ADVANCED PPE

NERMINE CHOUMANE

PRESENTED TO: Dr. Diana Malaeb, Pharm D Chair

LEBANESE INTERNATIONAL UNIVERSITY

SCHOOL OF PHARMACY

FALL 2012

4/24/2013

OUTLINE

I. Background

II. Journal club evaluation

a. Journal evaluation

b. Title evaluation

c. Authors evaluation

d. Abstract

e. Introduction

1. Trial funding

2. Rationale

3. Objective

4. Hypothesis

5. Reference

OUTLINE

f. Methods

1. Study design

2. Study population

3. Randomization & Treatment

4. Outcomes

a. Efficacy

b. Microbiology

c. Pharmacokinetic

5. Safety

6. Statistical analysis

OUTLINE

g. Result

1. Patient

2. Clinical outcomes

3. Safety

4. Microbiology

5. Pharmacokinetic

h. Discussion

1. Author’s comments

2. Strengths

3. Limitations

4. Author’s conclusion

III. Conclusion

IV. Other studies

A VIEW OVER

BACKGROUND

• Clostridium difficile (C. difficile) is a gram positive, spore‐forming anaerobic bacillus

• It is the leading cause of healthcare‐associated diarrhea

• It is the primary infective cause of antibiotic-associated diarrhea

• It has been responsible for a large number of outbreaks in hospitals

BACKGROUND

• CDI appears to be increasing in populations that are at low & high risk

• This can be attributed to emergence of hypervirulentstrain of C. difficile

(NAP1/BI/027)

North American pulse-field gel electrophoresis type 1 (NAP1),

Restriction endonuclease type BI,

Polymerase chain reaction ribotype 027

BACKGROUND – SIGNS & SYMPTOMS -

• CDI may be asymptomatic, but if symptoms are present, they may range in severity from mild-moderate diarrhea to life‐threatening pseudomembranous colitis

• Patients with healthcare‐associated CDI may experience ≥ 1of the following complications:

1. Clinical dehydration

2. Hypokalemia

3. Mild gastrointestinal bleeding

4. Ileus

BACKGROUND – COMPLICATIONS -

• Complications of severe CDI include:

1. Bowel perforation

2. Hypotension

3. Renal failure

4. Sepsis & Death

• CDI has been associated with:

1. Additional diagnostic and interventional procedures

2. Additional length of stay in hospital

3. Higher total hospital costs

BACKGROUND – TRANSMISSION -

• Transmission of C. difficile occurs primarily

through the fecal‐oral route following transient

contamination of the hands of healthcare

workers and patients/residents

• Contamination of the care environment also

plays a major role in the spread of C. difficile

BACKGROUND – RISK FACTORS -

• Risk Factors for CDI:

1. History of antibiotic use, particularly fluoroquinolones

2. Bowel disease/surgery

3. Chemotherapy

4. Prolonged hospitalization

5. Treatment with PPI

6. Immunosuppressive therapy

7. History of CDI

8. Recent surgery

9. Increased age

BACKGROUND – DIAGNOSIS -

• A patient is identified as a CDI case if:

1. S/He has diarrhea, fever, abdominal pain and/or ileus,

+a laboratory confirmation of a positive toxin assay for C. difficile

OR

2. S/He has a diagnosis of pseudomembranes on sigmoidoscopyor colonoscopy or histological/pathological diagnosis of CDI

OR

3. S/He has a diagnosis of toxic megacolon

• Toxin testing is most important clinically, but is hampered by its lack of sensitivity

• To overcome this problem =>

2-step method that uses EIA detection of glutamate

dehydrogenase (GDH) as initial screening and then uses the

cell cytotoxicity assay or toxigenic culture as the confirmatory

test for GDH-positive stool specimens only

• Results appear to differ based on the GDH kit used; therefore, until more data are available on the sensitivity of GDH testing, this approach remains an interim recommendation

BACKGROUND – DIAGNOSIS -

BACKGROUND – PREVENTION -

• Transmission of CDI can be prevented by strict

adherence to routine practices and additional

precautions

• Practices that are critical to prevent transmission of

CDI include:

1. Appropriate use of personal protective

equipment (PPE)

2. Hand hygiene

3. Appropriate cleaning and disinfection of

environmental surfaces and equipment

BACKGROUND – PREVENTION -

• Administration of currently available probioticsis not recommended to prevent primary CDI

