Időskorúak újabb súlyos infekciós fenyegetettsége: Clostridium difficile. Mit tud a fidaxomycin? A Magyar Gerontológiai és Geriátriai Társaság XXXV. Kongresszusa és a MGGT - PTE ÁOK Családorvosi Intézet -– Zala Megyei Kórház által szervezett idősgyógyászati konferencia Dr Székács Béla egyetemi tanár Semmelweis Egyetem II.sz Belgyógyászati Klinika Geriátriai Tanszéki Csoport Főv. Önkorm.Szt Imre Kh. és Rendelőintézet Geriátriai – Gerontopszichiátriai és Rehabilitációs Osztály Zalaegerszeg 2012 november 9.

Öregedés —>funkcionális kapacitás-vesztés % Kapacitás 20 40 60 80 100 életkor Bio Psycho Social

A biológiai funkcionális hanyatlás fontos része: az immunrendszer hatékonyság-csökkenése Age-Associated Changes of Lymphocytes at the Cellular Level Aging: a decrease in the diversity of the antigen-recognition repertoire (Franceschi and Cossarizza, 1995)(Goronzy and Weyand, 2005). Immunosenescent state: markedly decreased population of naïve lymphocytes and an oligoclonally expanded population of memory lymphocytes along with a reduced antigen recognition (Goronzy and Weyand, 2005). Következmények az idős, legyengült, elesett ápoltak körében: Nő a súlyos, toxikus, rendszerint széles spektrumú antibiotikumok alkalmazásához vezető fertőzések száma Fokozódik az ápolószemélyzet által is gyakran közvetített contaminációs infekciók érvényesülése A bélcsatorna normal mikrobiológiai flórája így súlyosan károsodhat

Clostridium difficile fertőzés Spóra képző, anaerob, gram pozitív baktérium (toxinA+B) 1978: C. difficile, mint a pseudomembranozus colitis kórokozója GI infekció (hasmenés, colitis) Klinikai állapot eltérő súlyosságú: lehet csak mérsékelt hasmenés, de kialakulhat nekrózis, vérzés, exitusba torkolló toxikus megacolon is. Pseudomembranosus colitis: a gyulladásos nyálkahártya sérülések fölé membrán tapad, életveszélyes állapotot jelent: Hasi görcsös-feszítő fájdalmak Láz, Folyadékvesztés, esetleg vérzés (bél-nekrózis), Tachycardia, Lethargia, Béldilatáció Labor: súlyos esetekben nagyfokú leukocytosis C. difficile is a spore-forming, anaerobic, gram-positive bacterium. This microbe is responsible for gastrointestinal infections that result in diarrhea and colitis ranging in severity from mild colitis to toxic megacolon and death. C. difficile remains the leading cause of healthcare-associated infections diarrhea in the US, and now rivals methicillin-resistant Staphylococcus aureus (MRSA) as the most common organism to cause healthcare-associated infections in the US. References: Gerding DN, et al. Clostridium difficile-associated diarrhea and colitis. SHEA Position Paper. Infect Control Hosp Epidemiol. 1995;16:459-477. Centers for Disease Control and Prevention. Clostridium difficile. Information for healthcare providers. Fact Sheet, August 2004 (updated 7/22/05). McDonald LC, Owings M, Jernigan DB. Clostridium difficile infection in patients discharged from US short-stay hospitals, 1996-2003. Emerg Infect Dis. 2006;12:409-415. Gerding DN, et al. Infect Control Hosp Epidemiol. 1995;16:459-477. McDonald LC, et al. Emerg Infect Dis. 2006;12:409-415. 4

CDI Epidemiologia (USA) Incidencia növekszik (idősek: Nurs.H 50%, Kh: 40% fertőzöttség, m&M ) Healthcare Cost and Utilization Project (HCUP) http://hcupnet.ahrq.gov. CDI és MRSA fertőzések száma 89 kórházban 2010-ban Unfortunately, the number of CDI cases appears to be increasing. According to the Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project (HCUP), the total number of patients assigned the ICD-9 code for CDI (008.45) in acute care facilities has increased from 138,954 in 2000 to nearly 350,000 in 2008.   Reference: HCUPnet. Healthcare Cost and Utilization Project (HCUP). Rockville (MD): Agency for Healthcare Research and Quality [accessed February 17, 2011]. http://hcupnet.ahrq.gov. 85+ E. Meyer et al. J. Hospital infection 82(3):181-186, 2012 65-84 Jelenleg az USA-ban az egészség által okozott fertőző hasmenések vezető oka, az MRSA „riválisa” 45-64 18-44 Újabb hypervirulens törzsek, például BI/NAP1/027, toxin”A” 16x,toxin”B”23x, binary toxin (CDT), FQ resistencia <18 5

