Clostridium Difficile: How Do We Stop the Flow?

10/1/2015

Disclosure

I do not have a vested interest or affiliation with any Clostridium difficile: How do we corporate organization offering financial support or grant monies for this continuing education activity, or stop the flow? any affiliation with an organization whose philosophy could potentially bias my presentation. Chad Cannon, PharmD, BCPS Critical Care Pharmacist St. Vincent’s Medical Center‐Riverside

Pharmacist Objectives Technician Objectives

• Review prevalence and risk factors associated • Recall prevalence and risk factors associated with C. diff with C. diff. • Outline updates needed to C. diff treatment • Identify updates need in C. diff treatment guidelines guidelines • Discuss preventative measures to help reduce • Develop preventative measure to reduce C. C. diff rates diff. rates • Evaluate new therapies on the horizon for C. • Discuss new therapies for treatment of C. diff. diff

Clostridium difficile Environmental Contamination

• Gram‐positive, anaerobe, spore‐forming • Electronic rectal bacillus organism thermometers • Toxin A and B • Inadequately cleaned • B1/NAP1/027 commodes or bedpans • Transmission person‐to‐person via fecal‐oral • Shared between patients route • Use household bleach in 1:10 dilution for best results • Sporicidal

Evans CT ,Safdar N. CID. 2015;60(S2):S66-71 Evans CT ,Safdar N. CID. 2015;60(S2):S66-71..

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Pathogenesis Prevalence

• 453,000 cases of C. diff infections • 29,000 deaths associated with C. diff • 15 cases per 1,000 hospital discharges • 20 cases per 100,000 person‐years in the community • C. diff Infections (CDI) Annual expenditures $1.5 billion in U.S.

Leffler DA,Lamont JT. NEJM 2015;372:1539-48. Evans CT ,Safdar N. CID. 2015;60(S2):S66-71.

Risk Factors

Antibiotics Age

Length of hospitalization Chemotherapy or immunocompromised

Gastrointestinal surgery or tube Proton pump inhibitors/histamine‐ 2 feeding blockers

Leffler DA,Lamont JT. NEJM 2015;372:1539-48. Leffler DA,Lamont JT. NEJM 2015;372:1539-48.

Complications Associated with C. Symptoms difficile • Presence of diarrhea • Fever • Pseudomembranous colitis • Abdominal cramping • Toxic megacolon • Peripheral leukocytosis • Perforations of the colon • Passage of mucus or occult blood in stool • Sepsis • Death

Surawicz CM et al. AM J Gastroenterol 2013;108:478-498. Surawicz CM et al. AM J Gastroenterol 2013;108:478-498.

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Diagnosis Testing

• Presence of diarrhea • Glutamate dehydrogenase • Passage of 3 or more unformed stools in 24 hour • Specificity < 90% or less • ELISA • Stool test positive for toxigenic C. difficile • Increased sensitivity for low‐level toxin production • Toxin or colonoscopy or histopathology • Polymerase Chain Reaction (PCR) findings demonstrating pseudomembranous • Detects B1/NAP1/027 colitis • Tissue Cytotoxic Assay • Sensitivity 94‐100%

Surawicz CM et al. AM J Gastroenterol 2013;108:478-498. Peterson LR, Robiscek A. Ann Intern Med. 2009;151:176-179.

Phases of C. diff Guideline Recommendations Severity Criteria Treatment Comment Mild‐to‐Moderate disease Diarrhea plus any additional Metronidazole 500 mg po tid If no improvement in 5‐7 days signs or symptoms not x 10 days. If unable to take consider change to meeting severe or metronidazole, vancomycin vancomycin. complicated 125 mg po qid for 10 days. Severe disease Serum albumin < 3 g/dL plus Vancomycin 125 mg po QID one of the following: for 10 days WBC ≥ 15,000 cells/mm3 Abdominal tenderness Antimicrobial Severe and complicated Any of the following Vancomycin 500 mg po QID Surgical consult suggested Post treatment disease attributable to CDI: and metronidazole 500 mg iv exposure Admission to ICU for CDI q8h, and vancomycin per Antibiotic treatment Normal microbiota asymptomatically Hypotension with or without rectum (vancomycin 500 mg of C. diff. vs. Regrowth of use of vasopressors in 500 ml saline as enema) qid impairs the pathogen Fever ≥ 38.5 °C microbiome Ileus or significant abdominal distention Mental status changes WBC ≥ 35,000 or < 2,000 Serum lactate levels > 2.2 mmol/L End organ failure Recurrent CDI Recurrent CDI within 8 weeks Repeat metronidazole or Consider Fecal microbiota of completion of therapy vancomycin pulse regimen transplant after 3 recurrences

Leffler DA,Lamont JT. NEJM 2015;372:1539-48. Surawicz CM et al. AM J Gastroenterol 2013;108:478-498.

