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BETH ISRAEL DEACONESSMEDICAL CENTER
HARVARD
MEDICAL
SCHOOL
Clostridium difficile 2013: More Difficult Than Ever
J. Thomas Lamont
Clostridium difficile
Aslam S, et al. Lancet Infect Dis. 2005;5:549-557.
Colored transmission electron micrograph of C difficile forming an endospore (red)
Spore-forming, anaerobic, gram-positive bacillus
The “Difficult” Clostridium
• Discovered by Hall and O’Toole in 1935 in stools of healthy newborns
• Gram positive toxin-producing bacillus,but harmless to infants
• Identified as cause of antibiotic associated colitis in 1977
• Now increasing in prevalence and severity worldwide
Pathogenesis of C. difficile diarrheaAntibiotic therapy
Reduces protective colonic flora
C. difficile spores ingested
Toxins released in lumen
Diarrhea& colitis
Pseudomembranous Colitis
“Super C diff”: Variant Strain
• Mutated txcD gene : increased toxins
• Expression of binary toxin
• Resistant to multiple antibiotics
• Increased fecal shedding of spores
• Increased severity, death, recurrence
• Associated with epidemicsNEJM : Dec 2005
Pathogenesis: Role of host immune response
• Infection elicits IgG and IgA response
• Antibodies directed at toxins
• High IgG antitoxin titer protective
• Vaccination in animals very protective
Serum IgG antitoxins appear during Infantile carrier state
Viscidi et al: J Inf Dis 1983
Are serum antitoxins protective?
The C. difficile Carrier State
Type Prevalence Possible Mechanism
Infants <1 yr 50-70 % Lack of toxin receptors
Hospitalized adults
14 % High titer serum antitoxin
Healthy adults < 1% Barrier function of microflora
A 76 yo man with resolving C difficile…
..Is on his last day of oral metronidazole therapy for C diff diarrhea . He has not had diarrhea for the last five days and states that he is back to normal. On the weekend his PCP ordered a stool assay for C diff toxins which returns positive. Which of these actions would you take now ?
1. Continue metro for 10 more days and re-test2. Switch to vanco for 10 days 3. Switch to Fidaxomycin for 10 days4. Finish metro and advise patient to call you if he
develops diarrhea
C diff carriage following successful Rx
Inf Control Hosp Epi Jan 2010
C diff Test Guidelines
• Best Bet: PCR, or screening test + PCR
• Test only unformed stools
• Do not perform a test of cure
• Correlate test results with clinical picture
• 60-70% of healthy infants will be pos at some time in year 1
Colonized byC. difficile84 (31%)
Hospital-acquired28 (10%)
Hospital patients(Acute medical ward)
LOS > 2 daysReceiving antibiotic
271 enrolled
Cases47 (17%)
Carriers37 (14%)
Hospital-acquired19 (7%)
Colonized on admission
19 (7%)
Colonized on admission
18 (7%)
Do serum antitoxins protect against C. difficile in hospital patients receiving
antibiotics ?
540 evaluated311 eligible
NEJM 2000;342:390
Serum IgG anti-toxin A levels are highin asymptomatic carriers of C. difficile
P=0.06 P=0.002 P=0.001 P=0.005
C. difficile Diarrhea: Pathogenesis
Antibiotic therapy
Reduced colonic barrier flora
C. difficile ingestion & colonization
Toxins released
Asymptomatic Diarrhea carriage & colitis
Effective anti-toxinresponse
Inadequate immuneresponse
Risk of C diff with Acid Suppression
Arch Int Med 2010;170:784
PPIs and Susceptibility to Enteric Infections
Can I ever take antibiotics again ?
A 65 yo woman had C difficile colitis after an oral fluoroquinilone which responded well to oral vancomycin with cessation of diarrhea after 5 days. She took a total of 14 days of vancomycin and now visits your office two months later. She has had no further diarrhea and feels well. She has two questions
Can I safely take antibiotics in the future or will I get C diff again ?
