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

Preceptor: Dr. Ali RahimiPreceptor: Dr. Ali Rahimi

University of Georgia College of University of Georgia College of PharmacyPharmacy

A Closer Look at A Closer Look at Clostridium difficile Clostridium difficile InfectionsInfections

BackgroundBackground

Clostridium Clostridium speciesspecies>190 species identified>190 species identifiedGram-positiveGram-positiveAnaerobicAnaerobicSpore forming bacilliSpore forming bacilliReleases exotoxins Releases exotoxins

which are associated which are associated with major diseases in with major diseases in humanshumans

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

BackgroundBackground Clostridium tetaniClostridium tetani

Causes tetanus through spread of potent Causes tetanus through spread of potent neurotoxinneurotoxin

Clostridium botulinumClostridium botulinum Causes botulism through spread of potent Causes botulism through spread of potent

neurotoxinsneurotoxins Clostridium perfringensClostridium perfringens

Causes gas gangrene through spread of Causes gas gangrene through spread of necrotizing, hemolytic exotoxinnecrotizing, hemolytic exotoxin

Clostridium difficileClostridium difficile Causes pseudomembranous colitis through Causes pseudomembranous colitis through

production of cytotoxin and enterotoxinproduction of cytotoxin and enterotoxin Relatively resistant to most commonly used Relatively resistant to most commonly used

antibioticsantibiotics Found in normal gut flora Found in normal gut flora

of 2-10% of humansof 2-10% of humans

PathophysiologyPathophysiology

Toxin A, Toxin A, the enterotoxinthe enterotoxin, causes:, causes: Damage to intestinal mucosaDamage to intestinal mucosa Intestinal fluid secretionIntestinal fluid secretion Inflammation via actin disaggregationInflammation via actin disaggregation Intracellular calcium releaseIntracellular calcium release Damage to neurons in the gutDamage to neurons in the gut

Toxin B, Toxin B, the cytotoxinthe cytotoxin, causes:, causes: Depolymerization of filamentous actinDepolymerization of filamentous actin More effective damage to colonic mucosaMore effective damage to colonic mucosa

PathogenesisPathogenesis

Pseudomembranous Pseudomembranous plaques formation plaques formation resulting in resulting in inflammation of mucosainflammation of mucosa

Enlargement and spread Enlargement and spread of plaques through gut of plaques through gut results in clinical results in clinical presentationpresentation Mild to severe diarrheaMild to severe diarrhea Mucosal necrosisMucosal necrosis Accumulation of Accumulation of

inflammatory cells and inflammatory cells and fibrinfibrin

Raised, yellowish-white pseudomembranous plaques

BackgroundBackground

Clostridium difficile Clostridium difficile infection (CDI) is infection (CDI) is the most common cause of infectious the most common cause of infectious diarrhea in hospitalized patientsdiarrhea in hospitalized patients

Once antibiotics disrupt normal gut Once antibiotics disrupt normal gut flora:flora: C. difficile C. difficile colonization occurs colonization occurs Toxins production results in manifestation of Toxins production results in manifestation of

CDICDI Diarrhea and colitis resultsDiarrhea and colitis results

CDI should be suspected in CDI should be suspected in anyany patients patients with diarrhea with recent history of with diarrhea with recent history of antibiotic useantibiotic use

CDI Risk FactorsCDI Risk Factors Clostridium difficile Clostridium difficile infections occur infections occur

most often in high risk groups:most often in high risk groups: Elderly (Elderly (>>65 years old)65 years old) Debilitated Debilitated Immunocompromised Immunocompromised Surgical patientsSurgical patients Nasogastric tubesNasogastric tubes Frequent laxative useFrequent laxative use History of antibiotic useHistory of antibiotic use

CDI RisksCDI Risks CDI can occur during, shortly after, or several CDI can occur during, shortly after, or several

months after the use of broad spectrum months after the use of broad spectrum antimicrobial treatmentantimicrobial treatment

CDI should be suspect in any patients with CDI should be suspect in any patients with diarrhea with recent history of diarrhea with recent history of antibiotic use antibiotic use within the past within the past THREE MONTHSTHREE MONTHS

Patients whose diarrhea began Patients whose diarrhea began 72 HOURS 72 HOURS after hospitalizationafter hospitalization

