Update in Clostridium difficile

1
Update in Clostridium difficile

• Martin Rodriguez
• University of Alabama at Birmingham
• No disclosures to report

2
Case 1

• 61 yo man with diabetes and PVD is admitted with
  left foot ulcer and osteomyelitis
• Receives IV doripenem followed by PO
  amoxicillin/clavulanate
• One week later develops diarrhea, 4-5 BM per day,
  no blood or mucus, no fever

3
Antibiotic-associated diarrhea

• Seen in up to 20 of patients treated with
  antibiotics
• C. difficile
• The cause in 15-25 of the cases
• Responsible for virtually all cases of
  pseudomembranous colitis
• Other etiologies
• Changes on the gastrointestinal motility
• Decreased carbohydrate metabolism and osmotic
  diarrhea
• Other pathogens (rare)

Bartlett JG. N Engl J Med 2002 346334
4
Clostridium difficile

• Gram positive, anaerobic, spore forming rod
• There are pathogenic and non pathogenic strains
• Common in the US
• 500,000 cases a year
• 20,000 deaths per year
• 0.5-1 of hospital admissions
• Estimated cost of over US 1 billion per year
• Increasing number of cases in recent years

5
Factors associated with developing C. difficile
infection

• Colonization
• Impairment of colonization resistance
• Host factors

Kelly CP. JAMA 2009 301954
6
Colonization with C. difficile

• Very common in healthy children under the age of
  1
• Rare cause of disease
• Common in adults
• 1-2 of healthy individuals
• 7-26 of hospitalized
• Local epidemiology
• Length of stay
• 5-7 among elderly individuals in nursing homes
• Up to 50 in facilities where C. difficile is
  endemic
• Increasing incidence in the US

7
Increasing frequency of C. difficile infection in
the US
Annual C. difficile rates for hospitals with gt500
beds per 10000 pt/days
Discharges per 100000 population
Archibald LK, et al. J Infect Dis 2004, 1891585.
McDonald LC, et al. Emerg Infect Dis 2006 12409
8
C. difficile infection in the US by region,
1987-2001
Incidence density (per 10,000 patient-days) of
C. difficile by region
Archibald LK, et al. J Infect Dis 2004, 1891585
9
C. difficile infection in the US, 1987-2001
Archibald LK, et al. J Infect Dis 2004, 1891585
10
Community-associated C. difficile infection in
the US

• CDC has reported cases from different states
• Some were women who recently delivered
• Community-associated with no recent exposure to
  healthcare or underlying illnesses
• A third had reported no antibiotics in previous 3
  months

MMWR 2005 541201. MMWR 2008 57340
11
Factors associated with developing C. difficile
infection

• Impairment of colonization resistance to C.
  difficile
• Use of antimicrobials
• 96 of patients had received antimicrobials
  within 2 weeks before the onset of symptoms
• Other proposed risk factors

Cohen SH, et al. SHEA and IDSA Guidelines.
Infect Control Hosp Epidemiol 2010 31
12
Which of the following antibiotics is most
frequently associated with CDI?

1. Levofloxacin
2. Piperazillin/tazobactam
3. Gentamicin
4. Azithromycin
5. Rifampin

13
Impairment of colonization resistance
predisposing antibiotics
Frequently associated Occasionally associated Rarely associated
Amino-penicillins Macrolides Aminoglycosides
Clindamycin Other penicillins Tetracyclines
Cephalosporins Trimethoprim-sulfamethoxazole Ureido-penicillins
Fluoroquinolones Rifampin
Gurwith MJ, et al. J Infect Dis 1977 135
SupplS104. Bartlett, Clin Infect Dis 1992
15573. Gerding, Clin Infect Dis 2004 38646.
Pepin, Clin Infect Dis 2005 401591. Loo VG, et
al. N Engl J Med. 20053532442
14
Fluoroquinolones and C. difficile infection
Pepin J, et al. CMAJ 2005 1731037
15
Impairment of colonization resistance

