Richard Allan Bettis, Fourth-Year Pharm.D. Candidate

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A Closer Look at Clostridium difficile Infections

• Richard Allan Bettis, Fourth-Year Pharm.D.
  Candidate
• Preceptor Dr. Ali Rahimi
• University of Georgia College of Pharmacy

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Background

• Clostridium species
• gt190 species identified
• Gram-positive
• Anaerobic
• Spore forming bacilli
• Releases exotoxins which are associated with
  major diseases in humans

C. difficile colitis results from the ingestion
of spores that vegetate, multiply, and secrete
toxins
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Background

• Clostridium tetani
• Causes tetanus through spread of potent
  neurotoxin
• Clostridium botulinum
• Causes botulism through spread of potent
  neurotoxins
• Clostridium perfringens
• Causes gas gangrene through spread of
  necrotizing, hemolytic exotoxin
• Clostridium difficile
• Causes pseudomembranous colitis through
  production of cytotoxin and enterotoxin
• Relatively resistant to most commonly used
  antibiotics
• Found in normal gut flora of 2-10 of humans

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Pathophysiology

• Toxin A, the enterotoxin, causes
• Damage to intestinal mucosa
• Intestinal fluid secretion
• Inflammation via actin disaggregation
• Intracellular calcium release
• Damage to neurons in the gut
• Toxin B, the cytotoxin, causes
• Depolymerization of filamentous actin
• More effective damage to colonic mucosa

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Pathogenesis

• Pseudomembranous plaques formation resulting in
  inflammation of mucosa
• Enlargement and spread of plaques through gut
  results in clinical presentation
• Mild to severe diarrhea
• Mucosal necrosis
• Accumulation of inflammatory cells and fibrin

Raised, yellowish-white pseudomembranous plaques
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Background

• Clostridium difficile infection (CDI) is the most
  common cause of infectious diarrhea in
  hospitalized patients
• Once antibiotics disrupt normal gut flora
• C. difficile colonization occurs
• Toxins production results in manifestation of CDI
• Diarrhea and colitis results
• CDI should be suspected in any patients with
  diarrhea with recent history of antibiotic use

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CDI Risk Factors

• Clostridium difficile infections occur most often
  in high risk groups
• Elderly (gt65 years old)
• Debilitated
• Immunocompromised
• Surgical patients
• Nasogastric tubes
• Frequent laxative use
• History of antibiotic use

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CDI Risks

• CDI can occur during, shortly after, or several
  months after the use of broad spectrum
  antimicrobial treatment
• CDI should be suspect in any patients with
  diarrhea with recent history of antibiotic use
  within the past THREE MONTHS
• Patients whose diarrhea began 72 HOURS after
  hospitalization

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CDI-Associated Antimicrobials

• Broad spectrum antimicrobials associated with
  CDIs
• Clindamycin
• Ampicillin
• Flouroquinolones
• Ciprofloxacin, levofloxacin, moxifloxacin
• Cephalosporins (2nd 3rd generation)
• Cefotaxime, ceftriaxone, cefuroxime, ceftazidime
• Aminoglycosides
• Erythromycin
• TMP-SMX
• Metronidazole
• Vancomycin

Used to treat CDI!
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Clinical Presentation

• Patients with CDI often present with
• Watery or perfuse diarrhea (as many as 20 bowel
  movements per day)
• Leukocytosis (50)
• Fever (28)
• Abdominal pain (22)
• Ileus (20)
• Pseudomembrane formation
• Malaise
• Nausea
• Anorexia

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Clinical Presentation

• Clinical diagnosis based upon diarrhea onset
  during or after antimicrobial use
• Delay in diagnosis can result in complications
• Life-threatening toxic megacolon
• Pseudomembranous enterocolitis

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Diagnosis

• Pathogens most often responsible for infectious
  diarrhea or enteritis
• Shigella species
• Salmonella species
• Escherichia coli
• Yersinia species
• Vibrio species
• Clostridium difficile
• Other etiologies less commonly seen or in extreme
  cases of immunodeficiency
• Parasites (Entamoeba histolytica, Giardia lamlia)
• Viruses (Cytomegalovirus)

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Differential Diagnosis

• Stool cultures are crucial to making an
  organism-specific diagnoses and determining
  antimicrobial sensitivity
• Recommended in patients with inflammatory
  diarrhea
• Poor yield of positive cultures
• If negative, then a 2nd analysis is recommended

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Diagnosis

• Detection of toxins
• C. difficile toxins A or B
• Enzyme assays for
• Glutamate dehydrogenase (GDH)
• Endoscopy
• Reserved when rapid diagnosis is needed
• Used when ileus is present
• Stool samples are unavailable
• Differential diagnoses with concurrent colonic
  diseases

Raised, yellowish-white pseudomembranous plaques
characteristic of CDI
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Prevention

• Clostridium difficile can be cultured in rooms of
  infected individuals UP TO 40 DAYS after
  discharge
• Strict hand washing
• Contact precautions
• Vaccines?

