Lecture 22 C. Difficile Infection Ng

DEFINITIONS:

AAD • AAD = antibiotic associated diarrhea

• Self-limiting diarrhea associated with antibiotic exposure (while on antibiotics or up to 8 weeks after antibiotics have been discontinued)

• Diarrhea caused by changes in composition & function of intestinal flora

• Therapy: supportive care & discontinuation of antimicrobials

CDI • Clostridium difficile is causative organism of diarrhea and colitis

ANTIBIOTIC ASSOCIATED DIARRHEA:

ONSET CATEGORIES:

• Early onset

• Occurring during antibiotic exposure

• Delayed onset (2-8 weeks after abx d/c)

INCIDENCE:

• 5-50% depending on age, antibiotic

• High-risk antibiotics:

o Clavulanate: stimulate bowel motility

o Erythromycin: motilin receptor agonist

o Broad-spectrum abs: intestinal flora alteration, overgrowth of pathogenic micro-organisms PATHOGENESIS:

1. Antibiotic exposure

2. Altered colonic flora

3. Interfered metabolism of carbs (osmotic

diarrhea) or bile acids (secretory diarrhea)

CHARACTERISTICS:

• 10-20% hospitalized patients with abx exposure will develop exposure (15-30% of AAD = C. diff)

• Diarrhea usually mild (3-4 loose stools/day); afebrile; no abd. pain; WBC not elevated; C. diff -ve

• Diarrhea usually resolves with discontinuation of antimicrobials

CLOSTRIDIUM DIFFICILE:

• Gram-positive, anaerobic, spore-forming bacilli

o Spores are acid-resistant

• Cause disease by release of potent exotoxins

o Toxin A: enterotoxin; causes diarrhea

o Toxin B: cytotoxin; cytotoxic to colonic epithelial cells

• Transmission: fecal:oral (ingestion of endospores)

CDI DEFINITIONS:

• Acute diarrhea and colitis often preceded by antimicrobial use, caused by anaerobic

spore-forming, toxin-producing bacterium

• Case definition in BC:

o Presence of diarrhea (ex// 3 liquid or loose stools within a 24-hr period) or toxic

megacolon without other known etiology, AND laboratory conformation of

presence of C. difficile toxin A and/or B OR

o Diagnosis of typical pseudo-membranes on sigmoidoscopy or colonoscopy OR

o Histological/pathological diagnosis of CDI with or without diarrhea

CDI CATEGORIES:

Hospital-acquired / healthcare associated CDI

• CDI diagnosis > 48-72 h after hospital admission, without CDI in the past 8 weeks OR

• CDI in patients hospitalized in previous 30-60 days OR

• CDI diagnosis > 72h after hospital admission; discharged from acute care facility in last 4 weeks

Community-acquired CDI

• Disease in a person who had no overnight stay in a healthcare facility within 12 weeks before infection OR within 48h of healthcare facility admission

New CDI • CDI case without previous history of CDI OR

• CDI case that has not had an episode of CDI in previous 8 weeks

Relapsed CDI • CDI case with recurrence of diarrhea within 2-8 weeks of previous CDI episode

EPIDEMIOLOGY: BC PICNet CDI Surveillance report 2015-16

• 2, 893 CDI cases

o 66.3% healthcare associated (HCA)

▪ Relapse in 9.8% of HCA cases

o 29.9% community-acquired

o 3.7% unknown origin

• CDI-associated complications at 30 days:

o 2.8% cases admitted to ICU

o 0.8% cases developed toxic megacolon

o 0.8% required entire or partial colectomy

RISK FACTORS:

HEALTHCARE-ASSOCIATED CDI:

• Antibiotic use

• Advanced age

• Prolonged hospital stay

• GI surgery, NG tubes, gastric acid-suppression, IBD

• Immunosuppression, organ transplantation, chemo

• Chronic kidney disease

• Exposure to an infant carrier or infected adult

COMMUNITY-ACQUIRED CDI:

• No known classic profile

RECURRENCE OF CDI:

• Age ≥ 65 years old

• Prolonged hospital stay (> 16 days)

