Microbiology
Gram Positive Rod
Anaerobic
Spore Former (tough to kill, good handwashing)
Toxin Producer
- Toxin A (enterotoxin) - causes inflammation of and fluid secretion into intestinal tract; neutrophil chemoattractant; stimulates cytokine release from monocytes
- Toxin B (cytotoxin) - Stimulates cytokine release from monocytes; causes systemic spread of inflammatory response
- Binary toxin (? function) - associated with more severe course
History of Pseudomembranous Enterocolitis
1950s – 1st descriptions
1974 – Abx-associated colitis recognized
1977 – C-diff recognized to cause colitis in lab
1978 – C-diff proved to be etiologic agent of Abx-associated colitis
Epidemiology Abx-Associated Diarrhea
Occurs in 3-29% of hospitalized pts on Abx, risk inc. with broad spectrum and longer duration
C-diff causes 10-25% of cases and 50-75% of Abx-associated Colitis cases
~100% of Pseudomembranous colitis cases are C-diff
10x (some say 20x) increase in C-diff colitis cases during last 10 yr, severity increasing
C-diff epidemic
Significant increase in C-diff occurrence - 26% increase from 2000-2001
Significant increase in severity of colitis - "B1 strain", produces binary toxin, 16x increased Toxin A, 23x increased Toxin B production, 2x increased mortality, association with fluoroquinolones
Pathogenesis
Contact C. diff. --> C. diff. in stool --> proliferation of C. diff in colon
Atbx exposure --> decreased normal colon flora --> proliferation of C. diff in colon
Immunosuppression --> proliferation of C. diff in colon
Immunosuppression --> dec anti-toxin antibodies --> increased A/B toxin production
Proliferation of C. diff. in colon --> increased toxin A/B production --> local inflammation and secretory diarrhea --> SIRS
(Interesting fact: 25-80% of infants have C diff in their stool, only a small number have problems, may be due to lack of toxin receptors in immature colon)
Antibiotics risks
Fluroquinolones more commonly cause, and clinda
25% secondary to periop abx (antibiotic stewardship)
Typically presents within 7 days of antibiotic exposure, can present out to 8 weeks
1-3 week hospitalization --> 15-45% C-Diff
Risk factors
Severe illness & ICU stay
GI surgery
Tube Feeding
PPIs
Older age
Prolonged hospitalization
Presentation
Watery diarrhea after antibiotics
Lower Abd colicky pain
Hematochezia
Fever, anorexia, nausea, malaise
Abd distension, Ileus - 20% of fulminant C. diff. cases present with ileus and no diarrhea
Polyarticular reactive arthritis can follow
Leukocytosis >30,000 - think C-diff, dead gut, or lymphoproliferative disorder (or UTI?)
Diagnosis
Stool studies
- C. Diff toxin (questionable if useful to get 2nd study)
Cell cytotoxicity assay 92.7 - 100% sensitive, 99-100% specific
Toxigenic culture - 96.4% sensitive, 99.1% specific
EIA for toxin A+B 66-96.2% sensitive, 93.5-100% specific
EIA for toxin A 65.4-88.3% sensitive, 93.5-100% specific
EIA for toxin A 65.4-88.3% sensitive, 65.4-100% specific
Real-time PCR 87-91.5% sensitive, 96-100% specific
-Fecal leukocytes (not helpful, but good to screen for other colitis)
Endoscopy
- Typically most pronounced in sigmoid colon
- Can segmentally involve any portion of colon (rare)
- Can rarely involve the small intestine (very rare)
- Colonoscopy – 90% sensitive
Toxin Assay – 90% sensitive (usually)
CT - ~ 100% sensitive, super non-specific
Medical Treatment
po Flagyl (500 mg po Q 8hr) - no longer first line with developing resistance
- In 1980s 90%+ response rate with <10% recurrance (better than vanco)
- More recently a 70% response rate with 33% recurrence (50% cure rate)
IV Flagyl (500 mg IV Q 6hr)
- Limited data suggests benefit with severe dz/ileus, no trials compare to PO
- Useful with ileus
po Vancomycin (125-500 mg po Q6hr) - drug of choice
- 80% cure rate in 1980s and 1990s
- Minimal absorption - therefore resistance issues less pertinent
- not secreted into GI tract if given IV
- Current drug of choice for moderate or severe cases
pr Vanco (500mg/100cc NS infuse at 1-3ml/min)
Fidaxomicin (Dificid, aka OPT-80)
- Macrocyclic antibiotic
- 8x more active in-vitro against c. diff. than Vanco
- minimal systemic absorption
- High fecal concentration
- Limited activity against normal gut flora
- Fidaxomicin vs. Vancomycin for C. Diff Infection. NEJM, Phase 3 MC (52 US, 15 Canada) Rand, Prosp, Placebo controlled Trial