Megelőző antibiotikus kezeléshez kapcsolódó C Megelőző antibiotikus kezeléshez kapcsolódó C. difficile infectio kockázat Nagy kockázat Közepes mérvű kockázat Alacsony mérvű kockázat Cephalosporinok Macrolidok Aminoglikozidák Clindamycin Co-trimoxazole Metronidazole Amipicillin/ amoxycillin Tetracyclinek Anti-pseudomonas penicillinek Fluoroquinolonok Rifampicin Vancomycin C.diff. fertőzés klinikai tünetei megjelennek: általában 8 héttel az antibiotikus kezelés után

Costridium difficile fertőzöttség kimutatása Teszt típusa Előny Hátrány Toxin kimutatás Enzim immunoassay Gyors,egyszerű,olcsó A legkevésbé érzékeny módszer, némely változata csak az „A” toxint mutatja ki (egyes törzsek viszont csak „B” toxint termelnek!) Szövettenyészet citotoxicitás+neutr.pr. Baktérium kimutatása Érzékenyebb, mint az enzim immunoassay Intenzív laborigény, speciális felszerelés, 1, vagy 2 napot is igényel a végső eredményhez, és nem is annyira érzékeny, mint azt jelenleg még vélik Glutamát dehidrogenáz detektálása (EIA+t.) Gyors, érzékeny, igen hasznos mint triage, vagy széklet szűrővizsgálat Nem specifikus, toxin kimutatás is szükséges a diagnózis megerősítéséhez, és nem 100%-an érzékeny PCR Gyors, érzékeny, a toxin génjét mutatja ki Költségigényes, speciális felszereltség, és néha túl-érzékeny… Széklet tenyésztés A legérzékenyebb vizsgáló módszer, ha megfelelően végzik Álpozitiv is lehet párhuzamos toxin kimutatás hiányában, az eredményig 2-4 nap is szükséges A comparison of enzyme immunoassay (EIA), tissue culture cytotoxicity, glutamate dehydrogenase (GDH), polymerase chain reaction (PCR), and stool culture for C. difficile is displayed in the table. There are clearly benefits and drawbacks to either of these choices, and the optimal testing method for CDI has yet to be established. 7

Orsz. Epid. Kp. , Orvosi Mikrobiol Orsz. Epid. Kp., Orvosi Mikrobiol. Szakmai Kollégium, Infektológiai Szakmai Kollégium 2011 ., módszertani levél 2011

Recurrens CDI - további therapia? Rekurrens CDI gyakori, súlyos probléma! Átlagos gyakorisága korosztályi megkülönböztetés nélkül: 20% az első epizód után (időseknél magasabb!) 45% az első relapsus/újrafertőződés után 65% a második, vagy további relapsus/újrafertőződés után Metronidazol??? (max 14 nap! hepatotoxicitás, hányinger, hányás) Vancomycin /újra?/ (csak bacteriostatikus!)??? Más, lehetőleg bactericid szer??? Unfortunately, up to 20% of patients treated for CDI will relapse after initial treatment. Recurrences have been reported in 45% of patients who have experienced a single recurrence. In addition, up to 65% of patients will experience two or more recurrences. Antibiotic resistance does not appear to be an issue in recurrent CDI. Prior observations suggest that more than 90% of initial recurrences can be retreated with the same agent used for initial treatment because the first recurrence does not appear to be related to in vitro resistance. This practice continues to be effective with one exception. If, upon recurrence, the infection may then be classified as severe, oral vancomycin should be used to treat this recurrent episode. For further recurrences, tapered or pulse dosing of vancomycin has been the most widely used regimen. References: Cohen SH, et al. Infect Control Hosp Epidemiol. 2010;31(5):431-455. Johnson S. J Infect. 2009;58(6):403-410. Cohen SH, et al. Infect Control Hosp Epidemiol. 2010;31(5):431-455. Johnson S. J Infect. 2009;58(6):403-410. Fidaxomicin! 9