• Administration of other antimicrobial during or after

initial treatment of CDI

• Presence of co-morbidities

• Hypoalbuminemia

• Inflammatory bowel disease

• Defective immune response against toxin A

PATHOGENESIS:

1. Antibiotics abnormal colonic microbiota

a. Modulation of bile acid metabolism increased 1o bile acids, decreased 20

2. Toxigenic C. difficile exposure germination triggered by presence of bile acids

3. Attachment to and colonization (or activation of prior colonization) of gut epithelium

4. Toxin production (toxins A and B) tissue damage disease symptoms

a. Effective antitoxin response asymptomatic carriage

b. Inadequate immune response diarrhea and colitis

i. Effective antitoxin response & restoration of microbiota resolution

ii. Inadequate immune response & re-infection recurrence

CDI COMPLICATIONS:

• Pseudomembranous colitis (PMC):

o Red, inflamed mucosa and areas of white exudate called pseudomembranes on

surface of large intestine

o Necrosis of mucosal surface occurs underneath the pseudomembranes

• Toxic megacolon

o Dilation of the colon

o Bowel expands, and may perforate

Lecture 22 C. Difficile Infection Ng

TREATMENT OF CDI:

CDI DIAGNOSIS:

• Criteria:

o Clinical sx: ≥ 3 watery, loose or unformed stools

within ≤ 24 hours

o Diagnostic test detecting presence of C. difficile

organism or toxin genes or toxin

• Testing for C. difficile or toxins only on unformed stool (Bristol

Stool Chart type 6/7) unless ileus due to CDI is suspected

• Test of cure not recommended

• Repeat testing should be discouraged

TESTING FOR C. DIFFICILE:

• Only stools from patients with diarrhea with clinically-

suspected CDI should be tested

o Carriage of C. difficile in 5-15% healthy adults, 80% of

newborns, > 50% long-term care facility residents

o Carriage is increased in patients on antibiotics

• Current clinically used methods (in order of ↓ sensitivity):

o Nucleic acid amplification tests (NAAT) – ex// PCR

▪ Detects gene for toxins

▪ Takes 1-2 hrs; expensive; standalone test

o Enzyme immunoassay A/B (EIA)

▪ Detects toxin A or toxin A&B

▪ Takes hours; cheap; standalone or 2-3 step alg

o Glutamate dehydrogenase (GDH) screening

▪ Takes 15-45 min; cheap; used as 2-3 step alg

▪ Does not detect toxins

CLINICAL MANIFESTATION: spectrum of asymptomatic carriage to fulminant disease

Vitals • 30-50% have low-grade fever

• ↑ HR, RR

• ↓ BP

General • Rigors, chills, malaise

GI • Watery diarrhea (mild to profuse), distinct smell (“barnyard smell”)

• Blood may be present (5-10%)

• Loss of appetite, nausea

• Abdominal pain, tenderness, cramping

• Pseudomembranous colitis, colonic ileus, toxic megacolon

Labs • ↑ SCr

• ↑ WBC (up to 50% of patients) o > 15 x 109 L : marker of severe disease o > 50 x 109 L: indication of fulminant, potentially fatal disease

• ↑ neutrophils, bands

• ↓ albumin

• ↑ lactate

CDI GOALS OF THERAPY:

• Alleviate symptoms; cure infection

• Prevent transmission of CDI; minimize risk of recurrence

• Prevent complications (need for surgery, toxic megacolon,

pseudomembranous colitis, mortality)

• Minimize unnecessary use of antimicrobials

• Patient education: monitoring of sx, infxn control strategies

• Minimize ADRs

CDI TREATMENT PRINCIPLES:

• Discontinue unnecessary antibiotics as soon as possible

• Fluid hydration, correction of electrolyte abnormalities

• Initiate empiric therapy without delay when severe/complicated CDI is suspected

• Avoid antiperistaltic agents (may obscure symptoms & precipitate toxic megacolon)

• Approach must be multifactorial, incorporating diagnostics, epidemiology, infection

control, antibiotic stewardship and prevention/treatment strategies

CDI TREATMENT ALTERNATIVES:

• No treatment (supportive only)?

