Clostridium difficile infections: Drug treatment re-evaluated

Clostridium difficile infections: Drug treatment re-evaluated Kimberly D. Leuthner, PharmD University Medical Center of Southern Nevada August 11, 2016

Random Fact: The human body has 10 13 human cells and a minimum of 10 14 bacterial cells So who s really the dominant species?

Objectives Review the epidemiology and pathogenesis of C. difficile infections (CDI) Understand the consequences of CDI Review the current guidelines for drug treatment for CDI Examine the different pharmacologic treatments for CDI Explore adjunctive treatments for CDI

C. difficile Microbiology Gram positive spore forming bacillus (rods) Obligate anaerobe Part of the GI Flora in 1-3% of healthy adult 70% of children < 12 months Some strains produce toxins A & B Toxins-producing strains cause Clostridium difficile Infection (CDI) CDI: mild, moderate, severe and fatal illness

Importance of Spores Resistant to heat, drying, pressure, and many disinfectants Resistant to all antibiotics because antibiotics only kill or inhibit actively growing bacteria Spores survive well in hospital environment Spores are not a reproductive form, they represent a survival strategy

Source of Infections Spores in hospital, nursing home, or long-term care environment associated with ill patients Large numbers of spores on beds, bed-rails, chairs, curtains, medical instruments, ceiling, etc. Asymptomatic carriers in those same environments Low risk compared to patients with active disease False negative lab tests (low sensitivity) Community? Jhung MA, et al. Emerg Infect Dis. 2008;14:1039-1045.

C. difficile in the Community 30 random households in Houston, TX 127 samples total 32.3% (41/127) were positive for C. difficile All isolates were positive for toxins A and B None positive for the binary toxin 83% (25/30) had 1 positive sample 12 households with 1 positive No samples had the same ribotype Alam MJ et al. Anaerobe 2014;27:31-33.

Community Source C. difficile # Samples # Positive 70 60 50 40 30 20 39.7% 10 0 33.3% 18.9% 33.3% Shoes Bathroom Surface Dust Alam MJ et al. Anaerobe 2014;27:31-33.

Transmission Fecal oral route Contaminated hands of healthcare workers Contaminated environmental surfaces Person to person in hospitals and LTCFs Reservoir Human: colonized or infected persons Contaminated environment Spores can survive for up 5 months on environmental surfaces

Clostridium difficile Infections (CDI) New 2011 Data 500,000 29,000 CDC Report "Antibiotic Resistance Threats in the United States, 2013 Lessa CF et al. NEJM 2015;372:825-34.

TREATMENT OF CDI

Treatment Consequences Adamu and Lawley. Curr Opin Microbiol 2013

Symptoms of CDI Asymptomatic colonization Diarrhea mild moderate severe Abdominal pain and distension Fever Pseudomembranous colitis Toxic megacolon Perforated colon sepsis death

Markers of Severe Disease Leukocytosis Prominent feature of severe disease Rapidly elevating WBC Up to >100 K >10 BM/day Albumin < 2.5 Creatinine 2x baseline Hypertension Pseudomembranous colitis Toxic megacolon Severe distension and abdominal pain

Current US IDSA CDI guidelines 2010 Episode Clinical Signs Severity Initial WBC <15,000 Scr <1.5 baseline Initial WBC 15,000 Scr 1.5 baseline Initial Second (1 st recurrence) Third (2 nd recurrence) Hypotension, shock, ileus, megacolon Mild or moderate Recommended agent Metronidazole Dosing regimen 500mg PO q8h x 10-14d Severe Vancomycin 125mg PO q6h x 10-14d Severe, complicated Vancomycin + Metronidazole V: 500mg PO q6h M: 500mg IV q8h If ileus: consider rectal administration of vancomycin ----------------------- ---------------- Same as initial Same as initial A-II ----------------------- ---------------- Vancomycin PO tapered and/or pulsed Strength A-I B-I C-III B-III Cohen SH, Gerding DN, et al. Infection control and hospital epidemiology. 2010 (May); 31(5)

