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COMMUNITY-ACQUIRED CLOSTRIDIUM DIFFICILE

Cheryl Juneau DrPH, , FNP-CElnora Mendias PhD, FNP-BCNihas Wagal BSMichael Loeffelholz PhDTor Savidge PhDSharon Croisant PhDSara Dann PhDSheryl Bishp PhD

University of Texas Medical Branch Galveston

UNIVERSITY OF TEXAS MEDICAL BRANCH (UTMB)GALVESTON, TEXAS

HIGH-BIOCONTAINMENT LABS (BSL4) AT UTMB OBJECTIVES

§ To describe the changing epidemiology of Clostridium difficile infection within the USA

§ To discuss the risk factors and symptoms of Clostridium difficile infection

§ To discuss the new treatment strategies for Clostridium difficile infection within USA

IMPACT OF C. DIFFICILE

§ Responsible for ½ million infections within the U.S. in 2011

§ 83,000 patients who developed the infection had a reoccurrence and 29,000 patients died within 30 days from initial diagnosis

https://www.cdc.gov/hai/organisms/cdiff/cdiff_clinicians.html

2015

ECONOMIC HEALTH CARE COSTS

Ghantoji, Sail , Lairson and Garey (2010) performed a systematic review of studies on economic healthcare costs of Clostridium difficile infection:

10 studies from the USA revealed cost estimates

­$2,871 to $4,846 per primary case

­$13,655 to $18,067 per case for recurrent infections

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THE PATHOGEN

§ C. difficle is a gram-positive, anaerobic spore-forming bacillus.

§ Leading cause of antibiotic diarrhea

§ Naturally resistant to several antibiotics

https://www.cdc.gov/hai/organisms/cdiff/cdiff_faqs_hcp.html 2012

PATHOGENESIS

Bacterium exists in 2 forms:

­ Active: Infectious component

­ Inactive form: Spore (noninfectious until ingested)

­ Toxin A and Toxin B

https://www.cdc.gov/hai/organisms/cdiff/cdiff_faqs_hcp.html 2012

DISEASES FROM CLOSTRIDIUM DIFFICILE

§ Pseudomembraneous colitis§ Sepsis§ Toxic megacolon§ Perforation of the colon

https://www.cdc.gov/hai/organisms/cdiff/cdiff_faqs_hcp.html 2012

EPIDEMIOLOGYTransmission: Fecal Oral route

Contaminated surface areas­ Rectal thermometer probes­Contaminated hands from health care workers­ Linens­ Furniture­ Toilet seats­ Finger nails­ Stethoscopes­ Jewelry­Diaper Pails

https://www.cdc.gov/hai/organisms/cdiff/cdiff_faqs_hcp.html 2012

RISK FACTORS§ Antibiotic use

§ Proton Pump Inhibitors

§ Age (>65 years)

§ Co-morbid conditions

§ Prolonged stay in health care facility

§ GI surgery/manipulation

§ Compromised immune systemhttps://www.cdc.gov/hai/organisms/cdiff/cdiff_faqs_hcp.html 2012

SYMPTOMS

§ Fever§ Nausea§ Watery diarrhea§ Abdominal pain§ Decrease appetite

https://www.cdc.gov/hai/organisms/cdiff/cdiff_faqs_hcp.html 2012

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CHANGING EPIDEMIOLOGY

§ Historically, CDI is associated as a nosocomial infection occurring among the elderly.

§ More recent evidence indicates CDI is occurring among patients who are younger and without co-morbidities and is increasing within communities.

Kuijper & Rupnik (2006)

CHANGING EPIDEMIOLOGYMore infections and increase in mortality

New epidemic strain noted: ­ Restriction enzyme analysis type B1­ North American Pulsed Field type 1 (NAP1) ­ PCR ribotype 027.

More virulent strain­ Increased production of toxins A & B and binary toxin­ BI/NAP1/027 has spread widely after outbreaks in Pittsburg (2000);

Atlanta (2001-2002) & Montreal (2003)https://www.cdc.gov/hai/organisms/cdiff/cdiff_faqs_hcp.html 2012

DEFINITIONS FOR C. DIFFICILE INFECTION (CDI)§ Hospital- Acquired CDI: Onset of symptoms greater than 48 hours after

admission or less than 4 weeks after discharge from health care facility

§ Community-Onset Healthcare Facility-Associated CDI (CO-HCFA): Onset of symptoms within x 4 weeks post discharge from a healthcare facility.