Which antibiotics are safe for me ?
Second episodes of C diff ?
• Second bout years later is very rare
• Antibodies acquired in infancy or after first bout are protective
• Choice of future antibiotics should be based on diagnosis and culture results
• Probiotic prophylaxis during antibiotic therapy may help
Recurrent C diff : a major problem
• Incidence 25-30% after succesful rx of first attack
• Recurrent diarrhea from 2 days to 6 weeks after stopping Met ,Vanc or Fidaxo
• Results from re-infection from spores in the environment before the barrier flora are reconstituted
• Multiple recurrences are common• Responds to repeat course of M,V,F
21
Comparative cure and recurrence rates
Cure Rates Recurrence Rates
1. Louie et al: MEJM, 2010; 2. Results of a phase III trial comparing tolevamer, vancomycin and metronidazole in patients with Clostridium difficile-associated diarrhea (CDAD), poster K-425a, p. 212. Abstr. 47th Intersci. Conf. Antimicrob. Agents Chemother. American Society for Microbiology, Washington, DC.
81.3%
72.0% 70%
90%
Metr
onidaz
ole2
Vancocin
2
27.1%
23.4%
0%
10%
20%
30%
Metr
onidaz
ole2
Vanco
cin2
88.2%
Fidaxomicin
1
Fidaxo
mici
n1
15.4%
85.8%
Vancocin
1
80%
25.3%
Vancocin
1
Recurrent C. difficile Diarrhea
Clostridium difficile diarrhea(n = 63)
22 (35%)Relapsed
19 (30%)Died
22 (35%)Single episode
10 / 22 (45%)Second relapse
Immune response to toxin A and protectionagainst C. difficile diarrhea and colitis
Adapted from N Engl J Med 2000;342:390 & Lancet 2001;357:189
Immune response to toxin A and protectionagainst C. difficile diarrhea and colitis
Adapted from N Engl J Med 2000;342:390 & Lancet 2001;357:189
Days after colonizationby Clostridium difficile
-3 1 3 6 9 12
Ser
um
Ig
G a
nti
-To
xin
A
1
2
3
Recurrent C. difficile diarrhea
Asymptomatic carriers
Single episode ofC. difficile diarrhea
The best treatment of C diff is to allow restoration
of the normal colonic flora
The problem :
It may take up to 12 weeks !
Strategies for Recurrent C. difficile
• 14 day repeat course of V or Fidaxo• Pulse-tapered 6 week course of Vanco • Probiotics are adjunctive not primary rx• Fidaxo (? as primary rx) to replace V,M• Boost Immunity with C diff antibody• Bacteriotherapy : stool transfer• Vaccination
Pulsed /tapered Vancomycin for Recurrent C. difficile
(Tedesco, 1985)
• Tapering course over six weeksWeek 1 125 mg qidWeek 2 125 mg bidWeek 3 125 mg dailyWeek 4 125 mg qodWeek 5-6 125 mg q3d
• Follow above with 4 weeks cholestyramine or probiotic
Placebon = 84
50 X109 CFUn = 85
100 X109 CFUn = 86
Antibiotic Diarrhea
44.1% 28.2%p = 0.02
15.5%p = 0.001
C. difficile Diarrhea
23.8% 9.4%p = 0.03
1.2 %p = 0.002
Am. J. Gastro 105: 1636, 2010
Protective Effects of Lactobacillus Probiotic
“My C diff won’t quit”
An 83 yo MD with severe CHF is awaitingaortic valve replacement for critical AS. Hehad severe C difficile infection 18 months agowhich required hospitalization. After successful initial rx he had three severe recurrences with fever and dehydration , all requiring hospitalization. His cardiac team have advised him that he cannot have his valve replaced until the C diff is cured. He is currently on a pulsed –tapered vanco regimen with probiotic coverage. He previously tried IVIG and rifaxamin. He refuses a stool transplant.