• Proposed risk factors
• Chemotherapy
• HIV infection
• Acid suppression
• PPIs and H2-blockers
• Tube feedings
• Exposure to NSAIDs, but not aspirin

Dial S, et al. JAMA 2005 2942989. Dial S, et
al. CMAJ 2004 17133. Lowe D, et al. Clin
Infect Dis 2006 431272. Bliss DZ, et al. Ann
Intern Med 1998 1291012. Dial S, et al. JAMA
2005 2942989
16
Host risk factors

• Comorbidities
• Hospitalized
• Length of stay
• Gastrointestinal surgery
• Age
• Immune deficiency

Kelly CP. JAMA 2009 301954. Sanchez, Clin
Infect Dis 2005 411621. Clabots, J Infect Dis
1992 166561. Dial, JAMA 2005 2942989. Dial,
CMAJ 2004 17133. Lowe, Clin Infect Dis 2006
431272. Bliss, Ann Intern Med 1998 1291012
17
Immune response to C. difficile and symptomatic
disease or relapse
Lamont JT. Trans Am Clin Climatol Assoc.
2002113167. Kyne L, et al. N Engl J Med 2000
342390
18
Pathogenesis of C. difficile infection

• Not all strains are pathogenic
• Toxins A and B
• Adhere to receptors on the colon epithelium
  causing necrosis and shedding
• Some strains produce toxin B only
• Toxin B appears to be the major pathogenic toxin
• Binary toxin
• Role is controversial

Schirmer J, et al. Biochim Biophys Acta 2004
167366. Lamont JT. Trans Am Clin Climatol Assoc.
2002113167
19
Pathogenesis of C. difficile toxins
www.cdiff-support.co.uk
20
Increasing severity of C. difficile infection

• Quebec
• More severe disease, particularly in elderly
  patients
• Pittsburg
• Incidence of severe disease doubled
• Increasing need for colectomy and mortality

Pepin J, et al. CMAJ 2005 1731037. Ramsay M, et
al. Ann Surg 2002 235363. Loo VG, et al. N Engl
J Med 2005 3532442. MMWR 2005 541201. MMWR
2008 57340
21
Epidemic strain of C. difficile the BI/NAP1/027
strain

• Carries a deletion in a regulatory gene
• Increased production of toxins A and B
• Also carries the binary toxin gene
• Resistance to fluoroquinolones
• High rates of infection and relapse
• Poorer response to therapy and more severe
  disease

Warmy M, et al. Lancet 2005 3661079. McDonald
LC, et al. N Engl J Med 2005 3532433
22
The NAP1 strain in the US (Oct 08)
http//www.cdc.gov/ncidod/dhqp/pdf/State_Map_NAP1_
10_2008.pdf
23
The NAP1 strain in Canada and Europe
OConnor JR, et al. Gastroenterology 2009
1361913.http//www.eurosurveillance.org/em/v12n06
/Figure_Cdiff027_Europe.jpg
24
Back to case 1

• 61 yo man with diarrhea after antibiotics
• Vital signs are stable, appears dehydrated,
  abdomen is distended, minimally tender in the LLQ
• Foot exam shows a 2 by 2 cm ulcer without
  purulence or erythema
• WBC 16500, creatinine 1.3 mg/dL, albumin 2.9

25
Clinical manifestations of C. difficile infection

• Median incubation time is 2-3 days
• Asymptomatic carriage is very common, 50 of
  hospitalized patients who are colonized
• Watery diarrhea, can also be mucoid or bloody
• Severe colitis, toxic megacolon
• Abdominal pain, fever
• Leukocytosis (even leukemoid), hypoalbuminemia
• Ileus with minimal or no diarrhea (less than 1)

Bartlett J, et al. Clin Infect Dis 2008 46S12.
Wanahita A, et al. Am J Med 2003 115543. Wolf
LE, et al. Mayo Clin Proc 1998 73943. Cohen SH,
et al. SHEA and IDSA Guidelines. Infect Control
Hosp Epidemiol 2010 31
26
Who should be tested for C. difficile infection?