Fidaxomicin (Dificlir) 22 September 2011 EMA/CHMP/724015/2011 Committee for Medicinal Products for Human Use (CHMP) Summary of opinion1 (initial authorisation) Dificlir fidaxomicin On 22 September 2011, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product Dificlir, 200mg, film-coated tablet intended in adults for the treatment of Clostridium difficile infections (CDI) also known as C. difficile-associated diarrhoea (CDAD). The applicant for this medicinal product is FGK Representative Service GmbH. They may request a re-examination of any CHMP opinion, provided they notify the European Medicines Agency in writing of their intention within 15 days of receipt of the opinion. The active substance of Dificlir is fidaxomicin, an antibacterial agent belonging to the macrocyclic class of antibacterials. Fidaxomicin is bactericidal and inhibits RNA synthesis by bacterial RNA polymerase. It interferes with RNA polymerase at a distinct site from that of rifamycins. The benefits with Dificlir are its ability to cure populations suffering CDI. The efficacy of fidaxomicin was investigated in two Phase 3 trials which enrolled a total of 1164 subjects with CDI. In the pooled clinical trials, fidaxomicin was shown to be associated with a non inferior cure rate as compared to vancomycin. The most common side effects are nausea, vomiting and constipation. A pharmacovigilance plan for Dificlir will be implemented as part of the marketing authorisation. The approved indication is: “DIFICLIR is indicated in adults for the treatment of Clostridium difficile infections (CDI) also known as C. difficile-associated diarrhoea (CDAD) (see section 5.1).

Lancet Infect Dis. 2012 Apr;12(4):281-9. Epub 2012 Feb 8. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial. Cornely OA, Crook DW, Esposito R, Poirier A, Somero MS, Weiss K, Sears P, Gorbach S; OPT-80-004 Clinical Study Group. Collaborators (82) Fidaxomicin: a vancomycinnel egyenertékű th.hatékonyságú! Of 535 patients enrolled, 270 were assigned fidaxomicin and 265 vancomycin. After 26 patients were excluded, 509 were included in the modified intention-to-treat (mITT) population. 198 (91·7%) of 216 patients in the per-protocol population given fidaxomicin achieved clinical cure, compared with 213 (90·6%) of 235 given vancomycin, meeting the criterion for non-inferiority (one-sided 97·5% CI -4·3%). Non-inferiority was also shown for clinical cure in the mITT population, with 221 (87·7%) of 252 patients given fidaxomicin and 223 (86·8%) of 257 given vancomycin cured (one-sided 97·5% CI -4·9%). In most subgroup analyses of the primary endpoint in the mITT population, outcomes in the two treatment groups did not differ significantly; although patients receiving concomitant antibiotics for other infections had a higher cure rate with fidaxomicin (46 [90·2%] of 51) than with vancomycin (33 [73·3%] of 45; p=0·031). Occurrence of treatment-emergent adverse events did not differ between groups. 20 (7·6%) of 264 patients given at least one dose of fidaxomicin and 17 (6·5%) of 260 given vancomycin died. INTERPRETATION: Fidaxomicin could be an alternative treatment for infection with C difficile, with similar efficacy and safety to vancomycin.

N Engl J Med 2011;364:422-31. Patients were enrolled at 52 sites in the United States and 15 sites in Canada A total of 629 patients were enrolled, of whom 548 (87.1%) could be evaluated for the per-protocol analysis …… The primary end point was clinical cure (resolution of symptoms and no need for further therapy for C. difficile infection as of the second day after the end of the course of therapy). The secondary end points were recurrence of C. difficile infection (diarrhea and a positive result on a stool toxin test within 4 weeks after treatment) and global cure (i.e., cure with no recurrence).

kevesebb relapsus-reinfekció! Fidaxomicin: kevesebb relapsus-reinfekció! F V Louie TJ, et al. N Engl J Med 2011;364:422-31. Rate of clinical cure with fidaxomicin non-inferior to that of vancomycin Fidaxomicin associated with significantly lower rate of CDI recurrence Similar adverse event profile F F F F V V V V V V F F

