CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA (CDAD)

Presented By:

Kevin L. Epps, PharmD

Infectious Disease Pharmacist

St. Vincent’s Medical Center

Learning Objectives

1) Discuss the epidemiology of CDAD2) Identify potential risk factors for CDAD3) Describe the pathophysiology of CDAD4) Review the B1/NAP1 strain5) Identify how CDAD presents6) Compare tests used to diagnose CDAD7) List treatment options for CDAD8) Discuss treatment options for recurrent CDAD9) Describe strategies for the prevention of

nosocomial transmission of CDAD10) Review new treatment options for CDAD on the

horizon

C. difficile-Associated Diarrhea (CDAD)

First discovered in 1935 Not associated with antibiotic-related diarrhea until late

1970’s Gram-positive, anaerobic, spore forming bacillus The most common cause of nosocomial infectious

diarrhea Occurs following antibiotic therapy Estimated annual cost $1.1 billion Increases hospital length of stay, average 3.6 days Increases hospital cost, $6,000-$10,000/case 30% increased incidence over last 20 years

Epidemiology

The most common cause of hospital-acquired diarrhea

3 million cases annually in United States C. difficile is the cause of approximately 25%

of all cases of antibiotic-associated diarrhea Most cases occur in hospital or long-term care

Rate of 25-60 per 100,000 people/year Incidence in the outpatient setting

Rate of 7.7 cases per 100,000 people/year 1-2.5% mortality rate

Risk Factors

History of antibiotic use in the last 10 weeks Antineoplastic agents Age >60 years Immunosuppressive therapy Multiple and severe underlying diseases Residing in a nursing home Increased length of hospitalization Use of antacids Sharing a room with a C. difficile- infected

patient

Medications That Can Cause CDAD

Common Clindamycin Ampicillin and amoxicillin Cephalosporins Quinolones

Less common Erythromycin Penicillins (other than ampicillin

or amoxicillin) Tetracyclines Sulfamethoxazole/trimethoprim Chloramphenicol

Rare Bacitracin Cisplatin Doxorubicin HCL Fluorouracil Methotrexate IV aminoglycoside IV metronidazole IV vancomycin Rifampin Sulfonamides Teicoplanin

Mylonakis E.,Ryan E., Calderwood S. Arch Intern Med. 2001: 161:525-533

C. difficile Colonization vs. CDAD

C. difficile colonization Tests + for C.difficile

organism and/or toxin Exhibits no clinical

symptoms

CDAD Tests + for C. difficile

organism and/or toxin Exhibits clinical

symptoms

C. difficile Colonization

Johnson S., Gerding DN. Clinical Infectious Diseases 1998;26:1027-36

C. difficile Colonization

Johnson S, Gerding DN, Clinical Infectious Diseases 1998;26:1027-36

Factors Contributing to C. difficile Colonization and Diarrhea

Poutanem SM, Simor AE, CMAJ 2004; July 6: 51-58

Pathophysiology

Isolated in only 0-3% of healthy adults Colonization occurs during hospitalization First step in colonization is the disruption of

normal flora of the colon Spores and vegetative cells are ingested Attaches to intestine and secrete toxin A and B Toxin A loosens the tight junction between

colonic epithelial cells causing diarrhea

Poutanem SM, Simor AE, CMAJ 2004; July 6: 51-58.

Pathophysiology

New Epidemic Strain

BI/NAP1 Strain Deletion repressor gene

tcdC 16X more toxin A production 23X more toxin B production

Binary toxin Fluoroquinolone resistance Associated with high risk of acute clinical deterioration Poor response to metronidazole therapy Three times likely to die within 30 days

New Epidemic Strain BI/NAP1 Strain

Mcdonald L., Killgore G., Thompson A., N Engl J Med 2005; 353:23: 2433-41

Annual incidence (per 100,000 population) of CDAD in Sherbrooke, Quebec stratified by age (1991-2003)

Pepin J, et al. Can Med Assoc J. 2004:171:466-472

Proportion of patients with CDAD by class of antibiotic received in the 2 months preceding the diagnosis of CDAD (1991-2003)