• Not everyone with diarrhea after antibiotics
  should be tested for CDI
• Clinically significant diarrhea
• 3 or more loose stools per day for at least 1-2
  days, samples that take the shape of the
  container
• Between 29-39 of ordered tests would not need to
  be processed if these recommendations are followed

Peterson LR, Robicsek A. Ann Intern Med 2009
151176
27
Which of the following tests is preferred for the
diagnostic evaluation of CDI?

1. Anaerobic stool culture
2. Stool for C. difficile PCR
3. Stool for C. difficile toxin EIA
4. Stool for C. difficile common antigen EIA
5. Stool for cell cytotoxicity assay

28
Diagnosis of C. difficile infection

• Anaerobic cultures
• Do not differentiate pathogenic from
  non-pathogenic
• Cell cytotoxicity assay
• Gold standard
• Cells are exposed to stool filtrates and observed
  for a cytopathic effect
• Antitoxin is added to see if the effect is
  neutralized
• Takes several days, expensive

Cardona DM, Rand KH. J Clin Microbiol 2008
463686. Peterson L, Robicsek A. Ann Int Med
2009 151176
29
Diagnosis of C. difficile infection

• Toxin EIA
• The most commonly used in the US
• Easy to perform, fast
• Sensitivity 63-94, specificity 75-100
• Yield only increases 1-10 with 2-3 specimens
• Some fail to detect toxin B, some strains produce
  toxin B and are negative for toxin A

Cardona DM. J Clin Microbiol 2008 463686.
Peterson L. Ann Int Med 2009 151176. Ticehurst
JR. J Clin Microbiol 2006 441145. Reller ME. J
Clin Microbiol 2007 452601. Sloan LM. J Clin
Microbiol 2008 461996
30
Diagnosis of C. difficile infection

• Common antigen EIA or latex
• EIA better than latex
• Two-step procedure
• Screening with common antigen EIA
• Detects pathogenic and non pathogenic
• Follow with confirmatory cell cytotoxicity assay
• Initial results were promising, more recent
  studies show sensitivity of 75

Cardona DM. J Clin Microbiol 2008 463686.
Peterson L. Ann Int Med 2009 151176. Ticehurst
JR. J Clin Microbiol 2006 441145. Reller ME. J
Clin Microbiol 2007 452601. Sloan LM. J Clin
Microbiol 2008 461996. Cohen SH, et al. SHEA
and IDSA Guidelines. Infect Control Hosp
Epidemiol 2010 31
31
Diagnosis of C. difficile infection

• Toxigenic cultures
• Anaerobic culture followed by toxin EIA
• Sensitivity and specificity above 90, takes time
• Quantitative PCR targeting toxin B
• Rapid turnaround time, only one sample is needed
• Sensitivity gt 84, specificity gt 90
• Three tests are FDA approved, also some in-house
  qPCRs available

Sloan LM, et al. J Clin Microbiol 2008 461996.
Stamper PD, et al. J Clin Microbiol 2009 47373.
EIN network March 2009
32
Diagnosis of C. difficile infection

• Combination of tests
• Common antigen EIA
• Toxin EIA
• If negative then get PCR

Larson AM, et al. J Clin Microbiol 2010 48124.
Swindells J, et al. J Clin Microbiol 2010 48606
33
Diagnosis of C. difficile infection

• SHEA and IDSA Guidelines
• EIA for toxins is rapid but less sensitive than
  other tests
• Two step method using common antigen EIA appears
  to have advantages but more data is needed
• PCR is promising

Cohen SH, et al. SHEA and IDSA Guidelines.
Infect Control Hosp Epidemiol 2010 31
34
Flexible sigmoidoscopy and colonoscopy