Current European CDI guidelines CDI Non-severe CDI (Risk of) first recurrence Severe disease or complicated course Metronidazole Vancomycin Fidaxomicin Vancomycin Fidaxomicin Metronidazole Vancomycin Fidaxomicin Metronidazole Purple: strongly supports use; Blue: moderately supports use Grey: minimally supports use; Pink: recommend to not use Debast SB et al. Clin Microbiol Infect 2014; 20 (Suppl. 2):1-26

DRUG TREATMENT OPTIONS

Metronidazole First line therapy for CDI Commonly utilized for 1 st recurrence Pros Readily available Relatively cheap Extensive experience Little to no resistance documented Cons Completely systemically absorbed Modest concentrations in lumen of large intestine Concentrations decrease as inflammation resolves

Vancomycin Second line therapy for recurrence of CDI Reserved for severe CDI Pros FDA approved No systemic absorption Concentrations of 1000x MIC in lumen Resistance very rare Cons Expensive Relatively cost prohibitive Not carried by many pharmacies outpatient Dosing variations 125 500mg TID or QID

Fidaxomicin Not utilized significantly Reserved for severe CDI or recurrences Pros FDA approved No systemic absorption Efficacy vs. vancomycin Inhibits toxin production May prevent recurrence Cons Expensive Not carried by many pharmacies outpatient

DRUG THERAPY EXAMINED: METRONIDAZOLE VS. VANCOMYCIN

Metronidazole vs. vancomycin Study Year Location N Single Blinded Randomized? Dose Clinical efficacy Recurrence Metro Vanco Metro Vanco Metro Vanco Teasley, 1983 82-83 MN 101 yes no yes 250mg QID 500mg QID 2/37 (5.4%) 0/45 (0%) 2/37 (5.4%) 6 /45 (13%) Wenisch, 1996 93-95 Austria 62 yes no yes 500mg TID 500mg TID 2/31 (6%) 2/31 (6%) 5/31 (16%) 5/31 (16%) Musher, 2006 02-04 USA (Houston) 34 no yes yes 250mg QID 125 mg QID 6/34 (17%) N/A 9/28 (32%) N/A Zar, 2007 94-02 Chicago 150 yes yes yes 250mg QID 125mg QID 13/79 (16%) 2/71 (3%) 9/66 (14%) 5/69 (7%) Johnson, 2013 05-07 World 552 no yes yes 375mg QID 125mg QID 76/278 (27%) 49/259 (19%) 48/202 (23%) 43/210 (21%) Recent studies show more treatment failures Something missing?

Susceptibility issues Routine susceptibility not done Difficult on anaerobic organisms Higher MICs may have gone unnoticed In vitro MIC increased 2-4 fold after exposure to 1-2 passages of sub-mic metronidazole Susceptibility inconsistencies in testing media Addition of hemin to media decreased metronidazole susceptibility of C. difficile Moura I et al. JAC 2013;Feb 68(2):362-5 Wu X et al. ICAAC 2015 Poster C-576

Metronidazole MIC creep? Author Location Time period Isolates MIC 50 MIC 90 Range All strains Hecht et al Various 1983 2004 110 0.125 0.25 0.025 0.5 Edlund et al Sweden 1998 50 0.125 0.25 0.125 0.25 Betriu et al Spain 2001 55 0.5 1 0.06 1 Citron et al USA 2003 18 0.5 1 0.25 1 Finegold et al USA (CA) 2003 72 0.5 1 0.25 2 Karlowsky et al Canada (Manitoba) 2007 208 0.5 1 0.25 4 Debast et al Europe 2008 398 0.25 0.5 <0.06-2 Reigadas et al Spain 2013 100 0.25 0.5 0.06-1 Snydman et al USA 2011-12 925 1 2 <0.06-4 BI/027/Nap1 strains Citron et al USA 2004 2005 NR 2 0.5 2 Debast et al Europe 2008 0.5 1 0.5-1 Snydman et al USA 2011-12 2 2 <0.06-4