Fidaxomicin versus Vancomycin metanalysis

Results of primary and secondary outcomes for studies 003 and 004. Results of primary and secondary outcomes for studies 003 and 004. Individual results for each prespecified primary and secondary outcome are presented for studies 003 and 004 separately and are combined using fixed-effects meta-analysis in the modified intent-to-treat and per-protocol populations. The primary endpoint Clinical Cure is shown as the converse No Clinical Cure, and the secondary endpoint Global Cure, as the converse No Global Cure, so that relative risks for fidaxomicin versus vancomycin of <1 consistently indicate reduced risk for poor outcome with fidaxomicin. Abbreviations: CI, confidence interval; RR, relative risk. Favours Fidaxomicin Favours Vancomycin Crook D W et al. Clin Infect Dis. 2012;55:S93-S103

Persistent diarrhea, recurrence, or death. Fidaxomicin Vancomycin Persistent diarrhea, recurrence, or death. Study treatment was administered for 10 days and clinical cure was assessed at 12 days, at which time persistent diarrhea (>3 stools/24 hours and toxin A and/or B positive or requiring anti–Clostridium difficile infection [CDI] treatment) was defined as clinical failure. The events occurring before day 12 are deaths and the step increase in events at day 12 represents cases assessed to have persistent diarrhea at the posttreatment assessment. Events from day 13 to day 40 represent CDI recurrence or deaths. Abbreviation: HR, hazard ratio. Crook D W et al. Clin Infect Dis. 2012;55:S93-S103

Comparison of intent-to-treat (ITT), modified ITT (mITT), and per-protocol analyses of the combined 003 and 004 study populations. Comparison of intent-to-treat (ITT), modified ITT (mITT), and per-protocol analyses of the combined 003 and 004 study populations. For the ITT analysis, persistent diarrhea or death refers to events occurring in the first 12 days of the 40-day follow-up as in the time-to-event analysis depicted for days 0–12 in the Kaplan-Meier curve. Persistent diarrhea, recurrence, or death refers to events occurring during the entire study period, days 0–40. For the mITT and per-protocol analyses, No Clinical Cure refers to the converse of Clinical Cure assessed at day 12. No Global Cure refers to the converse of Global Cure and included the 40-day follow-up. The converse of each endpoint is depicted so that relative risks for fidaxomicin versus vancomycin of <1 consistently indicate reduced risk of poor outcome with fidaxomicin. Abbreviations: CI, confidence interval; RR, relative risk. Favours Fidaxomicin Favours Vancomycin Crook D W et al. Clin Infect Dis. 2012;55:S93-S103

Potentialis kiegészítő/alternatív kezelések I: nontoxigenic C Potentialis kiegészítő/alternatív kezelések I: nontoxigenic C. difficile Non-toxigenic C. difficile prevented CDI in 87%-97% of hamsters Nontoxigenic C. difficile strains occur naturally Natural asymptomatic C. difficile colonization (toxigenic or nontoxigenic) decreases risk of infection Nontoxigenic C. difficile can be administered orally as spores to provide protection against CDI Mechanism by which nontoxigenic C. difficile prevents colonization by toxigenic strains not yet elucidated Human Phase I trials completed in early 2010 Nontoxigenic C. difficile is an alternative avenue for potential treatment of CDI. Nontoxigenic C. difficile strains occur naturally; natural asymptomatic colonization with C. difficile (either toxigenic or nontoxigenic) is associated with decreased risk of infection. Nontoxigenic C. difficile is appealing in that can be administered orally as spores to provide protection against CDI. However, the mechanism by which nontoxigenic C. difficile prevents colonization by toxigenic strains has not yet elucidated. Human phase 1 safety trials of this therapy were completed in early 2010, with further investigations ongoing. References: Gerding DN, Johnson S. Management of Clostridium difficile infection: thinking inside and outside the box. Clin Infect Dis. 2010;51:1306-1313. Sambol SP, Merrigan MM, Tang JK, Johnson S, Gerding D. Colonization for the prevention of Clostridium difficile disease in hamsters. J Infect Dis. 2002;186:1781-1789. Idős imm.rendszer gyengébb válaszú! 1. Gerding DN, Johnson S. Clin Infect Dis. 2010;51:1306-1313. 2. Sambol SP, et al. J Infect Dis. 2002;186:1781-1789; with permission 18

