Treating Clostridium difficile infection (CDI) the second time around

(1)

Treating Clostridium difficile

infection (CDI)

the second time around

Ciarán P. Kelly, MD

Professor of Medicine

Harvard Medical School

.

(2)

The “difficult” Clostridium

Objectives:

• CDI - More difficult than ever

• Who gets recurrent CDI?

• How do we manage recurrent CDI?

• What’s new in CDI therapy?

(3)

Difficulties with CDI

–

Increasing disease incidence

–

Increasing disease severity

–

Low cure rate (<70%)

– 10% of patients don’t respond to 10-14 days of treatment

– 4% of patients die from CDI

– 25% have recurrence

(4)

Antibiotic therapy

Disturbed colonic microflora

(loss of colonization resistance)

C. difficile exposure & colonization

Toxin A & Toxin B Diarrhea & colitis

Pathogenesis of Clostridium difficile

infection (CDI)

(5)

C. difficile toxin-induced

Pseudomembranous colitis

C. difficile toxins induce a marked acute

(6)

Antimicrobials Predisposing to CDI

Very Commonly Related Less Commonly Related Uncommonly Related Clindamycin Ampicillin Amoxicillin Cephalosporins Fluoroquinolones Other penicillins Sulfonamides Trimethoprim Cotrimoxazole Macrolides Aminoglycosides Bacitracin Metronidazole Teicoplanin Rifampin Chloramphenicol Tetracyclines Carbapenems Daptomycin Tigecycline Bouza E, et al. Med Clin North Am. 2006;90:1141-1163.

(7)

CDI case 28 (10%) CDI case 28 (10%) 271 enrolled 271 enrolled Hospital-acquired 47 (17%) Hospital-acquired 47 (17%) Colonized at Admission 37 (14%) Colonized at Admission 37 (14%) CDI case 19 (7%) CDI case 19 (7%) Carrier 19 (7%) Carrier 19 (7%) Carrier 18 (7%) Carrier 18 (7%)

Nosocomial C. difficile infection

& asymptomatic carriage are common

Hospital patients (Acute medical ward)

LOS > 2 days Receiving antibiotic

Hospital patients (Acute medical ward)

LOS > 2 days Receiving antibiotic

Kyne et al N Engl J Med 2000;342:390

Colonized by C. difficile 84 (31%) Colonized by C. difficile 84 (31%)

(8)

Asymptomatic carriers of C. difficile

have high serum IgG anti-toxin A

Adm ission Colon izatio n Disc harg e Ig G a n ti -t o x in A 0.5 1.0 1.5 2.0 2.5 Cases Non-colonized Carriers 3 day s afte r C olon izatio n Adm ission Colon izatio n Disc harg e Ig G a n ti -t o x in A 0.5 1.0 1.5 2.0 2.5 Cases Non-colonized Carriers 3 day s afte r C olon izatio n P=0.06 P=0.002 P=0.001 P=0.005

(9)

McDonald LC, et al. Emerg Infect Dis. 2006;12:409-415, and unpublished CDC data.

Rates of CDI Tripled in US Hospitals

between 2000 and 2005

0 20 40 60 80 100 120 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 Year D is c h a rg e s p e r 1 0 0 ,0 0 0 p o p u la ti o n x x x x x x x x x x Any diagnosis Primary diagnosis x ~x2 ~x3

(10)

C. difficile-related deaths

have increased in the US

Redelings et al. Emerg Infect Dis. 2007;13:1417-1419.

416% increase from 1999 to 2004 In 2004 CDI-related deaths:

××××4 those attributed to MRSA infection

××××6 those attributed to all other intestinal IDs combined

5.7 7.3 8.2 12.2 16.1 23.7 0 5 10 15 20 25 1999 2000 2001 2002 2003 2004

(11)

Clostridium difficile

Deaths increase in 2005

C. difficile-Related Deaths

Are Also Increasing in the UK

MRSA=methicillin-resistant Staphylococcus aureus.

Death certificates mentioning C. difficile and recording C. difficile as the underlying cause of death (England and Wales). Source: UK Office of National Statistics.

Redelings et al. Emerg Infect Dis. 2007;13:1417-1419.

UK deaths 2006:

• CDAD – 6,480 • MRSA – 1,652 UK death certifications

US deaths (age adjusted): 1999 – 5.7 per million

(12)

2003 vs 2002: x 4 CDI cases x 20 CDI deaths > 80% NAP1 strain >64 yr

Total

<17 yr 18-64 yr

CDI outbreak in Estrie

(Quebec)

(13)

Epidemic Strain

• Strain typed BI/NAP1/027

1,2

• Is highly resistant to fluoroquinolones

2,4

• Binary toxin genes are present

• Produces large quantities of toxins A and B

1,3

• Has a tcdC gene deletion

1

1. Warny M, et al. Lancet. 2005;366:1079-1084. 2. Hubert B, et al. Clin Infect Dis. 2007;44:238-244. 3. CDC Fact Sheet. July 2005.

4. McDonald LC, et al. N Engl J Med. 2005;353:2433-2441.

Adapted from McDonald LC, et al. N Engl J Med. 2005;353:2433-2441; with permission.

(14)

Recurrent C. difficile diarrhea

Common (~25% of treated patients) Mechanisms of recurrence:

NOT due to resistance to metronidazole or vancomycin

Metronidazole or vancomycin therapy

perpetuate loss of colonization resistance

Either:

“Relapse” - Persisting infection

“Re-infection” - New inoculum

different strain in ~50% of recurrent CDAD cases

(15)

Recurrent C. difficile diarrhea

(contd)

Risk factors:

Age > 65 years

Severe underlying illness

Concommitant antibiotic use

Prior recurrent CDAD

~ 20% risk after first CDAD episode ~ 40% risk after first recurrence

> 60% risk after 2 or more recurrences

Lack of protective immunity

(16)

Risk factors:

Age > 65 years = 1 point

Severe illness

(Horn’s Index) = 1 point

Concommitant

antibiotic use = 1 point

Score Recurrent CDI

in validation cohort

0 0%

1 17%

2 31%

3 67%

Prospective derivation and validation of a clinical prediction rule for recurrent C. difficile infection

Gastroenterology 2009;136:1206-14

Hu MY, Katchar K, Kyne L, Maroo S, Tummala S, Dreisbach V, Xu H, Leffler DA, Kelly CP.

(17)

Concomitant antibiotics (CAs) to treat other infections in 59% of patients during CDI treatment.

Lower initial response rate with CAs

86.1% with CAs vs 98.4% without (P=<.001) Higher recurrence rate with CAs

23.9% with CAs vs 8.1% without (P=<.001) Lower “global cure” rate with CAs

59.8% with CAs vs 90.3% without (P=<.001).

AGA Institute Late-Breaking Abstract Session: May 4, 2010, 2:15 PM

Randomized Clinical Trial (RCT) in Clostridium difficile Infection (CDI) Confirms Superiority of

Fidaxomicin over Vancomycin

(18)

Treatment of First Episode of CDI

• Mild CDI

– Discontinue other antibacterial agents if possible – Request stool testing

– Monitor course of disease

• Moderate or persisting CDI

(or patients who must

continue antibacterial therapy)

As for mild plus:

– Oral metronidazole

• 500 mg TID for 10–14 days or

• 250 mg QID for 10–14 days

Gerding DN, et al. Infect Control Hosp Epidemiol. 1995;16:459-477. Poutanen SM, Simor AE. Can Med Assoc J. 2004;171:51-58.

(19)

Vancomycin is more effective than

metronidazole in treating severe CDI

≥ 2 points = SEVERE 1 point: Age: > 60 years Temp: > 101°F [38.3°C] Albumin: < 2.5 mg/dL WBC > 15,000 cells/mm3 2 points: PMC at colonoscopy ICU patient

Zar et al. Clin Infect Dis 2007;45:302-7

98% 90% 97% 76% 50% 60% 70% 80% 90% 100% Mild / Moderate Severe Vancomycin Metronidazole Response P=0.4 P=0.02 Prospective, RCT (172 enrolled, 150 completed) Vancomycin 125 mg QID x 10d vs Metronidazole 250 mg QID x 10d Stratified for disease severity

(20)

Management of Severe CDI

• Early recognition

– Initiate therapy as soon as diagnosis is suspected

• Oral vancomycin (125 mg QID for 10 to 14 days) as initial

treatment

• If patient is unable to tolerate oral medication – iv metronidazole

– consider intracolonic vancomycin instillation (by enema)

• 0.5–1 g vancomycin (IV formulation) in 100 – 200 mL normal saline via rectal (or Foley) catheter

• Clamp for 60 minutes

• Repeat every 4–12 hours

Gerding DN, et al. Infect Control Hosp Epidemiol. 1995;16:459-477. Zar FA, et al. Clin Infect Dis. 2007;45:302-307. Louie T, et al. 47th Annual ICAAC Meeting, 2007, Abstract k-425-a. Apisarnthanarak A, et al. Clin Infect Dis. 2002;35:690-696.

(21)

Markers of Severe CDI

• Severe diarrhea (> 10 BM/day)

• Marked leukocytosis

– >15,000 assoc. severe CDI

– >25,000 assoc. increased fatality

• Rising serum creatinine • Falling serum albumin

• Colonic thickening on CT scan • Ascites on CT scan

• Pseudomembranes on endoscopy • Hemodynamic instability

• Severe abdominal distension, pain

Zar et al. Clin Infect Dis 2007

(22)

Colonic distension and small bowel ileus

in fulminant Clostridium difficile colitis

Severe / fulminant CDI may

present as an acute abdomen and/or mimic acute colonic

pseudo-obstruction

Abdominal pain & distension

• Little or no diarrhea

(23)

Sigmoidoscopic appearance of

severe CDI with PMC

Immediate bedside diagnosis in severe, complicated CDI

Guides surgical management

Perforation rare - death usually results from SIDS

(24)

Management of fulminant or refractory CDI

• Vancomycin 500 mg qid po • If ileus: – Metronidazole 500 mg iv tid plus – Vancomycin 500 mg qid via n/g tube or by enema

• If progressive or refractory:

– Early surgery evaluation/consultation

– Consider IVIG 400 mg/kg

– Monitor for progression

• WBC > 20,000

• Creatinine >1.5 baseline • Rising lactate (5.0)

(25)

An approach to treating

recurrent CDI

• First recurrence:

- Treat based on disease severity

- Metronidazole or Vancomycin x10-14 days

• Second recurrence:

– Oral vancomycin taper & pulsed dosing

(26)

Treatment of Multiple Recurrent CDAD

Non-randomized study*

* Placebo/antibiotic cohort from 2 clinical trials of Saccharomyces boulardii as adjunctive treatment.

† _{Includes vancomycin and rifampin (n=3) and vancomycin and metronidazole (n=3).} ‡ _{Includes high dose (2 g/day), taper, or pulse dosing.}

McFarland LV, et al. Am J Gastroenterol. 2002:97:1769-1775.

Vancomycin N Recurrence, n (%) P-Value

Medium dose (1g to <2 g/day) 14 10 (71) Low dose (<1 g/day) 48 26 (54) High dose (≥ 2 g/day) 21 9 (43)

Tapering dose 29 9 (31) 0.01

Pulse dosing 7 1 (14) 0.02

Other † 6 2 (33) All 125 57 (46)

Metronidazole N Recurrence, n (%)

Low dose (≤ 1 g/day) 29 13 (45) Medium dose (1.5 g/day) 5 2 (40) Other ‡ 4 1 (25)

All 38 16 (42)

(27)

An approach to treating recurrent CDI

• First recurrence:

- Metronidazole or Vancomycin x10-14 days

• Second recurrence:

– Oral vancomycin taper & pulsed dosing

• Third recurrence

– Vancomycin 125 mg qid for 14 days followed by Rifaximin 400 mg twice daily for 14 days

• Subsequent recurrences

– Intravenous immunoglobulin (IVIG) (400 mg/kg & repeat after 3 weeks)

– Vancomycin plus Probiotic?

• Lactobacillus spp, Saccharomyces boulardii • Fecal transplantation / bacteriotherapy

Kelly NEJM 2008

Rx Vancomycin Taper & Pulsed dosing: Week 1 125 mg qid Week 2 125 mg bid Week 3 125 mg daily Week 4 125 mg qod Week 5-6 125 mg q3d

(28)

New treatment approaches for

Recurrent C. difficile associated diarrhea

Antibiotic therapy C. difficile colonization Toxin production Diarrhea Recurrent diarrhea Probiotics Probiotics

(29)

S. boulardii for prevention of CDI:

Inconsistent study results

A. McFarland. JAMA. 1994;271:1913-8.

B. Surawicz et al. Clin Infect Dis. 2000;31:1012-7.

24% _19% 65% 35% 47% 44% 0% 20% 40% 60% 80% 100% 1st episode CDI (A) Recurrent CDI (A) Recurrent CDI (B) Placebo S. boulardii P=0.04 P=0.04

Sb

500 mg bid x 4 weeks

(30)

New treatment approaches for

Recurrent C. difficile associated diarrhea

Antibiotic therapy C. difficile colonization Toxin production Diarrhea Recurrent diarrhea Probiotics Probiotics Antibiotics Antibiotics

(31)

8% 10% 13% 24% 0% 10% 20% 30% Treatment Failure Recurrence Fidaxomicin Vanco P = NS P = 0.004

Fidaxomicin in CDI

Minimal absorption from human GI tract

“Selective” anti-C. difficile antibiotic

Preserves colonization resistance??

629 adults with CDI treated for 10 days with: 200 mg OPT-80 bid 78% “Cured” * 125 mg vancomycin qid 67% “Cured” * * P=0.006 * P=0.006

(32)

New treatment approaches for

Recurrent C. difficile associated diarrhea

Antibiotic therapy C. difficile colonization Toxin production Diarrhea Recurrent diarrhea Probiotics Probiotics Toxin binder Toxin binder Antibiotics Antibiotics

(33)

High serum IgG anti-toxin A levels are associated

with a lower risk for recurrent C. difficile diarrhea

Serum IgG anti-toxin A Day 12 <0.48 0.48-0.73 0.74-1.28 >1.28 R e c u rr e n t C . d if fi c il e d ia rr h e a ( % ) 0 25 50 75 100

Serum IgG anti-toxin A Day 12 <0.48 0.48-0.73 0.74-1.28 >1.28 R e c u rr e n t C . d if fi c il e d ia rr h e a ( % ) 0 25 50 75 100 For a level < 1.29 Odds ratio = 48 (95% CI, 3.5 - 663) For a level < 1.29 Odds ratio = 48 (95% CI, 3.5 - 663)

(34)

New treatment approaches for

Recurrent C. difficile associated diarrhea

Antibiotic therapy C. difficile colonization Toxin production Diarrhea Recurrent diarrhea Protection Anti-toxin immune response memory primary Active Immunization: Toxoid vaccine Active Immunization: Toxoid vaccine Passive: IVIG, HuMAbs, Hyperimmune globulin Passive: IVIG, HuMAbs, Hyperimmune globulin Probiotics Probiotics Toxin binder Toxin binder Antibiotics Antibiotics

(35)

Intravenous immunoglobulin therapy

for recurrent C. difficile diarrhea

Adult Pediatric Pre-IVIG Post-IVIG

Healthy controls Children with recurrent

C. difficile diarrhea S e ru m Ig G a n ti -t o x in A (O p ti c a l D e n s it y u n it s ) 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 P = 0.03 P = 0.01

Leung DY, Kelly CP et al J Pediatr 1993

(36)

25% 7%

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(37)

A C. difficile Toxoid Vaccine (Toxoids A and B)

Induces High Serum IgG Anti-Toxin A Response

Aboudola S, et al. Infect Immun. 2003;71:1608-1610.

(38)

Take home:

C. difficile: more difficult than ever

More prevalent

More severe (↑morbidity & ↑mortality)

NAP-1 “epidemic” strain widely prevalent in US

CDI management is changing:

Vancomycin 1st _{line for severe CDI}

& possibly for multiple recurrent CDI (taper / pulse)

New antibiotic and non-antibiotic

(39)