Bottom Line: Metronidazole Failures may be a PK/PD problem Mean concentrations in stool <0.25 9.5 μg/g Susceptibilities MIC 50 = 1 μg/ml MIC 90 = 2 μg/ml Based on these numbers failure should not be a significant surprise But is there more? Bolton et al. Gut 1986;27(10):1169-72

Refractory Disease (%) Stratifying CDI treatment based on severity: Active intervention Pre-Implementation Post-Implementation 40 35 P = 0.035 32.2 30 25 P = 0.16 20 18.8 15 10 11.1 P = 1.0 9.4 8.5 15.1 5 0 Overall CDI Mild-Moderate CDI Severe CDI Jardin, Palmer, Le, Beyda, and Garey. JHI 2013

Metronidazole response Age stratified risk factors for CDI < 50 (n=72) Age (years) 50-70 (n=97) >70 (n=73) P value Continued use of antibiotics 38 (53%) 61 (63%) 45 (62) 0.38 CDI severity 21 (29%) 59 (61%) 48 (66%) <0.001 Horn s index >2 14 (19%) 29 (30%) 28 (38%) 0.043 Older, more severe patients with continued antibiotics are more likely to be refractory to metronidazole treatment Pham VP et al. AAC Online 20 July 2015

Metronidazole vs. vancomycin 100% 90% 80% 70% Tolevamer Metronidazole (n=278) Vancomycin (n=259) P = 0.02 81.1% 72.7% 60% 50% 40% 44.2% 30% 20% 23.0% 20.6% 10% 0% Clinical Success Johnson S et al. Clin Infect Dis. 2014;59:345-354 4.5% Recurrence

DRUG THERAPY EXAMINED: VANCOMYCIN VS. FIDAXOMICIN

Response rate Fidaxomicin vs. vancomycin 100% 90% 80% Fidaxomicin 92% 90% 92% 91% Vancomyin P = 0.006 P = 0.0008 78% 80% 70% 60% 50% 40% 30% 20% 10% 67% 66% 0% Study 1 Study 2 Study 1 Study 2 Clinical cure Louie et al. N Eng J Med 2011;364:422-310 Cornley, et al. Lancet ID 2012 Apr; 12(4):281-9 Global response

Response rate Systemic Antibiotics Continued Fidaxomicin Vancomyin 100% 90% 80% 70% 92% 93% P = 0.04 90% 79% P = <0.01 81% 69% P = 0.02 73% 60% 59% 50% 40% 30% 20% 10% 0% No antibiotics 1 antibiotic No antibiotics 1 antibiotic Clinical cure Global response Mullane KM et al. CID 2011;53(5):440-447

Patients Recurrence 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Fidaxomicin Vancomycin P = 0.004 P = 0.002 P = <0.001 24% 25% 23% 13% 13% 12% Louie et al Cornley et al Mullane et al Louie et al. N Eng J Med 2011;364:422-310 Cornley, et al. Lancet ID 2012 Apr; 12(4):281-9 Mullane KM et al. CID 2011;53(5):440-447

Response Recurrence by organism type Fidaxomicin Vancomycin 30% 25% Hypervirulent 027 strain 24.4% 23.6% 25.5% 20% 15% 10% 7.8% 5% 0% BI/Nap1/027 Other strain Louie et al. N Eng J Med 2011;364:422-310 Cornley, et al. Lancet ID 2012 Apr; 12(4):281-9

Effects on microbiome Similar effects seen for multiple other organisms including Enterobacteriaceae, Clostridium spp. and Lactobacillus Louie TJ et al. CID 2012;55(S2):S132-42

Toxin production In vitro data Fidaxomicin suppressed toxin production Either toxin Sustained over time Vancomycin had no effect or increased toxin production Babakhani F et al. JAC 2013;68:515-522

Sporulation Total viable organisms No drugs Fidaxomicin OP-1118 Vancomycin Heat resistant spores No drugs Fidaxomicin OP-1118 Vancomycin Drug effects on sporulation Fidaxomicin > Vancomycin >> metronidazole or rifaximin Babakhani F et al. CID:55(S2):S162-9

Fidaxomicin Equal efficacy as vancomycin Significantly lower recurrence rates Potentially better efficacy when systemic antibiotics are continued Less alteration of the microbiome Suppresses toxin production Supported in small number of patients Prevents more organisms to sporulate Sounds almost perfect so why don t we use it?