CDI-Associated CDI-Associated AntimicrobialsAntimicrobials

Broad spectrum antimicrobials Broad spectrum antimicrobials associated with CDIs:associated with CDIs: ClindamycinClindamycin AmpicillinAmpicillin FlouroquinolonesFlouroquinolones

Ciprofloxacin, levofloxacin, moxifloxacinCiprofloxacin, levofloxacin, moxifloxacin

Cephalosporins Cephalosporins (2(2ndnd & 3 & 3rdrd generation) generation) Cefotaxime, ceftriaxone, cefuroxime, Cefotaxime, ceftriaxone, cefuroxime,

ceftazidimeceftazidime

AminoglycosidesAminoglycosides ErythromycinErythromycin TMP-SMXTMP-SMX MetronidazoleMetronidazole VancomycinVancomycin

Used to treat CDI!

Clinical PresentationClinical Presentation

Patients with CDI often present with:Patients with CDI often present with: Watery or perfuse diarrhea (as many as 20 Watery or perfuse diarrhea (as many as 20

bowel movements per day)bowel movements per day) Leukocytosis (50%)Leukocytosis (50%) Fever (28%)Fever (28%) Abdominal pain (22%)Abdominal pain (22%) Ileus (~20%)Ileus (~20%) Pseudomembrane formationPseudomembrane formation MalaiseMalaise NauseaNausea AnorexiaAnorexia

Clinical PresentationClinical Presentation Clinical diagnosis based Clinical diagnosis based

upon diarrhea onset upon diarrhea onset during or after during or after antimicrobial useantimicrobial use

Delay in diagnosis can Delay in diagnosis can result in complications :result in complications : Life-threatening toxic Life-threatening toxic

megacolonmegacolon Pseudomembranous Pseudomembranous

enterocolitisenterocolitis

DiagnosisDiagnosis Pathogens most often responsible for Pathogens most often responsible for

infectious diarrhea or enteritis:infectious diarrhea or enteritis: Shigella Shigella speciesspecies SalmonellaSalmonella species species Escherichia coliEscherichia coli YersiniaYersinia species species VibrioVibrio species species Clostridium difficileClostridium difficile

Other etiologies less commonly seen or in Other etiologies less commonly seen or in extreme cases of immunodeficiencyextreme cases of immunodeficiency Parasites (Parasites (Entamoeba histolyticaEntamoeba histolytica, , Giardia Giardia

lamlialamlia)) Viruses (Cytomegalovirus)Viruses (Cytomegalovirus)

Differential DiagnosisDifferential Diagnosis Stool cultures are crucial to making an Stool cultures are crucial to making an

organism-specific diagnoses and organism-specific diagnoses and determining antimicrobial sensitivitydetermining antimicrobial sensitivity Recommended in patients with inflammatory Recommended in patients with inflammatory

diarrheadiarrhea Poor yield of positive culturesPoor yield of positive cultures If negative, then a 2If negative, then a 2ndnd analysis is recommended analysis is recommended

DiagnosisDiagnosis Detection of toxins Detection of toxins

C. difficile C. difficile toxins A or Btoxins A or B Enzyme assays for Enzyme assays for

Glutamate dehydrogenase Glutamate dehydrogenase (GDH)(GDH)

EndoscopyEndoscopy Reserved when rapid Reserved when rapid

diagnosis is neededdiagnosis is needed Used when ileus is presentUsed when ileus is present Stool samples are Stool samples are

unavailableunavailable Differential diagnoses with Differential diagnoses with

concurrent colonic diseasesconcurrent colonic diseases

Raised, yellowish-white pseudomembranous plaques characteristic of CDI

PreventionPrevention Clostridium difficile Clostridium difficile can be cultured in rooms can be cultured in rooms

of infected individuals of infected individuals UP TO 40 DAYS UP TO 40 DAYS after after dischargedischarge Strict hand washingStrict hand washing Contact precautionsContact precautions Vaccines?Vaccines?