• Sensitivity for colonoscopy is 51
• The disease may be limited to the right colon
• Pseudomembranes are almost pathognomonic for C.
  difficile

Bartlett J, et al. Clin Infect Dis 2008 46S12
35
Radiologic studies

• Plain X rays
• Bowel wall thickening
• Loss of haustral markings
• Ileus or toxic megacolon
• CT scans
• Colonic-wall thickening
• Pericolonic stranding, ascites, pleural effusions

Bartlett J, et al. Clin Infect Dis 2008 46S12
36
C. difficile odor

• Some nurses believe they can recognize a
  characteristic odor
• In two small studies nurses predicted the
  presence of C. difficile (sensitivity 55-84
  specificity 77-83)
• Ongoing research is looking for volatile organic
  compounds in feces that could be used for
  diagnosis

Johansen A, et al. Age Ageing 2002 31487.
Marinella M, et al. Clin Infect Dis 2007
441142. Garner CE, et al. FASEB J 2007 211675
37
Case 1, continued

• The patients is admitted to the hospital and
  started on IV fluids
• The C. difficile toxin EIA comes back positive
• Amoxicillin/clavulanate is discontinued
• He is placed on contact precautions (gloves,
  gowns)

38
Which of the following infection control
interventions/s are also appropriate?

1. Alcohol based hand sanitizer after leaving the
   room
2. Wash hands with soap and water after leaving the
   room
3. Document a negative test prior to discharge if
   the patient is going to a nursing home
4. Special room cleaning after the patient is
   discharged (i.e. bleach)
5. B D
6. A C D

39
Infection control

• Contact precautions
• Gloves, gowns, wash hands with soap and water
• Chlorhexidine, isopropyl alcohol, and ethanol are
  inactive against spores
• Healthcare workers commonly carry C. difficile on
  the hands, clothing, and stethoscopes
• Little health risk, colonization in stool lt2
• Special room cleaning (bleach)

McFarland LV, et al. N Engl J Med 1989 320204.
Valiquette L, et al. Clin Infect Dis 2007 45
Suppl 2S112. Riggs MM, et al. Clin Infect Dis
2007 45992
40
You stop amoxicillin/clavulanate, what else would
you do for this patient?

1. Oral metronidazole 500 mg tid
2. Oral vancomycin 125 mg qid
3. Oral nitazoxanide
4. Oral cholestyramine

41
Treatment of C. difficile infection

• Discontinue the inciting antimicrobial when
  possible
• If this is not possible, consider using an agent
  that is less likely to promote CDI
• Fluid management
• Avoid antiperistaltic and opiate agents?
• Randomized pilot study in progress

Koo HL, et al. Clin Infect Dis 2009 48598
42
Metronidazole vs. vancomycin

• Similar efficacy in studies done in the 80s
• Metronidazole 250 mg qid or 500 mg tid vs.
  vancomycin 125 mg qid
• Metronidazole was favored in the past (cost, VRE)
• Decreased efficacy of metronidazole in recent
  years
• Responses to metronidazole around 75 vs. 95
  seen in the 1980s

Mogg GA, et al. Scand J Infect Dis Suppl
1980 (Suppl 22)41. Teasley DG, et al. Lancet
1983 21043. Wenisch C, et al. Clin Infect Dis
1996 22813. Gerding DN, et al. Clin Infect Dis
2008 46S32
43
Metronidazole vs. vancomycin

• In patients with severe disease vancomycin was
  superior in two recent randomized studies
• 97 vs. 76 (plt0.05) and 85 vs. 65 (plt0.05)
• Both antibiotics were similar in those with mild
  disease
• Another study found that vancomycin was superior
  until 2002, when the NAP1 emerged, since then the
  outcomes were similar

Zar FA, et al. Clin Infect Dis 2007 45302.
Louie TJ, et al. ICAAC 2007 K425A. Pepin J, et
al. Am J Gastroenterol 2007 1022781
44
Other available and investigational agents