Fidaxomicin place in therapy Currently reserved in many institutions Multiple relapses refractory to other treatment Severe CDI Has reserving fidaxomicin for the worst cases been a good idea? Answer: probably not Multiple properties of idealized CDI treatment Is the drug really all that expensive?

Estimated cost of treatment regimens Indication Drug Schedule Duration Cost (Redbook AWP) CDI Fidaxomicin 200 mg BID 10 days $3,307 Candidemia Micafungin 100 mg daily 14 days $3,300 Sepsis HAP Meropenem 500 mg q8h 14 days $1,500 Vancomycin IV 1 gram q8h 14 days $1,050 Cefepime 1 gram q8h 14 days $1,400 Vancomycin IV 1 gram q8h 14 days $1,050 VRE bacteremia Daptomycin 500mg daily 14 days $6,804 Is this unreasonable?

Healthcare Utilization for recurrent CDI 1st recurrence (n=64) 2+ recurrence (n=18) 100% 90% 80% 70% 60% 61.0% 50% 40% 45.3% 42.2% 39.0% 30% 20% 10% 0% Outpatient only 3.1% 0.0% Emergency Department only Hospitalization* 9.4% 0.0% ICU admission Aitken, DuPont, Garey. PLOS One 2014 July 24;9(7)

Median LOS (in days) Healthcare Costs 30 25 20 15 10 5 0 Total LOS Without recurrent CDI CDI-attributable LOS With Recurrent CDI CDI pharmacologic treatment CDI-attributable hospitalization Total Hospitalization Shah et al. ICAAC 2014 Poster K-356 Without recurrent CDI [$, IQR] $60 (23 200) $13,168 (7,525 24,455) $20,693 (11,287 41,386) With recurrent CDI [$, IQR] $140 (30 200) $28,218 (15,049 47,030) $45,148 (20,693 82,772)

Fidaxomicin affect on Hospital costs PO vancomycin (n=46) or fidaxomicin (n=49) Significantly more fidaxomicin used for recurrence (47.8% vs. 77.6%; p=0.008) Readmission: vancomycin 41.3% vs. fidaxomicin 20.4% (p=0.027) $500,000 $450,000 $400,000 When all said and done, is $350,000 the drug cost REALLY the $300,000 $250,000 most important factor? $200,000 $150,000 $100,000 $50,000 $0 $6,333 $62,112 Drug Acquisition costs Gallagher JC et al. AAC accepted manuscript 31 Aug 2015 $454,800 $196,200 183 days Hospital re-admission costs 87 days Vancomycin Fidaxomicin

OTHER ADJUNCTIVE THERAPY

IVIG* Probiotics Binding Resins Rifaximin Chasers FMT * Patients who produce antibody to toxins A and B usually do well so IVIG has been tried.

IVIG Treatment 1-6 Serum antibodies to toxins A and B are prevalent in healthy populations Antitoxin A IgG predicts clinical outcome of CDI Recent studies in severe disease 5,6 Well tolerated in small numbers of patients Conflicting data regarding outcome improvement Need for colectomy or mortality Often administered when surgery is considered imminent (severe, complicated cases) 1. Salcedo J, et al. Gut 1997;41:366-370. 2. Beales ILP. Gut. 2002;51:456. 3. Kyne L, et al. N Engl J Med. 2000;342:390-3974. 4. Kyne L, et al. Lancet. 2001;357:189-193. 5. McPherson S, et al. Dis Colon Rectum. 2006;49:640-645. 6. Juang P, et al. Am J Infect Control 2007;35:131-137.

