C.

diff
Thursday, March 19, 2015 5:49 PM

EPIDEMIOLOGY:
G(+) bacillus, anaerobic, spore-forming, toxin-producing, NOT invasive
Some strains non-toxigenic -> therefore not pathogenic
2 Phases:
A) Spores (outside the colon)
resistant to heat, acid, antibiotics

B) Toxin (once in the colon)

Inactivate pathways involved in cytoskeleton structure and signal transduction
-> cell retraction + apoptosis (shallow ulceration)
Disrupt intercellular tight jxns

Toxin A (Enterotoxin) Toxin B (Cytotoxin)

Carbohydrate receptor binding region No receptors yet identified
--> Ab testing on ELISA
Activates neutrophils, causes inflam'n 10x more potent inflam'n causing

Host Defenses:
Antitoxin Ab vs toxin A
High titres in asymptomatic carriers
Colonization with non-toxigenic strains
Affords protection, occupies that niche to prevent superinfection
IL-8

J-Strain (clindamycin-resistant)
1990s, early outbreaks
NAP1/BI/ribotype 027 strain
Hypervirulent, Epidemic
Larger quantities of toxins A + B
Produces binary toxin (an additional toxin)
Fluoroquinolone use strongly correlated with emergence of this strain
Quebec outbreak (2003)
Increased toxic megacolon, colectomy
Health-care associated
Ribotype 078
Netherlands (2005)
Younger population, community acquired, also increased severity

TRANSMISSION:
Fecal-oral, ingestion of spores
Asymptomatic carriers
20% pts with negative admission Cx become infected during hospitalization
 Netherlands (2005)
Younger population, community acquired, also increased severity

TRANSMISSION:
Fecal-oral, ingestion of spores
Asymptomatic carriers
20% pts with negative admission Cx become infected during hospitalization

RISKS:
Reported severe dz in patients with NO risk factors
Peripartum, healthy, no hx ABx use, no hospitalization, etc.
?retail food products, domestic animals as emerging source
ALWAYS SUSPECT C. DIFF!!!

1) Antibiotics -- disrupt barrier fxn of normal colonic flora

FQ (esp NAP1), clindamycin, broad-PCNs, cephalosporins
RARE: aminoglycosides, tetracyclines, chloramphenicol, metronidazole, vanco
Risk up to 3 months after ABx
2) Hospitalization
3) Age >65 yo -- decreased immune response, higher comorbidities
4) Severe Illness
5) PPIs / H2 Antagonists
6) Enteral Feeding
7) GI surgery
8) Obesity
9) Chemotherapy
10) Stem Cell Transplantation -- unable to form anti-toxin Ab

MANIFESTATIONS AND DIAGNOSIS:

Asx Carrier Diarrhea with Colitis Pseudomembranous colitis Fulminant colitis

------ Mult loose BMs/d More profuse diarrhea Severe diarrhea
Fecal WBCs Fecal WBCs OR diminished (paralytic
+/- occult bleeding +/- occult bleeding ileus, colonic dilatation)
------ Nausea, anorexia, Nausea, anorexia, fever, Lethargy, fever, tachycardia,
fever, malaise, malaise, dehydration abdo pain, lactic acidosis, low
dehydration WBC + left shift albumin
WBC + left shift WBCs ~40+
------ + Abdo distension ++ abdo tenderness Acute abdomen (peritoneal sx
+ Abdo tenderness ++ abdo distension suggest perforation)
Normal flex Diffuse/patchy Raised, adherent, yellow Do NOT do flex sig / c-scope
sig nonspecific colitis plaques (<2cm)
Rectosigmoid spared in 10%
20% Ulcer formation -> release Toxic Megacolon >7cm
hospitalized serum proteins, mucous + colonic dilation + systemic
adults inflammatory cells toxicity
- reservoir for Perforation: peritoneal sx,
shedding AXR w/ free air

Unexplained leukocytosis (WBC >15) --> C. diff toxin in 58%

20% Ulcer formation -> release Toxic Megacolon >7cm
hospitalized serum proteins, mucous + colonic dilation + systemic
adults inflammatory cells toxicity
- reservoir for Perforation: peritoneal sx,
shedding AXR w/ free air

