Upload
jerome-jennings
View
218
Download
1
Tags:
Embed Size (px)
Citation preview
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.
7.7. Morse SA, Brooks GF, Carroll KC, Butel JS, Mietzner TA. Morse SA, Brooks GF, Carroll KC, Butel JS, Mietzner TA. Chapter 21. Infections Caused by Anaerobic Bacteria. In: Chapter 21. Infections Caused by Anaerobic Bacteria. In: Morse SA, Brooks GF, Carroll KC, Butel JS, Mietzner TA, eds. Morse SA, Brooks GF, Carroll KC, Butel JS, Mietzner TA, eds. Jawetz, Melnick, & Adelberg's Medical Microbiology. 25th Jawetz, Melnick, & Adelberg's Medical Microbiology. 25th ed. New York: McGraw-Hill; 10. ed. New York: McGraw-Hill; 10. http://www.accesspharmacy.com/content.aspx?http://www.accesspharmacy.com/content.aspx?aID=6428842. Accessed January 28, 2013.aID=6428842. Accessed January 28, 2013.
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