Metronidazole Vancomycin

• Mechanism of action: • Mechanism of action: • Induces microbial cell death by DNA distruption and • Inhibits bacterial wall synthesis inhibition of nucleic acid synthesis • Dosing: • Dosing: • 125 mg oral qid • 500 mg oral qid • 500 mg tid oral or intravenous • 500 mg rectal qid • Metabolism: • Taper • 60‐80% metabolized by liver; remaining excreted in • Metabolism: feces • Excreted unchanged in feces • Side Effects: • Side effects: • Metallic taste, headache, nausea, disulfiram reaction • Upset stomach and nausea

Leffler DA, Lamont JT. Gastroenterology.2009;136:1899-1912. Leffler DA, Lamont JT. Gastroenterology.2009;136:1899-1912.

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Fidaxomicin Treatment Options to Avoid

• Mechanism of action: • Antidiarrheals/Antimotility • Inhibits bacterial protein synthesis through inhibition • Loperamide of transcription that relies upon the sigma subunit of RNA polymerase • Diphenoxylate • Dosing: • Bismuth • 200 mg oral twice daily x 10 days • Complications • Excretion: • Delay in resolution • Feces and Urine • Toxic Megacolon • Side Effect: • Nausea, vomiting, abdominal pain

Sullivan KM, Spooner LM. Ann Pharmacother. 2010;44:352-9. Surawicz CM et al. AM J Gastroenterol 2013;108:478-498.

Treatment Guideline Revisions? Treatment Guideline Revisions? Cont’d Severity Clinical Manifestations Treatment Severity Clinical Manifestations Treatment Asymptomatic carrier No symptoms or signs No treatment indicated Severe • Severe or bloody diarrhea • Hospitalization • Pseudomembranous colitis • Oral or nasogastric vancomycin 500 Mild • Mild diarrhea ( 3 to 5 unformed • Predisposing antibiotics • Ileus mg qid with or without IV bowel movements per day) cessation • Temperature > 38.9°C metronidazole 500 mg tid • • Afebrile status Hydration • WBC > 20,000 • Or oral fidaxomicin 200 mg po bid • • Mild abdominal discomfort or Monitoring clinical status • Albumin level < 2.5 mg/dL for 10 days instead of vancomycin if • tenderness Either administration of • Acute kidney injury the risk of recurrence is high • No notable laboratory abnormalities metronidazole 500 mg po tid or close outpatient Complicated • Toxic megacolon • Antibiotics as for severe infection monitoring without the • Peritonitis • Surgical consult for subtotal administration of • Respiratory distress colectomy or a diverting ileostomy antibiotics • Hemodynamic instability with vancomycin colonic lavage • Consideration of fecal microbial • • Moderate Moderate nonbloody diarrhea Consideration of transplantation or additional • Moderate abdominal discomfort or hospitalization and antibiotics tenderness cessation of predisposing • Nausea with occasional vomiting antibiotics First Recurrence • Oral vancomycin 125 mg po qid for • Dehydration • Hydration 14 days • WBC > 15,000/mm3 • Monitoring of clinical status • Or fidaxomicin po 200 mg bid for 10 • Blood Urea nitrogen or Creatinine • Either administration or days levels above baseline oral metronidazole 500 mg Second or further • Vancomycin in a tapered and po tid or first line therapy recurrence pulsed regimen with po vancomycin 125 mg • Fecal microbial transplantation qid for 14 days • Or fidaxomicin 200 mg po bid for 10 days Leffler DA,Lamont JT. NEJM 2015;372:1539-48. Leffler DA,Lamont JT. NEJM 2015;372:1539-48.

