C. difficile update: Implications for antibiotic stewardship Brenda L Tesini, MD

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Objectives Appreciate pathophysiology of C. difficile Review updated testing and treatment options Understand role of antibiotic stewardship in prevention and management of C. difficile infections

Question 1 What is the main modifiable risk factor for developing C.diff infection? Age Diabetes Antibiotics Probiotic use Smoking status

Question 2 Which antibiotics are first line agents for the treatment of C.diff infection (choose 2)? Metronidazole Fidaxomicin Doxycycline Vancomycin Bezlotoxumab

Question 3 Which are ways that you can help prevent C.diff infections in your residents? Audit for appropriate treatment Identify inappropriate antibiotic use Identify inappropriate PPI use All of the above

Outline Review pathophysiology of C.difficile infection Discuss current diagnostic and treatment guidelines Explore opportunities for your role in preventing of C.difficile infections

C. difficile Infections: Top CDC Priority Top 3 URGENT drug-resistant bacterial threats per CDC Most common healthcare-associated infection in the US Recurs in 1 out of 5 patients Source: CDC Report “antibiotic Resistance Threats in the United States, 2013” Miller BA et al. ICHE 2011

C. difficile Infections: impact to patients 1 out of 11 patients >65 yo with HA-CDI will die w/in 30 days of dx Nearly 500,000 cases annually Over 100,000 cases in LTCF* 29,000 deaths 450,000 29,000 $4,800,000,000 Source: CDC Report “antibiotic Resistance Threats in the United States, 2013” 2011 estimate *LTCF: long term care facilities Miller BA et al. ICHE 2011; Lessa FC et al. N Engl J Med 2015

Impact to health care system Most common microbial cause of healthcare-associated infections in the US 1 out of 11 pateints >65 yo with HA-CDI will die w/in 30 days of dx Over $4.8 BILLION /year in excess health care in acute facilities alone 2/3 of infections associated with hospital stay Nearly as many cases occurred in nursing homes as hospitals

Impact to long term care facilities (LTCF) 2/3 of C.difficile infections associated with hospitalization ¼ of those cases will present when at LTCF

MMWR 61(09);157-622012. Data from Emerging Infections Program, 2010

CDI Incidence in LTCF Crude and adjusted annual long-term care facility onset Clostridium difficile infection incidence rates across 10 US sites, 2011-2015 Gugh AY, et. Al AJIC 2018

Age impacts mortality 85+ years 75-84 years 65-74 years CDC, National Center for Health Statistics. Compressed Mortality File 1999-2011 on CDC WONDER Online Database, released July 2014. Data are compiled from Compressed Mortality File 1999-2011 Series 20 No. 2Q, 2014. Accessed at http://wonder.cdc.gov/cmf-icd10.html on May 4,2018

Pathogenesis Change in healthy intestinal flora Acquisition of C diff spores Overgrowth of C diff Toxin production and destruction of intestinal lining

Colonization Resistance and Dysbiosis Protective diverse microbiota Loss of Diversity and richness Lumen The normal microbiome consists of 1000 bacterial species The microbiota has a beneficial role including Synthesis of vitamins, fermentation of dietary carbohydrates, development and maturation of the immune system Competitive exclusion “colonization resistance” of pathogens Antibiotic lead to the loss of microbial diversity, which occurs in association with: Loss in abundance of key phyla such as Bacteroidetes, Firmicutes Loss of key functions/metabolic byproducts that inhibit C. difficile: i.e. loss of colonization pressure Often observed with a reciprocal increase in Proteobacteria, particularly the Enterobacteriaceae family Submucosa

Exposure to C. diff and Antibody Production C. difficile Toxin Antibody

C. difficile Colitis and FMT Fecal microbiota transplant (FMT) Cell cytotoxicity

Points of intervention Reduce risk factors Antibiotic stewardship Infection prevention Anti-C diff treatment

Antibiotic exposure: the most important C. diff infection risk factor

Antibiotic exposure: the most modifiable C. diff infection risk factor

Avoiding antibiotics Avoid antibiotic treatment of asymptomatic bacteruria Avoid antibiotic treatment of viral respiratory infections Pro-active wound care to avoid secondary infections

Thoughtful use of antibiotics Choose the most narrow spectrum antibiotics when possible Clarify antibiotic allergies and “de-label” inappropriate penicillin allergies Limit duration of antibiotic therapy based on disease-specific guidelines

Additional risk factors Advanced age is another risk factor Older adults are at higher risk of CDI Changes to the gut microbiome Immunosenescence >80% of CDI deaths are in patients aged ≥65 years 1 of 3 infections in >65 yo 2 of 3 healthcare-associated infections in >65 yo

Diagnosis Clinical suspicion of disease Diarrhea >3 loose stools for >1 day Takes the shape of the container Positive laboratory testing Detection of organism False positives – pick up colonization Detection of toxin False negatives – don’t pick up all infections

Appropriate Testing – “diagnostic stewardship” High rates of asymptomatic colonization 8% of patients upon admission to hospital Up to 25% of patients during prolonged admission 5-7% of patients in nursing homes NAAT used alone can increase “infection” rate by 50-80% Need to use toxin test with NAAT, particularly if no clinical screening for stool submission Diagnostic testing algorithms based on level of clinical screening