Kiegészítő/alternative kezelések II: Probioticumok Adjunctive treatment for recurrent CDI Randomized trials of Lactobacillus species have failed to demonstrate benefit to prevent recurrent CDI Saccharomyces boulardii for secondary prophylaxis once promising2,3 “Confirmatory” trial failed to confirm Overall no effect: 44% vs 47% recurrence (RR 0.91; 95% confidence interval 0.66 to 1.27)3 subgroup analysis showed borderline benefit with S. boulardii and high dose vancomycin (p=0.05) Reports of fungemia have been reported More study needed for probiotics in primary prevention The role of probiotics in the treatment and/or prevention of CDI has not yet been clearly defined. Randomized trials of Lactobacillus species have failed to demonstrate benefit to prevent recurrent CDI. Saccharomyces boulardii was originally believed to be beneficial for prevention of CDI, but confirmatory trials failed to reach their endpoint. Overall, there was no difference in recurrence (44% vs. 47%) between those who received this probiotic and those who did not. In addition, reports of fungemia have been reported. In summary, more studies are needed to determine the utility of probiotics for primary prevention of CDI. References: Dendukuri N, Costa V, McGregor M, Brophy JM. Probiotic therapy for the prevention and treatment of Clostridium difficile-associated diarrhea: a systematic review. CMAJ. 2005;173:167-170. Tung JM, Dolovich LR, Lee CH. Prevention of Clostridium difficile infection with Saccharomyces boulardii: a systematic review. Can J Gastroenterol. 2009;23:817-821. Surawicz CM, McFarland LV, Greenberg RN, et al. The search for a better treatment for recurrent Clostridium difficile disease: use of high-dose vancomycin combined with Saccharomyces boulardii. Clin Infect Dis. 2000;31:1012-1017. 1. Dendukuri N, et al. CMAJ. 2005;173:167-170. 2. Tung JM, et al. Can J Gastroenterol. 2009;23:817-821. 3. Surawicz CM, et al. Clin Infect Dis. 2000;31:1012-1017. 19

Potenciális kiegészítő/alternatív kezelések III: széklet mikrobiológiai flóra helyreállítása Theory: Restoration of fecal flora and colonization resistance Data: 1958 to 2000: 9 reports (68 patients); cure rate ~90%. 2003: 18 patients; fecal filtrate (stool transplant); 1 of 16 survivors had a single subsequent recurrence; pre-treated with vancomycin and omeprazole; instilled through nasogastric tube. Test donor: enteric pathogens, C. difficile, ova and parasites, HAV, HBV, HCV, HIV, RPR Restoration of fecal flora and colonization resistance is the theoretical basis for fecal transplant. Between 1958 and 2000, 9 reports of 68 patients who underwent fecal flora restoration were published, with an overall cure rate of ~90%. In a 2003 study, 18 patients received fecal filtrate (stool transplant), instilled through nasogastric tube following pretreatment with vancomycin and omeprazol. One of 16 survivors had a single subsequent recurrence. Remember to test the donor for enteric pathogens, C. difficile, ova and parasites, HAV, HBV, HCV, HIV, RPR. References: Persky SE, Brandt LJ. Treatment of recurrent Clostridium difficile-associated diarrhea by administration of donated stool directly through a colonoscope. Am J Gastroenterol. 2000;95:3283-3285. Borody TJ. "Flora Power“– fecal bacteria cure chronic C. difficile diarrhea. Am J Gastroenterol. 2000;95:3028-3029. Palmer R. Fecal Matters. Nat Med. 2011;17:150-152. 1. Persky SE, Brandt LJ. Am J Gastroenterol. 2000;95:3283-3285. 2. Borody TJ. Am J Gastroenterol. 2000;95:3028-3029. 3. Palmer R. Nat Med. 2011;17:150-152. 20