=> limited data + potential risk of bloodstream

infection

• Minimize the frequency and duration of antimicrobial therapy and the number of antimicrobial agents prescribed, to reduce CDI risk

BACKGROUND– TREATMENT -

• Medical Management of Clostridium difficile Infection:

Do not treat symptom‐free carriers of C. difficile

Discontinue antibiotics if possible, or consider changing to a lower CDI risk group of antibiotics such as aminoglycosides,TMP/SMX, tetracyclines, and/or metronidazole

Do not use antidiarrheals (e.g. loperamide [Immodium], diphenoxylate [Lomotil])

Supportive therapy with intravenous fluids and electrolytes may be sufficient to relieve symptoms

BACKGROUND– TREATMENT -

When severe or complicated CDI is suspected, initiate empirical treatment as soon as the diagnosis is suspected

If the stool toxin assay result is negative, the decisionto initiate, stop, or continue treatment must be individualized

Gastric acid suppression &(PPIs) have also been recognized as a risk factor for CDI and should be used selectively

Antimicrobial has been shown to be the single most successful strategy for preventing CDI

Dosages must be given orally in order to be fully effective in the gut

BACKGROUND– TREATMENT -

DOC if initial M-M CDI =>

Metronidazole 500 mg po tid for 10–14 days

DOC if initial Severe CDI =>

Vancomycin 125 mg po qid for 10–14 days

DOC if Severe complicated CDI =>

Vancomycin 500mg po qid /500 mg in 100 ml NS per rectum q.6hrs (if ileus is present)

+/-

Metronidazole 500 mg IV q.8hrs

BACKGROUND– TREATMENT -

If Severely ill patients =>

Colectomy

If first recurrence of CDI =>

Treat with the same regimen as for the initial

episode

If second or later recurrence of CDI =>

vancomycin therapy using a tapered and/or pulse regimen

BACKGROUND– OLDER TREATMENT -

Rifampin

Nitazoxanide

Rifaximin

Tigecycline

BACKGROUND– OTHER TREATMENT -

IVIG =>

Currently the only available antibody that could potentially be used for

treatment of CDI; Retrospective analyses have examined the use of IVIG single or repeated doses of 125 to 400 mg/kg in severe or recurrent CDI and have not shown a benefit

Monoclonal Antibodies

Use of 2 monoclonal antibodies against toxins A and B administered together in a Phase 2, randomized clinical trial

=> Lower recurrence rate in the monoclonal antibody group Vs

placebo

Vaccines =>

C. difficile toxoid-based vaccine being developed by Sanofi Pasteur is currently being studied in a Phase 2, randomized trial

Fidaxomicin

recently approved for treatment of this infection in the USA in May, 2011,

and in Europe in December, 2011

4/24/2013

A VIEW OVER

Fidaxomicin Vancomycin

Brands Dificid® - Vancocin® HCL Pulvules

- Vancocin ®HCL

- Vancoled®

- Vancolon®

Dosage form/

Strength

- Oral tablet 200mg - IV Powder for Solution:

1, 5, 10, 500, 750mg

- Oral Powder for

suspension: 250mg/5ml,

500mg/6ml

- Oral Capsule: 125, 250mg

FDA labeled indications - Clostridium difficile-

associated diarrhea

( only for adults)

- Antibiotic induced

pseudomembranous

enterocolitis – Clostridium

difficile infection

- Infective endocarditis

- Lower respiratory tract infection

- Staphylococcal enterocolitis

- Staphylococcal infectious

disease, Methicillin - resistant

Non-FDA labeled

indications

- None - Bacterial meningitis

MOA

- Locally acting bactericidal

macrolide antibiotic

primarily active against

Clostridia species including

Clostridium difficile via RNA

polymerase inhibition

- Tricyclic glycopeptide bactericidal

antibiotic inhibiting cell wall and

RNA synthesis

Adult Dose - 200mg orally

twice a day with or

without food for 10

days

- Antibiotic induced

pseudomembranous

enterocolitis: 500mg – 2g

orally daily divided every 6-

8hrs => 125mg q.6hrs

Pediatric dose - Not studied in patients <18

years old

- Antibiotic induced

pseudomembranous enterocolitis:

40mg/kg/d orally divided every 6-

8hrs for 7-10days; Maxim 2g/d

- east 60min in the first week of life

and every 8hrs thereafter up to age

of 1Month

Dose Adjustment

- Renal Failure:

None

- Hepatic Failure:

None

- Renal Failure(Adult & Pediatric):

15mg/kg as initial dose then

optimal dose and interval based on

serum drug concentration

- Hepatic Failure:

None

If missed a

dose/forget to use

your medicine

- Use it as soon as you can

- If it’s almost time for your

next dose, wait until then

to use the medicine and

skip the missed dose

- Do not use extra medicine

to make up for a missed

dose

- Use it as soon as you can

- If it’s almost time for your

next dose, wait until then to

use the medicine and skip

the missed dose

Do not use extra medicine to

make up for a missed dose

Storage & Stability - Store the medicine in a

closed container at room

temperature, away from

heat, moisture and direct

light

- Keep it away from children

and never share your

medicine with anyone

- Store the medicine in a closed

container at room

temperature, away from heat,

moisture and direct light

- Keep it away from children

and never share your

medicine with anyone

- After reconstitution, may

refrigerate for 14 days

Absorption - Minimal - Minimal

PPB - 31% - 55%

T1/2 - Drug: 11.7hrs

- Metabolite (OP-

1118): 11.2hrs

- 6hrs

Excretion - Feces >92%

- Urine= 0.59%

- Urine = 80-90%

Metabolism - Independent of

CYP450

- Independent of

CYP450

CI- Not determined - Allergy to corn/corn products

- Hypersensitivity to Vancomycin

Caution- Fidaxomicin is minimally

absorbed and should not

be used for treatment of

systemic infections

- Use of Fidaxomicin in the

absence of C.difficile

infection is not expected to

benefit patients and may

promote development of

drug resistant bacteria

- Drug eruption, pruritus, and

rash reported rarely

- Not effective by the oral route

for other types of infections

- Rapid bolus administration

may cause hypotension and

cardiac arrest (rare); administer

in diluted solution over a period

not <60 min

- Ototoxicity reported; caution

with underlying hearing loss

and amynoglycosides; Caution

with renal insufficiency and

adjust dose with renal

dysfunction

Caution - Pseudomembranous colitis

reported. May result in bacterial

resistance with prolonged use or

use in the absence of a

proven/suspected bacterial

infection or a prophylactic

indication; take appropriate

measures if superinfection

develops

- Reversible neutropenia reported;

monitor leukocyte count

periodically

- Thrombophlebitis may occur;

infuse slowly and rotate injection

sites and avoid IM injection

- Caution in elderly

Side effects- Common:

1) Nausea

2) Vomiting

3) Abd pain

4) GI hemorrhage

5) Anemia

6) Neutropenia

- Rare:

1) Pruritus & Rash

2) Hyperglycemia

3) Metab Acidosis

4) Abd distention/tenderness

5) Dysphagia

6) Bowel obstruction

7) Flatulence

8) Megacolon

9) Abn LFTs & ALP

- Common:

1) Nausea

2) Vomiting

- Serious:

1) Anaphylactic/anaphylactoid rxns

2) Hypotension, severe (rapid IV use)

3) Thrombophlebitis tissue necrosis (if

extravasated)

4) Vasculitis

5) Stevens-Johnson syndrome

6) Toxic epidermal necrolysis

7) Rash w/ eosinophilia and systemic sx

8) Interstitial nephritis

9) Nephrotoxicity

10) Ototoxicity

11) Neutropenia

12) Thrombocytopenia

13) Superinfection

14) Clostridium difficile associated diarrhea

DDI/ FDI - Metabolism of fidaxomicin

and formation of its main

metabolite (OP-1118) not

dependent on CYP

isoenzymes

- Fidaxomicin and OP-1118

are substrates of P-

glycoprotein (P-gp) transport

system.

A pharmacokinetic study

with co-administration of

fidaxomicin and a potent P-

gp inhibitor, cyclosporine,

was conducted

Fidaxomicin plasma levels

were increased, but not

clinically significant.