• Metronidazole 500 mg PO/IV TID or 250 mg QID

• Vancomycin 125 mg PO QID (tapering/pulsed course)

• Fidaxomicin 200 mg PO BID

• Other drugs with activity against C. difficile: tigecycline, rifaximin, rifampin, fusidic

acid, nitazoxanide, teicoplanin, bacitracin

o Insufficient evidence for these drugs in treatment of CDI

• Surgery (colectomy)

• Fecal microbiota transplant

MILD TO MODERATE CDI (1ST OR 2ND EPISODE):

• No significant difference between metronidazole and

vancomycin found for symptomatic or bacteriology cure; or

duration of diarrhea (mean duration: 2.4 – 3.2 days)

• Duration of treatment studied: uniformly 10 days

• Considering evidence + costs/ease of administration:

metronidazole is drug of choice

• If no improvement observed after 3-7 days, change

metronidazole to vancomycin

SEVERE CDI (1ST OR 2ND EPISODE):

• Vancomycin is drug of choice

• Severe, complicated CDI

o No studies comparing or combining metronidazole & vancomycin

• Fulminant CDI:

o Consider combination vancomycin PO and metronidazole IV

o Consider intra-colonic, high-dose vancomycin (vancomycin enema)

▪ Lack of evidence to determine if sufficient quantity of drug reaches

the right and transverse colon

o Ileus: consider higher dose vancomycin of 500 mg

o Consider colectomy (may be life-saving) DURATION OF TREATMENT: 10-14 days

• Prospective trials of metronidazole and vancomycin

studied for only 10 days

o No trials for 14 days

• Extending to 14 days considered for pts with slow response

• Metronidazole excretion into stool decreases with formed

stool (undetectable in formed stools)

o No utility in extending metronidazole course

RECURRENCE OF CDI: 6-25% or higher

• Consider other causes of diarrhea

• Treatment with either metronidazole or vancomycin for

initial CDI does not affect recurrence rates

• 1st recurrence (mild/moderate): metronidazole

• 2nd + recurrence: vancomycin PO

o Consider tapering/pulse dosing, ex: vancomycin 125 mg

PO QID x 14 days BID x 7 days daily x 7 days

q2-4 days x 14 days

• ID or GI consult

METRONIDAZOLE VS. VANCOMYCIN:

Metronidazole Vancomycin

Absorption & colonic concentration

Absorbed rapidly & almost completely (6-15% excreted in stool, decreased excretion into stool as colonic inflammation subsides)

Not absorbed; excreted in high concentrations into colon far above C. difficile MIC throughout dosing regimen at 125 mg PO QID

Dosing 500 mg PO/IV TID x 10-14 days 125 mg PO QID x 10-14 days 500 mg in 100 mL NS PR q6h as retention enema

Adverse effects

Dose-dependent peripheral neuropathy, nausea, metallic taste

Well-tolerated; nausea, abdominal pain, hypokalemia

Other Less expensive Risk of increasing prevalence of vancomycin-resistant Enterococci (VRE)

Lecture 22 C. Difficile Infection Ng

SUMMARY OF TREATMENT OF CDI:

Clinical definition Supportive clinical data Recommended treatment

Initial episode, mild/moderate

WBC ≤ 15 and SCr < 1.5x premorbid level

Metronidazole 500 mg PO TID x 10-14 days

Initial episode, severe

WBC > 15 and SCr ≥ 1.5x premorbid level

Vancomycin 125 mg PO QID x 10-14 days

Initial episode, severe, complicated

Hypotension, shock, ileus, megacolon

Vancomycin 500 mg PO/NG QID plus metronidazole 500 mg IV q8h If ileus, consider adding vancomycin PR

First recurrence Same as for initial episode

Second recurrence

Vancomycin in tapered and/or pulsed regimen

MONITORING:

Vitals • Frequency depending on clinical presentation

• Hydration status

GI • Daily abd. exam (bowel sounds, stool frequency, consistency, abd. pain and distension)

• Bristol Stool Chart (patient record)

Labs • CBC with diff daily

• Lytes daily: Na, K, Cl

Imaging • AXR

Trigger tool

• For Acute Care facilities

• Signal to prevent outbreak

FIDAXOMOCIN FOR CDI:

Pharmacology • Narrow spectrum macrocyclic antibiotic (new macrolide)

• Spectrum of activity: o Gram +ve aerobic and anaerobic activity o Low activity against gut micro-organisms

MOA • Inhibition of RNA synthesis by bacterial RNA polymerases

• Bactericidal against C. difficile in vitro

• Inhibits C. diff sporulation & toxin production in vitro

PK/PD • Minimal systemic absorption

• Time-dependent

• Fecal concentrations in colon exceed MIC throughout dosing interval

Dosing • 200 mg PO BID x 10 days

Trial implications

• Fidaxomicin non-inferior to vancomycin for clinical cure, but significantly lower rates of CDI recurrence

• No significant difference in need for emergency colectomy or other complications

Considerations • Fidaxomicin has not been compared to metronidazole

• Has not demonstrated superiority to other CDI treatments

• Cost of fidaxomicin is significantly higher than vancomycin

Place in therapy

• Restrict for patients who failed, are intolerant, or allergic to BOTH metronidazole and vancomycin o Mild or mod disease not improving by day 4-6 on

metronidazole AND allergic to oral vancomycin o Severe disease AND allergic to oral vancomycin o May consider for initial therapy in outpatients at

high risk of complications from relapse IF able to afford drug through extended health coverage

FECAL MICROBIOTA TRANSPLANT (FMT):

Definition • Replacement of entire fecal flora via instillation of stool from a healthy donor into the GIT

MOA • Restoration of intestinal microbiota diversity

• Confers improved resistance against pathogen colonization

Efficacy • Reported cure rates 85-95%

• Success from FMT may be long lasting

Delivery routes

• Retention enema

• Fecal instillation via naso-duodenal or jejunal tube

• Fecal instillation via rectal tube, colonoscopy, self-administered enemas

• Oral, capsulized frozen stool

Safety • Available case reports and trials suggest it is safe

• Short- and long-term adverse effects has not been characterized o Reported: diarrhea, cramping, belching

(resolved within 3h)

• Concerns: o Potential transmission of infectious

organisms from donor to recipient o Upper GI delivery concerns (upper GI bleed,

peritonitis, enteritis) o Long-term effects of altering gut

microbiome in immune status, nutritional status, autoimmunity, psych changes, etc

Current use

• Recurrent or relapsing CDI failing vancomycin taper or pulsed regimen

• Moderate CDI not responding to standard therapy for at least a week

• Severe (perhaps even fulminant) with no response to standard therapy after 48 h

PROBIOTICS FOR AAD/CDI:

• Many studies on primary & secondary prophylaxis, and adjunctive treatment

• Vast heterogeneity in study populations, probiotic preparations, dosages,

study flaws, endpoints, inconsistencies in CDI diagnostic criteria

o Studied strains: Lactobacillus spp., Bifidobacteria spp., Streptococcus

thermophiles, Saccaromyces boulardii

• Latest guidelines do not recommend probiotic use for txt or prophylaxis

INFECTION PREVENTION AND CONTROL STRATEGIES:

• Antimicrobial stewardship

• Contact precautions: gloves and gowns on entry to a room or

immediate patient area

o Maintained for duration of diarrhea and usually continued

for 48-72 hrs after stool normalize

• Hand hygiene (esp. before eating & after using toilet)

o Soap and water is preferred method

o Hand sanitizer is ineffective against C. difficile spores

• As a pharmacist:

o Review antibiotic regimens of all patients in the ward to

ensure that prescribing habits reduce the risk of CDI

o Work with physicians to ensure that appropriate

management of CDI is followed

TAKE HOME MESSAGES:

• Tests alone cannot distinguish between CDI and non-infectious AAD

• Imperative to use clinical judgment to distinguish between AAD and CDI to

avoid unnecessary/overuse of CDI treatment

• CDI treatment depends on severity and patient’s episode number of CDI

o Primary treatments are metronidazole PO/IV, vancomycin PO & FMT

• Management of CDI requires multifactorial approach, including infection

control, antimicrobial stewardship, prevention and treatment strategies