• Teicoplanin
• Fusidic acid
• Rifaximin
• Bacitracin
• Nitazoxanide
• Rifampin
• Probiotics

• Tolevamer
• Ramoplanin
• Rifalazil
• Fidaxomicin
• Monoclonal antibodies against toxins A and B

Louie TJ, et al. ICAAC 2005. Fulco P, et al.
Expert Rev Anti Infect Ther 2006 4939.
www.clinicaltrials.gov. Lowy I, et al. N Engl J
Med 2010 362197
45
Monitoring response

• Follow closely
• Number of stools
• WBC count
• Temperature, abdominal examination
• Symptomatic improvement commonly seen by day 1-2
• Mean time to diarrhea resolution is 36 days
• Testing for C. difficile or its toxins as a test
  of cure is not recommended

46
Case 1, continued

• The patient receives metronidazole 500 mg PO tid
• No improvement after 3 days, metronidazole is
  given IV
• Worsening abdominal distention and requires NG
  tube
• WBC increases to 22000, creatinine 2.1, lactate
  2.4 mmol/L, albumin 1.9 mg/dL

47
What other interventions would you consider at
this time?

1. Consult surgery for possible need for colectomy
2. Add vancomycin enemas
3. Add IV vancomycin
4. A B
5. A B C

48
Classification of severity of C. difficile
infection

• SHEA and IDSA Guidelines
• Severe disease
• WBCgt15000 or increase in creatinine gt50
• Severe complicated disease
• As above plus hypotension, ileus, toxic
  megacolon, perforation, need for colectomy or ICU
  admission
• Other scores have been proposed, none has been
  universally accepted

Cohen SH, et al. SHEA and IDSA Guidelines.
Infect Control Hosp Epidemiol 2010 31
49
Management of severe disease

• High dose vancomycin (PO or NG, 500 mg qid)
  and/or IV metronidazole (500-750 mg tid)
• In the presence of ileus use intraluminal
  vancomycin
• Long catheter in the small intestine
• Direct intracolonic instillation
• Vancomycin retention enemas (500 mg in 100 cc of
  NS via rectal Foley catheter qid)
• Combination of these approaches is commonly used

Pasic M, et al. N Engl J Med 1993 329583.
Olson MM, et al. Infect Control Hosp Epidemiol
1994 15371.
50
Other interventions to consider in severe disease

• Colectomy
• A case series suggested decreased mortality
• More beneficial age gt 65, immunocompetent, WBC
  gt20000, or lactate 2.2-4.9
• IVIG
• Some experts recommend it
• A retrospective study found no benefit
• Stool transplantation
• A few case reports with good response

Lamontagne F, et al. Ann Surg 2007 245267.
Cohen SH, et al. SHEA and IDSA Guidelines.
Infect Control Hosp Epidemiol 2010 31. Juang P,
et al. Am J Infect Control 2007 35131. You DM,
et al. Ann Intern Med 2008 148632
51
Treatment of C. difficile infection
Cohen SH, et al. SHEA and IDSA Guidelines.
Infect Control Hosp Epidemiol 2010 31
52
Case 1, continued

• NG and rectal vancomycin are added
• Progressive abdominal distention, lactate
  increases to 3, goes to OR for colectomy
• The patient develops multiorgan failure and
  expires 5 days after surgery

53
Case 2

• 52 yo man with AIDS on HAART, CD4 104, VLlt50
• Diagnosed with Pseudomonas UTI
• Two weeks after treatment with cefepime he
  develops C. difficile infection, treated with
  metronidazole
• After stopping metronidazole he has a relapse,
  treated with metronidazole again, relapses 3
  weeks later

54
How would you manage this patient?

1. Metronidazole for 2 more weeks
2. Check isolate for metronidazole resistance
3. Use oral vancomycin
4. Offer fecal transplant
5. Use probiotics (Saccharomycis boulardi)