Treatment Guideline Revisions? Fecal Microflora with C. diff therapies

Severity Clinical Manifestations Treatment Moderate • Moderate nonbloody diarrhea • Consideration of • Single center, phase 2 and 3 study • Moderate abdominal discomfort hospitalization and or tenderness cessation of • Specific objectives of study • Nausea with occasional vomiting predisposing antibiotics • Dehydration • Hydration • C. difficile present at diagnosis of CDI • WBC > 15,000/mm3 • Monitoring of clinical • Blood Urea nitrogen or status • Degree of impairment of normal microbiota Creatinine levels above baseline • Either administration or oral metronidazole 500 • mg po tid or first line Comparison of clearance of C. difficile with therapy with po different therapies vancomycin 125 mg qid for 14 days • Pattern of recovery of the normal microbiota

Leffler DA,Lamont JT. NEJM 2015;372:1539-48. Louie TJ et al. CID.2015;60(S2):S91-97.

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Fecal Microflora cont’d Treatment Guideline Revisions? Severity Clinical Manifestations Treatment Organisms Healthy Volunteers Patients w/ C. diff Severe • Severe or bloody diarrhea • Hospitalization (n=5) (n=98) • Pseudomembranous colitis • Oral or nasogastric vancomycin Clostridium spp 7.8 ±4.1 CFU/G 6.7± 2.0 CFU/G • Severe abdominal pain 500 mg qid with or without IV • Vomiting metronidazole 500 mg tid Bacteroides spp 11.8 ±0.2 CFU/G 6.5 ±3.2CFU/G • Ileus • Or oral fidaxomicin 200 mg po • Temperature > 38.9°C bid for 10 days instead of • WBC > 20,000 vancomycin if the risk of Drug 0 or 1 41014212838‐42 • Albumin level < 2.5 mg/dL recurrence is high Tolevamer 7.3 ±1.4 7.5 ±1.1 7.5 ±1.2 6.8 ±1.6 5.8 ± 1.9 4.3 ±2.0 2.5 ±0.7 • Acute kidney injury (14) (14) (13) (13) (11) (7) (5) Vancomycin 7.5 ±1.5 3.4 ± 1.8 2.3 ±0.9 2.0 ± 0.0 4.2 ±2.4 ( 4.2 ± 2.2 4.4 ±1.9 (20) (17) (18) (16) 15) (12) (8) Metronidazole 5.7 ±2.2 4.6 ±2.2 3.5 ±2.2 4.0 ±2.9 5.2 ±2.8 4.9 ±1.8 ( 4.2 ±2.3 (14) (14) (10) (13) (7) 7) (3)

Leffler DA,Lamont JT. NEJM 2015;372:1539-48. Leffler DA,Lamont JT. NEJM 2015;372:1539-48.

Vanco/Flagyl C. diff in Critically Ill Critically Ill Cont’d

Outcome Monotherapy Combination P‐value • Single centered, observational, comparative (n=44) (n=44) study In‐hospital mortality 16 (36.4) 7 (15.9) 0.03 Time to death, days, median 21 (5‐174) 15 (6‐32) 0.23 • Primary objective (range) • In‐hospital mortality Clinical success day 6 9 (20.5) 6 (13.6) 0.57 Day 10 27 (61.4) 25 (56.8) 0.83 • Secondary objective Day 21 33 (75.0) 37 (84.1) 0.43 • Clinical success at days 6 ,10, and 21 Length of stay after CDI 20.5 (10‐64) 18.0 (6‐166) 0.99 diagnosis, days, median (range) • Hospital length of stay after CDI diagnosis Length of ICU stay after CDI 9 (4‐60) 11.0 (3‐68) 0.93 • Length of ICU stay after CDI diagnosis diagnosis, days, median (range)

Rokas KE et al. CID.2015;61(6):934-41. Leffler DA,Lamont JT. NEJM 2015;372:1539-48.

Treatment Guideline Revisions? 1st Recurrence Fidaxomicin vs. Cont’d Vancomycin Severity Clinical Manifestations Treatment First Recurrence • Oral vancomycin 125 mg po qid • Multi‐center, randomized, controlled trial for 14 days • Or fidaxomicin po 200 mg bid • Primary Objective for 10 days • Recurrence within 28 days after completing therapy • Secondary Objective • Time to recurrence

Leffler DA,Lamont JT. NEJM 2015;372:1539-48. Cornely OA et al. CID. 2012;55:(S2):S154-61.

