Terapia dell infezione da Clostridium difficile. Massimo Coen I Div Mal Inf AO L Sacco

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1 Terapia dell infezione da Clostridium difficile Massimo Coen I Div Mal Inf AO L Sacco

2 Disease Severity Mild CDI 3 5 BM/day WBC 15,000/mm 3 Defining CDI Disease Severity Mild abdominal pain due to CDI Moderate CDI 6 9 BM/day WBC 15,001 to 20,000/mm 3 Moderate abdominal pain due to CDI Severe CDI 10 BM/day WBC 20,001/mm 3 ; Severe abdominal pain due to CDI Any one of the 3 defining characteristics assigns a patient to the more severe category. Louie T, et al. The 47th Annual ICAAC Meeting, Sept , 2007; Chicago, IL. Abstract k-425-a.

3 Severe disease in Zar s study 2 pts endoscopic evidence of pseudomembranous colitis 1 pt age>60 TA > 38,3 albumin < 25 g/l WBC > 15,000 mmc Severe disease >= 2 pts Zar FA, et al. Clin Infect Dis 2007;45:

4 General Measures careful management of fluid and electrolyte balance antimotility agents, such as narcotics and loperamide, should be stopped as these are associated with adverse outcomes [Shivashankar et al. 2013] use of concomitant systemic antibiotics is associated with a decreased cure rate and an increased risk of recurrent CDI [Garey et al. 2008; Mullane et al. 2011].

5 Initial Treatment Options for CDI Historical response (96%) and relapse rates (20%) similar between metronidazole and vancomycin 1 More recently, efficacy of metronidazole for severe disease called into question 2-4 Prospective trials report vancomycin to be superior to metronidazole in severe CDI Aslam S, et al. Lancet Infect Dis. 2005;5: Fernandez A, et al. J Clin Gastroenterol. 2004;38: Gerding DN. Clin Infect Dis. 2005;40: Musher DM, et al. Clin Infect Dis. 2005;40: Lahue BJ, Davidson DM. The 17th ECCMID Meeting, March 31 to April 4, 2007; Munich, Germany. Abstract 1732_ Zar FA, et al. Clin Infect Dis 2007;45: Louie T, et al. The 47th Annual ICAAC Meeting, Sept , 2007; Chicago, IL. Abstract k-425-a.

6 Initial Treatment Options for CDI Metronidazole 250 mg QID or 500 mg TID Vancomycin 125 mg QID Development of resistance rare Historical first-line agent Effective in enteral (oral or rectal) form only Typically reserved for severe disease, those failing to respond to metronidazole, or cases in which metronidazole is contraindicated IV=intravenously; PO=orally. Fekety R. Am J Gastroenterol. 1997;92: Gerding DN, et al. Infect Control Hosp Epidemiol. 1995;16: American Society of Health-System Pharmacists. Am J Health-Syst Pharm. 1998;55:

7 Metronidazole vs Vancomycin Zar et al 1 classified patients as mild or severe CDI In mild disease, vancomycin was slightly better than metronidazole (98% vs 90%) Not statistically significant In severe disease, vancomycin was significantly better than metronidazole (97% cure vs 76% cure) 1. Zar FA, et al. CID. 2007;45:

8 Fidaxomicin is a macrocyclic antimicrobial agent with little or no systemic absorption after oral administration and narrow spectrum against Gram-positive aerobic and anaerobic bacteria, including C. difficile [Gerber and Ackermann, 2008] In vitro studies showed that fidaxomicin was more active than vancomycin against C. difficile [Ackermann et al. 2004; Finegold et al. 2004; Karlowsky et al. 2008].

9 Fidaxomicin In multicenter, randomized, double-blind phase III clinical trials, patients with CDI were randomized to receive fidaxomicin (200 mg twice daily) or vancomycin (125 mg 4 times daily) orally for 10 days [Louie et al. 2011; Cornely et al. 2012] In one study, the rate of clinical cure with fidaxomicin was similar to vancomycin (88.2% versus 85.8%, respectively), but fewer patients in the fidaxomicin group had a recurrence (15.4% versus 25.3%, p = 0.005) [Louie et al. 2011].

