile toxins induce a marked acute Inflammatory response with intestinal injury

6 Antimicrobials Predisposing to CDI Very Commonly Related Clindamycin Ampicillin Amoxicillin Cephalosporins Fluoroquinolones Less Commonly Related Other penicillins Sulfonamides Trimethoprim Cotrimoxazole Macrolides Uncommonly Related Aminoglycosides Bacitracin Metronidazole Teicoplanin Rifampin Chloramphenicol Tetracyclines Carbapenems Daptomycin Tigecycline Bouza E, et al. Med Clin North Am. 2006;90: Loo VG, et al. N Engl J Med. 2005;353:

7 Nosocomial C. difficile infection & asymptomatic carriage are common Hospital Hospital patients patients (Acute (Acute medical medical ward) ward) LOS LOS > 2 days days Receiving Receiving antibiotic antibiotic enrolled Colonized by by C. C. difficile (31%) Hospital-acquired Hospital-acquired (17%) (17%) Colonized Colonized at at Admission Admission (14%) (14%) CDI case 28 (10%) Carrier 19 (7%) CDI case 19 (7%) Carrier 18 (7%) Kyne et al N Engl J Med 2000;342:390

8 Asymptomatic carriers of C. difficile have high serum IgG anti-toxin A Carriers Non-colonized Cases IgG anti-toxin A P=0.06 P=0.002 P=0.001 P=0.005 Admission Admission Colonization Colonization 3 3 days days after after Colonization Colonization Discharge Discharge Kyne et al N Engl J Med 2000;342:390

9 Rates of CDI Tripled in US Hospitals between 2000 and 2005 Discharges per 100,000 population x x Any diagnosis Primary diagnosis x x x x Year x x ~x2 x x ~x3 x McDonald LC, et al. Emerg Infect Dis. 2006;12: , and unpublished CDC data.

10 C. difficile-related deaths have increased in the US 25 Age adjusted death rate per million % increase from 1999 to 2004 In 2004 CDI-related deaths: 4 those attributed to MRSA infection 6 those attributed to all other intestinal IDs combined Redelings et al. Emerg Infect Dis. 2007;13:

11 C. difficile-related Deaths Are Also Increasing in the UK UK Clostridium death difficile certifications Deaths increase in 2005 UK deaths 2006: CDAD 6,480 MRSA 1,652 US deaths (age adjusted): per million per million MRSA=methicillin-resistant Staphylococcus aureus. Death certificates mentioning C. difficile and recording C. difficile as the underlying cause of death (England and Wales). Source: UK Office of National Statistics. Redelings et al. Emerg Infect Dis. 2007;13:

12 CDI outbreak in Estrie (Quebec) 2003 vs 2002: x 4 CDI cases x 20 CDI deaths > 80% NAP1 strain >64 yr Total yr <17 yr Pepin et al. Can Med Assoc J 2004; 171:

13 Epidemic Strain Strain typed BI/NAP1/027 1,2 Is highly resistant to fluoroquinolones 2,4 Binary toxin genes are present Produces large quantities of toxins A and B 1,3 Has a tcdc gene deletion 1 1. Warny M, et al. Lancet. 2005;366: Hubert B, et al. Clin Infect Dis. 2007;44: CDC Fact Sheet. July McDonald LC, et al. N Engl J Med. 2005;353: Adapted from McDonald LC, et al. N Engl J Med. 2005;353: ; with permission.

14 Recurrent C. difficile diarrhea Common (~25% of treated patients) Mechanisms of recurrence: NOT due to resistance to metronidazole or vancomycin Metronidazole or vancomycin therapy perpetuate loss of colonization resistance Either: Relapse - Persisting infection Re-infection - New inoculum different strain in ~50% of recurrent CDAD cases Wilcox et al. J Hosp Infect. 1998;38:

15 Recurrent C. difficile diarrhea (contd) Risk factors: Age > 65 years Severe underlying illness Concommitant antibiotic use Prior recurrent CDAD ~ 20% risk after first CDAD episode ~ 40% risk after first recurrence > 60% risk after 2 or more recurrences Lack of protective immunity Kyne et al. Lancet 2001;357:189-93

16 Prospective derivation and validation of a clinical prediction rule for recurrent C. difficile infection Gastroenterology 2009;136: Hu MY, Katchar K, Kyne L, Maroo S, Tummala S, Dreisbach V, Xu H, Leffler DA, Kelly CP. Risk factors: Age > 65 years = 1 point Severe illness (Horn s Index) = 1 point Concommitant antibiotic use = 1 point Score Recurrent CDI in validation cohort 0 0% 1 17% 2 31% 3 67%

17 AGA Institute Late-Breaking Abstract Session: May 4, 2010, 2:15 PM Randomized Clinical Trial (RCT) in Clostridium difficile Infection (CDI) Confirms Superiority of Fidaxomicin over Vancomycin S Johnson, DW Crook, OA Cornely, KP High, M Miller, SL Gorbach Concomitant antibiotics (CAs) to treat other infections in 59% of patients during CDI treatment. Lower initial response rate with CAs 86.1% with CAs vs 98.4% without (P=<.001) Higher recurrence rate with CAs 23.9% with CAs vs 8.1% without (P=<.001) Lower global cure rate with CAs 59.8% with CAs vs 90.3% without (P=<.001).