55
Recurrences of C. difficile infection

• Rates are similar for metronidazole and
  vancomycin
• 1535 of patients, 33-65 of those with gt2
  previous episodes
• For the first recurrence treat with the same drug
  
• If the first episode was severe use vancomycin
• Do not use metronidazole beyond first recurrence
  (after 2 weeks risk of neuropathy increases)

Pepin J, et al. Clin Infect Dis 2006 42765.
Louie TJ, et al. ICAAC 2007 K425A. Cohen SH, et
al. SHEA and IDSA Guidelines. Infect Control
Hosp Epidemiol 2010 31
56
Strategies for multiple episodes of recurrent
disease

• Tapering doses of vancomycin after usual
  treatment
• 1 week of 125 mg qid
• 125 bid during week 2
• 125 qd during week 3
• 125 qod during week 4
• 125 mg every 3 d during weeks 56

Tedesco FJ, et al. Am J Gastroenterol 1985
80867. McFarland LV, et al. Am J Gastroenterol
2002 971769
57
Strategies for multiple episodes of recurrent
disease

• Vancomycin followed by 2 weeks of rifaximin
• 7/ 8 patients remained symptom free
• IVIG
• 300-500 mg/Kg
• Responses in 43-66 (small studies)
• Toxin binders
• Bile acid binding resins they bind vancomycin
• Tolevamer

Johnson S. Clin Infect Dis 2007 44846.
McPherson S. Dis Colon Rectum 2006 49640.
Wilcox MH. J Antimicrob Chemother 2004 53882.
Kunimoto D. Digestion 1986 33225. Moggs GA. Br
J Surg 1982 69137. Galang M. Clin Infect Dis
2007 44846. Louie TJ. ICAAC 2007 K425A
58
Probiotics in recurrent disease

• S. boulardii is the best studied
• 2 randomized studies found lower rates of relapse
• After vancomycin 500 qid for 10 days, 28 days of
  S. boulardii vs. placebo, relapse in 17 vs. 50
• Meta-analysis and systematic reviews have not
  found enough evidence to support their use
• Risks
• Bacteremia and fungemia in debilitated patients
• Increased mortality in severe pancreatitis

McFarland, JAMA 1994 272518. Surawicz, Am J
Gastroenterol 1989 841285. Surawicz, Clin
Infect Dis 2000 311012. Pillai A, Cochrane
Database Syst Rev 2008 1CD004611. Dendukuri,
CMAJ 2005 173167. Besselink, Lancet 2008
371634. Salminen, Clin Infect Dis 2006 42e35.
Cassone, J Clin Microbiol 2003 415340.
Enache-Angoulvant, Clin Infect Dis 2005 411559
59
Case 2

• He receives vancomycin and probiotics
• Two weeks after stopping vancomycin he relapses
  again, tries tapering doses of vancomycin but has
  another relapse
• So is it now the time for fecal transplant?

60
Stool transplantation in recurrent disease

• Infusion of feces obtained from healthy hosts
• Per NG tube, EGD, colonoscopy, or retention
  enemas
• Case series have reported excellent results
• One series 15/16 patients
• Need to screen for infections in the donor
• Processing the sample
• Same day
• Need a blender, NS, and paper coffee filter

Borody TJ, et al. Am J Gastroenterol 2000
953028. Aas J, et al. Clin Infect Dis 2003
36580
61
Preparation of donor stool
Aas J, et al. Clin Infect Dis 2003 36580
62
Case 2, continued

• His mother donated a sample
• No relapses at 18 months of follow up

63
Conclusions

• In recent years C. difficile infection has
  increased in frequency and severity
• New associations, community-acquired cases
• Approach to diagnosis may change in the near
  future
• Vancomycin is preferred for severe disease,
  metronidazole appears to be similar in non-severe
  cases
• Consider alternative routes of administration in
  severe disease, consider colectomy
• Recurrent disease is common, no standard approach