Chronic low dose vancocin for multiple relapsers
• Suitable for elderly patients with comorbidity or limited life span
• Failure of prior attempts to wean • Recurrences are life threatening• Not suitable for fecal transfer• 125 mg vanco daily or qod• Disadvantages: cost ,VRE, no trial
data
Severe or Fulminant C diff
• High mortality 25-35 % esp in elderly
• C diff can start mild and worsen if rx delayed or antidiarrheals given
• Prompt dx and rx critical here
• Evidence –based rx lacking
Markers of Severe Infection
• WBC > 15000; fever ; dehydration• Colonic thickening ,megacolon , ascites• Confluent pseudomembranes • Hemodynamic instability• Severe abdominal distension, pain• Elevated creatinine level• Decreased mental status
Management of Fulminant Colitis
• Oral Vancomycin 500 qid or Fidaxomicin 200 mg bid ( Dificid)
• IV Metronidazole 500 q8h• Vanco enema 500mg in 100 ml/saline• Sub Total Colectomy for Perforation or Megacolon• IVIG not recommended• Overall Mortality : 35 %
Shea Guideline: Inf Con Hosp Epi: May 2010
A 42 yo man had acute C diff infection …
..that recurred twice and finally responded to a tapered pulsed regimenof vanco followed by a two week course of S boulardii ( Florastor ).Two weeks after cessation of therapy he had recurrence of diarrhea and RLQ cramps with distention and gas. A C diff assay was negative times two. His symptoms worsened and he was started on vanco125 qid with improvement in his symptoms. After cessation of vanco he again developed mild diarrhea 3-4 X daily , frequent passage of clear mucus and tenesmus.
Colonoscopy and bxs are normal. Serum tTTG antibody was negative.
What would you recommend now ?
1. Stool assay for C diff2. EGD and bx3. UGI and SBFT4. Rx for IBS
Post-infectious IBS
• IBS : 10% relate onset to infection
• GI Infection: 3-30% followed by IBS
• Risk Factors :– Females, age <60– Severe infection, antibiotics– Preexisting IBS
Mimics of recurrent C diff
• Post-infectious IBS
• Collagenous or microscopic colitis
• Celiac disease triggered by infection
• IBD flare with C diff infection
“The vanco doesn’t work anymore"
• 71 yo female with multiple bouts of C diff now on Vanco 125 bid. Complains of 3-4 pasty stools per day and feeling poorly. Stool test pos for C diff toxins.
• Diarrhea while taking vanco is not due to bacterial resistance- it doesn’t exist !
• Clinical resistance occurs in patients with severe or fulminant disease
Control Of C diff in hospitals
1. Handwashing/vinyl gloves2. Spores rest. to ethanol3. Limit fluoroquinolone use4. Isolate active patients5. Role of PPIs not yet clear
Stool Transfer for Recurrent C.difficile
• Rationale: Normal flora, especially Bacteroides spp, inhibit C.difficile
• Stool donor: Healthy relative or family member who is stool pathogen free
• Stool suspension via NJ tube,enema or colonoscopy
• Success in open trials : cure in 144/159 pts
Am J Gastro 2000
Fecal Transfer via Nasojejunal Tube for Recurrent C difficile
Louie et al, NEJM 2011.
Fidaxomicin vs Vanco for acute C diff
noninferior
Fewer relapses with Fidaxomicin vs Vanco may relate to persistence of
Bacteroides fragilis
0
1
2
3
4
5
6
7
8
9
50 mg bidOPT-80
100 mg bidOPT-80
200 mg bidOPT-80
125 mg qidVancomycin
Me
an
log
10
CF
U p
er
gra
m f
ec
es
Day 0
Day 10
MABs to toxins A and B prevent recurrence ( NEJM Jan 21, 2010 )
Vaccination for C. difficile
C difficile :Take Home Points
• Incidence, severity and relapse rising
• Host immune response critical
• Vanco >Flagyl for severe disease
• Make sure its C diff
• Role of Fidaxomycin still unclear ($$$)
• Stool transfer when all else fails
• Vaccine development promising