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• Clostridium difficile can be cultured in rooms of
  infected individuals
• UP TO 40 DAYS
• after discharge

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Is There A Problem?

• Most frequently acquired exogenously from
• Hospital
• Nursing home
• Long-term care facility
• gt20 fecal colonization among patients
  hospitalized for gt1 week
• C. difficile spores can persist for months on
  most surfaces
• Risk of colonization increases with length of
  stay
• Other risk factors
• Poor hand hygiene of hospital personnel
• Use of electronic rectal thermometers
• Enteral tube feeding

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Why So Serious?

• Both the incidence and severity of Clostridium
  difficile infections have increased
  significantly in the past decade
• Clostridium difficile infection rates in U.S.
  hospitals tripled between 2000 and 2005
• CDI rates in Canada have quadrupled since 1997
• Increased rates directly attributed to an
  increase in mortality from 1.7 to 6.9

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Why So Serious?

• Causality attributed to emergence of specific
  strain-types of outbreaks known synonymously as
• North American pulsed-field type (NAP-1)
• Toxinotype III
• REA type BI
• PCR ribotype 027
• Emergence may be explained in part by patterns of
  antibiotic use in hospitals

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CDI Epidemic

• North American pulsed-field type (NAP-1)
• Highly resistant to fluoroquinolones
• Carries deletion mutations in toxin regulatory
  gene
• Results in higher levels of toxin production
• 16 to 23 times more toxin A and B!
• Results in significantly more serious disease
• More resistant to standard therapy

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Fluoroquinolones

• Most recent drug class implicated in hospital
  outbreaks of C. difficile infections
• Increasing fluoroquinolone resistance seen in
• Campylobacter, Salmonella, Clostridium difficile

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Treatment
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Treatment

• Discontinue offending agent
• Diarrhea may resolve in up to 25 of patients
  within 48 hours of discontinuation
• Fluid and electrolyte replacement as necessary
• Most patients will require antibiotics
• Vancomycin
• Metronidazole

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Treatment

• Metronidazole
• Drug of choice for mild to moderate CDI
• Less expensive

• Vancomycin (Oral)
• IV does not achieve high enough gut
  concentrations
• Contraindications, intolerance, or poor response
  to metronidazole
• Retention enema delivery if ileus or inability to
  reach infection site
• Concerns of vancomycin resistant enterococci
  (VRE)

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CDI Treatment Guidelines

• Published by IDSA in 2010
• Metronidazole 500mg PO TID for 10-14 days
• For mild to moderate CDI
• Vancomycin 125mg PO QID for 10-14 days
• For initial episode of severe CDI
• Vancomycin /- 500mg metronidazole IV
• For severe, complicated CDI
• Vancomycin dose is 500mg PO QID 500mg IV in
  100mL NS rectally

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Treatment
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Contraindicated Regimens

• Drugs that inhibit peristalsis or slow gut
  transit time should NOT be used in patients with
  fever or bloody stool
• Diphenoxylate
• Loperamide
• Evidence to support an increase risk for
  development of hemolytic-uremic syndrome due to
  delayed intestinal clearance and increased toxin
  absorption

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Recurrence

• Treatments similar in diarrhea resolution,
  incidence of side effects, and relapse rates
• Relapse occurs in approximately 20 of patients
• Relapse usually occurs within 1 to 2 weeks but
  can be delayed for up to 12 weeks
• Frequency increases with subsequent recurrences
• One prior episode gt40 recurrence risk
• gt2 prior episodes gt60 recurrence risk

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Recurrence

• Risk factors for recurrence
• History of recurrence
• Advancing age
• Additional antimicrobials
• Inadequate immune response to C. difficile
  toxins

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Recurrence Treatment

• Optimal management of multiple relapses is
  unclear
• Alternative regimens
• Fecal transplantation
• Vancomycin rifampin
• Vancomycin followed by rifaximin
• Nitazoxanide
• IVIG
• Poor regimens
• Bacitracin, cholestyramine, colestipol, fusidic
  acid, probiotics

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Recurrence

• There is more than just C. difficile amidst
  normal gut flora
• Further disruption of gut flora only causes
  susceptibility to other infections

Where is the selective agent?
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Treatment Failure Recurrence

• Resistance to antimicrobials is rarely the cause
  of relapse
• Relapse occurs because treatment
• Fails to eliminate C. difficile spores
• Makes patients vulnerable to another infection by
  impairing normal flora

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CDI Treatment Guidelines

• Fidaxomicin?

