Disclosure Clostridium difficile update and new therapies Corey Frederick, PharmD PGY-2 Pharmacy Resident, Infectious Diseases Jackson Memorial Hospital Miami, Florida I do not have a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity, or any affiliation with an organization whose philosophy could potentially bias my presentation 2 Objectives Upon completion of this activity, the participant should be able to: Understand the pathophysiology and mechanism of disease surrounding C. difficile infections Recognize currently accepted therapeutic regimens to treat active C. difficile disease Identify new treatment modalities and regimens surrounding the management of C. difficile Assessment Questions If a patient test positive only for the glutamate dehydrogenase test, they should always be given full treatment for C. difficile. One of the first steps in managing an active C. difficile infection is to evaluate if any currently active antibiotics can be discontinued. For patients with severe C. difficile infection, rifaximin is considered to be first-line therapy. 3 4 Clinical Case PN is a 55 YO WF who presents with weakness, abdominal pain and frequent diarrhea (9 unformed stools per day x 5 days) Past Medical History Orthotopic liver transplant (2 months ago) NASH Type II DM HTN Blood pressure WBC Serum creatinine Started on oral vancomycin + IV metronidazole Vitals 110/65 mmhg 22 x 10³ c/mcl 3.4 mg/dl History Initially discovered in 1935 Normal intestinal flora in newborns Latin adjective difficilis due to difficulty to grow in culture High rates of pseudomembranous colitis at Barnes Hospital in 1970s Clindamycin colitis After 2 courses of therapy, the patient has recurrent C. difficile infection for the second time The primary team contacts pharmacy regarding use of nitazoxanide in this patient 5 http://www.ppdictionary.com/bacteria/gpbac/difficile.jpg 6 1
History History Tedesco et al, 1974 linked cases of pseudomembranous colitis to clindamycin use Yearly Clostridium difficile-related mortality rates per million population in the USA Mortality rate increased from 5.7 per million in 1999 to 23.7 per million in 2004 Hypervirulent strain NAP1-BI-027 identified as cause Tedesco et al. Ann Intern Med 1974; 81(4):429-33. Redelings et al. Emerg Infect Dis 2007; 13(9): 1417-1419. 7 Redelings et al. Emerg Infect Dis 2007; 13(9): 1417-1419. 8 Epidemiology CDC estimates 14,000 deaths per year Each case estimated to cost $3600 in excess healthcare expenses Almost 50% of infections occur in <65 years of age 90% of deaths occur in patients >65 years of age Stopping C. difficile Infections. CDC Vital Signs. Mar 2012. http://www.cdc.gov/vitalsigns/hai/stoppingcdifficile/ 9 Bacteriology Gram-positive, anaerobic bacillus Found in water, soil, food, healthcare environment Exists in vegetative and spore form During periods of environmental stress, sporulation occurs Spore formulation extremely stable Resistant to alcohol sanitizers, high temperatures, harsh chemicals, antibiotics 10 Bacteriology Select strains contain flagella Unsure of role in active disease Member of normal GI flora Colonization resistance Bacteriology Toxins A/B are primary virulence factors Historically, toxin A associated with enterotoxin activity Toxin B discovered to be potent cytotoxin 10 x more potent than toxin A in causing epithelial intestinal damage in-vivo http://bioweb.uwlax.edu/bio203/s2009/kumm_jakl/bucolic/flagella.gif 11 12 2