- Aminoglycosides, oral/

parenteral

- Bacitracin

- Clofarabine

- Colistimethate

- Succinylcholines

- Warfarin

- Gallium nitrate

- Polymyxin B

- Tenofovir disoproxil

- Typhoid vaccine, live oral

- Antivirals

Pregnancy &

Lactation

- Category B

- Unknown if crosses

placenta and if it’s

excreted in human milk

- Category C

- In breastfeeding, infant risk

cannot be ruled out

Monitor - Resolution of S&S of

Clostridium difficile

infection is indicative of

efficacy

- Hypersensitivity reactions (eg,

Stevens-Johnson syndrome,

vasculitis)

- Infusion reactions (eg,

hypotension, arrhythmias, "red

neck")

- Thrombophlebitis

- Ototoxicity

- Renal function

- Diarrhea

- Pseudomembranous colitis

- Neutropenia

- Superinfection infusion

Monitor - Chemical peritonitis

(intraperitoneal route)

- Leukocyte count periodically

- >10 mcg/mL (trough, adult)

- 5-10 mcg/mL (trough,

neonate/child)

- 25-40 mcg/mL (peak,

neonate/child)

- Toxic Levels: >20 mcg/mL

(trough)

- Toxic Levels: >40 mcg/mL

(peak)

- Timing:

1. Trough just before next

dose

2. Peak 60min post

infusion

JOURNAL CLUB EVALUATION

• The New England Journal of Medicine (NEJM) is

an English-Language peer reviewed medical

journal published by the Massachusetts

Medical Society

• It describes itself as the oldest continuously

published medical journal in the world

• Established in 1812

JOURNAL CLUB EVALUATION

• The journal publishes weekly editorials, papers on original research, review articles, correspondence, and case reports

• It has the highest impact factor of the journals of clinical medicine => IF, 2010= 53.486

• Issues/Year: 52

• It requires that articles it publishes not have been published or released elsewhere

• The article was published in february 3, 2011 -----> up to date

• Journal homepage: www.nejm.org

JOURNAL CLUB EVALUATION

• Editors:

Walter Prentice Bowers, 1921–1937

Robert Nason Nye, 1937–1947

Joseph Garland, 1947–1967

Franz J. Ingelfinger, 1967–1977

Arnold S. Relman, 1977–1991

Jerome P. Kassirer, 1991–1999

Marcia Angell, 1999–2000

Jeffrey M. Drazen, 2000–present

TITLE EVALUATION

Negative pointsPositive points

Population of interest not

defined

Non conclusive

Type of study design not

mentioned

Gives a brief idea about the

article

Incomplete purposeName of study design

mentioned

AUTHORS EVALUATION

Contributors

Thomas J. Louie, M.D

. Professor of : 1. Medicine

2. Microbiology, Immunology &

Infectious Diseases

. MD at University of Alberta

. Involved in clinical trials with the focus around the evolution

of new antimicrobial agents and biologic response modifiers

in seriously ill patients with infections

AUTHORS EVALUATION

Kathleen M. Mullane, D.O

. Internal Medicine – Certified

. Infectious Disease Medicine - Board Eligible

. Practice Affiliations: UNIVERSITY OF CHICAGO

. Hospital affiliations: 1. University of Chicago

Medical Center

2. Loyola University Medical

Center

3. University Hospital

AUTHORS EVALUATION

1- Pamela Sears, Ph.D., inventor of Fidaxomicin patent &

employee of & owning stock options in OPTIMER

pharmaceuticals

2- Youe-Kong Shue, Ph.D., employee of & owning stock options in

OPTIMER pharmaceuticals

3- Sherwood Gorbach, M.D., part-time employee of OPTIMER

pharmaceuticals & holding a patent on lactobacillus GG

probiotic & B-glucan

4- Karl Weiss, M.D., honoraria & consulting fees from

pharmaceutical companies

AUTHORS EVALUATION

5- Thomas J. Louie, M.D., specialised in infectious

disease

6- Mark A. Miller, M.D.,

7- Arnold Lentnek, M.D.,

8- Yoav Golan, M.D.,

AUTHORS EVALUATION

The authors are highly educated (PhD,D.O.&

M.D.) & are reputable source of trust in medical

field

× Most of the authors work at OPTIMER

pharmaceuticals which is the funder & producer

of Fidaxomicin

× No biostatician nor pharmacists

(the source of drug information & counseling)

ABSTRACT EVALUATION

ABSTRACT EVALUATION

Divided into 4 sections

Brief & provide a summarized idea about the article

Primary & secondary end points mentioned

Methodology matches the one of article

Target & number of population identified

Dose & duration of treatment mentioned

Statistical analyses listed

P value listed

Objective listed in the background

ABSTRACT EVALUATION

× Mean Age group unspecified

× Study design type not listed

× Not all reporting tools are identified

× Adverse events not listed

INTRODUCTION EVALUATION

49

INTRODUCTION EVALUATION

Trial Funding

• Trial was funded by “OPTIMER PHARMACEUTICALS”