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Fidaxomicin (Dificid)

• Narrow spectrum, macrocyclic antibiotic active
  against gram-positive aerobes and anarobes
• Lacks activity against gram-negative bacteria
• Poor activity against normal gut flora
• Relatively selective activity against C.
  difficile
• Inhibits bacterial protein synthesis by binding
  to sigma subunit of RNA polymerase
• Negligible systemic absorption with oral
  administration
• High fecal concentrations

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Fidaxomicin (Dificid)

• As effective as vancomycin and may be associated
  with lower rates of relapse
• 1st antimicrobial FDA approved by the FDA for CDI
  treatment in over 25 years
• Orphan drug designation to all formulations for
  treatment of CDI in pediatric patients lt16 years
  and younger
• Administered 200mg PO BID

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Fidaxomicin versus Vancomycin for Clostridium
difficile Infection
Published in February 2011!
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Study Design

• Prospective, multi-centered, double-blind,
  randomized, parallel-group trial
• Non-inferiority study
• All patients were enrolled at 52 sites in the
  United States and 15 sites in Canada
• Conducted from May 2006 to August 2008

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Grading Recommendations
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Eligibility Criteria

• gt 16 years of age
• Diagnosis of CDI
• Presence of diarrhea defined as gt3 unformed bowel
  movements in a 24-hour period
• Presence of C. difficile toxin A, B, or both in
  stool sample obtained within 48 hours of
  randomization
• Could not be recipient of any potentially
  effective concurrent CDI treatments
• Oral bacitracin, fusidic acid, rifaximin

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Exclusion Criteria

• Patients receiving any potentially effective
  concurrent CDI treatments
• Oral bacitracin, fusidic acid, rifaximin
• Patients with
• Life-threatening or fulminant CDI
• Toxic megacolon
• Previous exposure to fidaxomicin
• History of ulcerative colitis or Crohns disease
• gt1 occurrence of CDI within 3 months before study
  start

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Efficacy Outcomes

• Primary endpoint
• Rate of clinical cure in the modified
  intention-to-treat and per-protocol populations
  at the end of therapy or at the time of early
  withdrawal
• Secondary endpoints
• Recurrence of CDI during 28-day period after the
  end of the course of therapy
• Global cure in the modified intention-to-treat
  and per-protocol populations

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Treatment

• Randomized into two groups
• Vancomycin 125mg every 6 hours
• Fidaxomicin 200mg every 12 hours
• Dosing scheduled with placebo for q6h dosing
• Both medications were over-encapsulated to
  conceal identities
• Oral dosing for 10 days

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Definitions

• Modified intention-to-treat (MITT) population
• Patients with documented CDI who underwent
  randomization and received at least one dose of
  study medication
• Per-protocol population
• Patients who received gt1 dose of fidaxomicin who
  received treatment for gt3 days (treatment
  failure) or gt8 days (clinical cure)
• Documented adherence to protocol
• Underwent end-of-therapy evaluation

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Study Enrollment

• 629 patients enrolled and randomized
• 596 included in modified intention-to-treat
  analysis (received gt 1 dose of Dificid)
• 548 included in per-protocol analysis

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Randomization
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Follow-up
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Follow-up

• Assessed daily for clinical cure or clinical
  failure
• Assessed weekly for 28 days after last dose for
  recurrence
• Only patients who remained in the study and had a
  follow-up assessment between days 36 and 40 after
  randomization

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Patients

• Adherence to medication similar in two groups
• Did not differ significantly with baseline
  characteristics

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Statistical Analysis

• Rate of clinical cure (Primary endpoint)
• Non-inferiority margin of -10 percentage points
• If within 10-percentage points, then non-inferior
• Recurrence and overall cure (Secondary endpoint)
• Post hoc hypothesis tests
• Based upon age, inpatient vs outpatient status,
  prior occurrence, disease severity, and strain
  type
• Time to resolution of diarrhea
• Kaplan-Meier method
• Gehan-Wilcoxon test for comparison of resolution
  times

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Results
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Primary Endpoint

• Rate of clinical cure
• Subgroup analyses based patient characteristics
  showed no statistical differences between
  treatments in either treatment groups in both
  study populations

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Secondary Endpoints

• Recurrence of CDI
• Treatment with fidaxomicin
• Associated with a significantly lower rate of
  recurrence
• Lower rates of recurrence with Non-NAP-1
  strains(69 relative reduction)
• Treatment with vancomycin
• Associated with a significantly higher recurrence
• 3.3 times higher rates with Non-NAP-1 strains