Probiotics No good randomized clinical trials that suggest any beneficial effect Many cases of lactobacillus bacteremia and saccharomyces fungemia Prophylaxis with these agents has not demonstrated fewer CDI cases Prophylaxis with metronidazole or vancomycin has not been shown to be effective Meta analysis Suggests some benefit of Lactobacillus rhamnosus for antibiotic associate diarrhea but not CDI Saccharomyces boulardii for CDAD recurrences Other probiotic preps are under investigation 1. McFarland. Am J Gastrointerolo. 2006;101(4):812-822. 2. Surawicz et al. Clin Infect Dis. 2000;31:1012-1017.

Recurrent CDI Saccharomyces boulardii for CDI Prevention* Placebo S. boulardii 65% 60% 47% 44% 40% 35% 24% 19% 20% 0% 1st 1 st episode of CDI 1 (1) P=0.04 Recurrent CDI 1 (1) Recurrent CDI CDI (2) 2 *Metronidazole or vancomycin for 10 14 days plus placebo or S. boulardii 1 g daily 4 wks 1. McFarland. JAMA. 1994;271:1913-1918. 2. Surawicz et al. Clin Infect Dis. 2000;31:1012-1017.

Rifaximin Chaser Eight women with multiple recurrences Rifaximin 400 mg BID for 2 weeks immediately after completing last course of vancomycin 7/8 (87.5%) no further diarrhea recurrence Single case of rifaximin resistance (identified after therapy) with recurrent CDI after a second course of rifaxmin Effective in interrupting recurrent episodes but resistance may become an issue Johnson S, et al. Clin Infect Dis. 2007;44:846-848.

Fecal Microbiota Transplantation Restoration of bacterial homeostasis Preparation of donor specimen Fresh (<6 hours) ~30 g or ~2 cm 3 volume Add 50 ml 0.9% normal saline, and Homogenize with blender Filter suspension twice with paper coffee filter Delivered by nasogastric tube following vancomycin Results 1/16 survivors had a single subsequent recurrence Aas J, et al. Clin Infect Dis. 2003;36:580-585.

FMT case studies since 2010 > 500 cases reported 92% success rate with the 1 st treatment 98% if a 2 nd infusion was necessary Longest follow up: 17 months 0/77 recurrence without antibiotics 30/77 received additional antibiotics 8/30 recurrences related to antibiotic use Patient perspective 97% of patients would undergo another FMT if needed 57% voted for FMT as their preferred first treatment option Brandt, L. ACG. 2012

Treatment regimens: Vancomycin x14d Duodenal infusion of donor feces post 4d vancomycin Vancomycin x14d plus duodenal infusion donor feces on day 4-5

13 15

Microbiota diversity increases after stool transplant

Binding Resin: Cholestyramine Rational: toxin mediated disease Bind toxin = decreased diarrhea Antibiotic (mg/ml) Cholestyramine 0 Antibiotic activity Vancomycin 2.17 100% Vancomycin + cholestyramine 0.41 18.9% bind vancomycin which make these a specific contraindication IDSA 2010

Adjunct Therapy Recommendations Insufficient evidence to support administration of probiotics, toxinbinding resins and polymers or monoclonal antibodies European CDI 2014

Final conclusions Metronidazole should probably not 1 st line Efficacy waning especially in older, severely infected patients Vancomycin probably initial treatment of choice Pick a place for fidaxomicin Not the treatment for every patient or 1 st episodes Adjunct therapies Limited clinical data for treatment Potential benefits for prevention of recurrence Most evidence with probiotics but risk vs. benefit Binding resins bind toxin and active antimicrobials

Quote for treating CDI If you are treating your mother-in-law use metronidazole If you are treating your step-mother use vancomycin If you are treating your mother use fidaxomicin Stephen M. Brecher, PhD ICAAC 2013

Questions?