Clostridium difficile Clostridium difficile can be cultured in can be cultured in rooms of infected rooms of infected

individuals individuals

UP TO 40 DAYS UP TO 40 DAYS

after dischargeafter discharge

Is There A Problem?Is There A Problem? Most frequently acquired exogenously from:Most frequently acquired exogenously from:

HospitalHospital Nursing homeNursing home Long-term care facilityLong-term care facility

>>20% fecal colonization among patients 20% fecal colonization among patients hospitalized for >1 weekhospitalized for >1 week C. difficile C. difficile spores can persist for spores can persist for monthsmonths on most on most

surfacessurfaces Risk of colonization increases with length of stayRisk of colonization increases with length of stay

Other risk factors:Other risk factors: Poor hand hygiene of hospital personnelPoor hand hygiene of hospital personnel Use of electronic rectal thermometersUse of electronic rectal thermometers Enteral tube feedingEnteral tube feeding

Why So Serious?Why So Serious? Both the incidence and severity of Both the incidence and severity of

Clostridium difficile Clostridium difficile infections have infections have increased significantlyincreased significantly in the past decadein the past decade

Clostridium difficile Clostridium difficile infection rates in U.S. infection rates in U.S. hospitals hospitals tripledtripled between 2000 and 2005between 2000 and 2005

CDI rates in Canada have CDI rates in Canada have quadrupledquadrupled since since 19971997 Increased rates directly attributed to an increase Increased rates directly attributed to an increase

in mortality from 1.7% to 6.9%in mortality from 1.7% to 6.9%

Why So Serious?Why So Serious? Causality attributed to emergence of specific Causality attributed to emergence of specific

strain-types of outbreaks known strain-types of outbreaks known synonymously as:synonymously as: North American pulsed-field type (NAP-1)North American pulsed-field type (NAP-1) Toxinotype IIIToxinotype III REA type BIREA type BI PCR ribotype 027PCR ribotype 027

Emergence may be explained in part by Emergence may be explained in part by patterns of antibiotic use in hospitalspatterns of antibiotic use in hospitals

CDI EpidemicCDI Epidemic North American pulsed-field type (NAP-1)North American pulsed-field type (NAP-1)

Highly resistant to fluoroquinolonesHighly resistant to fluoroquinolones Carries deletion mutations in toxin regulatory Carries deletion mutations in toxin regulatory

genegene Results in Results in higher levels of toxin higher levels of toxin productionproduction

16 to 23 times more toxin A and B!16 to 23 times more toxin A and B!

Results in significantly Results in significantly more serious diseasemore serious disease More resistant More resistant to standard therapyto standard therapy

FluoroquinolonesFluoroquinolones Most recent drug class implicated in hospital Most recent drug class implicated in hospital

outbreaks of outbreaks of C. difficileC. difficile infections infections Increasing fluoroquinolone resistance seen Increasing fluoroquinolone resistance seen

in:in: Campylobacter, Salmonella, Campylobacter, Salmonella, Clostridium difficileClostridium difficile

TreatmentTreatment

TreatmentTreatment

Discontinue offending Discontinue offending agentagent

Diarrhea may resolve in up to 25% of Diarrhea may resolve in up to 25% of patients within 48 hours of patients within 48 hours of discontinuationdiscontinuation

Fluid and electrolyte replacement as Fluid and electrolyte replacement as necessarynecessary

Most patients will require antibioticsMost patients will require antibiotics VancomycinVancomycin Metronidazole Metronidazole

TreatmentTreatment

Vancomycin (Oral)Vancomycin (Oral) IV does not achieve high enough gut IV does not achieve high enough gut

concentrationsconcentrations Contraindications, intolerance, or poor Contraindications, intolerance, or poor

response to metronidazoleresponse to metronidazole Retention enema delivery if ileus or inability to Retention enema delivery if ileus or inability to

reach infection sitereach infection site Concerns of vancomycin resistant enterococci Concerns of vancomycin resistant enterococci

(VRE)(VRE)

MetronidazoleMetronidazole Drug of choice for mild to moderate CDIDrug of choice for mild to moderate CDI Less expensiveLess expensive

CDI Treatment GuidelinesCDI Treatment Guidelines Published by IDSA in 2010Published by IDSA in 2010 Metronidazole 500mg PO TID for 10-14 daysMetronidazole 500mg PO TID for 10-14 days

For mild to moderate CDIFor mild to moderate CDI Vancomycin 125mg PO QID for 10-14 daysVancomycin 125mg PO QID for 10-14 days

For initial episode of severe CDIFor initial episode of severe CDI Vancomycin +/- 500mg metronidazole IVVancomycin +/- 500mg metronidazole IV

For severe, complicated CDIFor severe, complicated CDI Vancomycin dose is 500mg PO QID + 500mg IV in Vancomycin dose is 500mg PO QID + 500mg IV in