§ Community-Acquired CDI: Onset of symptoms within the community or within 48 hours of admission to hospital and x symptom onset x more than 12 weeks from a hospital discharge.

§ Indeterminate: Onset of symptoms x 4-12 weeks post discharge from the hospital

Cohen (2010)

SIGNIFICANCE

Risk factors for community acquired Clostridium difficile appear different from hospital acquired infections.

§ In a study by Wilcox et al (2008):

§ Exposure to antibiotics such as penicillin and cephalosporin drugs were more frequent among cases than controls

§ ½ of the patients had no antibiotic exposure within the past month and 1/3 had no antibiotic exposure nor hospitalization

SIGNIFICANCE

Khanna et al (2012) examined CA-CDI and HA-CDI in Olmsted County, Minnesota from 1991-2005

n Results indicated that Persons with CA-CDI were:

n Younger (median age 50 vs. 72 years)

n Female (76% vs. 60%)

n Few co-morbidities

SIGNIFICANCEMcFaland et al (2007) assessed patients with C. difficile associated disease (CDAD):

§ 20 (11%) of the 184 patients were diagnosed with community-acquired C. difficile associated disease (CA-CDAD)

§ More than half had no prior exposure to antibiotics and experienced shorter duration of hospital stays and lower mortality

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IMPACT

§ Compared to patients with hospital-acquired CDI, patients with community-acquired CDI have lower mortality but some may have poorer prognosis

§ CDC funded a large study to assess colectomy rates of colectomies from 5 tertiary care hospitals between 2000 and 2006. Rates for patients with hospital acquired CDI were lower than those with community-acquired CDI (4.3/1,000 vs 16.5/1,000 cases)

Kasper et al., 2000-2006.

EXPLORATORY STUDY

Purpose:

To determine the incidence and proportion of positive CDI in hospitalized and non-hospitalized patients submitting stool specimens for C. difficile testing to the UTMB Clinical Microbiology Laboratory between September 2011 and May, 2014.

ANALYSIS METHODS§ Diagnostic testing was performed using a loop-mediated isothermal

amplification (LAMP)-based assay to amplify and detect a portion of the toxin A gene tcdA which has been shown to be sensitive for the detection of toxigenic C. difficile.

§ Data was entered into SPSS20 and analyzed using descriptive statistics(incidence rate, means, standard deviations, medians, ranges, percentages, frequencies) as well as test of associations (chi square, correlations), risk (odds ratios) and differences (t-tests, analyses of variance and covariance)

§ Proportion positive was calculated by the number of positive stool specimens for C. difficile divided by the number of stool specimens submitted within each group for C. difficile toxin testing through the UTMB laboratories during the study period.

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DIAGNOSIS

CDI diagnosis is based on symptom presentation:

n New onset of 3 or more unformed stools within 24 hoursn Low-grade temperaturen Nausean Anorexia n Abdominal pain n Positive diagnostic assay

https://www.cdc.gov/hai/organisms/cdiff/cdiff_faqs_hcp.html 2012n

n

DIAGNOSTICS

n Stool toxin test as part of multistep algorithm

n Glutamate dehydrogenase (GDH) assay with stool toxin

n GDH with toxin and Nucleic Acid Amplification (NAAT) or NAAT with toxin is recommended

n

n COHEN 2017

TREATMENT OF CLOSTRIDIUM DIFFICILE INFECTION

n Initial episode: Non-severe (leukocytosis with WBC</=15,000 cells/mL or creatinine </= 1.5 mg/dL) n Vancomycin 125mg QID for 10 days or Fidaxomicin 200mg BID for 10 days

n Metronidazole 500mg TID for 10 days only as alternative if above is unavailable

Initial episode: Severe (leukocytosis with WBC>/= 15,000 cells/mL or elevated serum creatinine > 1.5mg/dL )

Vancomycin 125mg QID for 10 daysFidaxomicin 200mg BID for 10 days

Initial episode: Fulminante (Hypotension, shock, ileus or megacolon)

Vancomycin 500mg QID

Cohen 2017 update

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TREATMENT OF RECURRENT INFECTIONS

n First recurrence: Vancomycin 125 mg QID if metronidazole was used

n ORn Prolonged Tapered & pulsed regimen of

Vancomycin:Vancomycin 125mg OID for 10-14 days then twice daily for 7 days; then daily for 7 days; then every 2-3 days for 2-8 weeks.

