Emerging Diseases: A New Strain of Toxigenic C' difficile

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Emerging Diseases A New Strain of Toxigenic C.
difficile

• Presented for the Association of Professionals
  in Infection Control (APIC) by Elizabeth Race
  M.D. Associate Professor of Infectious Disease
• University of Texas

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Clostridium difficile

• A gram anaerobic spore forming bacillus
  associated with nosocomial diarrhea as well as
  the more severe (potentially fatal)
  pseudomembranous colitis
• Studies dating back to the 1970s highlighted the
  role of two toxins, A B, in the pathogenesis of
  C. difficile associated disease (CDAD)
• Health care associated transmission occurs
  primarily due to environmental contamination with
  C. diff spores
• Major risk factor is exposure to antimicrobial
  agents to which the strain of c. diff is
  resistant, creating selective pressure favoring
  emergence of CDAD

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In its spore form, C. difficile can withstand
drying and heat, and is resistant to
disinfectants. The spores can survive up to five
months in the environment. C. difficile has been
cultured in rooms of infected individuals up to
40 days post discharge. (Patient Safety
Advisory, Pennsylvania Patient Safety Reporting
Systems, June 2005)
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Mode of Transmission C. difficile is shed in
feces. Any surface, device or material that
becomes contaminated with feces may serve as a
reservoir for C. difficile spores. C. difficile
spores are transferred to patients mainly via the
hands of health care personnel who have touched a
contaminated surface or item. (CDC Fact Sheet -
Information for Health Care Providers).
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Cleaning Protocol OMH March 2006

• Emphasis on timely contact precautions for
  patients with diarrhea
• Daily cleaning of all contact precautions rooms
  housing pt suspected of or diagnosed with CDAD
• EPA disinfectant approved for hospitals
• One swipe of all high touch surfaces with a 110
  sodium hypochlorite (bleach) and H2O solution
• Bedrails, call bell, telephone, TV remote,
  over-bed table, bathroom door knob, water
  faucets, light switch, commodes and flush handle

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• Guiac Cards
• Fecal Occult blood
• Useful Screening test or satanic ritual?

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New, Epidemic, Multiple Toxin Strain of C. diff

• Epidemic strain in Ohio confirmed by Centers for
  Disease Control (CDC)
• Certain C. diff strains have the propensity to
  cause multistate outbreaks , these are usually
  multi-drug resistant strains
• Rates of severe disease and mortality have
  historically been lt 3, but with emergence of
  newer strains of C. diff (possibly imported from
  Canada) the mortality rate appears to be rising
• Each episode of CDAD has been estimated to cost gt
  3600. With a total U.S. cost of gt one billion
• McDonald CL, et al. An epidemic toxin
  gene-variant strain of C. difficile. nEJM 2005
  353 2433-41

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Both the rate and severity of C. difficile
colitis is increasing

• NNIS data collection noted upsurge in CDAD rates
  from late 1980 through 2001
• Between 2000 and 2001, a 26 increase was noted
  in proportion of patients discharged from
  non-federal U.S. hospitals with CDAD
• Between 2000 and 2001, Univ. of Pittsburgh noted
  a doubling of CDAD rate as compared to prior 10
  years
• 26 patients with CDAD required colectomy and 18
  patients died
• McDonald Cl, et al. An Epidemic gene-variant
  strain of C. difficile. NEJM 2005, 353 2433-41

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Increased Severity of CDAD

• Rates increased from 0.68 to 1.2
• Life threatening disease increased from 1.6 to
  3.2
• 44 colectomies and 20 deaths
• Dallal RM et al. Pittsburgh, PA 2000

• Cases rose by gt 30 over previous 10 years
• Overall mortality 15.3 up from 3.5
• Disease particularly severe in transplant
  recipients
• Morris AM et al. Portland, OR 1994 - 2000

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Reasons for Increased CDAD Incidence and Severity

• Changes in underlying host susceptibility
• Changes in antimicrobial prescribing
• New strain with increased virulence
• Changes in infection control practice

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Those over 65 suffer an increasingly large burden
of CDAD and mortalityProportion of U.S.
Acute-care Hospital discharges with C. diff
listed as any diagnosis by age
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Host defenses against diarrheal disease versus
Microbial virulence traits

• Hygiene
• Gastric acid
• Mucus
• Immunity
• Motility
• Flora

• Adherence
• Enterotoxin
• Cytotoxin
• Invasiveness
• Penetration
• Ability to penetrate normal or abnormal mucosal
  lining