Pepin J, et al. Can Med Assoc J. 2004:171:466-472

Isolates of C. difficile and Proportion of Isolates Belonging to the BI/NAPA1 Strain

Mcdonald L., Killgore G., Thompson A., N Engl J Med 2005; 353:23: 2433-41

Distribution of Minimum Inhibitory Concentrations of Levofloxacin for Current BI/NAP1 and Non-BI/NAP1 C. difficile Isolates

Mcdonald L., Killgore G., Thompson A., N Engl J Med 2005; 353:23: 2433-41

Antibiotic use During Hospitalization Six Weeks Prior to Diagnosis Of C. difficile

Loo V. G. M.D. Poirier L. M.D., N Engl J Med 2005; 353:23: 2442-2449

Age-Specific 30-day Mortality Attributed to CDAD

Loo V. G. M.D. Poirier L. M.D., N Engl J Med 2005; 353:23 2442-41

C. difficile

Bedside tables Handrails Bedside rails Call buttons Telephones Light switches

Door handles Faucets Sinks Bathtubs IV pumps Walkers

4 hours after C. difficile sheds it can change to a spore Ingesting as few as 2 spores can cause disease C. difficile spores have been cultured from:

Clinical Presentation

Time from antibiotic exposure to onset of symptoms 1 day – 6 weeks

Most cases occur on day 4-9 of antibiotic therapy Clinical Features

Watery diarrhea Lower abdominal pain Fever Anorexia Nausea Malaise

Diagnosis

Tissue culture cytotoxin assay Immunoassay for detection of toxin A or toxin

A and B Stool culture Latex agglutination test Flexible sigmoidoscopy

Tissue Culture Cytotoxin Assay

Gold standard for toxin detection Detects only toxin B which is 1,000 times more

potent than toxin A Advantages

Highly specific (99 - 100%)

Disadvantages Detects only toxin B Expensive Results not available for 48 hours

Immunoassay

Most frequently used diagnostic method of C. difficle Test for toxin A or toxin A and B Testing for toxin A and B is preferred

Detects 5-10% more cases

Advantages Results available in 4 hours Less expensive than cytototoxin assay

Disadvantages Less sensitive than cytotoxin assay

The Bristol Stool Chart

Lewis SJ, Heaton KW. Scand J Gastroenterol. 1997; 32:920-924

Stool Culture

Anaerobic culture of stool Advantages

High degree of sensitivity Allows for strain typing in the event of outbreaks

Disadvantages Results available in 72-96 hours Labor intensive No distinction between toxinogenic and nontoxinogenic

strains nontoxinogenic strains are not associated with clinical

illness) False +

Latex Agglutination Test for C. difficile

Not used Test for glutamate dehydrogenase

Clostridial protein Present in both toxigenic and nontoxigenic strains

Flexible Sigmoidscopy

Used when rapid diagnosis is needed Delay in results of cytotoxin assay Immunoassay negative for CDAD

Findings Red edematous inflamed mucosa and numerous

plaques

Differential Diagnosis

Bartlett J.G., NEJM 2002;346: 334-339Bartlett J.G., NEJM 2002;346: 334-339

Asymptomatic Colonization

Treatment not recommended Effects not sustained May prolong carriage after treatment ends

Treatment

Discontinue antibiotic therapy 20 - 25% CDAD resolves

Substitute another antibiotic that is less likely to cause C. difficile overgrowth

Discontinue any antidiarrheals and opioid Treatment options

Oral Metronidazole Oral Vancomycin

Treatment: Metronidazole

Metronidazole considered drug of choice for mild to moderate initial episode Dose

500mg p.o. tid for 10-14 days As effective as vancomycin and less expensive Does not increase colonization of vancomycin

resistant enterococci (VRE) Adverse Effects

Nausea Metallic taste Disulfiram like reaction Avoid in pregnancy

Treatment: Vancomycin

P.O. Vancomycin Severe initial episode Pregnancy and lactation

Dose 125mg p.o. qid

Adverse Effects Chills Nausea Vomiting Stevens-Johnson syndrome

Treatment of C. difficile Colitis

Schroeder M.S., American Family Physician 2005;71,5:921-928

A Comparison of Vancomycin and Metronidazole for the Treatment of CDAD, Stratified by Disease Severity