Bacteriology NAP1 strain associated with increased virulence Original outbreak in North America Spread throughout the world Associated with fluoroquinolone use Increased toxin production, produces binary toxin Binary toxin works in cohesion with toxins A/B Pathogenesis Risk Factors for C. difficile infection: Recent exposure to antibiotics Clindamycin, fluoroquinolones, cephalosporins, penicillins Acid-suppressing agents Antineoplastic chemotherapy Kidney disease Recent hospitalization Advanced age (e.g. >65 years) 13 14 Pathogenesis Two major factors: Disruption of normal flora, exogenous source Spores are ingested, colonize in the colon Spores resistant to harsh environment Large bowel has ideal anaerobic conditions Pathogenesis Vegetative form releases toxins A/B Host s IgG response to toxin A determines outcome Germination occurs and reach mature stage causing disease 15 Rupnik M et al. Nat Rev Microbiol 2009; 7(7): 526-36. 16 Pathogenesis Toxin A works on intestinal epithelium Causes fluid secretion, inflammation, and tissue necrosis Toxin B contributes with cytotoxin activity Ex-vivo studies demonstrate increased pro-inflammatory signaling and epithelial damage with Toxin B 17 https://medtube.net/images/min/31df805628ebd37f2b05f77c948f02c1/620/620/0 18 3
Recurrent Infections Estimated that 25% of patients will experience recurrence of disease Not related to resistance amongst bacteria to particular agent Hypothesized to be related to antibiotic-resistant spores After course of therapy, spores germinate into mature vegetative form Evidence shows lack of gut diversity after regimen is associated with recurrence Suppression of indigenous microbiota allows expansion for C. difficile spores 19 Signs & Symptoms Spectrum of disease Mild, self-limiting diarrhea Severe diarrhea with >20 loose stools per day Pseudomembranous colitis, toxic megacolon, sepsis, death IDSA Guidelines define severe disease as: WBC >15,000 SCr >1.5 x premorbid baseline Other indictors of severe disease: Abdominal distension, hypotension, fever, radiological evidence of colonic dilation 20 Diagnosis & Testing Diagnosis involves >3 watery loose stools in 24 hours and positive diagnostic test Stool cultures are time/labor intensive High false-positive rates due to detection of non-toxigenic strains Results return 48-96 hours later Diagnosis & Testing Antigen test detects presence of glutamate dehydrogenase Rapid and relatively inexpensive, results available in 1 hour Present in toxigenic and non-toxigenic strains Often, toxin testing will be performed as well Most tests detect presence of toxin A & B, or B only Relatively inexpensive, easy to perform If both tests positive, active C. difficile infection http://thepowerofpoop.com/wp/wp-content/uploads/2013/03/stool-sample.jpg 21 22 Diagnosis & Testing Clinical scenario where glutamate dehydrogenase (+), toxin A/B (-) PCR testing is extremely sensitive and specific for toxin producing C. difficile organism Significantly more expensive then other testing methods Therapeutic Considerations Only disease state caused by antimicrobial use, that is treated with antimicrobials Initial or recurrent? Moderate or severe? Lack of consensus regarding disease severity stratification Latest treatment guidelines published by the SHEA/IDSA in 2010 ESCMID guidelines published in 2014 23 24 4
Current SHEA/IDSA Recommendations Initial infection: Discontinue any unwarranted antibiotics Mild-to-moderate disease: Metronidazole 500 mg PO TID x 10-14 days Severe disease: Vancomycin 125 mg PO QID x 10-14 days Current ESCMID Recommendations Initial infection: In non-epidemic scenarios, may stop antibiotics and monitor clinical response for 48 hours Non-severe disease: Metronidazole 500 mg PO TID x 10 days Vancomycin 125 mg PO QID x 10 days Fidaxomicin 200 mg PO BID x 10 days Severe disease: Vancomycin 125 mg PO daily QID x 10 days Fidaxomicin 200 mg PO ID x 10 days 25 26 Current SHEA/IDSA Recommendations Treatment