100mL NS rectally100mL NS rectally

Treatment Treatment

Contraindicated Contraindicated RegimensRegimens

Drugs that inhibit peristalsis or slow gut Drugs that inhibit peristalsis or slow gut transit time transit time should should NOTNOT be used be used in in patients with fever or bloody stoolpatients with fever or bloody stool DiphenoxylateDiphenoxylate LoperamideLoperamide

Evidence to support an increase risk for Evidence to support an increase risk for development of hemolytic-uremic development of hemolytic-uremic syndrome due to delayed intestinal syndrome due to delayed intestinal clearance and increased toxin absorption clearance and increased toxin absorption

RecurrenceRecurrence Treatments similar in diarrhea resolution, Treatments similar in diarrhea resolution,

incidence of side effects, and relapse ratesincidence of side effects, and relapse rates Relapse occurs in approximately 20% of Relapse occurs in approximately 20% of

patientspatients Relapse usually occurs within 1 to 2 weeks Relapse usually occurs within 1 to 2 weeks

but can be delayed for up to 12 weeksbut can be delayed for up to 12 weeks Frequency increases with subsequent Frequency increases with subsequent

recurrencesrecurrences One prior episode: >40% recurrence riskOne prior episode: >40% recurrence risk >>2 prior episodes: >60% recurrence risk2 prior episodes: >60% recurrence risk

RecurrenceRecurrence Risk factors for recurrence:Risk factors for recurrence:

History of recurrenceHistory of recurrenceAdvancing ageAdvancing ageAdditional antimicrobialsAdditional antimicrobialsInadequate immune Inadequate immune

response to response to C. difficileC. difficile toxins toxins

Recurrence & TreatmentRecurrence & Treatment Optimal management of multiple relapses is Optimal management of multiple relapses is

unclearunclear Alternative regimens:Alternative regimens:

Fecal transplantationFecal transplantation Vancomycin + rifampinVancomycin + rifampin Vancomycin followed by rifaximinVancomycin followed by rifaximin NitazoxanideNitazoxanide IVIGIVIG

Poor regimensPoor regimens Bacitracin, cholestyramine, colestipol, fusidic acid, Bacitracin, cholestyramine, colestipol, fusidic acid,

probioticsprobiotics

There is more than There is more than just just C. difficile C. difficile amidst normal gut amidst normal gut floraflora

Further disruption Further disruption of gut flora only of gut flora only causes causes susceptibility to susceptibility to other infectionsother infections

RecurrenceRecurrence

Where is the

selective agent?

Treatment Failure & Treatment Failure & RecurrenceRecurrence

Resistance to antimicrobials is Resistance to antimicrobials is rarely the cause of relapserarely the cause of relapse

Relapse occurs because treatment:Relapse occurs because treatment: Fails to eliminate Fails to eliminate C. difficile C. difficile sporesspores Makes patients vulnerable to another Makes patients vulnerable to another

infection by impairing normal florainfection by impairing normal flora

CDI Treatment GuidelinesCDI Treatment Guidelines Fidaxomicin?Fidaxomicin?

Fidaxomicin (Dificid)Fidaxomicin (Dificid) Narrow spectrumNarrow spectrum, macrocyclic antibiotic active , macrocyclic antibiotic active

against gram-positive aerobes and anarobesagainst gram-positive aerobes and anarobes Lacks activity Lacks activity against gram-negative bacteriaagainst gram-negative bacteria PoorPoor activity against normal gut flora activity against normal gut flora Relatively Relatively selective activity selective activity against against C. difficileC. difficile Inhibits bacterial protein synthesis by binding to Inhibits bacterial protein synthesis by binding to

sigma subunit of RNA polymerasesigma subunit of RNA polymerase Negligible systemic absorption with oral Negligible systemic absorption with oral

administrationadministration HighHigh fecal concentrations fecal concentrations

Fidaxomicin (Dificid)Fidaxomicin (Dificid) As effective as vancomycin and may be associated As effective as vancomycin and may be associated

with lower rates of relapsewith lower rates of relapse 11stst antimicrobial FDA approved by the FDA for antimicrobial FDA approved by the FDA for CDI CDI

treatment in over 25 yearstreatment in over 25 years Orphan drug designation to all formulations for Orphan drug designation to all formulations for

treatment of CDI in pediatric patients treatment of CDI in pediatric patients <<16 years and 16 years and youngeryounger

Administered 200mg PO BIDAdministered 200mg PO BID

Fidaxomicin versus Fidaxomicin versus Vancomycin for Vancomycin for Clostridium Clostridium difficile difficile InfectionInfection

Published in February 2011!Published in February 2011!