ORFidaxomicin 200mg BID for 10 days

n Cohen 2017 updates

TREATMENT OF RECURRENT INFECTIONS

Second or subsequent Recurrence:­ Vancomycin: Tapered and Pulsed regimen­ OR­ Vancomycin 125 mg QID for 10 days followed by Fidaxomicin 400 mg 20 days­ OR­ Fidaxomicin 200 mg BID for 10 days­ OR­ Fecal microbiota transplant

­ Cohen 2017

NEW TREATMENT STRATEGIES

Novel Antibiotics:

­Fidaxomicin: A macrocyclic antibiotic thought to inhibit bacterial RNA synthesis

­Fecal Transplants:

­C. difficile toxoid vaccine (ACAM-CDIFF)

Juneau, Dann et.al., (2013)

VACCINE TRIALS: ACTOXUMAB AND BEZLOTOXUMAB PHASE 3Two double-blind randomized, placebo-controlled trials.

­ 2,655 adults who had received oral standard of care for recurrent CDI.

­ Participants received infusion of bezlotoxumab; actoxumab plus bezlotoxumab or placebo.

Wilcox, Gerding, Poxton et al (2017)

VACCINE TRIALS: ACTOXUMAB AND BEZLOTOXUMAB PHASE 3Initial Cure­Bezlotoxumab: 80%­Bezlotoxumab pulus actoxumab: 73%­Placebo: 80%

Sustained Cure (cure without recurrent infection in 12 weeks)­Bezlotoxumab: 64%­Bezlotoxumab plus actoxumab: 58%­Placebo: 54%

Wilcox, Gerding, Poxton et al (2017)

FECAL TRANSPLANTSHouston Medical Center

First FMT trial: ST. Luke’s Episcopal Hospital in 2013­Approximately 200 patients have been treated­ Study I compared fresh, frozen and lyophilized FMT product delivered by colonoscopy:

­ Study II included a Cryoprotectant carbohydrate which compared frozen product given by enema or freeze dried in enteric coated capsules. There was greater than 90% efficacy in both

­ Study III: (New) a Dose ranging study of lyophilized product given in oral capsules

Dr. DuPont/Elam (2017)Ellis (2017)

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CONTROL MEASURES AND PREVENTION

§ Good hand washing

§ Soap vs. alcohol-based products

§ Cleaning exam tables with sporicidal agent registered with the US Environmental Protection Agency

§ Judicious use of antibiotics

§ https://www.cdc.gov/hai/organisms/cdiff/cdiff_faqs_hcp.html2012

FUTURE RESEARCH

GI Microbiota

REFERENCES­ Aberra FN, Gronczewski CA, Katz JP. Clostridium Difficile Colitis. Medscape Reference: Drugs, Diseases and Procedures.

http://emedicine.medscape.com/article/186458-overview. Updated May 18, 2012.

­ Aroniadis OC, Brandt LJ. Fecal microbiota transplantation: past, present, and future. Current Opinion in Gastroenterology. 2012; doi:10.1097/MOG.0b013e32835a4b3e

­ Carroll KC, Loeffelholz M. Conventional versus molecular methods for the detection of Clostridium difficile. J Clin Microbiol. 2011; 49(9)(suppl 9): 49s-52s.

­ CDC. Frequently asked questions about Clostridium difficile for healthcare providers. Htttp://www.cdc.gov/HAI/organisms/cdiff-faqs-HCP.htm.

­ Cohen SH, Gerding DN, Johnson S, 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 Disease Society of America (IDSA). Infect Control Hosp Epidemiol. 2010; 31(5): 431-455

­ Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile Infection in adults: 2017 Update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Disease Society of America (IDSA). Retrieved electronically from https://academic.oup.com/cid/advance-article-article/doi/10.1093/cid/cix1085/4855916.

­ Ellis, Carole. New Fecal Transplant Method Treats C. difficile “Like Instant Coffee”. ContagionLive NewsLetter. April2017. Retrieved electronically http://www.contagionlive.com/news/new-fecal-transplan-method-treats-c-difficile-like-ins October 9, 2017.