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Treatment Guideline Revisions? Vancomycin vs Fidaxomicin Cont’d • Recurrence within 28 days Severity Clinical Manifestations Treatment Second or further • Vancomycin in a tapered and • No prior episode recurrence pulsed regimen • Vanco 22.6 % vs. Fidaxomicin 11.7% (p= < 0.001) • Fecal microbial transplantation • Or fidaxomicin 200 mg po bid • One prior episode for 10 days • Vanco 35.5% vs. Fidaxomicin 19.7% (p= 0.045) • Time to recurrence • Recurrence within 14 days • Vanco 27.4% vs. Fidaxomicin 7.6% (p=0.03) • Recurrence within 15 to 28 days • Vanco 11.1% vs. Fidaxomicin 13.1% (p=ns)

Cornely OA et al. CID. 2012;55:(S2):S154-61. Leffler DA,Lamont JT. NEJM 2015;372:1539-48.

Fecal transplant for recurrence Fecal transplant cont’d

Outcome First Infusion of Infusion of Donor Vancomycin Vancomycin with • Single centered, open‐label, randomized, Variables Donor Feces Feces Overall (N=13) Bowl Lavage controlled trial N=16 (N=16) (N=13) Rate of 13/16 (81.3%) 15/16 (93.8%) 4/13 (31%) 3/13 (23%) • Cure Primary Objective without • Cure without relapse within 10 weeks after Relapse Microbiota Diversity in Patients before and after infusion of therapy Donor Feces, as compared with Diversity in Health Donors • Secondary Objective • Change in microbiota diversity

Nood EV et al. NEJM. 2013;368:407-415. Nood EV et al. NEJM. 2013;368:407-415.

Antimicrobial Stewardship Stewardship Executive Order

Targets for Combating Resistance Antimicrobial stewardship is a coordinated Goals by 2020 program that promotes the appropriate use of • Slow the Emergence of Resistant Bacteria and Prevent the Spread of • Reduce by 50% the incidence of antimicrobials (including antibiotics), improves Resistant Infections overall Clostridium difficile infection • Strengthen National One‐Health • Reduce by 60% carbapenem‐ Surveillance Efforts to Combat resistant Enterobacteriaceae patient outcomes, reduces microbial resistance, Resistance infections acquired • Advance Development and Use of and decreases the spread of infections caused Rapid and Innovative Diagnostic Tests • Reduce by 35% multidrug‐resistant for Identification and Pseudomonas spp. infections by multidrug‐resistant organisms Characterization of Resistant Bacteria acquired during hospitalization • Accelerate Basic and Applied • Research and Development for New Reduce by at least 50% overall Antibiotics, Other Therapeutics, and methicillin‐resistant Staphylococcus Vaccines aureus (MRSA) bloodstream • Improve International Collaboration infections and Capacities for Antibiotic Resistance Prevention, Surveillance, Control, and Antibiotic Research and Development

Dellit TH et al. CID. 2007;44:159-77. https://www.whitehouse.gov/sites/default/files/docs/carb_national_strategy.pdf

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Restriction of Antibiotics Penicillin Allergies

Title An Evaluation of the impact of antibiotic stewardship on reducing the use of high‐risk antibiotics and its effect on the • PCN most common reported drug allergy incidence of Clostiridium difficile infection in hospital setting • Historical teaching 10% cross reactivity with Study Single‐center, retrospective study, April 2004 to June 2010 Intervention Restriction of high‐risk antibiotics 2nd and 3rd generation cephalosporin cephalosporins, fluroqinolones, and clindamycin Primary Outcome Evaluate impact of restricting high‐risk antibiotics and CDI • Avoiding beta‐lactams can potentially lead to incidence rates adverse effects and/or inferior coverage Result •  use of high level antibiotics (coefficient ‐17.3, p <0.0001 •  total antibiotic use (coefficient ‐14.2, p=0.0074) • True cross reactivity ≤ 2% with cephalosporin •  C. diff by 0.0047/100 bed‐days per month (P=0.0081) Conclusion Antibiotic restriction policy contributed to a reduction in high‐ • Anaphylaxis ≤ 0.0015% risk antibiotic usage and incidence of CDI

Aldeyab MA et al. J Antimicrob Chemother 2012;67:2988-2996. Campagna JD. J Emerg Med.2012;42(5):612-620.

