Clostridium difficile Infections: Diagnosis, Treatment, and

PreventionTheresa Cuoco, MD

OutlineIntroduction Risk Factors for DiseaseMethods for DetectionAntibiotic TherapyNonstandard Adjunctive InterventionsInfection Control and Prevention

Introduction Gram positive, spore forming, toxin producing

1935: “difficult clostridium” (isolation on conventional media)

Obligate anaerobic bacterium Survives 10-15 minutes following exposure to air

Hardy spore Resistant to heat, acid, alcohol, and abx; ingested, and germinates

Transmitted via fecal-oral route Causes disease by production of toxins that bind to receptors

on colonic epithelium A enterotoxin: attracts neutrophils and monocytes B cytotoxin: mediates mucosal damage (10x more potent)

DefinitionThe presence of symptoms

Usually diarrhea (at least 3 unformed stools in 24hrs) <1% of cases: no diarrhea; ileus and colonic distention AND EITHER

Stool test positive orColonoscopic or histopathologic findings of

pseudomembranous colitis96% of patients received abx within 14 days prior to

onset of diarrhea; nearly all within past 3 monthsMedian time to onset 2-3 days after colonization

Spectrum ofClostridium difficile Infection

(CDI)Asymptomatic carrier

Colonization with nontoxigenic strain affords protection High circulating titers of IgG antitoxin

Mild diarrhea (≥ 3 stools in 24hr) Fever, cramping, abdominal pain, leukocytosis

Severe diarrhea (≥ 10 stools in 24hr)Pseudomembranous colitis Fulminant colitis

Severe pain, distention, fever, shock, lactic acidosis, WBC

Toxic megacolon with paralytic ileus

Increasing Severity

Age-adjusted Death Rate Due to Enterocolitis from C. difficile1999 to 2006 Per 100,000 Population [From: Heron 2009(http://www.cdphe.state.co.us/hf/patientsafety/CDItoolkit.pdf)

Hypervirulent Strain: NAP1/B1/027“North American Pulsed-field Type”Deletion in gene that down regulates toxin

productionProduces 16-23 times more toxin

Produces a binary toxinResistance to fluoroquinolonesIncreased sporulation

Risk Factors for Development of CDI Antibiotic use: disruption of colonic flora

Broad spectrum, multiple abx, and duration of therapy Host immune status Advanced age, duration of hospitalization, & female gender Comorbidities GI procedures and enteral feeding Gastric acid suppression (risk 1.4-2.75 times higher with PPI) Chemotherapeutic agents (antimicrobial/immunosuppressive) Hematopoietic stem cell transplantation

Antibiotics ImplicatedFrequently Associated

Occasionally Associated

Rarely Associated

Fluoroquinolones Macrolides AminoglycosidesClindamycin Trimethoprim TetracyclinesPCN (broad spectrum)

Sulfonamides Chloramphenicol

Cephalosporins (broad spectrum)

Metronidazole

Vancomycin

Diagnosis and Detection of CDIOnly performed on unformed stool unless ileus

suspectedTesting asymptomatic patients, including use as a

test of cure NOT recommended Repeat testing during same diarrheal episode

discouraged

Detection of CDI1. Cytotoxicity Assay2. Culture3. Immunoassays4. Toxin Gene Detection5. Endoscopic evidence

Cytotoxicity AssayStool mixed with cultured test cells

Monitored for toxin effects (cell rounding)Requires up to 48 hours Often used as reference test in the evaluation of

other diagnostic testsHighly sensitive; not practical

CultureCycloserine, cefoxitin, fructose agar (CCFA)Most sensitiveCan take 2 to 9 daysColonies with specific odor and fluoresce with

Woods lamp

Immunoassays – “EIA”Majority of labs use this technique – quick, inexpensiveSome only detect toxin A and strains emerging with

only toxin BModerate and variable sensitivity 63-94%

Frequent false negatives

Specificity 75-100%Alternative 2 step process: high negative predict value

EIA detection of Glutamate Dehydrogenase (GDH): enzyme produced by C diff

toxin testing

Toxin Gene Detection: PCRDetects presence of gene involved in toxin

productionRapid, sensitive and specificUsed at MUSC

Pseudomembranes

Endoscopic appearance Gross appearance

Raised yellow or off-white plaques up to 2 cm in diameterscattered or confluentedema, erythema, friability, and inflammation