­ Elam, Kara. UTHealth’s Dr. DuPont Discusses the Therapeutic “Miracle’ of Fecal Microbial Transplantation. BioNew-TX, 2015. Retrieved electronically https://bionews-tx.com/news/2015/04/20/exclusive-uthealths-dr-dupont-discusses-the-therapeutic-miracle-of-fecal-microbial-transplantation/ October 9, 2017.

­ Ghantoji, S, Sail K, Lairson, D, Garey, K. Economic healthcare costs of Clostridium difficile infection: A systematic review. J Hosp Infection. 2010;74:309-318.

­ Hensgens, M.P., Keess, E.C., Squire,M.M., et al. Clostridium difficile Infection in the community: a zoonotic desease? Clinical Microbiology and Infection: 2012

­ Johnson AP, Wilcox MH. Fidaxomicin: a new option for the treatment of Clostridium difficile infection. Journal of Antimicrobial Chemotherapy. 2012; doi:10.1093/jac/dks302.

REFERENCES­Juneau C, Mendias, E, Wagal, N, Loeffelholz, Michael et al Community-Acquired Clostridium Difficile Infection: Awareness and Clinical Implications. 2013. The Journal for Nurse Practitioners

­Kasper AM, Nyazee HA, Yokoe DS, et al. A multicenter study of Clostridium difficile infection-related colectomy. 2000-2006. Infect Control Hosp Epidemiol. 2012: 33(5):470-476.

­Khanna SK, Pardi DS, Aronson SL et al. The epidemiology of community-acquired Clostridum difficile infection: a population –based study. AM J Gastroenterol. 2012:107:89-95.

•Kuijper, EJ, Coignard B, Tull P: ESCMID Study Group for Clostridium difficile; EU Member States:European Centre for Disease Prevention and Control. Emergence of Clostridium difficile-associated disease in North America and Europe. Clin Microbiol Infect. 2006; 12 (suppl.6) 2-18

•Kuntz JL, Chrischilles EA, Pendergast JF, Herwaldt LA, Polgreen PM. Incidence and risk factors for community-associated Clostridium difficile infection: a nested case-control study. BMC Infect Dis. 2011:11:194.

•Laino C, Chang L. Digestive disorders health center, C. diff on the rise outside the hospital. WebMD. http://www.webmd.com/digestive-disorders/news/20110920/c-diff-on-the-rise-outside the hospital. Sept. 20, 2011. Accessed May 17, 2012

•McFarland LV, Mulligan ME, Kwok RY, Stamm WE. Nosocomial acquisition of Clostridium difficile infection. N Eng J Med. 1989;320(4):204-210

•Nelson, D., Williams, C., & Graham, Neil. Infectious Disease Epidemiology Theory and Practice. Aspen Publications: Gaithersbury, Maryland. Pp. 119-146. 2001.

•Rupnik M. Wilsoc, MH, Gerding DN. Clostridium difficile Infection: new developments in epidemiology and pathogenesis. Nat Rev Microbiol. 2009; 7(7) 526-536

•Wilcox, MH, Mooney L, & Bendall R et al. A case-control study of community-associated Clostridium difficile infection. Journal of Antimicrobial Chemother 2008; 62: 388-396

REFERENCES

Mark H. Wilcox, M.D., Dale N. Gerding, M.D., Ian R. Poxton, Ph.D., Ciaran Kelly, M.D., Richard Nathan, D.O., Thomas Birch, M.D., Oliver A. Cornely, M.D., Galia Rahav, M.D., Emilio Bouza, M.D., Christine Lee, M.D., Grant Jenkin, M.D., Werner Jensen, M.D., You-Sun Kim, M.D., Junichi Yoshida, M.D., Lori Gabryelski, B.S.M.T., Alison Pedley, Ph.D., Karen Eves, B.S., Robert Tipping, M.S., Dalya Guris, M.D., Nicholas Kartsonis, M.D., and Mary-Beth Dorr, Ph.D., for the MODIFY I and MODIFY II Investigators*N Engl J Med 2017; 376:305-317January 26, 2017DOI: 10.1056/NEJMoa1602615

US National Library of Health. ClinicalTrials.gov., http://www.clinicaltrials.gov/ Accessed Oct 15, 2012.