629 C-diff cases included
Excluded fulminant & recurrent cases
Fidaxomicin 200 mg po Q12 x 10 days VS
- 88-92% clinical cure rate
- 13.3-15.4% recurrance rate
- 74.6-77.7% global cure rate
Vancomycin 125 mg po Q 6hr x 10 days
- 85.8-89.8% clinical cure rate
- 24.0-25.3% recurrance rate
- 64.1-67.1% global cure rate
Real benefit is in the recurrence rate
Nitanzoxanide
- anti-parasitic agent
- Blocks anaerobic metabolism pathways
- some success in treating refractory cases
- large, prospective, double blind study underway comparing with Vanco
Other Abx Cessation
- 15-23% of cases will resolve sponatneously with antibiotic cessation
- Continuation associated with refractriness
Avoidance of antiperistaltics
- Delay excretion of toxin
- Linked with development of toxic megacolon
Probiotics
- repopulation of non-pathogenic flora
- mixed results but appear to help minimize recurrence
- ? prophylactic role
- eg: saccharomyces boulardii (Florastor 250 mg po tid) or acidophilus with pectin 50 million units/capsule, 1 PO TID
- Can cause secondary infections
IV Ig (400 mg/kg IV/day x 3 days)
- pooled human immunoglobulin contains IgG to Toxins A and B
- Case reports and small series with apparent benefit, no prospective data
Toxin Binders
- cholestyramine and colestipol bind c. diff. toxins
- has not translated to clinical efficacy (has been abandoned)
- can bind Vancomycin
Steroids
- 1 anecdotal report suggested benefit with short course methylprednisone use
- not currently accepted as treatment
Developing Treatment Options
Monoclonal Ab to Toxin A
C-diff vaccine
Colonoscopic tube placement with Vanco instillation
Ileostomy with colonic Vanco lavage
Stool transfusion
- Colonoscopically-directed stool application
- NG administration of stool
- Unproven at this point, extreme
Treatment of Carriers - not indicated
Prevention
Barrier precautions
Hand washing
Antibiotic prudence;
Discontinuation of isolation: continue until treatment course completed (10-14 days) and stool normalized, f/u c. diff toxin assays not recommended as means of assessing clearance (can continue to shed toxin for several weeks after infection is cleared), colonscopy can be utilized to confirm clearance in difficult cases
Recurrent C-diff Colitis
10-20% of cases recur
Typical recurrence occurs within 1 week after discontinuation of treatment
Result of residual spores converting into vegetative form
Treat the same as initial cases
Some evidence of benefit from probiotics, pulsed/tapered doses of flagyl/vanco, IV Ig
Fulminant C-diff Colitis - “The rules of engagement have changed.”
C-diff Colitis + SIRS = Fulminant C-diff
3-8% develop, 30-90% Mortality
Independent predictors of mortality: WBC>30,000, immunosuppression, lactate >5, Age>75, need for pressors, organ failure
Systemic Inflammatory Response Syndrome (SIRS)
- 1.) no infectious focus
- 2.) Evidence of system if inflammation with 2 or more of the following: temp>38 or <35; HR>90; RR >20; PaCO2 < 32; WBC > 12,000, <4,000, or >10% bands on differential
Can result from acute pancreatitis, vasculitis, burns, trauma, etc…
Overall mortality: 7%
Fulminant C-diff Colitis
SIRS poorly responsive to initial resuscitation or requiring ongoing resuscitation
WBC > 20,000
Ileus
Severely thickened wall on CT
Factors leading to mortality:
- WBC count > 50,000/mm3; 18.6 (CI 3.7 to 94.7)
- Lactate > 5 mmol/L; 12.4 (CI 2.4 to 63.7)
- Immunosuppression; 7.9 (CI 1.7 to 24.3)
- Age > 74 years; 6.5 (CI 1.7 to 24.3)
- Vasopressor therapy of shock; 3.4 (1.3 to 8.7); 5.0 odds ratio (1.10 - 22.2)
- mental status changes 12.6 odds ratio (2.45-64.7)
- Length 1.4 (1.1-1.64)
Operative Management of Fulminant C-diff Colitis
Indications for Surgery in C-diff Colitis
- Peritonitis, Toxic Megacolon, Fulminant C-diff colitis
Total Colectomy with end Ileostomy & Hartman’s Pouch - leave drain to drain ascites from inflammation, prevent rectal stump blowout
Segmental Colectomy in rare instances
Improves survival unless WBC< 20
Key = operate prior to pressor requirements or organ failure
Sailhamer study Arch Surg 2009; 144:433-39
Patients managed in the surgical department have a higher rate of colectomy, lower mortality and lower mortality after colectomy than patients managed in non-surgical department