• It’s the producer of Fidaxomicin that was previously named “OPT-80”

• Most of the members of the clinical study group are employees

• Dr. Pamela Sears (the inventor) works at OPT

Authors’ interference & Bias cannot be eliminated

INTRODUCTION EVALUATION

Rationale:

• Incidence & severity of CDI are increasing

• Recurrent relapses of patients after old therapy

• Nowadays, young-healthy & peripartum women are at a high risk

• Emergence of hypervirulent CD strain NAP1/BI/027

• Reduced rates of clinical response & increased rates of recurrence seen in more recent studies are causes of concern

INTRODUCTION EVALUATION

Objective :

To evaluate the results of a phase 3 noninferiority

study comparing Fidaxomicin with Vancomycin in

629 patients with Clostridium difficile infection

× Not clearly identified and retrieved

INTRODUCTION EVALUATION

General Overview about the MO and the

drugs:

Clostridium difficile background well presented

Fidaxomicin defined in details

INTRODUCTION EVALUATION

Fidaxomicin (previously called OPT-80)

is a new macrocyclic antibiotic that is more active

in vitro than vancomycin by a factor of 8 against

C.difficile, including NAP1/B1/027 strains

Has minimal systemic absorption and high fecal concentration and limited activity in vitro/vivo against normal gut flora

× Vancomycin was not described clearly

× Alternative treatments were absent

INTRODUCTION EVALUATION

• Hypothesis :

• H0: NO DIFFERENCE BETWEEN FIDAXOMICIN &

VANCOMYCIN

• H1: FIDAXOMICIN IS SUPERIOR TO VANCOMYCIN

REJECTED OR ACCEPTED?!!!

INTRODUCTION EVALUATION

References:

• 36 references are identified

• Majority are 1ry literatures : case studies, articles….

• Secondary literatures: NEJM, AAC, CGH, JCM

Trustful & highly informative sources

Provide powerful relevance with

topic: microbiology,gastroenterology,infectious

diseases…

Wide medical background extending to other

fields on medicine(gynecology)

Other cited clinical trials & articles were also

involved

METHODS EVALUATION

STUDY DESIGN EVALUATION

The OPT-80-003 Clinical Trial Study Group, is a

• Prospective

• Multicenter

• Double-blinded

• Randomized

• Parallel group trial

Conducted between May 9, 2006 & August 21, 2008

Sponsored by “Optimer Pharmaceuticals”

Data analysis performed by authors & others in OPT

who provided a written manuscript & submitted it

Included patients from different states of USA and Canada

STUDY DESIGN EVALUATION

Done according to ethical principles of the

Declaration of Helinski & Current Good Clinical

practices

Study protocol approved by the institutional review

boards

All patients provided an informed consent

Data monitored & retrieved by INC research

Exclusion CriteriaInclusion Criteria

Life-threatening/fulminant CDI. ≥16 years old with CDI

. CDI → 1) Diarrhea: >3 unformed bowel

movement daily before

randomization

2) CD toxin A/B/Both in stool

specimen, 48hrs before

randomization

Toxic Megacolon

Patient could have received 4 doses of

Metronidazole/Vancomycin/, 24 hrs before

randomization

Previous treatment with FidaxoNo other concurrent treatment

(oral bacitracin,fusidic acid or rifaximin)

History of Ulcerative colitis/Crohn’s disease

>1 CDI occurrence in 3 Months before start

of study

STUDY POPULATION EVALUATION

Inclusion & Exclusion criteria are adequate

All participants provided written informed consent

Number of Patient screened = 629

Wide age group (>16 YO) CDI can affect all age

groups

The study included patients from USA (52 states)

and from Canada ( 15 states)

STUDY POPULATION EVALUATION

Multicenter hence:

High patient variability

Results can be generalized

× Patient characteristics not listed

× More expensive

× More effort to ensure compliance to clinical

protocol across all centers

RANDOMIZATION & TREATMENT EVALUATION

2 Groups

First episode

(primary occurrence)

Primary occurrence in 3Months before start of

study

Fidaxomicin

200mg BID po for 10 days

Vancomycin

125mg q.6hrs pofor 10 days

Second episode

(1rst recurrence)

