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Clostridium difficile: 2012 Update. Julia B. Garcia-Diaz, MD, MSc Ochsner Clinic Foundation October 20 th , 2012. Case Presentation . 61 yo male was admitted to the hospital with the complain of bloody diarrhea

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Clostridium difficile 2012 update
Clostridium difficile: 2012 Update

Julia B. Garcia-Diaz, MD, MSc

Ochsner Clinic Foundation

October 20th, 2012


Case presentation
Case Presentation

  • 61 yo male was admitted to the hospital with the complain of bloody diarrhea

  • 4 days before admission, he was diagnosed with gastroenteritis (fever 39.5, diarrhea) and was given ciprofloxacin. In spite of taking the antibiotics, he continued to pass watery stool mixed with blood

  • Past history: liver disease with esophagealvarices for which band ligation was done twice & also pancytopenia due to hypersplenism


Laboratory
Laboratory

  • Stool: WBC 5-10/HPF, RBC 10-20/HPF.

  • Positive stool occult blood

  • Stool Clostridium difficile: positive

  • CBC

    • WBCs 2.1 x 103 /cm

    • Hemoglobin 10.8 gm/dl

    • Hematocrit 31.2

    • Platelet count 36,000


Laboratory1

Phosphorus 2.9 mg/dl

Calcium of 8.2 mg/dl

Albumin 2.3 gm/dl

Alkaline phosphatase83 U/L

AST 21 U/L

ALT 18 U/L

GGT 18 U/L

Total Bilirubin 2.9 mg/dl

Laboratory

  • Direct1.8 mg/dl

  • BUN 27 mg/dl

  • Creatinine 0.7 mg/dl

  • Sodium 133 mEq/L

  • Potassium 3.3 Meq/L


Abdominal ultrasound showed shrunken cirrhotic liver measuring 12 cm

Gallbladder showed small stones.

The spleen was hugely enlarged measuring 19.98 x 7.77 cm


Hospital course
Hospital Course measuring 12 cm

  • The patient was started on oral vancomycin 250mg q6h and metronidazole treatment 500mg q8h

  • 4 days later: the patient started complaining of severe abdominal pain and examination showed markedly distended abdomen with evidence of guarding and rigidity

  • A KUB was done and it showed marked distension of the colon reaching up to 9.5 cm in diameter


Hospital course1
Hospital Course measuring 12 cm

  • A cecostomy tube was placed in to help in deflation of the colon followed by sigmoidoscopy or total colonoscopy.


Hospital course2
Hospital Course measuring 12 cm

  • The patient had successful insertion of cecostomy tube and sigmoidoscopy was performed with improvement of the abdominal distension


Hospital course3
Hospital Course measuring 12 cm

  • Rapid deterioration with hepatic coma and hepatorenal failure occurred.

  • 4 days later the patient died.


An epidemic toxin gene strain of clostridium difficile mcdonald lc nejm 2005 353 1433
AN EPIDEMIC, TOXIN GENE STRAIN OF measuring 12 cmCLOSTRIDIUM DIFFICILEMcDonald LC. NEJM 2005;353:1433

  • Reported increase 2000-01 – 21%

  • Pittsburgh – 26 colectomies and 18 deaths


CONCLUSIONS measuring 12 cm

C. difficile appears to be causing more disease and more serious disease. Possible role of strain BI/NAP1

• Toxin A and B – high production


C l mcdonald dale gerding
C.L. McDonald measuring 12 cmDale Gerding

  • 23 states and 5 countries

  • 2004: diagnosis (ICD-9) showed 25% increase over 2003

  • Average rate is 5-10/1000 discharges (US hospitals)

  • Guidelines (SHEA/IDSA): Spring ’07

  • Antibiotics: cephalosporinsand FQ

  • NAP-1 strain: reference lab CDC if epidemic in new area

  • Strain does not change management


A PREDOMINANTLY CLONAL MULTI-INSTITUTIONAL OUTBREAK OF CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA WITH HIGH MORBIDITY AND MORTALITYLooV. NEJM 2005;353:2442

METHOD:

Prospective study in 12 Quebec hospitals

• Risk factors

• Clinical features

• Strain types: PFGE, binary toxin, tcdC deletion


  • Main CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA WITH HIGH MORBIDITY AND intervention:

    • Infection control

    • Single rooms, contact precautions, early detection and Rx, dedicated equipment, soap, household bleach and education

  • Antibiotic control 5-10% decrease

  • Toxin assay: cytotoxinat 24 hr

  • Treatment: metronidazolein ~ 80%

  • Rates in 12 hospitals consortium and region decrease >50%


Rates among 12 hospitals
Rates Among 12 Hospitals CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA WITH HIGH MORBIDITY AND


Voluntary CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA WITH HIGH MORBIDITY AND laboratory reports of C. difficile positive faecal specimens:

England, Wales and Northern Ireland* 1990 - 2011


Increase in CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA WITH HIGH MORBIDITY AND Clostridium difficile–related Mortality Rates, United States, 1999–2004


The first case
The First Case CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA WITH HIGH MORBIDITY AND

  • 22 year old female, patient of Dr. William Osler

  • “A miserable, emaciated creature in a wretched physical condition.”