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Secondary Endpoints

• Global cure or resolution of diarrhea without
  recurrence
• Fidaxomicin resulted in significantly higher
  global cure rates than vancomycin
• Median time to resolve diarrhea was shorter in
  the fidaxomicin group than the vancomycin group
• Not statistically significant

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Overall Outcomes
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Safety

• Safety
• No differences between either groups in regards
  to rates of adverse events or serious adverse
  events

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Study Conclusions

• Treatment with fidaxomicin results in lower rates
  of recurrence and correspondingly improved rate
  of global cure
• Rates of recurrence in non-NAP1 strains are lower
  with fidaxomicin

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Strengths

• Study design
• Study location
• Data monitored and retrieved by a contract
  reasearch organization (INC Research)
• Data from study in regards to treatment of CDI
  with NAP-1 strains, concurrent antibiotic
  therapy, and clinical status resembled other
  studies

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Additional Limitations

• Sponsored by the manufacturers of Dificid
  (Optimer Pharmaceuticals)
• Data analyzed by Optimer Pharmaceuticals
  investigator
• First draft of manuscript written by part-time
  employee of Optimer Pharmaceuticals
• Many definitions relied on subjective data
  (symptomology and opinions) not lab data (GDH, C
  diff toxins)
• No mention about statistical significance of
  clinical cure rates between the two agents in
  regards to more severe infections
• Data included similar factors attributing to
  secondary endpoints of global cure and recurrence
• Where were the authors limitations?

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   Chapter 50. Miscellaneous Antimicrobial Agents
   Disinfectants, Antiseptics, Sterilants. In B.G.
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   Clinical Pharmacology, 12e. Retrieved January 27,
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   px?aID55830289.
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   Difficile Infection, Including Pseudomembranous
   Colitis. In Fauci AS, Kasper DL, Jameson JL,
   Longo DL, Hauser SL, eds. Harrison's Principles
   of Internal Medicine. 18th ed. New York
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   ontent.aspx?aID9119877. Accessed January 29,
   2013.
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   Nicoll D, Pignone M, eds. Pocket Guide to
   Diagnostic Tests. 5th ed. New York McGraw-Hill
   . http//www.accesspharmacy.com/content.aspx?aID3
   139168. Accessed January 29, 2013.
4. Louie TJ, Miller MA, Mullane KM, et al.
   Fidaxomicin versus vancomycin for Clostridium
   difficile infection. N Engl J Med 2011 364
   422-31.
5. Martin S., Jung R. (2011). Chapter 122.
   Gastrointestinal Infections and Enterotoxigenic
   Poisonings. In R.L. Talbert, J.T. DiPiro, G.R.
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   Pharmacotherapy A Pathophysiologic Approach, 8e.
   Retrieved January 27, 2013 from
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   3383.

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rEFERENCES

1. Morse SA, Brooks GF, Carroll KC, Butel JS,
   Mietzner TA. Chapter 11. Spore-Forming
   Gram-Positive Bacilli Bacillus Clostridium
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   Butel JS, Mietzner TA, eds. Jawetz, Melnick,
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   Mietzner TA. Chapter 21. Infections Caused by
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Thank you !
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Definitions

• Clinical cure defined as
• Resolution of diarrhea for 2 consecutive days (lt3
  unformed stools)
• Maintained resolution for duration of therapy
• No further requirement for CDI treatment upon 2nd
  day (or 48 hours) after treatment end
• Patients with marked reduction in number of
  unformed stools at end of treatment, but still
  had mild abdominal discomfort were considered to
  have met clinical cure provided no new CDI
  treatment was required

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Definitions

• Clinical failure defined as
• Persistence of diarrhea
• Need for additional therapy for CDI
• Both of the above
• Global cure defined as
• Resolution of diarrhea without recurrence

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Definitions

• Clinical recurrence defined as
• Reappearance of gt3 diarrheal stools in a 24-hour
  period within 4-weeks after the cessation of
  therapy
• C. difficile toxin A, B, or both, in stool
• Need for retreatment for CDI

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Disease Severity

• Mild disease
• 4-5 unformed BMs/day
• lt12,000 white cell count
• Moderate disease
• 6-9 unformed BMs/day
• 12,001-15,000 white cell count
• Severe disease
• gt10 unformed BMs/day
• gt15,001 white cell count

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Other Outcomes

• Microbiologic evaluation
• Fecal samples for toxins to verify CDI obtained
• Microbiologic testing obtained at time of
• Screening or enrollment
• Early termination
• End-of-therapy visit due to clinical failure
• Visits for the diagnosis and treatment of
  recurrence

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Other Outcomes

• Pharmacokinetic evaluation
• Blood samples obtained before and 3-5 hours after
  first dose of study medication on day 1 and at
  conclusion of therapy
• Fecal samples obtained at conclusion of therapy

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Comparison