First recurrence in 3Months before start of

study

Fidaxomicin

200mg BID po for 10 days

Vancomycin

125mg q.6hrs pofor 10days

RANDOMIZATION & TREATMENT EVALUATION

The Independent Ethics Committee or

Institutional Review Board at each study site

approved the protocol

The study was conducted in accordance with

the ethical principles in the Declaration of

Helsinki, consistent Good Clinical Practices &

applicable regulatory requirements

RANDOMIZATION & TREATMENT EVALUATION

An interactive voice-response system

& a Computer generated randomization

schedule provided randomization # and

medication kit # for each patient

Placebo & Fidaxomicin & Vancomycin were

overencapsulated to look the same

RANDOMIZATION & TREATMENT EVALUATION

Daily assessment during 10 days course of

therapy for clinical cure/failure

If Clinical cure, patient followed for recurrence

with:

1. Weekly assessment for 28 days after last dose

of study medication had been given

2. Immediate patient-initiated reassessment by

study team if diarrhea recurred

RANDOMIZATION & TREATMENT EVALUATION

Doses & frequency of administration are within the normal

range

Route of administration(PO) was compatible with the drug

recommendation

Following up patients due to high recurrence of CDI

Randomization was done accurately by highly technical

methods

Rational division of patients into 1st & 2nd episode

OUTCOME EVALUATION – EFFICACY -

Primary efficacy variable :

Rate of clinical cure in MITT & PP population at the

end of therapy or at the time of early withdrawal

from the study => Resolution of Sx + no need for further Tx

MITT = Modified intention-to-treat population with CDI

+ randomization + at least 1 dose of study

medicine

PP = Per-protocol population consist of MITT patients +

treatment for at least 3 days if treatment failure or at

least 8 days if clinical cure; in both cases, patients had

adherence to the protocol and underwent an end-of-therapy

evaluation

OUTCOME EVALUATION – EFFICACY -

Secondary efficacy variable :

1) Recurrence of CDI during the 4 week period after the end

of the course of therapy

2) Global cure in MITT & PP population

1ry & 2ry end points are clearly identified

They are also rational because our aim in

CDI treatment is to evaluate clinical

cure, recurrence & global cure for

better monitoring & follow up of patients

OUTCOME EVALUATION – MICROBIOLOGY -

Fecal samples for toxin assays to verify CDI were done:

• At early end of treatment

• At end of treatment

• At time of diagnosis of recurrence

Tests performed at individual study sites:

• R.M. Alden Research Laboratory

C.difficile isolation & susceptibility with the use of CLSI M11-A7 agar dilution method

• Edward Hines,Jr,Veterans Affairs Hospital

Restriction-endonuclease typing

OUTCOME EVALUATION – PHARMACOKINETIC -

Blood samples:

Before & 3-5h after the 1st dose on day 1 & at the

end of therapy/early end of visit

SAFETY EVALUATION

Involves patients who received ≥ 1 dose & ≥ 1 assessment after

this dose

Assessed from the day informed consent was provided to the last

dose or visit

It inludes:

1. Physical examination

2. Electrocardiography (ERT)

3. Clinical lab testing (Hematologic & Biochemical tests & Urinalysis)

Adverse events:

Classified according to “ Medical Dictionary for Regulatory Activities “but

adverse events reported > 1 for a patient was counted only once

SAFETY EVALUATION

An adverse event can be reported more than

once for a patient

But: each patient was counted only once in the

incidence count for a particular adverse event

Safety evaluations were scheduled on basic

time

Assessment methods are accurate

STATISTICAL ANALYSIS EVALUATION

The trial was designed as a noninferiority study

One sided lower 97.5% CI was used in the analysis of primary endpoints with a noninferiority margin of

-10% points

If the lower boundary of CI limit was within -10% point

margin Clinical noninferiority was demonstrated

Secondary endpoints of recurrence and overall cure, were analyzed by post hoc hypothesis with the use of two sided tests of populations at a significance level of 0.05

STATISTICAL ANALYSIS EVALUATION

The post hoc analyses assesses treatment

differences according to :

1. Age

2. Inpatient VS outpatient status

3. Prior occurrence of CDI VS no prior occurrence

4. Disease severity (mild, moderate & severe)

5. Strain type

The time to resolution of diarrhea analysed with

the use of Kaplan-Meier method & Gehan-Wilcoxon

test for comparison of resolution time curves

STATISTICAL ANALYSIS EVALUATION

All summary statistics are presented as:

1. Means ± SD for continuous variables

2. Numbers & percentages for categorical variables

Post hoc analyses detects patterns & relationships btw subgroups of sampled population using a proper statistical method

Two sided looks at where most of the population are likely to lie

One sided looks at the percentage of units that are greater or less than a certain point

RESULTS EVALUATION

629 patients enrolled & underwent randomization

327 patients with

Vancomycin

302 patients with

Fidaxomicin

309 patients in

MITT

287 patients in MITT

283 patients in PP

analysis

265 patients in PP

analysis

221 patients had

clinical cure &

evaluated for

recurrence

221 patients had

clinical cure &

evaluated for

recurrence

MITT

596

PP

548

Vanco

309

Fidaxo

309

Vanco

283

Fidaxo

265

91.4% adhered to

Tx

91.7% adhered to

TX

96.1% adhered to

Tx

95.8% adhered to

Tx

221 cured =>

%78.1

221 cured =>

83.4%

RESULTS EVALUATION – PATIENTS -

Adherence to the study medication was similar in the 2 groups:

MITT 91.7% (Fidaxo) took the assigned doses

91.4% (Vanco)

PP 95.8%(Fidaxo) took the assigned doses

96.1%(Vanco)

Number of clinical failures & clinical cures were identified

Reasons why patients were excluded from the study were also mentioned :

1. They did not complete the treatment

2. No end of therapy evaluation

3. Other protocol evaluation

4. Clinical failure

RESULTS EVALUATION – PATIENTS -

Safety population

623

Vancomycin

323

Fidaxomicin

300

60.4% with SE 62.3% with SE

24.1%

Serious SE

25%

Serious SE

Comparison was done at the level of:

1. Age

2. Gender

3. Number of unformed stools per day

4. Response to MTZ

5. Treatment of CDI

6. Previous episodes of CDI

7. BI/NAP1/027 strain (%)

RESULTS EVALUATION – PATIENTS -

RESULTS EVALUATION – PATIENTS -

1. Results showed no significant

difference between groups with respect to

baseline characteristics

2. Patients characteristics clearly

tabulated, well elaborated & informative

3. Number of patients enrolled in this

study is correct (MITT n= 596)