Methods: From October 1994-June 2002 patients were stratified according to whether they had mild or severe disease

Location: Saint Francis Hospital (Evanston, IL) Study design: Prospective, randomized, double-blind,

placebo controlled trial One point each given for:

Age > 60 Temperature >38.3° C Albumin <2.5 mg/dl Peripheral WBC >15,000 cell/mm3 within 48h of enrollment

Zar et al., CID 2007;45: 302-307

A Comparison of Vancomycin and Metronidazole for the Treatment of CDAD, Stratified by Disease Severity

Two points each given for: Endoscopic evidence of pseudomembranous colitis Treatment in the ICU

Patients with ≥ 2 points were considered to have severe CDAD Assessment of Efficacy

Cure- Resolution of diarrhea by day 6 of treatment and a negative result of a C. difficile toxin A assay at days 6 and 10 of treatment

Failure- Persistent diarrhea and/or positive result of a C. difficile toxin A assay after 6 days of treatment, colectomy, or death after 5 days of therapy

Relapse- Recurrence of C. difficile toxin A-diarrhea by day 21 after initial cure

Zar et al., CID 2007;45: 302-307

A Comparison of Vancomycin and Metronidazole for the Treatment of CDAD, Stratified by Disease Severity

Zar et al., CID 2007;45: 302-307

Rate of Cure of CDAD by Disease Severity and Treatment

No. of patients cured/

no. of patients treated (%)Disease Severity

Mtz group Vm group Total Pa

Mild 37/41 (90) 39/40 (98) 76/81 (94) 0.36

Severe 29/38 (76) 30/31 (97) 56/69 (86) 0.02

All 66/79 (84) 69/71 (97) 135/150 (90)

Zar et al., CID 2007;45: 302-307

Rates of Relapse of CDAD by Disease Severity and Treatment

No. of patients who experienced relapse/

no. of patients cured (%)Disease Severity

Mtz group Vm group Total Pa

Mild 3/37 (8) 2/39 (5) 5/76 (7) 0.67

Severe 6/29 (21) 3/30 (10) 9/59 (15) 0.30

All 9/66 (14) 5/69 (7) 14/135 (10) 0.27

Zar et al., CID 2007;45: 302-307

Characteristics of Patients with Severe CDAD with Respect to Response to Metronidazole Therapy

Zar et al., CID 2007;45: 302-307

Recommendations for the Treatment of CDAD

Infect Control Hosp Epidemiol 2010; 31(5)

Treating CDAD with a Nonfunctioning or Partially Functioning Gastrointestinal Tract

Metronidazole 500mg IV tidADD

Vancomycin 500mg p.o. qidPlus for ileus consider

Intracolonic vancomycin as retention enema 500mg in 100 ml of normal saline every 6 hours given as

retention enema

Recurrent CDAD

Estimated recurrence rate 20-30% After initial relapse, the risk of recurrence has

been reported as high as 65% Occurs 1-42 days High-risk patients

Females Chronic renal failure Previous episodes of CDAD Abdominal surgery Increased age

Treatment of Recurrent CDAD

Vancomycin Vancomycin + cholestyramine Vancomycin + rifampin IVIG Probotics Donor Stool Transplantation

Recurrent Treatment: Vancomycin

Tapered course of oral vancomcyin Week Dose

1 125 mg qid 2 125 mg bid 3 125 mg daily 4 125 mg every

other day 5 and 6 125 mg every 3 days

Pulsed vancomycin 125–500mg vancomycin every 2-3 days for 3

weeks Supported by CDAD guidelines

Recurrent Treatment: Vancomycin + Cholestyramine

Dose Oral vancomycin 125mg qid + oral cholestyramine

4 g bid

Cholestyramine binds toxin Stagger doses of vancomycin and

cholestyramine by 3 hours Not supported by CDAD guidelines

Recurrent Treatment: Vancomycin + Rifampin

Dose Oral vancomycin 125-500mg qid + oral rifampin

600mg bid for 7 days

Not supported by CDAD guidelines

Recurrent Treatment: IVIG

Intravenous immunoglobulin (IVIG) Passive immunotherapy Dose 150 - 400mg/kg Has been shown to be useful in addition to antibiotic therapy