18 Treatment of First Episode of CDI Mild CDI Discontinue other antibacterial agents if possible Request stool testing Monitor course of disease Moderate or persisting CDI (or patients who must continue antibacterial therapy) As for mild plus: Oral metronidazole 500 mg TID for days or 250 mg QID for days Gerding DN, et al. Infect Control Hosp Epidemiol. 1995;16: Poutanen SM, Simor AE. Can Med Assoc J. 2004;171:51-58.

19 Vancomycin is more effective than metronidazole in treating severe CDI Prospective, RCT (172 enrolled, 150 completed) Vancomycin 125 mg QID x 10d vs Metronidazole 250 mg QID x 10d Stratified for disease severity 2 points = SEVERE 1 point: Age: > 60 years Temp: > 101 F [38.3 C] Albumin: < 2.5 mg/dl WBC > 15,000 cells/mm 3 2 points: PMC at colonoscopy ICU patient Response Vancomycin 100% 90% 80% 70% 60% 50% 98% P=0.4 90% Mild / Moderate Metronidazole 97% Severe 76% P=0.02 Zar et al. Clin Infect Dis 2007;45:302-7

20 Management of Severe CDI Early recognition Initiate therapy as soon as diagnosis is suspected Oral vancomycin (125 mg QID for 10 to 14 days) as initial treatment If patient is unable to tolerate oral medication iv metronidazole consider intracolonic vancomycin instillation (by enema) g vancomycin (IV formulation) in ml normal saline via rectal (or Foley) catheter Clamp for 60 minutes Repeat every 4 12 hours Gerding DN, et al. Infect Control Hosp Epidemiol. 1995;16: Zar FA, et al. Clin Infect Dis. 2007;45: Louie T, et al. 47th Annual ICAAC Meeting, 2007, Abstract k-425-a. Apisarnthanarak A, et al. Clin Infect Dis. 2002;35:

21 Markers of Severe CDI Severe diarrhea (> 10 BM/day) Marked leukocytosis >15,000 assoc. severe CDI >25,000 assoc. increased fatality Rising serum creatinine Falling serum albumin Colonic thickening on CT scan Ascites on CT scan Pseudomembranes on endoscopy Hemodynamic instability Severe abdominal distension, pain 2 points points = SEVERE 1 point: point: Age: Age: > years years Temp: Temp: > 101 F 101 F [38.3 C] [38.3 C] Albumin: Albumin: < mg/dl mg/dl WBC WBC > 15,000 15,000 cells/mm cells/mm points: points: PMC PMC at at colonoscopy colonoscopy ICU ICU patient patient Zar Zaret et al. al. Clin Clin Infect Infect Dis Dis

22 Colonic distension and small bowel ileus in fulminant Clostridium difficile colitis Severe / fulminant CDI may present as an acute abdomen and/or mimic acute colonic pseudo-obstruction Abdominal pain & distension Little or no diarrhea Kelly & LaMont. Gastrointestinal Pharmacotherapy, W. B. Saunders 1993;

23 Sigmoidoscopic appearance of severe CDI with PMC Immediate bedside diagnosis in severe, complicated CDI Guides surgical management Perforation rare - death usually results from SIDS

24 Management of fulminant or refractory CDI Vancomycin 500 mg qid po If ileus: Metronidazole 500 mg iv tid plus Vancomycin 500 mg qid via n/g tube or by enema If progressive or refractory: Early surgery evaluation/consultation Consider IVIG 400 mg/kg Monitor for progression WBC > 20,000 Creatinine >1.5 baseline Rising lactate (5.0)

25 First recurrence: An approach to treating recurrent CDI - Treat based on disease severity - Metronidazole or Vancomycin x10-14 days Second recurrence: Oral vancomycin taper & pulsed dosing Kelly NEJM 2008