Penicillin Allergy and Resistance Colorectal Surgery Prophylaxis

• Retrospective, matched cohort study ,2010‐12 • • Kaiser Foundation Hospitals Southern California Retrospective, case‐control study, 2 surgical units • Primary Objective: • July 2012‐ September 2013 • Determine the total number of hospital days used in hospitalized patients with active penicillin “allergy” compared to patients with no • Identify risk factors among surgical patients for penicillin “allergy” history • Secondary Objective: CDI • Determine antibiotics used and prevalence rates of C. diff, MRSA, and VRE between cases and controls. • Ertapenem associated with increase risk of CDI • Results: • (Adjusted OR 3.13, {95% CI, 1.13‐8.86}, P= 0.028 •  hospital days 0.59 (9.9%; 95% CI, 0.47‐0.71) •  C. diff prevalence 1.234 ( 95% CI, 1.156‐1.317) • Cefazolin prophylaxis no association • MRSA prevalence 1.141 (95% CI, 1.071‐1.317) • VRE prevalence 1.301 (95% CI, 1.125‐1.504) • (Adjusted OR 0.373, {95% CI, 0.129‐ 1.08}, P= 0.68

Macy E, Contreros R. J Allergy Clin Immunol. 2014;133:790-6. Lee S et al. Infect. Control Hosp. Epidemiol. 2015;00(0):1-4.

Indications for Stress Ulcer Acid Suppressors Prophylaxis

Histamine‐2 receptor antagonists Proton pump inhibitors • Intensive Care Unit • Mechanism of Action: • Mechanism of Action: • Coagulopathy • Competitive inhibition of • Inhibition of parietal cell • histamine H2 receptors of the H+/K+ ATP pump Mechanical ventilation > 48 hours gastric parietal cells • • Acute Kidney Injury • Indications: Indications: • Acid reflux • GERD • Acute/Chronic Hepatic Injury • Indigestion • Hypersecretory disorders • GERD • Duodenal ulcer • Non‐Intensive Care Inpatient • Side Effects: • Side Effects: • Not recommended • Headache, diarrhea, • Headache, dizziness, thrombocytopenia constipation

Bardou M et al. Nat. Rev. Gastroenterol. Hepatol. 2015;12:98-107. Grube RR. Am. J Health Syst. Pharm. 2007;64(13):1396-400.

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Proton Pump Inhibitors and C. diff in Acid Suppression and C. diff Critically Ill • Proton pump inhibitors Study Single Center, Retrospective, Case‐Control study Subjects • 408 patients from Beth Israel Deaconess Medical Center • Meta‐analysis from 2001 to 2008 • Examined association between PPIs and CDI Objective • Describe the relationship between PPI use and hospital‐ acquired CDI in critically ill patients • CDI and PPIs adjusted: OR 1.65; (95% CI, 1.47‐ • Evaluate duration of inpatient PPI exposure as a risk factor 1.85) for CDI Results • Long PPI exposure (2 or more days) ; OR 2.03, 95% CI (1.23‐ • Histamine 2 receptor antagonist 3.36) ; p= 0.006 • Meta‐analysis • Antibiotic use; OR 2.52, 95% CI (1.23‐5.18); p=0.012 Conclusion • Duration of PPI use is significantly associated with C. diff • Examined association between H2RAs and CDI associated diarrhea • Risk is evident after only two days of therapy • CDI and H2RAs OR 1.44, 95% CI (1.22‐1.7) • Consider alternative agents for stress ulcer prophylaxis

Tleyjeh IM et al. PLoS ONE 7(12):e50836. Tleyjeh IM et al. PLos ONE 8(3):e56498.. Barletta JF, Sclar DA . Critical Care. 2014;18:714

Different Types of Probiotics Probiotics Active Saccharomyces boulardii Lactobacillus Lactobacillus Ingredients species acidophilus, Lactobacillus casei • Live microorganisms that when ingested, produce and Lactobacillus some therapeutic or preventative health benefit rhamnosus

• Health‐promoting concept ~ 100 years old Trade name Florastor® Floranex® Bio‐K+® • Clinical studies validated use of probiotics Florajen® Culturelle® • Viral diarrhea Dosage Capsule/Powder for Capsules/Granules/ Capsules/liquid • Antibiotic‐associated diarrhea forms Suspension Chewable tablets • C. difficile‐associated diarrhea Dosage  AAD: 250mg BID Floranex • Capsules: 1‐2 • Traveler’s diarrhea initiated within 48 hrs of  2 capsules BID‐ capsules daily abx x 2 weeks after d/c QID • Liquid: 1 bottle • Pouchitis of abx  4 tablets or 1 daily x 1 month, • Irritable bowel syndrome  Acute diarrhea: 200mg packet TID‐QID then ½ bottle • Atopic dermatitis TID for 2 days followed Culturelle daily OR ¼ by 100mg TID x 5days • 1‐2 capsules bottle (2 tbsp) daily daily