Side Effects: Anaphylactic Reaction Decreased BP Increased HR Fever Chills

Disadvantages Expensive

$50.00/GM 70kg pt. $1,750/infusin

Distributed by allocation No standard treatment protocol

Not supported by CDAD guidelines

Recurrent TreatmentProbiotics

Concept dates back to 1908 Eli Metchnikoff Living organisms When taken orally improve microbial balance blocking C. difficile

proliferation Mechanism of action of probiotics

Inhibition of pathogen attachment Inhibition of action of microbial toxin Stimulation of immunoglobulin A Production of pathogen-inhibitory substances Trophic effects on intestinal mucosa

Probiotics S. boulardii (Florastor, Biocodex) L. acidophilus - L. bulgaricus (Lactinex) L. reuteri (Primadophilus) L. rhamnosus (Culturelle)

Not supported by CDAD guidelines

Recurrent Treatment: Donor Stool Transplantation

Has been shown to be effective in a small number of patients Given via nasogastric tube or via rectal instillation

Due to potential spread of other infections should be considered near the end of the list of treatment strategies

Surgical Treatment

Surgery usually unnecessary 0.4-5%

Indications for surgery Colonic perforation Toxic megacolon Fulminant colitis Sepsis Multiple organ failure

Complications

Dehydration Electrolyte imbalance Pseudomembranous colitis-exudate made of inflammatory debris

and fibrin that may form on epithelial surface Toxic mega

colon-enlargement Sepsis Death

rare

Schroeder M.S, M.D., American Family Physician 71;5:922

Complications

Dehydration Electrolyte imbalance Pseudomembranous colitis-exudate made of inflammatory debris

and fibrin that may form on epithelial surface Toxic mega

colon-enlargement Sepsis Death

rare

Wolf P, Kasyan A, N Engl J Med 353;23: 2491

Complications

Dehydration Electrolyte imbalance Pseudomembranous colitis-exudate made of inflammatory debris

and fibrin that may form on epithelial surface Toxic mega

colon-enlargement Sepsis Death

rare

Wolf P, Kasyan A, N Engl J Med 353;23: 2491

Treatment Options for CDAD Under Investigation

Nitazoxanide Rifaximin PAR-101 Tolevamer Ramoplanin Vaccine IgG Monoclonal Antibody

Treatment Under Investigation:Nitazoxanide (Alinia®)

Phase III Approved in U.S. December 2003

Treatment of intestinal parasites Blocks anaerobic metabolic pathways Low concentrations inhibit C. difficile At least as effective as metronidazole in treating

CDAD 500mg bid for 7-10 days

10 days less recurrence than 7 days (58% vs. 74%) $240/10 day AWP

Treatment Under Investigation:Rifaximin (Xifaxan®)

Phase III Nonabsorbed rifamycin that effectively treats travelers’

diarrhea Active in vitro against aerobic and anaerobic gram (+)

and (-) organisms In vitro activity against C. difficile Study dose Rifaximin 400mg bid-tid for 10-14 days High level resistance (MIC > 256 ug/ml) in 3% strains

tested in one series

Treatment Under Investigation:PAR-101 (Difimicin®)

Phase III Formally called OPT-80 Nonabsorbable, 18-membered macrocyclic

antimicrobial RNA polymerase inhibitor Narrow antimicrobial spectrum

Treatment Under Investigation:Tolevamer

Phase III Anionic polymer Binds C. difficile toxins A and B Unique nonantibiotic treatment option Performed well in a Phase II trial Well tolerated except for findings of hypokalaemia

Treatment Under Investigation:Ramoplanin®

Phase III (Oscient Pharmaceuticals) Nonabsorbed, glycolipo-depsipeptide Shown activity in vitro and in vivo against C. difficile Isolated in 1984 Derived through fermentation of Actinoplanes spp. Exerts effect by preventing the formation of

peptidoglycan Has been shown in small trial to be equally efficacious

to vancomycin The Pullman Study Ramoplanin 200mg twice daily Ramoplanin 400mg twice daily Vancomycin 125mg four times daily