Study DesignStudy Design

Prospective, multi-centered, double-Prospective, multi-centered, double-blind, randomized, parallel-group trialblind, randomized, parallel-group trial

Non-inferiority studyNon-inferiority study All patients were enrolled at 52 sites in All patients were enrolled at 52 sites in

the United States and 15 sites in Canadathe United States and 15 sites in CanadaConducted from May 2006 to August 2008Conducted from May 2006 to August 2008

Grading Grading RecommendationsRecommendations

Eligibility CriteriaEligibility Criteria >> 16 years of age 16 years of age Diagnosis of CDIDiagnosis of CDI

Presence of diarrhea defined as >3 unformed bowel Presence of diarrhea defined as >3 unformed bowel movements in a 24-hour periodmovements in a 24-hour period

Presence of Presence of C. difficile C. difficile toxin A, B, or both in stool sample toxin A, B, or both in stool sample obtained within 48 hours of randomizationobtained within 48 hours of randomization

Could not be recipient of any potentially effective Could not be recipient of any potentially effective concurrent CDI treatmentsconcurrent CDI treatmentsOral bacitracin, fusidic acid, rifaximinOral bacitracin, fusidic acid, rifaximin

Exclusion CriteriaExclusion Criteria

Patients receiving any potentially effective concurrent Patients receiving any potentially effective concurrent CDI treatmentsCDI treatmentsOral bacitracin, fusidic acid, rifaximinOral bacitracin, fusidic acid, rifaximin

Patients with:Patients with:Life-threatening or fulminant CDILife-threatening or fulminant CDIToxic megacolonToxic megacolonPrevious exposure to fidaxomicinPrevious exposure to fidaxomicinHistory of ulcerative colitis or Crohn’s diseaseHistory of ulcerative colitis or Crohn’s disease>1 occurrence of CDI within 3 months before study start>1 occurrence of CDI within 3 months before study start

Efficacy OutcomesEfficacy Outcomes Primary endpointPrimary endpoint

Rate of Rate of clinical cure clinical cure in the modified intention-to-treat in the modified intention-to-treat and per-protocol populations at the end of therapy or at and per-protocol populations at the end of therapy or at the time of early withdrawalthe time of early withdrawal

Secondary endpointsSecondary endpointsRecurrenceRecurrence of CDI during 28-day period after the end of of CDI during 28-day period after the end of

the course of therapythe course of therapyGlobal cure Global cure in the modified intention-to-treat and per-in the modified intention-to-treat and per-

protocol populationsprotocol populations

TreatmentTreatment

Randomized into two groupsRandomized into two groupsVancomycin 125mg every 6 hoursVancomycin 125mg every 6 hoursFidaxomicin 200mg every 12 hoursFidaxomicin 200mg every 12 hours

Dosing scheduled with placebo for q6h dosingDosing scheduled with placebo for q6h dosing

Both medications were over-encapsulated Both medications were over-encapsulated to conceal identitiesto conceal identities

Oral dosing for 10 daysOral dosing for 10 days

DefinitionsDefinitions Modified intention-to-treat (MITT) populationModified intention-to-treat (MITT) population

Patients with documented CDI who underwent Patients with documented CDI who underwent randomization and randomization and received at least one dose of received at least one dose of study medicationstudy medication

Per-protocol populationPer-protocol population Patients who received Patients who received >>1 dose of fidaxomicin who 1 dose of fidaxomicin who

received treatment for >3 days (treatment failure) received treatment for >3 days (treatment failure) or >8 days (clinical cure)or >8 days (clinical cure)

Documented adherence to protocolDocumented adherence to protocol Underwent end-of-therapy evaluationUnderwent end-of-therapy evaluation

Study EnrollmentStudy Enrollment

629 patients enrolled and randomized629 patients enrolled and randomized 596 included in modified intention-to-treat 596 included in modified intention-to-treat

analysis (received analysis (received >> 1 dose of Dificid) 1 dose of Dificid) 548 included in per-protocol analysis548 included in per-protocol analysis