OTC Product Information: Florastor® OTC Product Information: Floranex® Vanderhoof JA, Young R. CID.2008;46:S67-72. OTC Product Information: Bio-K+®

Probiotic Literature New Therapies

• Meta‐analysis review • Probiotics may be more effective in primary CDI prevention than in secondary prevention of recurrent CDI

Phase 3 Phase 1 Phase 2 Cadazolid CRS3123 Ramoplanin Surotomycin SMT 19969 Actoxumab/Bezlotox umab

Evans CT, Johnson S. CID. 2015;60:(S2):S122-8.

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Ramoplanin Surotomycin

• Glycolipodepsipeptide antibiotic • Minimally absorbed, narrow‐spectrum, cyclic • Under Investigation for relapse prevention lipopeptide • Mechanism of action: • Mechanism of Action: • Inhibits peptidoglycan biosynthesis by limiting lipid II • Acts through depolarization of the membrane, leading to availability the loss of a proton gradient and cell death • Exosporium may be target of killing • Bactericidal killing • “ambush” type of vegetative killing • Administered orally • Exponential and stationary phase cell killer

Kraus CN et al. Antimicrob Agents Chemother. 2015;59:2525-30. Alam MZ et al. Antimicrob Agents Chemother. 2015;59:5165-5170.

Cadazolid Actoxumab/Bezlotoxumab

• Novel fluoroquinolone‐oxazolidinone antibiotic • Human monoclonal antibodies • Mechanism of action: • Mechanism of action: • Inhibition of protein synthesis • Bind and neutralize TcdA and TcdB • Excreted unchanged in feces • Under investigation for prevention of recurrence • Phase II: similar clinical cure as vancomycin • Phase II study • Decrease in recurrence rates in cadazolid group • Administered with standard of care decrease recurrence

Baldoni D et al. J Antimicrob Chemother. 2014;69:706-714. Yang Z. et al. Infect. Immun. 2014;83:822-31.

Frozen Oral Stool Transplant Conclusion

• Open‐label, single‐group, feasibility study • C. difficile infections continue to  • Primary Objective: st • Evaluate the safety and rate of resolution of diarrhea following • Oral vancomycin 1 line therapy for administration of Fecal microbiota transplantation hospitalized patients • Intervention: • Patients received 15 capsules on 2 consecutive days • Bundle approach needed to  C. difficile • Results: infection rates • 14 of 20 patients had clinical resolution (OR 0.70, 95% CI, 0.47‐ • New therapies coming but can’t invent our 0.85) • 19 of 20 patients had resolution after 2nd treatment (OR 0.90, way out of this problem! 95% CI, 0.68‐ 0.98)

Yongster I et al. JAMA. 2014;312(17):1772-1778.