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Guiac The tao of Poo
       
   
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Pathogenesis

• Alteration of fecal flora
• Antibiotics esp. broad spectrum or drugs with
  enhanced anti-aerobic activity
• Anti-neoplastics or immunosuppressants
• Colonic colonization with toxigenic C. difficile
  associated with
• GI surgery, feeding tubes, stool softeners, GI
  stimulants, antiperistaltics, antacids, enemas.
  (proton pump inhibitors do ? risk but not as
  risky as surgery or antibiotics
• Advanced age and severe underlying illness
• Toxin A deficient strain may cause disease
• Growth of organism with elaboration of toxin
• Further alteration of fecal flora .antibiotics

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Normal Inhabitants of Healthy GI tract

• Normal Colonic Flora
• Anaerobes
• Bacterioides fragilis
• Clostridium
• Peptostreptococcus
• Peptococcus
• Others
• Aerobes
• Escheria coli
• Klebsiella
• Proteus
• others

• Organisms/ g feces
• 10 ¹¹
• 108
• 10 5-7
• 10 5-7
• 10 5-7

-Mandell Infectious Diseases
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The frequency of C. diff acquisition in the
hospital is directly proportional to the length
of stay
Johnson and Gerding J Infect Dis. 1998 26 1027
- 36
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Antimicrobial Agents Historically Associated with
CDAD
Infrequent
Rare
Frequent
Parenteral aminoglycosides Bacitracin Metronidazol
e Vancomycin
Ampicillin Amoxicillin Cephalosporins Clindamycin
Tetracyclines Sulfonamides Erythromycin Chloramphe
nicol Trimethoprim Quinilones
With new strains
Mandell Infectious Diseases
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Pathogenicity

• Human disease ranges from asymptomatic
  colonization to
• Diarrhea
• Pseudomembranous colitis
• Toxic megacolon
• Death

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• Disease caused by 2 toxins, Toxin A (an
  enterotoxin) and Toxin B (a cytotoxin)
• Pathogenicity is genetically located in a
  pathogenicity locus (PaLoc) of 5 genes
• In general, C. diff strains either possess the
  entire PaLoc and are toxigenic, or lack the PaLoc
  and are non-toxigenic (and do not cause disease)
• A few strains possess atypical or variant toxin A
  or B genes (and are able to cause human CDAD and
  PMC)
• Binary toxin may also be present, but its
  clinical significance was unknown
• New with Canadian strain
• Appears to be causing the increased morbidity and
  mortality of CDAD

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A New, Multiple Toxin-Positive Strain of C. diff

• McDonald examined 187 C. diff strains from 6
  states (GA, IL, ME, NJ, OR, PA) obtained during
  2000-3 outbreaks
• Compared them with a database of over 6000
  historical strains
• Described the dominant strain Restriction
  Endonuclease Analysis (REA) Group B1 North
  American PFGE type 1 (NAP1) toxinotype III pos
  for binary toxin CDT with an 18bp tcdC deletion
  (B1/NAP1)
• Pan quinilone- resistant
• McDonald CL, et al. An epidemic gene-variant
  strain of C. difficile. NEJM 2005 353-2433-41.

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Clinical Manifestation

• Incubation period
• Unknown, disease onset 1 day to 6 weeks following
  antibiotic exposure
• Watery diarrhea, lower abdominal pain, fever,
  leukocytosis (elevated WBC)
• Pseudomembranous colitis
• Toxic megacolon
• Perforation, peritonitis
• Death in 24 38
• Especially if surgical consult not obtained early

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Leukocytosis and CDAD

• Toxin A is a potent neutrophil chemo attractant
• In a case control study of 109 patients with
  CDAD, 50 had WBC gt 10,000/mm³
• (Arch Int Med 1986 146 95-100)
• Mean WBC 15,800 in 35 CDAD patients vs. 7,700 in
  controls (Am J Gastroenterology 2000 95 3023)
• CDAD was found in 16 of patients with WBC gt
  15,00/mm³ and 25 of patients with WBC gt 30,000
  mm³ (Clin Infect Dis 2002 34 1585 92)
• 58 of 60 patients with unexplained WBC gt 15,000
  had C. diff toxin in stool

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Recurrent CDAD

• Seen in 5 40 of cases
• Advanced age, severe underlying illness
• Re-exposure to antibiotics
• More likely in those who do not mount antibody
  response during initial therapy
• Up to half may be re-infection not recurrence
• True recurrences
• Likely due to intra-luminal persistence of spores