Treatment1. Discontinue inciting antibiotic

Implement infection control measures

2. Confirm with testing Empiric therapy may be warranted based on

severity of symptoms

3. Avoid antiperistaltic agents – precipitates megacolon

4. Determine clinical severity Mild-moderate, severe, severe-complicated

Mild to Moderate DiseaseMetronidazole vs Vancomycin equivocalMetronidazole – first line

500 mg po q8 or 250 mg po q6 500 mg IV q8 if oral therapy not feasible Limitations: peripheral neuropathy, nausea, metallic

Vancomycin 125 mg po Q6 **must be given orally

Duration: 10-14 days If underlying infection requiring prolonged abx, continue CDI

treatment throughout abx course + 1 additional week

Initial Recurrent Disease“Recurrence of symptoms within 8-10 weeks after cessation

of specific antibiotic therapy”Up to 20-25% of patients adequately treatedConfirm diagnosisUp to ½ of recurrent episodes are reinfections rather than

relapses with original strainMost present 1-3 weeks after discontinuing abx therapy

(but up to 2-3 months)Why? Persistent spores, impaired host immune responseTreatment with same regimen as initial but stratify based

on disease severity

Second Recurrence Confirm diagnosisSubset with high rate of repeat recurrenceAvoid metronidazole due to cumulative neurotoxicity Vancomycin: tapered and/or pulsed dosing – allows spores to

germinate 125 mg po QID for 7-14 days 125 mg po BID for 7 days 125 mg po QD for 7 days 125 mg QOD for 7 days 125 mg po q 3 days for 14 days

Fidaxomicin 200 mg po BID for 10 days

Subsequent recurrence Confirm diagnosisVancomycin 125 mg po QID for 14 days followed

by rifaximin 400 mg BID for 14 daysBased on small case series

Fidaxomicin 200 mg po BID for 10 days

Fidaxomicin (Dificid)Macrocyclic macrolide antibiotic Bactericidal Narrower antimicrobial spectrum = less disruption

of normal floraFDA approved in 2011What’s the hype?

Fidaxomicin

Limited to non-NAP1 strains

Severe CDI: markersSevere diarrhea

>10 bowel movements/day

Leukocytosis >15K – severe >25 increased fatality

High or rising serum Cr (50% increase)

Low serum albumin (<2.5 mg/dL)

Severe abdominal distention, pain

Ileus or toxic megacolonColonic thickening on CT Ascites on CTPseudomembranes on

endoscopyHemodynamic instabilityOrgan Failure

Pepin J, et al. Can Med J Assoc 2004: 171:466-472.Bartlett JG, Gerding DN. Clin Infect Dis 2008: 46(Suppl):S12-S18

Severe CDINo consensus definitionZar et al Clin Infect Dis 2007: ≥2 points = severe

Treatment: Vancomycin 125 mg po QID for 10-14daysNo supportive evidence for higher dosing Improved rates of cure with vanc vs metronidazole but

not significant when using strict intention to treat analysis

1 point 2 pointsAge > 60 Endoscopic pseudomembranesTemp > 38.3C Treatment in ICUAlbumin < 2.5 mg/dLWBC > 15,000

Severe, Complicated CDI Hypotension, shock, ileus, or megacolonVancomycin 500 mg po or per NGT ±

metronidazole 500 mg IV q8If complete ileus: add vancomycin 500 mg in

100cc NS as retention enema q6Surgery considered if age ≥ 65 and WBC ≥20,

lactate > 2.2, peritoneal signs, severe ileus, toxic megacolon Increased periop mortality with lactate > 5 and WBC

> 50Subtotal colectomy with ileostomy and rectum

spared

Nonstandard Adjunctive InterventionsWhy explored?Standard antibiotics ineffective in 8-36%NO current antibiotics kill sporesRates of infection and relapse are increasingSpecific therapies:

Probiotics/PrebioticsAnion binding resinsFecal flora reconstitutionC diff immune whey (antibody) IVIG

Prevention StrategiesLow level evidence for link of prevention to

outcomes“People” measuresEnvironmental MeasuresAntimicrobial restrictions“Bundled prevention strategies”

Person measuresImmediate infection control measures once CDI is

suspectedGowns/glovesHand washing with soap and water

Friction and detergent action

Private room with contact precautionsIf single room not possible, cohort patients with

separate commodes

Environmental Cleaning and DisinfectionDisposable rectal thermometers

In place of electronicInadequately cleaned commodes or bedpansChlorine/hypochlorite containing cleaners

Antimicrobial StewardshipMinimize frequency, duration of therapy, and

number of antibiotic agentsReduce use of “high risk” antimicrobialsStewardship programs based on local

epidemiologyRestriction of cephalosporins and clindamycin

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