for first recurrence Restart initial regimen Stratify treatment choices by disease severity Treatment of second recurrence is vancomycin or tapered/pulse regimen Guidelines provide brief reference regarding nitazoxanide, IVIG Additional therapies not include in guidelines: Fidaxomicin (2011), fecal microbiota transplants (FMTs), tigecycline Metronidazole (Flagyl ) 500 mg PO/IV TID x 10-14 days Interacts with bacterial DNA resulting in inhibition of protein synthesis and cell death Well absorbed, secreted through inflamed intestinal mucosa Adverse effects: peripheral naturopathy, metallic taste 27 28 http://images.ddccdn.com/images/pills/mtm/flagyl%20500%20mg.jpg Oral vancomycin 125-500 mg PO/PR QID x 10-14 days Inhibits cell wall synthesis by binding to cell wall precursor d-alanyl-d-alanine Not well absorbed, high concentrations found in feces Adverse effects: nausea, bad taste 1983: metronidazole and vancomycin similar efficacy Relapse rates similar Metronidazole does not contribute to VRE Significantly cheaper No stratification of disease severity Not randomized, placebo-controlled, blinded http://www.cvs.com/webcontent/images/drug/drugitem_7772.jpg 29 Teasley et al. Lancet 1983; 2(8358)1043-6. 30 5
Recent studies demonstrate metronidazole and vancomycin may not be equally efficacious Prospective, observational study Eliminated oral vancomycin from formulary Zar et al studied 150 patients Prospective, randomized, double-blind, placebo-controlled trial Agent Metronidazole Vancomycin Outcome Metronidazole (n=207) Complete clinical cure 103 (50%) Refractory to therapy 46 (22%) Overall cure 66/79 (84%) 69/71 (97%) P=.006 Mild disease 37/41 (90%) 39/40 (98%) P=.36 Initial response, recurrence of disease 58 (28%) Severe disease 29/38 (76%) 30/31 (97%) P=.02 Musher DM et al. Clin Infect Dis 2005; 40: 1586-90. 31 Zar et al. Clin Infect Dis 2007; 45: 302-7. 32 Tolevamer Study had large impact on therapeutic algorithms Introduced categories for risk stratification Increased interest in using binders to treat active C. difficile infections Potentially decrease rate of recurrence Theoretically, will bind to toxins and not affect surrounding normal flora Differences potentially due to decreased blood flow in severe disease Metronidazole secreted through inflamed mucosa through bloodstream Oral vancomycin not well absorbed Two phase 3 RCTs studied tolevamer, vancomycin, and metronidazole Agent Tolevamer Metronidazole Vancomycin Overall clinical success Severe clinical success 236/534 (44.2%) 202/278 (72.7%) 210/259 (81.1%) 35/95 (36.8%) 37/57 (64.9%) 28/33 (84.8) P=.042 Recurrence rates were similar amongst all arms 33 Johnson S et al. Clin Infect Dis 2014; 59(3): 345-54. 34 Combination Therapy Fidaxomicin SHEA-IDSA guidelines weakly support use of oral vancomycin + IV metronidazole for fulminant severe infection Vancomycin can be given via retention enema Ileus may impair GI transit Issues with retention of enema, ability to reach colon Fidaxomicin (Dificid ) Approved in 2011 200 mg PO BID x 10 days Inhibits RNA polymerase thereby inhibiting protein synthesis Narrow spectrum of activity, Clostridium sp. Adverse effects: Nausea, abdominal pain 35 https://s3.amazonaws.com/hmidrugcmsdrugimages/prod/us/78e901e8911c45c5812843399892bbd0-dificid_bottle_.jpg 36 6