Unexplained leukocytosis (WBC >15) --> C. diff toxin in 58%

Diarrhea usually begins in next 1-2 days

Unusual Presentations:
Protein-Losing Enteropathy + Ascites
Hypoalbumin
Inflam'n of bowel wall -> leakage of albumin into lumen
C. diff + IBD
Diff to distinguish from flare, but treated very differently
IBD pts generally do NOT have pseudomembranes on endoscopy
Rely on toxin assays
Small Bowel Enteritis
Elderly, mult comorbidities, prior colectomy

DIAGNOSIS:
Significant diarrhea (>3 loose BMs/day x 2 days)
Toxin degrades at room temperature
Undetectable within 2-hours after collection
Specimens kept at 4'C

Sens Spec
PCR / Nucleic acid Detects toxin A + B genes ++++ ++++
amplification test (NAAT) Higher false + rate (97%)
1-hour
EIA for Glutamate Detect non-toxigenic strains ++ ++
Dehydrogenase GDH Ag enzyme produced constitutively (83%)
Hours
EIA for Toxins A + B Detect only toxigenic strains ++ ++++
False negative rate (LESS SENSITIVE) (75%) (99%)
- need 100-1000 pg toxin to be present
Hours
C. diff Cytotoxin Cx stool to cells -> if toxin present, cytopathic ++++ ++++
Neutralization Assay effect -> rounding of fibroblasts (97%)
(CCNA) Labour intensive, 2 days
**GOLD STANDARD**
Toxigenic Culture (TC) Detect non-toxigenic strains +++++ ++++
Selective Anaerobic Cx Cx on selective medium with toxin testing (99%)
Labour intensive, 2 days

TESTING:
NAAT for toxigenic C. diff (stand-alone test)
GDH screen --> if (+) need confirmatory test with EIA for toxins
Use PCR if discordant EIA results
TESTING:
NAAT for toxigenic C. diff (stand-alone test)
GDH screen --> if (+) need confirmatory test with EIA for toxins
Use PCR if discordant EIA results

Endoscopy:
Useful if:
High clinical suspicion + negative lab assays
Immediate dx needed (before lab results can be obtained)
Failure of CDI to respond to ABx therapy
Atypical presentation (ileus, minimal diarrhea)
Pseudomembranes = pathognomonic
Also Staph aureus, Klebsiella oxytoca, C. perfringens, Candida, Salmonella
Pseudomembranes not seen in 10-20%
Esp if recurrent infection
Pts with IBD + superimposed CDI
==> so biopsy can be helpful

TREATMENT:

General Principles:
Stop the inciting Abx ASAP
Otherwise prolonged diarrhea, risk of recurrence
If can't, try to change to ABx less freq associated
IV aminoglycosides, sulfonamides, macrolides, vancomycin, tetracycline
Can even treat throughout course + 1 week after completion to prevent recurrence
Contact Precautions
Avoid antimotility (ie. Loperamide, opiates)
Correct electrolytes, fluids

Indications:
Symptoms + positive assay
Tx no indicated in asymptomatic patients

Mild-Moderate Diarrhea Metronidazole 500mg PO TID x 10 days

Severe Albumin <30 Vancomycin 125mg PO QID x 10 days
+ WBC > 15
or abdo tenderness
Severe + Complicated ICU admission Vancomycin 500mg PO QID
Hypotension +
Fever >38.5 Metronidazole 500mg IV q8hr
WBC >35 or <2 +/-
Lactate >2.2 Vancomycin 500mg PR enema QID
Ileus/abdo distension
Mental status change
End organ failure
Recurrent Within 8 weeks of completion of tx 1st -- treat as above
2nd -- Vanco taper +/- others
 Lactate >2.2 Vancomycin 500mg PR enema QID
Ileus/abdo distension
Mental status change
End organ failure
Recurrent Within 8 weeks of completion of tx 1st -- treat as above
2nd -- Vanco taper +/- others