Mechanism of Action for Ramoplanin

Emerson C.R. Marzella N..Pharmacy and Therapeutics 2007; 32:535-543

Treatment Under Investigation: C. difficile Vaccine

Phase II Acambis (Cambridge, United Kingdom) Vaccine contains inactivated C. difficile toxins A and B Four doses of toxoid vaccine has been shown to be

immunogenic and well tolerated Vaccine has been successful in animal models Early trials in humans have been satisfactory for

healthy young adults Phase 1 trial in healthy elderly subjects aged ≥ 65

completed

Treatment Under Investigation:IgG Monoclonal Antibody

Phase II Human monoclonal antibodies against toxins A (MDX-

066) and B (MDX-1388) Evaluated in:

Cell neutralisation assays Hamster model of CDAD

Studies have begun in humans Reduced mortality from 100% to 45% in the hamster

model

CDAD Prevention

Frequent hand washing with soap and water Use of gloves when caring for patients Cleaning of environmental surfaces with sporicidal

agents Isolation of symptomatic patients in private rooms Restriction of antibiotics when outbreaks occur Avoidance of rectal thermometers Antimicrobial Stewardship

Key Points

C. diffilice is a gram positive spore forming bacillus Transmitted via fecal oral route The most common cause of hospital-acquired diarrhea Most cases occur in hospital or long-term care facilities Clindamycin, Cephalosporins, and Quinolones are common

causes of CDAD New epidemic strain that produces 16X more toxin A and 23X

more toxin B production Immunoassay test for toxin A and B is the preferred diagnostic

test Metronidazole is the treatment of choice for mild to moderate

initial episode Vancomycin is the treatment of choice for severe CDAD

References

1) Yassin SA, Young-Fadok TM, Zein NN, pardi DS: Clostridium difficile-Associated Diarrhea and colitis. Mayo Clin Proc. 2001:76:725-730

2) Delme’e M. :Laboratory diagnosis of clostridium difficile disease. CMI, 7, 411-4163) Ciesla WP, Bobak DA: Management and Prevention of Clostridium difficile- Associated Diarrhea. Current

Infectious Disease Reports 2001, 3:109-1154) Florea NR, KUTI JL, Nightingale CH, Nicolau DP: Treatment of Clostridium difficile-associated Disease.

Connecticut Medicine 2003, 67: 153-1555) McConnell EA: Prevent the spread of Clostridium difficile. Nursing 2002, 32: 24-266) Schroeder MS: Clostridium difficile-Associated Diarrhea. American Family Physician 2005, 71: 921-9287) Poutanen SM, Simor AE: Clostridium difficile-associated diarrhea in adults. CMAJ 2004, 171: 51-588) Sheff B:Minimizing the Threat of C. difficile. Nurse Management 2002, 32-379) Bartlett JG: Antibiotic- Associated Diarrhea. N Engl J Med 2002, 346:334-33810) Elmer G:Probiotics: “Living drugs”. Am J Health-Syst Phar 2001, 58:1101-110911) 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 boulardii12) Surawicz CM: Probiotics, antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in humans. Best

Practice & Research Clinical Gastroenterology. 2003 17:775-78313) Cleary RK: Clostridium Difficile-Associated Diarrhea and Colitis. Colon Rectum. 1998;41:1435-144914) Mylonakis E, Ryan ET, Calderwood SB. Clostridium difficile-Associated Diarrhea. Arch Intern Med. 2001 161:525-

53315) Zar F, Bakkanagari S.R. et al: A comparison of Vancomycin and Metronidazole for the Treatment of Clostridium

difficile-Associated Diarrhea, Stratified by Disease Severity.16) Emerson C.R. Marzella N.: Ramoplanin: Promising Treatment Option for Clostridium difficile-Associated Diarrhea

and Vancomycin-Resistant Enterococcus

CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA (CDAD)

Presented By:

Kevin L. Epps, PharmD

Infectious Disease Pharmacist

St. Vincent’s Medical Center