RandomizationRandomization

Follow-upFollow-up

Follow-upFollow-up

Assessed daily for clinical cure or Assessed daily for clinical cure or clinical failureclinical failure

Assessed weekly for 28 days after Assessed weekly for 28 days after last dose for recurrencelast dose for recurrence Only patients who remained in the study Only patients who remained in the study

and had a follow-up assessment between and had a follow-up assessment between days 36 and 40 after randomizationdays 36 and 40 after randomization

PatientsPatients

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

Statistical AnalysisStatistical Analysis Rate of clinical cure (Primary endpoint)Rate of clinical cure (Primary endpoint)

Non-inferiority margin of -10 percentage pointsNon-inferiority margin of -10 percentage points If within 10-percentage points, then non-inferiorIf within 10-percentage points, then non-inferior

Recurrence and overall cure (Secondary Recurrence and overall cure (Secondary endpoint)endpoint) Post hoc hypothesis testsPost hoc hypothesis tests Based upon age, inpatient vs outpatient status, prior Based upon age, inpatient vs outpatient status, prior

occurrence, disease severity, and strain typeoccurrence, disease severity, and strain type

Time to resolution of diarrheaTime to resolution of diarrhea Kaplan-Meier methodKaplan-Meier method Gehan-Wilcoxon test for comparison of resolution Gehan-Wilcoxon test for comparison of resolution

timestimes

ResultsResults

Primary EndpointPrimary Endpoint

Rate of clinical cureRate of clinical cureSubgroup analyses based patient Subgroup analyses based patient

characteristics showed characteristics showed no statistical no statistical differences between treatments differences between treatments in in either treatment groups in both study either treatment groups in both study populationspopulations

Secondary EndpointsSecondary Endpoints RecurrenceRecurrence of CDI of CDI

Treatment with fidaxomicin Treatment with fidaxomicin Associated with a Associated with a significantly lower rate of significantly lower rate of

recurrencerecurrenceLower rates of recurrence Lower rates of recurrence with Non-NAP-1 with Non-NAP-1

strainsstrains(69% relative reduction) (69% relative reduction)

TreatmentTreatment with vancomycinwith vancomycinAssociated with a significantly higher recurrenceAssociated with a significantly higher recurrence3.3 times higher rates with Non-NAP-1 strains3.3 times higher rates with Non-NAP-1 strains

Secondary EndpointsSecondary Endpoints Global cure Global cure or resolution of diarrhea without or resolution of diarrhea without

recurrencerecurrence Fidaxomicin resulted in significantly higher global Fidaxomicin resulted in significantly higher global

cure rates than vancomycincure rates than vancomycin Median Median time to resolve diarrhea time to resolve diarrhea was shorter in the was shorter in the

fidaxomicin group than the vancomycin groupfidaxomicin group than the vancomycin group Not statistically significantNot statistically significant

Overall OutcomesOverall Outcomes

SafetySafety SafetySafety

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

Study ConclusionsStudy Conclusions Treatment with fidaxomicin results in lower Treatment with fidaxomicin results in lower

rates of recurrence and correspondingly rates of recurrence and correspondingly improved rate of global cureimproved rate of global cure

Rates of recurrence in non-NAP1 strains are Rates of recurrence in non-NAP1 strains are lower with fidaxomicinlower with fidaxomicin

StrengthsStrengths Study designStudy design Study locationStudy location Data monitored and retrieved by a contract Data monitored and retrieved by a contract

reasearch organization (INC Research)reasearch organization (INC Research) Data from study in regards to treatment of CDI Data from study in regards to treatment of CDI

with NAP-1 strains, concurrent antibiotic with NAP-1 strains, concurrent antibiotic therapy, and clinical status resembled other therapy, and clinical status resembled other studiesstudies

Additional LimitationsAdditional Limitations

Sponsored by the manufacturers of Dificid Sponsored by the manufacturers of Dificid (Optimer Pharmaceuticals)(Optimer Pharmaceuticals)

Data analyzed by Optimer Pharmaceuticals investigatorData analyzed by Optimer Pharmaceuticals investigator First draft of manuscript written by part-time employee First draft of manuscript written by part-time employee

of Optimer Pharmaceuticalsof Optimer Pharmaceuticals Many definitions relied on subjective data Many definitions relied on subjective data

(symptomology and opinions) not lab data (GDH, (symptomology and opinions) not lab data (GDH, C diffC diff toxins)toxins)

No mention about statistical significance of clinical cure No mention about statistical significance of clinical cure rates between the two agents in regards to more rates between the two agents in regards to more severe infectionssevere infections

Data included similar factors attributing to secondary Data included similar factors attributing to secondary endpoints of global cure and recurrenceendpoints of global cure and recurrence

Where were the author’s limitations?Where were the author’s limitations?