  • Underwent surgical resection of a gastric tumor on August 26, 1892

  • Postoperatively developed diarrhea that became progressively more severe

  • Died on post op day 15

“Diphtheritic membrane”


History cont d
History Cont’d CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA WITH HIGH MORBIDITY AND

A fatal case of pseudomembranous colitis in 1948 was linked to streptomycin use, led to reexamination of the 1892 case

“Myriads of gram positive cocci” found- Staphylococcus aureus postulated as cause

Studies in 1950’s and 60’s document an association but did not prove causation


History
History CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA WITH HIGH MORBIDITY AND

  • Clostridium difficile was first described in 1935, but its association with disease was not identified until 1978.


Microbiology
Microbiology CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA WITH HIGH MORBIDITY AND

  • An anaerobic, spore forming gram positive rod; first described as a member of the normal flora of healthy infants in 1935

  • Due to the difficulty in cultivating the organism, it was originally called Bacillus difficilis

  • Given its current name 3 years later


Toxin production
Toxin Production CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA WITH HIGH MORBIDITY AND

  • 5-25% of strains do not produce toxins and don’t cause disease

  • Toxin A

    • 308 kdenterotoxin and cytotoxin

    • Chemoattractant for neutrophils

    • Activator for macrophages and mast cells

  • Toxin B

    • 269 kd potent cytotoxin

    • Disrupts the actin cytoskeleton

    • Found to be a potent necrotizing enterotoxin

    • Probably acts synergistically with toxin A


Epidemiology
Epidemiology CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA WITH HIGH MORBIDITY AND

  • The most common recognized cause of nosocomial diarrhea

  • Incidence and severity increasing:

    • A new strain has been identified that carries and additional toxin (iota toxin)

    • C. difficile acquiring resistance to more antimicrobials

  • Frequency varies by institution

  • Results in 3.6 excess hospital days, cost of $3,700/pt

  • Readmissions for CDAD cost $128,000 per hospital per year

  • Conservative estimate of US cost per year $1.1 billion


Acquisition of the organism
Acquisition of the Organism CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA WITH HIGH MORBIDITY AND

  • In healthy adults intestinal carriage rates of toxigenicC. difficile are 5% or less

  • Carriage in healthy adults thought to be transient

  • High prevalence in newborns- up to 60-70%- all asymptomatic

  • In hospitalized patients colonization begins upon admission in patients given antimicrobials

    • 13-20% within the first week

    • 50% in patients hospitalized for more than 4 weeks

  • Even relatively minute amounts of antimicrobials can predispose to colonization


Pathogenesis of infection
Pathogenesis of Infection CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA WITH HIGH MORBIDITY AND

  • Three critical events necessary for CDAD

    • Disruption of the normal colonic microflora by antimicrobials or other means

    • Ingestion by the patient of a toxigenic strain of C. difficile and its arrival intact in the lower GI tract

    • One or more additional requirements for developing invasive disease

      • Advancing age

      • Severe underlying disease of any kind

      • Prolonged hospital stays

      • Manipulation of the GI tract (NG tubes, enemas, surgery, motility altering drugs)

      • Acid neutralizing drugs


Medications associated with c difficile
Medications Associated with CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA WITH HIGH MORBIDITY AND C. difficile

  • Most common antimicrobials

    • Clindamycin

    • Ampicillin/amoxicillin

    • Cephalosporins

    • Fluoroquinolones

  • Infrequent- Tetracyclines, macrolides, TMP/SMX

  • Rare or never- IV aminoglycosides, metronidazole, vancomycin, bacitracin

  • Chemotherapeutics with antibacterial activities

    • Ifosfamide, carboplatinetoposide 8% incidence

    • Others Mtx, 5FU, doxorubicin, cyclophosphamide

  • Bowel preparation regimens


Clinical disease spectrum
Clinical Disease Spectrum CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA WITH HIGH MORBIDITY AND

  • Asymptomatic colonization 2-5 or more X more common than clinical illness of any type

  • Mild diarrhea, minimal discomfort

  • Typical CDAD:

    • Crampy abdominal pain

    • Profuse diarrhea with mucoid, greenish watery stool with a characteristic odor

    • Low grade fever and leukocytosis

  • More severe disease with high fever, marked leukocytosis


Disruption of protective CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA WITH HIGH MORBIDITY AND

colonic flora (AB or AN)

Colonization with toxigenic C. difficile

by fecal-oral transmission

Toxin A and B production

A/B: Cytoskeletal damage, loss of tight junctions.