Commercial C. difficile Diagnostic Tests Sensitivity Specificity Substance detected GDH Immunoassay (EIA) High Low Common C. difficile antigen Toxin Immunoassay (EIA) Moderate Free toxins NAAT (PCR) Low-moderate Toxin (tcd A or tcd B) genes A more recent large study showed sensitivity of 2 toxEIAs to be 68% to 83% with specificities of approximately 99%. The overall poor performance of toxin immunoassays led to the recommendation that these should not be used as stand-alone tests, but rather as a part of a 2-stage or 3-stage algorithm GDH: glutamate dehydrogenase; EIA: Enzyme immunoassay; NAAT: nucleic acid amplification test Modified from Planche T. et al Infectious Disease Clinics of North America, 2015;29:63-82

Two Step Algorithm – can use if no clinical screening GDH EIA NAAT Negative Result No evidence of CDI +ve -ve Positive Laboratory confirmation Confirmation No evidence of CDI

NAAT – use when clinical screening of samples Lab rejects formed stool Patients on laxatives not tested Lab has no rejection policy No institutional policy for testing NAAT Positive Result Laboratory Confirmation of CDI No evidence of CDI -ve NAAT Positive Result Laboratory Confirmation of CDI No evidence of CDI -ve Confirmed +ve by EIA

No consensus on the best laboratory method Multi-step testing: Diagnosis summary No consensus on the best laboratory method Multi-step testing: NAAT alone GDH then toxin (by EIA) GDH then toxin then NAAT if needed NAAT then toxin In a carefully screened population, may consider NAAT alone McDonald et al. 2018 Clinical Infectious Disease (www.idscociety.org)

Treatment – top 5 new points Discontinue inciting antibiotic May influence CDI recurrence Vancomycin or fidaxomicin are the drugs of choice Metronidazole no longer recommended except for mild disease when access to drug of choice is limited Due to lower efficacy especially in moderate and severe infection Fecal microbiota transplant for multiple recurrences Antibiotic stewardship key for CDI prevention

Treatment: Initial episode Clinical Severity Treatment recommendation Change from 2010 Comments Nonsevere Vancomycin 125 mg QID OR Fidaxomicin 200 mg BID Duration: 10 days Fidaxomicin added Metronidazole removed Duration 10 days only Metronidazole acceptable alternative if other agents not available Severe Metronidazole NOT considered acceptable alternative Fulminant Vancomycin 500 mg QID AND IV metronidazole 500 mg q8h If ileus: Consider adding rectal installation of vancomycin Addition of IV metronidazole particularly important if ileus present

Treatment: recurrent episodes Recurrence Initial treatment Treatment recommendation Change from 2010 Comments First Metronidazole Vancomycin 125 mg QID x 10 days Same treatment as initial episode no longer recommended Vancomycin Prolonged tapered and pulsed vancomycin OR Fidaxomicin 200 mg BID Suggested taper: 125 mg QID for 10-14 days, then BID x 1 week, then Daily x 1 week, then Every 2-3 days for 2-8 weeks Second Any FMT Addition of fixadimicin and FMT Can consider rifaximin 400 mg TID x 20 days instead of vancomycin taper

Vancomycin vs Metronidazole All Cause 30-day Mortality Vancomycin: improved mortality in moderate to severe disease Not definitively shown in all studies Exclusion of metronidazole remains controversial Stevens et al. JAMA Int Med 2017

Vancomycin vs. Fidaxomicin Recurrence within 4 weeks: Vancomycin 26% Fidaxomicin 13% Cornely OA, et al. Lancet Infectious Diseases 2012;12:281-289

Cost comparison Antibiotic Dose / Formulation Outpatient Ave wholesale price per 10-day course metronidazole 500 mg PO q8h (tabs) 500 mg PO q8h (suspension) 500 mg IV q8h (500 mg bag) $21 $125-170 $32-75 Vancomycin 125 mg PO q6h (125 mg cap) 500 mg PO q6h (250 mg cap) 125 mg PO q6h (suspension) 500 mg PO q6h (suspension) $1250-3775 $2615-13900 $64 $255 Fidaxomicin 200 mg PO q12h (tabs) $4418

Bezlotoxumab – secondary prevention General risk of recurrence is around 25% Recued recurrence in pre-defined high risk groups Around 10% reduction Not included in IDSA/SHEA guidelines based on limited evidence Reduced readmission rates

Prevention – role of proton pump inhibitors Clinical association btwn use and risk of CDI Lack of robust studies to determine causality Discontinue unnecessary PPIs Need to determine individual patient’s risk vs benefit Consider H2-blocker instead in appropriate patients

Prevention – probiotics and alternatives Lack of evidence to support probiotics No FDA-approved formulation Cannot recommend for primary prevention Seldom harmful Alternatives Yogurt Kefir Bakken CID 2014

Prevention – antibiotic stewardship program Restriction of fluoroquinolones Resistant strains decreased in prevalence Associated with decrease in highly pathogenic NAP1 strain Develop guidelines for diagnosis and treatment of common infections Urinary tract infections Pneumonia Skin & skin structure infection Use local antibiogram data to guide empiric antibiotic choices Limit 3rd generation cephalosporin use Avoid fluoroquinolones

How YOU can prevent harm from CDI Audit for appropriate treatment Identify inappropriate antibiotic use Identify inappropriate PPI use

Question 1 What is the main modifiable risk factor for developing C.diff infection? Age Diabetes Antibiotics Probiotic use Smoking status

Question 2 Which antibiotics are first line agents for the treatment of C.diff infection (choose 2)? Metronidazole Fidaxomicin Doxycycline Vancomycin Bezlotoxumab

Question 3 Which are ways that you can help prevent C.diff infections in your residents? Audit for appropriate treatment Identify inappropriate antibiotic use Identify inappropriate PPI use All of the above