REFERENCESREFERENCES1.1. Deck D.H., Winston L.G., Winston L.G. (2012). Chapter 50. Deck D.H., Winston L.G., Winston L.G. (2012). Chapter 50.

Miscellaneous Antimicrobial Agents; Disinfectants, Antiseptics, & Miscellaneous Antimicrobial Agents; Disinfectants, Antiseptics, & Sterilants. In B.G. Katzung, S.B. Masters, A.J. Trevor (Eds), Basic & Sterilants. In B.G. Katzung, S.B. Masters, A.J. Trevor (Eds), Basic & Clinical Pharmacology, 12e. Retrieved January 27, 2013 from Clinical Pharmacology, 12e. Retrieved January 27, 2013 from http://www.accesspharmacy.com/content.aspx?aID=55830289.http://www.accesspharmacy.com/content.aspx?aID=55830289.

2.2. Gerding DN, Johnson S. Chapter 129. Clostridium Difficile Infection, Gerding DN, Johnson S. Chapter 129. Clostridium Difficile Infection, Including Pseudomembranous Colitis. In: Fauci AS, Kasper DL, Including Pseudomembranous Colitis. In: Fauci AS, Kasper DL, Jameson JL, Longo DL, Hauser SL, eds. Harrison's Principles of Jameson JL, Longo DL, Hauser SL, eds. Harrison's Principles of Internal Medicine. 18th ed. New York: McGraw-Hill; 2012. Internal Medicine. 18th ed. New York: McGraw-Hill; 2012. http://www.accesspharmacy.com/content.aspx?aID=9119877. http://www.accesspharmacy.com/content.aspx?aID=9119877. Accessed January 29, 2013.Accessed January 29, 2013.

3.3. Jang J. Microbiology. In: McPhee SJ, Lu CM, Nicoll D, Pignone M, eds. Jang J. Microbiology. In: McPhee SJ, Lu CM, Nicoll D, Pignone M, eds. Pocket Guide to Diagnostic Tests. 5th ed. New York: McGraw-Hill; . Pocket Guide to Diagnostic Tests. 5th ed. New York: McGraw-Hill; . http://www.accesspharmacy.com/content.aspx?aID=3139168. http://www.accesspharmacy.com/content.aspx?aID=3139168. Accessed January 29, 2013.Accessed January 29, 2013.

4.4. Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011; vancomycin for Clostridium difficile infection. N Engl J Med 2011; 364: 422-31.364: 422-31.

5.5. Martin S., Jung R. (2011). Chapter 122. Gastrointestinal Infections Martin S., Jung R. (2011). Chapter 122. Gastrointestinal Infections and Enterotoxigenic Poisonings. In R.L. Talbert, J.T. DiPiro, G.R. and Enterotoxigenic Poisonings. In R.L. Talbert, J.T. DiPiro, G.R. Matzke, L.M. Posey, B.G. Wells, G.C. Yee (Eds), Pharmacotherapy: A Matzke, L.M. Posey, B.G. Wells, G.C. Yee (Eds), Pharmacotherapy: A Pathophysiologic Approach, 8e. Retrieved January 27, 2013 from Pathophysiologic Approach, 8e. Retrieved January 27, 2013 from http://www.accesspharmacy.com/content.aspx?aID=8003383.http://www.accesspharmacy.com/content.aspx?aID=8003383.

REFERENCESREFERENCES6.6. Morse SA, Brooks GF, Carroll KC, Butel JS, Mietzner TA. Morse SA, Brooks GF, Carroll KC, Butel JS, Mietzner TA.