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References References

1) Evans CT, Safdar N. Current Trends in the Epidemiology and Outcomes of Clostridium difficile 10) Nood EV et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. NEJM. Infection. CID.2015;60(S2):S66‐71. 2013;368:407‐15. 11) Dellit TH et al. Infectious Disease Society of America and the Society for Healthcare Epidemiology of 2)Leffler DA, Lamont JT. Clostridium difficile. NEJM. 2015;372:1539‐48. America Guidelines for developing an Institutional Program to enhance antimicrobial stewardship. 3) Surawicz CM et al. Guidelines for Diagnosis, Treatment, and Prevention of Clostridium difficile CID.2007;44:159‐77. Infections. AM J Gastroenterol. 2013;108:478‐498. 12) https://www.whitehouse.gov/sites/default/files/docs/carb_national_strategy.pdf. Accessed August 4) Petson LR, Robicsek A. Does my patient have Clostridium difficile Infection. Ann Intern Med. 17,2015. 2009;151:176‐179. 13) Aldeyab MA et al. An evaluation of the impact of antibiotic stewardship on reducing the use of high‐ risk antibiotics and its effect on the incidence of Clostridium difficile infection in hospital settings. 5) Leffler DA, Lamont JT. Treatment of Clostridium difficile‐Associated Disease. Gastroenterology J Antimicrob Chemother 2012;67:2988‐96. 2009;136:1899‐1912. 14) Campagna JD et al. The use of cephalosporins in penicillin‐allergic patients: a literature review. J 6) Sullivan KM, Spooner LM. Fidaxomicin: A macrocyclic Antibiotic for the management of Emerg Med. 2012;42(5):612‐620. Clostridium difficile Infection. Ann Pharmacother. 2010;44:352‐9. 15) Pichichero ME. A review of the evidence supporting The American Academy of Pediatrics recommendations for prescribing cephalosporin antibiotics for penicillin‐allergic patients. 7) Louie JT et al. Differences of the Fecal Microflora with Clostridium difficile Therapies. CID. Pediatrics.2005;115:1048‐57. 2015;60(S2):S91‐7. 16) Macy E, Contreras R. Health care use and serious infection prevalence associated with penicillin 8) Rokas KE et al. The addition of intravenous metronidazole to oral vancomycin is associated “allergy” in hospitalized patients: A cohort study. J Allergy Clin Immunol. 2014;133:790‐6. with improved mortality in critically ill patients with clostridium difficile infection. CID. 17) Lee S et al. Ertapenem prophylaxis associated with an increased risk of Clostridium difficile infection 2015;61(6):934‐941. among surgical patients. Infect. Control Hosp. Epidemiol. 2015;00:(0):1‐4. 18) Bardou M et al. Stress‐related mucosal disease in the critically ill patient. Nat. Rev. Gastroenterol. 9) Cornely OA et al. Treatment of first recurrence of Clostridium difficile infection: Fidaxomicin Hepatol. 2015;12:98‐107. versus vancomycin. CID.2012;55(S2):S154‐61.

References References

19) Grube RR et al. Stress ulcer prophylaxis in hospitalized patients not in intensive care unit. Am. J 29) Kraus CN et al. Ambush of Clostridium difficile spores by ramoplanin: Activity in an in vitro Health Syst. Pharm. 2007;64(13):1396‐400. model. Antimicrob Agents Chemother. 2015;59:2525‐30. 20) Tleyjeh IM et al. Association between proton pump inhibitor therapy and Clostridium difficile 30) Alam MZ et al. Mode of action and bactericidal properties of surotomycin against growing infection: A contemporary systemic review and meta‐analysis. PLoS ONE 7(12):e50836. and nongrowing Clostridium difficile. Antimicrob Agents Chemother. 2015;59:5165‐5170. 21) Tleyjeh IM et al. The association between histamine 2 receptor antagonist use and Clostridium 31) Baldoni D et al. Cadazolid, a novel antibiotic with potent activity against Clostridium difficile: difficile infection: A systematic review and meta‐analysis. PLoS ONE 8(3):e56498. safety, tolerability and pharmacokinetics in healthy subjects following single and multiple oral 22) Barletta JF, Sclar DA. Proton pump inhibitors increase the risk for hospital‐acquired Clostridium doses. J Antimicrob Chemother. 2014;69:706‐714. difficile infection in critically ill patients. Critical Care. 2014;18:714. 32) Yang Z. et al. Mechanisms of Protection against Clostridium difficile Infection by the 23) Vanderhoof JA, Young R. Probiotics in the United States. CID. 2008;46:S67‐72. Monoclonal Antitoxin Antibodies Actoxumab and Bezlotoxumab. Infect Immun. 2014;83:822‐ 24) OTC Product Information: Florastor® oral capsules, saccharomyces boulardiilyo oral capsules. 31. Biocodex, San Bruno, CA, as appeared on the labeling supplied by the manufacturer 01/2011 33) Youngster I et al. Oral, Capsulized, Frozen fecal Microbiota transplantation for relapsing 26) OTC Product Information: Floranex®, lactobacillus. Rising, Allendale, NJ, as appeared on the labeling Clostridium difficile. JAMA. 2014;312(17):1772‐1778. supplied by the manufacturer 04/2014 27) OTC Product Information: Bio‐K+®. Bio‐K+ International, Laval QC H7V 4B3, Canada, as appeared on the labeling supplied by the manufacturer 28) Evans CT, Johnson S. Prevention of Clostridium difficile infection with probiotics. CID. 2015;60(S2):S122‐8.