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Diagnosis of CDAD

• CDAD Case Definition
• Diarrhea
• gt 6 watery stools over 36 hours or gt 8 over 48
  hours
• Pseudomembranes seen on endoscopy
• OR
• Diagnostic test for toxin producing org
• In a situation when there is no other recognized
  etiology for diarrhea

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Guiac cards Anals of Internal Medicine
   
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C. Diff Diagnostic Tests
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General Principles of Diagnosis of CDAD

• Fecal leukocytes are found in 30 60 of pts
  with CDAD it is not helpful to use this test to
  screen for which pts to test for CDAD
• Patients who develop diarrhea after 3 or more
  days of hospitalization, who have received
  antimicrobials within 2 months, should be tested
  initially only for C. difficile
• Testing of asymptomatic patients for C.
  difficile, including tests of cure is not
  recommended. Cessation of diarrhea and improved
  condition during treatment is the goal not
  erradication of spores
• (Infect Cont Hosp Epid 1995 16 459-477. Ann
  Int. Med 1995 123 835- 840)

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Therapeutic Options for CDAD

• Treatment
• Cease offending antimicrobial
• Administer prescription orally
• Nearly all pts respond
• Continue tx for at least 10 days
• Avoid antiperistaltics
• Alternative or multiple administration routes for
  ileus or toxic megacolon
• Early surgical consultation

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CDAD Primary Treatment

• Metronidazole, 250mg qid or 500mg tid orally x 10
  days is preferred
• Vancomycin 125 500mg qid orally x 10 days is an
  alternative that should be avoided if possible to
  reduce risk of vancomycin resistant enterococci
  (VRE) in hospitals

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Treatment CDAD and colitis

• Nonspecific measures
• Discontinue or change implicated antimicrobial
• Supportive measures (fluids)
• Avoid antiperistaltic agents
• Contact isolation precautions
• Antimicrobial treatment
• Metronidazole 250mg orally tid x 7 14 days
• Vancomyin 125mg orally qid x 7 14 days
• Metronidazole 500mg IV q 6 hrs (only until oral
  agents are tolerated)

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CDAD Recurrence Treatment

• First reccurrence manage again with
  metronidazole in same dose and duration as
  original episode the majority of pts respond
  without further recurrence
• For subsequent recurrences, there is no consensus
  but
• Vanc 125mg qid orally plus rifampin 300mg bid
  orally x 10 days
• (Buggy et al. J. Clin. Gastroenterology 1987
  9155-9)

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Relapse Management CDAD or Colitis

• Spectrum of Treatments
• Metronidazole or vanc po x 10 days followed by
  cholestyramine (4 g tid) lactobacilli (as
  Lactinel, 1 g po qid) x 3 wks
• Vancomycin 125mg po qid x 10 14 days, followed
  by vanc 125mg po qod x 3 wks
• Vanc 125mg po qid x 4 6 wks, then taper over 4
  8 wks
• Vanc 125mg po qid, plus rifampin 600mg po q day x
  10 14 days

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Relapse management cont

• Vanc 125mg po qid plus Saccharomyces boulardiix x
  10-14 days, then S. boulardii for 4 wks
• Intravenous gamma globulin 400mg/kg every 3 weeks
  (in children)
• Rectal instillation of feces (50g fresh stool
  from healthy donor in 500ml of saline, delivered
  by enema
• Broth cultures of bacteria from healthy donors
  (stool culture using stool from healthy donor, 10
  strains were selected based on in vitro
  inhibition of C. difficile grown in broth culture
  10 to 9th power/ml 2ml of each mixed in
  anaerobic glove box with 180ml saline and given
  by enema)

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Relapse management cont

• Lactobacllus G-G, 1 g po qid x 3 wks

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Management of CDAD in the Presence of Severe Ileus

• Vanc orally or via NG 500mg q 6 hrs (discontinue
  suction for 45-60 minutes post dose)
• Metronidazole 500mg q 6 hrs IV
• Vanc enemas 500mg q 6 hrs in 100cc NS via 18 G
  Foley catheter in the rectum 30cc balloon
  inflated clamp catheter for 60 min. post dose
• 6 of 8 pts responded in 4 17 days
• 2 died, one following colectomy
• (Inf Cont Hosp Epidemiology 199415371-381)

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New and Evolving Therapies

• Ramoplanin
• Developed to eradicate VRE
• Toxin binding
• Tolevamer
• Probiotics
• Stool enemas or living related stool transplants
• Immunoglobulin therapy
• Vaccine under development