10 Fidaxomicin Subsequent post hoc analyses of these trials showed that, when patients received systemic antibiotics concurrent with CDI treatment, the cure rate was significantly higher for fidaxomicin compared to vancomycin (90% versus 79.4%; p = 0.04), and recurrence rates were lower for fidaxomicin (16.9% versus 29.2%; p = 0.048) [Mullane et al. 2011]

11 Costi in per giorno di trattamento vancomicina 125 x 4 metronidazolo 500 x 3 fidaxomicina 200 x 2 0,95/die 0,24/die 122/die

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13 Treatment of Mild to Moderate Disease Stop antibiotic(s) if medically reasonable Metronidazole Oral 500 mg TID for days is standard therapy 5 20% failure rate 20% relapse rate Can use a full 2 nd course for failure/relapse but beyond 2 courses, switch to vancomycin no metronidazole resistance

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15 Management of Severe CDI Early recognition is critical Initiate therapy as soon as diagnosis is suspected Manage : Oral vancomycin (125 mg QID for 10 to 14 days) as initial treatment If patient is unable to tolerate oral medication, consider intracolonic vancomycin instillation (by enema) g vancomycin (IV formulation) in 0.1 to 0.5 L of 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. The 47th Annual ICAAC Meeting, Sept , 2007; Chicago, IL. Abstract k-425-a. Apisarnthanarak A, et al. Clin Infect Dis. 2002;35:

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17 Surgical management May consist of total colectomy with end-ileostomy or diverting loop ileostomy and intracolonic lavage with polyethylene glycol followed by liquid vancomycin. Mortality rates from surgery for CDI are high and studies have shown that outcomes from early surgery are better than outcomes from delayed surgery. It has been shown that intraoperative colonic lavage with polyethylene glycol and postoperative colonic vancomycin flushes led to colon preservation in over 90% of patients and had significantly improved survival compared with historical controls who had undergone colectomy [Neal et al. 2011; Tsiouris et al. 2012].

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20 Treatment of Recurrent CDI First recurrence can be treated in the same way as a first episode according to disease severity 1 Metronidazole should not be used beyond first recurrence or for >14 days 2 Concerns for hepatotoxicity and polyneuropathy Further recurrences can be treated with oral vancomycin taper and/or pulse dosing 2,3 1. Gerding DN, et al. Infect Control Hosp Epidemiol. 1995;16: McFarland LV, et al. Am J Gastroenterol 2002;97: Tedesco FJ, et al. Am J Gastroenterol. 1985;80:

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22 Multiple Recurrent CDI Rates of recurrent CDI 20% after first episode 1 45% after first recurrence 2 65% after two or more recurrences 3 Metronidazole or vancomycin resistance after treatment not reported Repeated, prolonged courses of metronidazole not recommended (risk for peripheral neuropathy) Several empirical approaches have been advocated but most have no controlled data 1. Aslam S, et al. Lancet Infect Dis. 2005;5: McFarland LV, et al. Am J Gastroenterol. 2002:97: McFarland LV, et al. JAMA. 1994;271:

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24 Unproven Adjunctive Therapies for Recurrent CDI Probiotics Saccharomyces boulardii Lactobacillus GG May reduce the likelihood of further recurrences in some patients when added to and continued after treatment with metronidazole or vancomycin 1-3 Rifampin Efficacy in one series (n=7) when added to vancomycin 4 Nitazoxanide Rifaximin chaser Response demonstrated in patients (n=35) who failed prior metronidazole therapy 5 and similar response and recurrence rates when compared with metronidazole for initial therapy (n=110) 6 Effective when used for 14 days after vancomycin therapy (n=8) 7 1. McFarland LV, et al. JAMA. 1994;271: McFarland LV. J Med Microbiol. 2005;54: Surawicz CM, et al. Clin Infect Dis. 2000;31: Buggy BP, et al. J Clin Gastroenterol. 1987;9: Musher DM, et al. J Antimicrob Chemother. 2007;59: Musher DM, et al. Clin Infect Dis. 2006;43: Johnson S, et al. Clin Infect Dis. 2007;44:

25 Recurrent CDI: Rifaximin Chaser Eight women with multiple recurrences Rifaximin 400 mg BID for 2 weeks immediately after completing last course of vancomycin Seven of eight patients had no further diarrhea recurrence Single case of rifaximin resistance (identified after therapy) with recurrent CDI after a second course of rifamixin Effective in interrupting recurrent episodes but resistance may become an issue Johnson S, et al. Clin Infect Dis. 2007;44:

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27 Grazie per l attenzione!