26 Treatment of Multiple Recurrent CDAD Non-randomized study* Vancomycin N Recurrence, n (%) P-Value Medium dose (1g to <2 g/day) (71) Low dose (<1 g/day) (54) High dose ( 2 g/day) 21 9 (43) Tapering dose 29 9 (31) 0.01 Pulse dosing 7 1 (14) 0.02 Other 6 2 (33) All (46) Metronidazole N Recurrence, n (%) Low dose ( 1 g/day) (45) Medium dose (1.5 g/day) 5 2 (40) Other 4 1 (25) All (42) Total (45) * Placebo/antibiotic cohort from 2 clinical trials of Saccharomyces boulardii as adjunctive treatment. Includes vancomycin and rifampin (n=3) and vancomycin and metronidazole (n=3). Includes high dose (2 g/day), taper, or pulse dosing. McFarland LV, et al. Am J Gastroenterol. 2002:97:

27 An approach to treating recurrent CDI Rx Rx Vancomycin Taper & Pulsed First recurrence: dosing: - Metronidazole or Vancomycin x10-14 days Second recurrence: Oral vancomycin taper & pulsed dosing Third recurrence Week Week 1 Week Week 2 Week Week 3 Week Week 4 Week Week mg mg qid qid mg mg bid bid mg mg daily daily mg mg qod qod mg mg q3d q3d Vancomycin 125 mg qid for 14 days followed by Rifaximin 400 mg twice daily for 14 days Subsequent recurrences Intravenous immunoglobulin (IVIG) (400 mg/kg & repeat after 3 weeks) Vancomycin plus Probiotic? Lactobacillus spp, Saccharomyces boulardii Fecal transplantation / bacteriotherapy Kelly NEJM 2008

28 New treatment approaches for Recurrent C. difficile associated diarrhea Probiotics Antibiotic therapy C. difficile colonization Toxin production Diarrhea Recurrent diarrhea

29 S. boulardii for prevention of CDI: Inconsistent study results Placebo S. boulardii 100% 80% 65% 60% 40% 24% 19% 35% 47% 44% 20% 0% 1st episode CDI (A) P=0.04 Recurrent CDI (A) Recurrent CDI (B) Sb 500 mg bid x 4 weeks A. McFarland. JAMA. 1994;271: B. Surawicz et al. Clin Infect Dis. 2000;31:

30 New treatment approaches for Recurrent C. difficile associated diarrhea Probiotics Antibiotics Antibiotic therapy C. difficile colonization Toxin production Diarrhea Recurrent diarrhea

31 Fidaxomicin in CDI Minimal absorption from human GI tract Selective anti-c. difficile antibiotic Preserves colonization resistance?? 30% Fidaxomicin Vanco 24% 629 adults with CDI treated for 10 days with: * P= mg OPT-80 bid 78% Cured * 125 mg vancomycin qid 67% Cured * 20% 10% 0% 8% 10% Treatment Failure 13% P = NS P = Recurrence

32 New treatment approaches for Recurrent C. difficile associated diarrhea Probiotics Antibiotics Antibiotic therapy C. difficile colonization Toxin production Toxin binder Diarrhea Recurrent diarrhea

33 High serum IgG anti-toxin A levels are associated with a lower risk for recurrent C. difficile diarrhea Recurrent C. difficile diarrhea (%) For a level < 1.29 Odds ratio = 48 (95% CI, ) 0 < >1.28 Serum IgG anti-toxin A Day 12 Kyne et al. Lancet 2001;357:189-93

34 New treatment approaches for Recurrent C. difficile associated diarrhea Probiotics Antibiotics Toxin binder Antibiotic therapy C. difficile colonization Toxin production Diarrhea memory primary Active Active Immunization: Immunization: Toxoid Toxoidvaccine Anti-toxin immune response Passive: Passive: IVIG, IVIG, HuMAbs, HuMAbs, Hyperimmune Hyperimmune globulin globulin Recurrent diarrhea Protection

35 Intravenous immunoglobulin therapy for recurrent C. difficile diarrhea Serum IgG anti-toxin A (Optical Density units) P = 0.03 P = 0.01 Adult Pediatric Pre-IVIG Post-IVIG Healthy controls Children with recurrent C. difficile diarrhea Leung DY, Kelly CP et al J Pediatr 1993 Wilcox. J Antimicrob Chemother 2004;53:882-4.

36 25% 7% Recurrent CDI

37 A C. difficile Toxoid Vaccine (Toxoids A and B) Induces High Serum IgG Anti-Toxin A Response Patients Vaccine recipients Aboudola S, et al. Infect Immun. 2003;71:

38 Take home: C. difficile: more difficult than ever More prevalent More severe ( morbidity & mortality) NAP-1 epidemic strain widely prevalent in US CDI management is changing: Vancomycin 1 st line for severe CDI & possibly for multiple recurrent CDI (taper / pulse) New antibiotic and non-antibiotic approaches to therapy needed & being

39 The difficult Clostridium Aslam S et al. Lancet Infect Dis. 2005;5: