Clostridium difficile:

Whats new?

Michael Edmond, MD, MPH, MPA

Richard P. Wenzel Professor of Internal Medicine Chair, Division of Infectious Diseases Hospital Epidemiologist

Clostridium difficile
Gram-positive rod Anaerobe Spore-forming
Antibiotics have no activity against C. difficile spores

Toxin-producing Transmission typically occurs via the oral-fecal route

Evolving Epidemiology of CDI

2-4 fold increase in incidence over the past decade Increasing incidence of community-acquired cases (up to 30% of cases) New risk groups (peripartum women, children) Increased morbidity & mortality of CDI due to emergence of a hypervirulent strains

LoVecchio A, Zacur GM. Curr Opinion Gastroenterol 2012;28:1-9.

Number of papers published

CDI Terminology
Hospitalization 48 h CO-HCFA HO-HCFA <4 weeks CO-HCFA 4-12 weeks Indeterminate >12 weeks CA-CDI

CO = community onset HO = healthcare facility onset CA = community associated HCFA = healthcare facility associated

Cohen SH. SHEA/IDSA Guideline. Infect Control Hosp Epidemiol 2010;31:431=455.

Source of C. difficile infection

Active surveillance study in Monroe County, NY over a 6-month period in 2008; 366 cases identified

Dumyati G et al. Emerg Infect Dis 2012;18:392-400.

Risk factors for CDI

Advanced age Duration of hospitalization Exposure to antibiotics (higher risk with longer exposure & multiple antibiotics) Cancer chemotherapy HIV Inflammatory bowel disease Malnutrition Solid organ & bone marrow transplantation Previous GI surgery Tube feeding H2 blockers, PPIs
LoVecchio A, Zacur GM. Curr Opinion Gastroenterol 2012;28:1-9.

Epidemiology of CDI
15-year (1991-2005), population-based study of CDI in Olmstead County, MN Community-acquired (n=157) Age, median Female gender Antibiotic exposure H2B/PPI Cancer Recurrent CDI 50 76% 78% 22% 17% 28% Healthcare facility acquired (n=192) 72 60% 94% 47% 32% 30%

P <0.001 0.002 <0.001 <0.001 <0.0001 0.66

Khanna S. Am J Gastroenterol 2012;107:89-95.

Economic burden of CDI

Median cost per case US Total Direct costs Indirect costs Total costs $9,000 - $12,000 $1,000 - $7,000 $13,000 - $16,000 $500 million $300 million $800 million

McGlone SM. Clin Microbiol Infect 2012;18:282-289.

PPIs & CDI

Meta-analysis of 30 studies
5 cohort studies 25 case-control studies PPIs associated with increased risk of CDI (OR 2.15, CI95 1.81-2.55)

Deshpande A. Clin Gastroenter Hepatol 2011; epub ahead of print.

Gastric acid suppression & CDI

5-year retrospective study of 101,796 patients at an academic medical center Adjusted for comorbid conditions, age, antibiotics Adjusted OR

Howell MD. Arch Intern Med 2010;170:784-790.

Statins & CDI

Case control study of 24,551 cases of CDI with treatment started after day 5 of hospital admission at 234 US hospitals 5 controls matched on age, hospital, year/quarter and must have been in the hospital for >8 days Controlled for age, race, gender, Charlson comorbidity score, PPI use, antibiotic use Hospitalized patients on statins were 22% less likely to develop CDI (adjusted OR 0.78, CI 95 0.76-0.84)

Motzkus-Feagans CA et al. Gut 2012 (epub ahead of print)

NAP1/BI/027 Strain
New strain of C. difficile that emerged over the last decade More virulent than other strains
Excessive toxin production Increased sporulation Production of binary toxins associated with severe diarrhea

Dissemination promoted by high use of quinolones, since this strain is resistant

Household transmission of CDI

Population-based study of all cases of CDI in Quebec over 12 years (1998-2009) 2,222 index cases of CDI 8 secondary cases in households (0.4%) Interval between onset of symptoms in the index case & secondary case:
Range: 1 50 days Mean: 17 days Median: 13 days

Pepin J. J Infect 2012; epub ahead of print.

Intestinal microbiome
Up to 100 trillion bacteria colonize the human gut, representing an estimated 200 to 1000 distinct bacterial species. Colonization resistance is the process by which the indigenous gut microbiota protects a host from infectious microbes. Recent genomic studies of the intestinal microbiota, both in human populations and mouse models, have revealed that antibiotics have unexpectedly widespread and enduring effects on endogenous gut microbes.

Wardwell LH. Curr Infect Dis Reports 2011;13:28-34.

Pathogenesis of CDI
Ingestion of spores Spores germinate Antibiotic administered Environmental contamination Asymptomatic carrier

Altered intestinal flora Protective immune response Toxin production No protective immune response

Bacteria & spores in feces

CD diarrhea

Clinical manifestations

Asymptomatic carriage

Moderate Mild, diarrhea selflimiting diarrhea

Pseudomembranous colitis

Bowel perforation

Septic shock

Death

7-50% in acute care hospitals 5-7% in longterm care

Clinical manifestations
Diarrhea may contain mucus or occult blood Hematochezia or melena are rare Fever Cramping abdominal pain Leukocytosis Severely ill patients may have ileus or toxic megacolon with minimal or no diarrhea

Risk factors for severe CDI

Age >70 years WBC >20,000/mL Albumin <2.5 g/L Creatinine >2.0 mg/dL Small bowel obstruction or ileus
Severe CDI was defined as any of the following: Death within 30 days Required ICU admission Required colectomy Intestinal perforation
Henrich TJ. Emerg Infect Dis 2009;15:415-22.

Risk factors for colectomy

Age >65 years Community onset Colectomy required in 1% of CDI cases

Kasper AM et al. Infect Control Hosp Epidemiol 2012;33:470-476.

Testing Principles
Testing should only be performed on unformed stool Do not patients that are asymptomatic For patients shown to be C. difficile positive, do not re-test during the same episode of diarrhea, and do not perform a test of cure

Cohen SH. SHEA/IDSA Guideline. Infect Control Hosp Epidemiol 2010;31:431=455.

Meta-analysis of PCR Utility

Deshpande A et al. Clin Infect Dis. 2011;53:e81-e90

Meta-analysis of PCR Utility

Deshpande A et al. Clin Infect Dis. 2011;53:e81-e90

Prevention & Treatment of CDI

Handwashing, gowns/gloves, cleaning Ingestion of spores Spores germinate Antibiotic administered Environmental contamination Asymptomatic carrier ASP Altered intestinal flora Protective immune response Probiotics, stool tx Toxin production Toxin binders CDI antibiotic treatment CD diarrhea No protective immune response

Bacteria & spores in feces

Treatment Principles
Discontinue treatment with the inciting antibiotic as soon as possible Avoid antiperistaltic drugs (may precipitate toxic megacolon) Use oral route when possible Consider colectomy for severely ill patients

Impact of other antibiotics on treatment of CDI

Analysis of 999 patients from the fidaxomicin vs. vancomycin trial Median time to resolution of diarrhea was 97 hours for those who received concomitant antibiotics during the treatment period vs. 54 hours for subjects receiving no concomitant antibiotics with treatment (P< .001.

Mullane KM. Clin Infect Dis 2011;53:440-447.

Antimicrobial Treatment Options

Vancomycin vs. Metronidazole

RCTs assessing initial clinical cure

84% 94% 91%

73% 94% 91%

Drekonja DM et al. Ann Intern Med 2011;155:839-847.

Vancomycin vs. Metronidazole

RCTs assessing initial clinical cure with subsequent recurrence

7% 17% 12%

14% 17% 5%

Drekonja D M et al. Ann Intern Med 2011;155:839-847.

Vancomycin vs. other drugs

RCTs assessing initial clinical cure

85% 74% 65% 86% 79% 75%

88% 77% 75% 76% 86% 11%

Drekonja D M et al. Ann Intern Med 2011;155:839-847.

2011 by American College of Physicians

Comparative Effectiveness of C. difficile treatments

Vancomycin, metronidazole & fidaxomicin are equally effective in initial cure rates for nonsevere disease Recurrence rate is common with all drugs, but less with fidaxomicin (when compared to vancomycin) Whether vancomycin results in better outcomes for patients with severe disease (when compared to vancomycin) remains unclear

Drekonja D M et al. Ann Intern Med 2011;155:839-847.

IDSA/SHEA Treatment Recommendations

CDI Initial episode, mild-moderate Initial episode, severe Initial episode, Severe & complicated Clinical data WBC < 15,000 Creatinine <1.5 x baseline WBC >15,000 Creatinine >1.5 x baseline Hypotension or shock, ileus, megacolon Treatment Metronidazole 500 mg po TID x 10-14 days Vancomycin 125 mg po QID x 10-14 days Vancomycin 500 mg po/NG QID + metronidaozle 500 mg IV TID; if complete ileus consider vancomycin PR Same as initial episode Vancomycin with taper &/or pulsed regimen

First recurrence Second recurrence

Cohen SH. SHEA/IDSA Guideline. Infect Control Hosp Epidemiol 2010;31:431-455.

Rifaxamin chaser
Has been used following vancomycin to prevent recurrent CDI in small case series Dose is 100-200 mg twice daily x 2 weeks Cost of 2 week course = $363

Recurrence of CDI
Occurs in 25% of cases Typically occurs due to regrowth of vegetative bacteria from spores that are resistant to antibiotics Usually occurs within 1-2 weeks of completing treatment Once recurrence develops, 45-65% may experience multiple recurrences Risk factors:
Age > 65 years Co-morbidities Previous recurrence Dialysis Hypervirulent strain

Fecal Microbiome in Recurrent CDI

In healthy people, vast majority of fecal bacteria are Bacteroidetes or Firmicutes Patients with recurrent CDI have decreased diversity in fecal microbiome

Chang JY. J Infect Dis 2008;197:435-438.

Stool Transplantation for CDI

Rationale:
The fundamental problem in CDI is not the presence of C. difficile per se, but the absence of healthy flora to keep the growth of C. difficile suppressed Goal of stool transplantation is to re-estsablish normal intestinal flora

Stool Transplantation: History

Used in veterinary medicine for centuries to treat ruminal acidosis & equine diarrhea First performed on humans in 1958 on 4 patients in Colorado with fulminant pseudomembranous colitis
At that time CDI was uncommon but mortality was 75% All 4 patients improved within hours & were discharged to home within days
Eiseman B. Surgery 1958;44:854-859.

Stool Transplantation: Indications

Recurrent or relapsing CDI
At least 3 episodes of mild-moderate CDI & failure of a 68 weeks taper of vancomycin At least 2 episodes of severe CDI resulting in hospitalization

Moderate CDI not responding to vancomycin for at least 1 week Severe (or fulminant) CDI with no response to standard therapy after 48 hours
Bakken JS. Clin Gastroenterol Hepatol 2011;9:1044-1049.

Stool Transplantation: Donor Selection

Exclusion criteria
HIV, HAV, HBV, HCV infection or exposure within 12 months High-risk sexual behavior Illicit drug use Tattoo or body piercing within 6 months Risk factors for variant Creutzfeldt-Jakob disease Travel to areas where diarrheal illnesses are endemic in last 6 months GI comorbid disease (IBD, IBS, chronic constipation, chronic diarrhea, GI malignancy/polyposis) Antibiotics within 3 months Immunosuppressants or chemotherapy drugs
Bakken JS. Clin Gastroenterol Hepatol 2011;9:1044-1049.

Stool Transplantation: Donor Testing

Stool tests C. difficile PCR Routine bacterial culture Giardia antigen Cryptosporidium antigen Ova and parasites (Acid fast stain for cyclospora, isospora) Serum tests HIV antiboddy HAV IgM HBsAg, anti-HBc HCV antibody RPR

Bakken JS. Clin Gastroenterol Hepatol 2011;9:1044-1049.

Stool Transplantation: Route of Administration Nasogastric tube Nasoduodenal tube Colonoscope Retention enema

Protocol for Stool Transplantation

Recipient is treated with vancomycin for 4 days prior to transplant but discontinues the night before Recipient is treated with a PPI the night before and morning of transplant 30 gm of fresh donor stool and 70 cc of water are placed in a blender to produce a slurry

Protocol for Stool Transplantation

Slurry is poured through a coffee filter and the resulting filtrate is passed through a second coffee filter NG tube is placed in the recipient and placement is confirmed by x-ray 25 cc of the fecal slurry is administered via the NG tube; the NG tube is flushed with 25 cc of water and the tube is immediately removed

Stool tranplantation: DIY instructions

Equipment needed: Normal saline (200 mL bottle) standard 2 quart enema bag kit (available drug stores) kitchen blender

Add 50 mL of stool (volume occupied by solid stool) from donor obtained immediately prior to administration (<30 minutes) to 200 mL normal saline in the blender. Mix in the blender until liquefied to milkshake consistency. Pour mixture (~250 mL) into the enema bag. Administer enema to patient using instructions provided with enema bag kit. Patient should hold the infusate as long as possible and lie still as long as possible on his or her left side so that the urge to defecate is prevented.

Silverman MS. Clin Gastroenterol Hepatol 2010; 8:471-473.

Stool Transplantation Outcomes

Symptoms typically resolve within 24-48 hours No adverse effects reported

Stool Transplantation for CDI: Published Results

Paper 1 2 3 4 Papers published after 5 4/15/11 6 7 TOTAL
1. 2. 3. 4. 5. 6.

N 317 70 26 43 27 32 77 592

Resolution Relapse 284 66 25 37 25 22 69 528 89% 15 37 6% 11 4 1 6

Review of 27 papers published prior to 4/15/11

Gough E. Clin Infect Dis 2011;53:994-1002. Mattila E. Gastroenterology 2011;142:490-496. Kelly CR. J Clin Gastroenterol 2011;46:145-149. Hamilton MJ. Am J Gastroenterol 2012 (epub ahead of print). Kassam Z. Arch Intern Med 2012;172:191-193. Jorup-Ronstrom C. Scand J Gastroenterol 2012 (epub ahead of print).

Changes in fecal microbiome with stool transplant

61 yo woman with >8 month h/o diarrhea due to C. difficile BMs every 15 minutes; wearing a diaper at all times; 59 pound weight loss Failed multiple courses of vancomycin, metronidazole, nitanoxazide, probiotics Underwent transplant of stool from husband 1st solid BM day +2 constipated within 1 month no recurrence of CDI at 6 months

Khoruts A. J Clin Gastroenterol 2010;44:354-360.

Follow our blog!

On the web: www.stopinfections.org OR On Facebook: hospital.infection OR On Twitter: @mike_edmond @eliowa