MILD, MODERATE:
Metronidazole 500mg PO TID or . 250mg po QID x 10-14 days
Peripheral neuropathy, nausea, metallic taste
Can use IV if need to b/c has biliary excretion which is increased across intestinal mucosa
during CDI -- so get fecal concentrations
?resistance -- decreased fecal levels with PO once stools more formed as colonic
inflammation subsides
Do NOT get repeat stool testing
50% remain positive 6 weeks after tx

SEVERE:
Age >60yrs
T >38.3
Albumin <30 *Cr >1.5x pt's normal
WBC >15 (sometimes used)
Pseudomembranous colitis (2 pts)
ICU admission (2 pts)

TcdA = neutrophil chemoattractant, increases WBC

Vancomycin 125mg PO QID x 10-14 days
--> if no improvement then increase to vancomycin 500mg PO QID
Zar 2007 CID: RCT showing cure with vancomycin (97%) vs metronidazole (76%)
Can consider Vancomycin PR 500mg q6hr enema if can't take PO
But risk of colonic perforation
Only if no response to standard therapy, profound ileus
If ileus = metronidazole 500mg IV q8hrs

Complications:
Toxic Megacolon
Abdominal distension + reduction in diarrhea (paralytic ileus from loss of colonic muscular
tone)
Perforation
Necrotizing Colitis
SIRS -> Multiorgan System Failure
Early surgical referral
Subtotal Colectomy -- ileostomy, leave the rectum
After inflammation subsides can do ileorectal anastomosis
Diverting Loop Ileostomy with colonic lavage
Need more studies
Loop ileostomy, lavage with PEG and post-op vancomycin flushes via ileostomy
Preserves the colon

RECURRENT DISEASE:
Complete abatement of CDI sx on therapy --> relapse once stopped
Different from persistent diarrhea (doesn't resolve during therapy)
1/2 = are reinfections
 Need more studies
Loop ileostomy, lavage with PEG and post-op vancomycin flushes via ileostomy
Preserves the colon

RECURRENT DISEASE:
Complete abatement of CDI sx on therapy --> relapse once stopped
Different from persistent diarrhea (doesn't resolve during therapy)
1/2 = are reinfections
1/2 = are relapses
Usually 1-3 wks, but up to 3 months
RISKS FOR RECURRENCE:
>65 yrs
Severe underlying medical do
Need for ongoing Abx
Prev recurrence (45-65% chance of additional episodes)

1st Recurrence:
Treat as initial episode (above)
Fidaxomicin 200mg PO BID x 10 days
Similar cure rates as vancomycin
Reduced risk of recurrence (19%) vs vanco (35%)
Same rates or recurrence for NAP1 strains
Macrolide Abx with narrow spectrum (disrupts less normal flora)

2nd Recurrence:
Vancomycin taper
125mg po QID x 14 days
125mg po BID x 7 days
125mg po daily x 7 days
125mg po q2days x 6 days
125mg po q3days x 15 days
Fidaxomicin 200mg po BID x 10 days
Rifixamin
Vancomycin followed by rifaximin x 2 weeks
+/- Probiotics
Saccharomyces boulardii 500mg po BID
Overlap with antibiotics + 2 wks after taper

>3rd Recurrence:
Fidaxomicin 200mg po BID x 10 days (if not yet used)
Fecal transplant
Monoclonal Ab against C. diff toxins A + B
Reduces recurrence
Other ABx
Fusidic acid, rifampin, rifaxamin, bacitracin
Nitazoxanide
As effective as vanco, small study
Teicoplanin -- $$$
Anion-Binding Resins
Colestipol 5g q12 hrs x 2 weeks
Cholestyramine 4g q6-8hrs x 2 weeks
Given with tapered vancomycin (take 3-hrs apart from vanco b/c will also bind vanco)
IVIG
Contains C. diff antitoxin
 Teicoplanin -- $$$
Anion-Binding Resins
Colestipol 5g q12 hrs x 2 weeks
Cholestyramine 4g q6-8hrs x 2 weeks
Given with tapered vancomycin (take 3-hrs apart from vanco b/c will also bind vanco)
IVIG
Contains C. diff antitoxin
Hasn't proven to be all that