Potentialis jövőbeli Th. CDI ellen I. C. difficile Toxoid Vaccina Seroconversion rates in young vs elderly healthy subjects (50 μg dose) Day Study 009 ≥65 yrs; median age = 70 Study 008 18–55 yrs; median age = 26 10 20 30 40 50 60 70 80 25 75 100 Seroconversion Rate (%) Toxin A Toxin B Both toxins 100% 75% 42% 25% Recently, a toxoid vaccine was developed to explore primary & secondary protection strategies. The vaccine appears to produce a high-level anti-toxin A and anti-toxin B immunoglobulin G (IgG) responses. The figure shows the different kinetics between healthy adults and healthy elderly who received the vaccine at the 50 μg dose. Here, we see 100% seroconversion to toxin A following 2 doses of the vaccine in both groups. We also see seroconversion following one vaccine. There is also a 75% seroconversion rate to toxin B after 2 doses of the vaccine in adults; 45% seroconversion to toxin B in the elderly. Reference: Foglia G et al. Presented at: Anaerobe Society of Americas; July 2010; Philadelphia, PA. Abstract CD 1093. Probléma: idős imm.rendszer gyengébb válasza! Foglia G, et al. Anarobe Society of Americas 2010; Abstract CD 1093. 21

Potentialis jövőbeli CDI Th Potentialis jövőbeli CDI Th. II Monoclonalis ellentestek Monoclonal Antibodies: (mAbs) Recent study of mAbs in 200 CDI patients receiving metronidazole or vancomycin Recurrence rates: 7% in mAb group vs. 25% in placebo group Time to CDI recurrence Monoclonal antibodies (mAbs) are another potential future therapy of CDI. In a recent study of two neutralizing, fully mAbs against C. difficile toxins A (CDA1) and B (CDB1) in 200 CDI patients receiving metronidazole or vancomycin, the rate of recurrence of C. difficile infection was lower among patients treated with monoclonal antibodies (7% vs 25%, respectively). Moreover, the recurrence rates among patients with the epidemic BI/NAP1/027 strain were 8% for the antibody group and 32% for the placebo group (P=0.06). The figure demonstrates time to CDI recurrence among the mAb and placebo treatment arms. Reference: Lowy I, Molrine DC, Leav BA, et al. Treatment with monoclonal antibodies against Clostridium difficile toxins. N Engl J Med. 2010;362:197-205. Lowy I, et al. N Engl J Med. 2010;362:197-205. 22

Clostridium difficile fertőzés cost/benefit alapú, valóban hatékony kezelési lehetőségei összefoglalva Enyhe, közepes súlyosságú: metronidazol Súlyos: vancomycin Relapsus/újrafertőződés: vancomycin megnövelt dózisa Második, vagy még többszöri relapsus/reinfectio, életveszély: fidaxomycin (Dificlir) A „kiegészítő kezelések” igazában/önállóan nem váltak be, immunválaszra alapozottaknál probléma az új antigének iránti gyengébb időskori immun-reakció.

Köszönöm a figyelmet!

SHEA/IDSA Treatment Recommendations Clinical scenario Supportive clinical data Recommended treatment Mild to moderate Leukocytosis (WBC < 15,000 cells/uL) or SCr level < 1.5 times premorbid level Metronidazole 500 mg 3 times per day PO for 10-14 days Severe Leukocytosis (WBC ≥ 15,000 cells/uL) or SCr level ≥ 1.5 times premorbid level Vancomycin 125 mg 4 times per day PO for 10-14 days Severe, complicated Hypotension or shock, ileus, megacolon Vancomycin 500 mg 4 times per day PO or by nasogastric tube plus metronidazole 500 mg IV q 8 hrs According to the SHEA/IDSA guidelines, mild to moderate disease is defined as WBC <1500 cells/μL or SCr level <1.5 times the premorbid level. In these patients, the recommended therapy is metronidazole 500 mg 3 times per day PO for 10-14 days. Alternately, severe disease is defined as WBC ≥1500 cells/μL or SCr level ≥1.5 times the premorbid level. The recommended treatment for severe CDI is vancomycin 125 mg 4 times per day PO for 10-14 days. Severe, complicated disease is defined as hypotension or shock, ileus, or toxic megacolon. These patients should receive vancomycin 500 mg 4 times per day PO or by nasogastric tube plus metronidazole 500 mg IV every 8 hrs. It is important to note that the vancomycin dose in this setting is based on original, empiric, studies; it is not clear that 500 mg is necessary. Reference: Cohen SH, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults: 2010 Update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31(5):431-455. Cohen SH, et al. Infect Control Hosp Epidemiol. 2010;31(5):431-455. 25