BETH ISRAEL DEACONESSMEDICAL CENTER

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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