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Monotherapy vs. Combination Therapy

• Single-blind randomized clinical trial
• 39 inpts with primary episode of CDAD randomized
  to receive 10 days of metronidazole vs. 10 days
  metronidazole rifampin
• 65 on monotherapy improved by day 10 vs. 63 of
  pts on combination therapy
• Proportion of pts who relapsed similar between
  the 2 treatment arms
• Lagrotteria D, et al. Clin Infect Dis 2006
  43547 - 552

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Infection Prevention and Control Measures

• Contact Isolation precautions
• Empiric
• All incontinent pts with undiagnosed diarrhea
• All pts unable to perform hygiene (washing hands
  after bowel movements, or who are incontinent
  (children, debilitated, elderly)
• All pts diagnosed with CDAD
• Gloves and gowns for all patient contact
• Dedication of pt care equipment
• Antimicrobial restriction

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Infection Prevention and Control Measures cont

• Meticulous hand washing with soap and water NOT
  alcohol based hand rub
• Upon leaving room and removing gloves
• At least 15 seconds
• Rinse well with warm H2O
• Pat dry
• Use paper towel to shut off faucet

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IPC measures cont

• Private room or cohort
• Room and equipment disinfection
• 110 bleach solution
• Single swipe and throw away
• High touch surfaces
• Commodes implicated
• Endoscopes implicated
• When not properly sterilized
• No reuseable rectal thermometers single use
  only

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C. Difficile Iceberg
Infected patients (symptomatic)
Colonized patients
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The same study found that wearing two gowns, one
forwards and one backwords, improved concealment
by up to 60 but made examination and many
procedures difficult.
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Evidence for Measures to Reduce Risk of Diarrhea

• Antimicrobial useage restriction
• Prophylactic treatment of pts receiving atx
• Saccharomycees boulardii
• Lactobacillis species

• proven
• possible
• untested

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Evidence for Measures to Reduce Risk of Diarrhea
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Probiotics for Abx-Associated Diarrhea

• Incidence of abx-assoc diarrhea is 5 25
  depending on the series, C. diff responsible for
  approx. 24 of abx-assoc diarrhea (and for 90 of
  cases of pseudomembraneous colitis)
• Placebo-controlled, double-blind clinical trial
  of 193 patients given Saccharomyces boulardii
  within 72 hrs of B-lactam abx to prevent diarrhea
• Diarrhea developed in only 7.2 of pts given S.
  boulardii, vs. 14.6 of pts given placebo
• McFarland LV, et al. Am J. Gastroenterology 1995
  90439

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2006 Guidelines for Probiotic Use in Abx-Assoc.
Diarrhea and CDAD

• Prevention of Abx-Assoc Diarrhea
• Adults S. boulardii 1gm/day
• Strength of evidence good
• Children LGG 1-2 x 10 to the 10th cfu/d
• Strength of Evidence good
• Prevention of CDAD
• No evidence to support primary prevention
• Recurrent CDAD
• Adults S. boulardii 1 gm/ day
• Strength of Evidence good
• Children Insufficient evidence

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Need for Antimicrobial Controls?

• Antimicrobial use restriction is indicated if a
  specific antimicrobial , particularly
  clindamycin, is identified as a risk for C.
  difficile- associated diarrhea in the
  institution
• - Society for Healthcare Epidemiology of America

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Newer Antibiotics Role in the Current C.
difficile Epidemic

• Fluroquinolones
• Eradication of Healthy Intestinal Anaerobes
  Increases Rates of C. diff colitis and VRE
• Gatifloxacin (Tequin) and Moxifloxacin (Avelox)
  have markedly greater anaerobic activity than
  Levofloxacin or Ciprofloxacin

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Potential for VRE and C. diff Colitis

• Two Major Factors
• Anti anaerobic activity of an antimicrobial agent
• B. fragilis is a normal protective barrier for
  the intestinal tract
• Fecal concentration of an antimicrobial
• Depends on biliary (intestinal exposure) vs.
  of renal excretion
• Wistrom, et al. JAC 2001 47 43-50 Donskey, et
  al. NEJM 2000 3431925-1932

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Anti-anaerobic Activity of Fluroquinolones
HoellmanApplebaum AAC 1998 422459-2462
Zhanel. Drugs 2002 6213-59
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The Major Modifiable Risk Factor Antibiotic Use

• Limit use of drugs with enhanced anti-anaerobic
  activity
• Limit duration of all antibiotics to absolute
  minimum

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  and with an opposing view, C. difficile,
Legionella, and smallpox.