Fidaxomicin Prospective, multicenter, double-blind, RCT Agents Fidaxomicin Vancomycin Clinical cure 253/287 (88.2%) 265/309 (85.8%) Rate of recurrence 39/253 (15.4%) 67/265 (25.3%) Concluded fidaxomicin helps flora maintain colonization resistance P=.005 Fidaxomicin Cost effectiveness? Average 10 day cost of vancomycin: $50 10 day fidaxomicin cost: $2,800 Lack of studies in following populations Immunocompromised hosts, refractory or several recurrences Lack of mechanisms to predict high risk of recurrence Reduced activity against NAP1 strains? Louie TJ et al. NEJM 2011; 364: 422-31. 37 38 Rifaximin Rifaimin (Xifaxan ) 200-400 mg PO BID/TID x varying duration Binds to RNA polymerase inhibiting bacterial RNA synthesis Poorly absorbed, high concentrations in feces Adverse effects: peripheral edema, dizziness Rifaximin SHEA/IDSA guidelines reference studies for use in recurrence Small case studies with varying infection severity RCT, double-blind, placebo-controlled Agent Rifaximin Placebo Recurrent diarrhea 7/33 (21%) 17/35 (49%) P=.018 Recurrent CDI 5/33 (15%) 11/35 (31%) P=.11 Concern for resistance amongst Clostridium sp. http://images.medscape.com/pi/features/drugdirectory/octupdate/slx03010.jpg 39 Garey KW. J Antimicrob Chemother 2011; 66: 2850-2855. 40 Tigecycline Tigecycline Tigecycline (Tygacil ) 100 mg IV x 1, 50 mg IV BID x varying durations Binds to 30S ribosomal unit, inhibits protein synthesis Large volume of distribution, wide spectrum of activity Adverse effects: severe nausea/vomiting ESCMID recommend tigecycline for salvage therapy with marginal strength May replace IV metronidazole in severe, recurrent infection In-vitro: suppresses toxin production & spore formation Treatment failures reported, wide spectrum of activity 41 42 7
Nitazoxanide Nitazoxanide Nitazoxanide (Alinia ) 500 mg PO BID x 10 days Interferes with electron transport chain essential to bacteria metabolism Indications for cryptospordium and giardia infections Adverse effects: abdominal pain, nausea, vomiting SHEA/IDSA mention use in recurrent infection Musher et al, Clin Infect Dis 2006 Agent Nitazoxanide Metronidazole Clinical response, 7 days 68/76 (89.5%) 28/34 (82.4%) Recurrence, 31 days 26/35 (74.3%) 19/33 (57.6%) *P value=.34 Musher et al, Clin Infect Dis 2009 Agent Nitazoxanide Vancomycin Clinical response, 7 days 17/22 (77%) 20/27 (74%) Recurrence, 31 days 2/27 (7.4%) 1/27 (3.7%) Trial ended prematurely, low recruitment http://buygenericsmd.com/pictures/nizonide.jpg 43 Musher et al. Clin Infect Dis 2006; 43: 421-7. Musher et al. Clin Infect Dis 2009; 48: 341-6. 44 Intravenous Immunoglobulin Probiotics Adjuvant role in severe/fulminant recurrent infection Dose: 75-400mg/kg (400 mg/kg) daily for 1-5 days Prevents colonization resistance Vast variability of studies Provides immune response to toxins A/B Role in immunocompromised patients No RCTs to demonstrate efficacy Both guidelines provide weak recommendations for use STAW + Kefir case series Meta analyses and reviews have not shown efficacy for treatment Bacteremia reported in immunocompromised patients Abougergi MS et al. Dig Dis Sci 2011; 56:19-26 45 Bakken JS. Clin Infect Dis; 2014. 59(6): 858-61. 46 Fecal Microbiota Transplant On the Horizon Transplantation of fecal microbiota from healthy donor to patients with active infection Colonoscopy, nasogastric tube, retention enema Monoclonal antibodies Modulate effects of cytotoxins A/B Decrease recurrence, efficacy for resolution of symptoms? Multiple studies: Meta analysis: 20 case series of 536 patients 467 (87%) had resolution of diarrhea Adverse effects: mild diarrhea (94%), abdominal cramping (31%) Case studies demonstrate not completely benign Gastrostomy tube dislodged, sepsis Ramoplanin Broad spectrum glycolipodepsipeptide Demonstrates efficacy against resistant strains, major effect on vegetative and spore states Vaccine Vaccine against cytotoxins A/B currently in development Phase II studies currently underway Cammarota G et al. J Clin Gastroenterol 2014; online access. Solari PR et al. Clin Infect Dis 2014; 59(2): 319. 47 48 8