Chapter 11. Spore-Forming Gram-Positive Bacilli: Bacillus & Chapter 11. Spore-Forming Gram-Positive Bacilli: Bacillus & Clostridium Species. In: Morse SA, Brooks GF, Carroll KC, Clostridium Species. In: Morse SA, Brooks GF, Carroll KC, Butel JS, Mietzner TA, eds. Jawetz, Melnick, & Adelberg's Butel JS, Mietzner TA, eds. Jawetz, Melnick, & Adelberg's Medical Microbiology. 25th ed. New York: McGraw-Hill; 10. Medical Microbiology. 25th ed. New York: McGraw-Hill; 10. http://www.accesspharmacy.com/content.aspx?http://www.accesspharmacy.com/content.aspx?aID=6427523. Accessed January 28, 2013.aID=6427523. Accessed January 28, 2013.

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8.8. Olsen K.M., HUTCHINS G. . (2011). Chapter 38. Evaluation of Olsen K.M., HUTCHINS G. . (2011). Chapter 38. Evaluation of the Gastrointestinal Tract. In R.L. Talbert, J.T. DiPiro, G.R. the Gastrointestinal Tract. In R.L. Talbert, J.T. DiPiro, G.R. Matzke, L.M. Posey, B.G. Wells, G.C. Yee (Eds), Matzke, L.M. Posey, B.G. Wells, G.C. Yee (Eds), Pharmacotherapy: A Pathophysiologic Approach, 8e. Pharmacotherapy: A Pathophysiologic Approach, 8e. Retrieved January 27, 2013 from Retrieved January 27, 2013 from http://www.accesspharmacy.com/content.aspx?http://www.accesspharmacy.com/content.aspx?aID=7977385.aID=7977385.

Thank you !Thank you !

DefinitionsDefinitions Clinical cure Clinical cure defined asdefined as::

Resolution of diarrhea for 2 consecutive days Resolution of diarrhea for 2 consecutive days ((<<3 unformed stools)3 unformed stools)

Maintained resolution for duration of therapyMaintained resolution for duration of therapyNo further requirement for CDI treatment No further requirement for CDI treatment

upon 2upon 2ndnd day (or 48 hours) after treatment day (or 48 hours) after treatment end*end*

Patients with marked reduction in number of Patients with marked reduction in number of unformed stools at end of treatment, but still unformed stools at end of treatment, but still had mild abdominal discomfort were had mild abdominal discomfort were considered to have met clinical cure considered to have met clinical cure provided provided no new CDI treatment was requiredno new CDI treatment was required

DefinitionsDefinitions

Clinical failure Clinical failure defined asdefined as::Persistence of diarrheaPersistence of diarrheaNeed for additional therapy for CDINeed for additional therapy for CDIBoth of the above*Both of the above*

Global cure Global cure defined as:defined as:Resolution of diarrhea without recurrenceResolution of diarrhea without recurrence

DefinitionsDefinitions

Clinical Clinical recurrence recurrence defined as:defined as:Reappearance of Reappearance of >>3 diarrheal stools in a 3 diarrheal stools in a

24-hour period within 4-weeks after the 24-hour period within 4-weeks after the cessation of therapycessation of therapy

C. difficile C. difficile toxin A, B, or both, in stooltoxin A, B, or both, in stoolNeed for retreatment for CDINeed for retreatment for CDI

Disease SeverityDisease Severity Mild diseaseMild disease

4-5 unformed BMs/day4-5 unformed BMs/day <<12,000 white cell count12,000 white cell count

Moderate diseaseModerate disease 6-9 unformed BMs/day6-9 unformed BMs/day 12,001-15,000 white cell count12,001-15,000 white cell count

Severe diseaseSevere disease >>10 unformed BMs/day10 unformed BMs/day >>15,001 white cell count15,001 white cell count

Other OutcomesOther Outcomes Microbiologic evaluationMicrobiologic evaluation

Fecal samples for toxins to verify CDI obtainedFecal samples for toxins to verify CDI obtainedMicrobiologic testing obtained at time of:Microbiologic testing obtained at time of:

Screening or enrollmentScreening or enrollmentEarly terminationEarly terminationEnd-of-therapy visit due to clinical failureEnd-of-therapy visit due to clinical failureVisits for the diagnosis and treatment of recurrenceVisits for the diagnosis and treatment of recurrence

Other OutcomesOther Outcomes Pharmacokinetic evaluationPharmacokinetic evaluation

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

Fecal samples obtained at conclusion of Fecal samples obtained at conclusion of therapytherapy

ComparisonComparison