A: Mucosal injury, inflammation, fluid secretion.

Colitis andDiarrhea


Diagnosis
Diagnosis CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA WITH HIGH MORBIDITY AND

  • Endoscopy (pseudomembranous colitis)

  • Culture

  • Cell culture cytotoxin test

  • EIA toxin test

  • PCR toxin gene detection


Diagnosis1
Diagnosis CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA WITH HIGH MORBIDITY AND

  • Endoscopy looking for pseudomembranes

    • Quick, and specific

    • Pseudomembrane formation usually starts on the right side

    • Pseudomembrane formation a late manifestation

  • Culture

    • Takes several days

    • Need cytotoxic assay of organism after culture

  • Immunoassays


Eia toxin tests
EIA toxin tests CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA WITH HIGH MORBIDITY AND

  • Can detect toxin A, toxin B, or both

  • Rapid, cheap, and specific

  • Less sensitive than cytotoxin test

  • Toxin A tests will miss rare C. difficile isolates that produce toxin B only (Toxin A-negative, toxin B-positive outbreak, Winnipeg, 1998)


Treatment
Treatment CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA WITH HIGH MORBIDITY AND

  • General principles

    • Whenever possible withdraw the offending antibiotic

    • Be patient; some improvement seen in first 2 days but mean time until resolution of diarrhea is 2-4 days

    • Don’t call them nonresponders until 6 days of therapy

    • Treat for 10 days

    • Avoid antiperistaltic agents

    • No role for test of cure assays


Metronidazole
Metronidazole CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA WITH HIGH MORBIDITY AND

  • MIC 90of 0.4 ug/ml vs. C. difficile

  • 98% cure rate documented

  • Well absorbed in the upper GI tract: in healthy volunteers fecal concentration of drug low to undetectable

  • Bactericidal fecal concentrations achieved in the stool of patients with CDAD: fecal concentrations decrease as diarrhea improves

    • Drug secreted directly across inflamed mucosa

    • Decreased intestinal transit time with diarrhea decreases absorption


Vancomycin
Vancomycin CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA WITH HIGH MORBIDITY AND

MIC 90of 1.6 ug/ml

Fecal concentrations of 2,000 to 5,000 ug/ml with po drug

Cure rates 98-100%

Second line therapy due to concerns of selecting for vancomycin resistant Enterococcus (VRE)

No drug in GI tract when given IV

Can be given by enema


A Comparison of CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA WITH HIGH MORBIDITY AND Vancomycin and Metronidazole

for the Treatment of Clostridium difficile–Associated

Diarrhea, Stratified by Disease Severity

Zar et al. Clinical Infectious Diseases 2007; 45:302–7


Treatment of multiple relapses
Treatment of Multiple Relapses CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA WITH HIGH MORBIDITY AND

No controlled studies, lots of anecdotes and “personal favorite” regimens

Tapering courses of vancomycin or metronidazole

Vancomycin plus rifampin

Rifaximin chasers

Yogurt or other Lactobacillus preparations

Saccharomycesboulardii plus antibiotics

Intravenous immune globulin

Cholestyramine with or without antimicrobials


Treatment1
Treatment CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA WITH HIGH MORBIDITY AND

  • Indications for surgery:

    • fulminant disease

    • colonic perforation

    • toxic megacolon

    • failure of medical therapy

  • The role of intracolonicvancomycin in severe C. difficile–associated pancolitis can be an alternative to surgery or as a bridge to surgery in severely ill patients


Infection control issues
Infection Control Issues CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA WITH HIGH MORBIDITY AND

  • Two main approaches

    • Efforts directed at preventing horizontal spread including barrier methods, environmental cleaning

    • Efforts to minimize the possibility that organism exposure will result in a clinical infection, using antimicrobial restriction and limiting overall use of antimicrobials


Barrier methods
Barrier Methods CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA WITH HIGH MORBIDITY AND

Contact isolation including private room for all patients with diarrhea until C. difficile has been ruled out

When should they come out of isolation? Since many healthy persons and persons without diarrhea who are in hospitals carry C. difficile in their intestinal tract there is no rationale for continuing isolation for patients who no longer have diarrhea, or to test them for carriage once the diarrhea has ceased


Handwashing
Handwashing CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA WITH HIGH MORBIDITY AND

Environmental Cleaning

Bleach is the single most effective agent for spore killing

Handwashing between all patient encounters

Switch to alcohol based foams: is it contributing to C. difficile transmission?


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