Clinical Case PN is a 55 YO WF who presents with weakness, abdominal pain and frequent diarrhea (9 unformed stools per day x 5 days) Past Medical History Orthotopic liver transplant (2 months ago) NASH Type II DM HTN Blood pressure Started on oral vancomycin + IV metronidazole Vitals 110/65 mmhg After 2 courses of therapy, the patient has recurrent C. difficile infection for the second time The primary team contacts pharmacy regarding use of nitazoxanide in this patient WBC Serum creatinine 22 x 10³ c/mcl 3.4 mg/dl 49 Clinical Case Nitazoxanide has not been studied to show benefit in this scenario Pharmacy recommended rifaximin chaser of 550 mg PO BID x 14 days After chaser therapy, patient s diarrhea resolved and was discharged 50 Conclusion Assessment Questions Update to SHEA/IDSA guidelines anticipated in summer 2015 Align with ESCMID? Pharmacy staff can have a significant role in prevention of C. difficile infection Work alongside infection control Appropriate use of antibiotics Managing resources 51 If a patient test positive only for the glutamate dehydrogenase test, they should always be given full treatment for C. difficile. FALSE One of the first steps in managing an active C. difficile infection is to evaluate if any currently active antibiotics can be discontinued. TRUE For patients with severe C. difficile infection, rifaximin is considered to be first-line therapy. FALSE 52 Additional References Abougergi MS, Broor A. Intravenous immunglobulin for the treatment of severe Clostridium difficile colitis: An observational study and review of the literature. J of Hosp Med 2010; 5(1): E1-E9. Aldape MJ, Heeney DD. Tigecycline suppresses toxin A and B production and sporulation in Clostridium difficile. J Antimicrob Chemother 2015; 70: 153-59. Chang JY, Antonopoulos DA, et al. Decreased diversity of the fecal microbiome in recurrent Clostrdium difficile-associated diarrhea. Journal of Infect Dis 2008; 197: 435-8. Cohen S et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the SHEA and the IDSA. Infect Control Hosp Epidemiol 2010; 31(5): 431-455. Cornely OA, Miller MA et al. Treatment of first recurrence of Clostridium difficile infection: fidaxomicin versus vancomycin. Clin Infect Dis 2012; 55(S2): S154-61. Debast SB, Bauer MP. European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection. Clin Microbiol Infect 2014; 20(2): 1-26. Gerding DN, Muto CA. Treatment of Clostridium difficile infection. Clin Infect Dis 2008; 46: S32-42. Gerding DN, Young VB. Clostridium difficile infection. Mandell, Douglas, and Bennett s Principles and Practice of Infectious Diseases, Eight Edition. Copyright 2015, Saunders. Ghosh S. Assessment of severity of Clostridium difficile infection. Can J Gastroenterol 2011; 25(7): 358. Johnson S, Schriever C et al. Interruption of recurrent Clostridium difficile-associated diarhea episodes by serial therapy with vancomycin and rifaxmin. Clin Infect Dis 2007; 44: 846-8. Heinlen L, Ballard JD. Clostridium difficile Infection. Am J Med Sci 2010; 340(3): 247-252. Oldfield IV EC, Oldfield EC III. Clinical update for the diagnosis and treatment of Clostridium difficile infection. World J Gastrointest Pharmacol Ther 2014; 5(1): 1-26. Rupnik M, Wilcox MH, Gerding DN. Clostridium difficile infection: new developments in epidemiology and pathogenesis. Nat Rev Microbiol 2009; 7(7): 526-36. Sun X, Feng H. The enterotoxicity of Clostridium difficile toxins. Toxins 2010; 2: 1848-1880. Tonna I, Welsby PD. Pathogenesis and treatment of Clostridium difficile infection. Postgrad Med J 2005; 81: 367-369. Clostridium difficile update and new therapies Corey Frederick, PharmD PGY-2 Pharmacy Resident, Infectious Diseases Jackson Memorial Hospital Miami, Florida 53 9