RESULTS EVALUATION – PATIENTS -

4. Mean±SD for continuous variables mentioned

5. % & # for categorical variables mentioned

Clinical Cure

MITT

Vancomycin

85.8%

Fidaxomicin

88.2%

PP

Vancomycin

89.9%

Fidaxomicin

92.1%

RESULTS EVALUATION – CLINICAL OUTCOMES -

MITT= 85.8 - 88.2= -2.4% points

PP = 89.8 – 92.1= -2.3% points

CI = 97.5% with a noninferiority margin of -10%

In MITT & PP population, we have

respectively a reduction of 2.4% and 2.3%

points in Clinical cure with Vanco vs Fidaxo

We are 97.5% confident that MITT & PP population

have met the criteria for Clinical cure

RESULTS EVALUATION – CLINICAL OUTCOMES -

Recurrence

MITT

Vancomycin

25.3%

Fidaxomicin

15.4%

PP

Vancomycin

24%

Fidaxomicin

13.3%

RESULTS EVALUATION – CLINICAL OUTCOMES -

MITT= 15.4 - 25.3= -9.9% points

CI = 95% (-16.6 to -2.9), p= 0.005

PP = 13.3 – 24= -10.7% points

CI = 95% (-17.9 to -3.3), p= 0.004

In MITT & PP population, we have

respectively a reduction of 9.9% and 10.7%

points in Recurrence with Fidaxo vs Vanco

We are 95% confident that Tx with Fidaxo was associated with a

significant lower rate of recurrence than was with Vanco in both

MITT & PP populations

RESULTS EVALUATION – CLINICAL OUTCOMES -

Global Cure

MITT

Vancomycin

64.1%

Fidaxomicin

74.6%

PP

Vancomycin

67.1%

Fidaxomicin

77.7%

RESULTS EVALUATION – CLINICAL OUTCOMES -

MITT= 74.6 - 64.1= 10.5% points

CI = 95% (3.1 to 17.7), p= 0.006

PP = 77.7 – 67.1= 10.6% points

CI = 95% (3.1 to 17.9), p= 0.006

In MITT & PP population, we have

respectively an addition of 10.5% and 10.6%

points in Global cure with Fidaxo vs Vanco

We are 95% confident that Tx with Fidaxo resulted in a

significant higher rate of Global cure than was with Vanco in

both MITT & PP populations

RESULTS EVALUATION – CLINICAL OUTCOMES -

Diarrhea Resolution

MITT

Vancomycin

78hrs

Fidaxomicin

58hrs

PP

Vancomycin

69hrs

Fidaxomicin

55hrs

RESULTS EVALUATION – CLINICAL OUTCOMES -

Shorter duration of diarrhea resolution

with Fidaxo vs Vanco in MITT & PP

population

RESULTS EVALUATION – CLINICAL OUTCOMES -

Subgroup analyses of Clinical cure rates according to different

characteristics showed No significant difference between

treatments in both MITT & PP populations according to subgroup

Ex.1:

RESULTS EVALUATION – CLINICAL OUTCOMES -

Patient with previous episode of CDI

MITT

Vancomycin

88.9% cured

Fidaxomicin

87.5% cured

PP

Vancomycin

93.8% cured

Fidaxomicin

95.8% cured

Ex.2:

RESULTS EVALUATION – CLINICAL OUTCOMES -

Patient with NAP1/BI/027 strain

MITT

Vancomycin

80.7% cured

Fidaxomicin

87.5% cured

PP

Vancomycin

93.8% cured

Fidaxomicin

95.8% cured

Subgroup analyses of Recurrence rates according to different

characteristics showed that Fidaxo was associated with lower

rates of recurrence vs Vanco in both MITT & PP populations

according to subgroup

Ex.1:

RESULTS EVALUATION – CLINICAL OUTCOMES -

Patient ≥65 years old

MITT

Vancomycin

30.5% RR

Fidaxomicin

19.4%RR

PP

Vancomycin

30.1% RR

Fidaxomicin

18.8% RR

Ex.2:

RESULTS EVALUATION – CLINICAL OUTCOMES -

Patient with Non-NAP1/BI/027 strain

MITT

Vancomycin

28.1% RR

Fidaxomicin

10.3% RR

PP

Vancomycin

25.5% RR

Fidaxomicin

7.8% RR

BUT: Similar rate of recurrence in pts with

NAP1/BI/027 strain ≠ Non-NAP1/BI/027

RESULTS EVALUATION – CLINICAL OUTCOMES -

Patient with NAP1/BI/027 strain

MITT

Vancomycin

20.9% RR

Fidaxomicin

27.1% RR

PP

Vancomycin

23.6% RR

Fidaxomicin

24.4% RR

RESULTS EVALUATION – SAFETY -

No significant difference in rate of ADR (mild GI & nonspecific sx) or serious adverse events 9.7% (Fidaxo) & 9% (Vanco)

Occurrence of adverse events were 62.3% (Fidaxo) & 60.4% (Vanco)

Occurrence of serious adverse events were 25% (Fidaxo) & 24.1% (Vanco)

More serious adverse events related to lab tests results in Fidaxo(4.7%) vs Vanco(1.2%)

No subjects discontinued the study as a result of intolerance or allergy

RESULTS EVALUATION – MICROBIOLOGY -

In vitro, antimicrobial activity against CDI showed minimum inhibitory concentrations:

1. ≤ 0.25mcg/ml for Fidaxomicin

2. 2 mcg/ml for Vancomycin

No relationship between MIC & clinical outcome (cure or recurrence)

This test only gives info about microbiologic characteristics of both Antibiotics

RESULTS EVALUATION –PHARMACOKINETIC-

Mean plasma concentration of Fidaxomicin at day1:

22.8 ± 26.5ng/ml (range 0.4 to 185)

No plasma accumulation was found between day 1 & the end of therapy

Mean end of therapy fecal concentration:

1225 ± 795 mcg/g (range 31.7 to 4640)

4900 times as high as minimum inhibitory

concentration

RESULTS EVALUATION

• 1. Fidaxomcin rapidly kills C.diff (bacteriocidal)

whereas Vancomycin inhibits growth

(bacteriostatic)

2. Fidaxomicin has prolonged Antibiotic effect

preserves bacteroides in the fecal flora which

are markers of normal anaerobic microflora

3. Microflora maintain “ COLONIZATION

RESISTANCE” & prevent further emergence of

CDI

DISCUSSION EVALUATION

DISCUSSION EVALUATION

Author’s Comments:

• The clinical profile of CDI has worsened in the past decade

Increased mortality & morbidity

• Emergence of new & more virulent strains (BI/NAP1/027)

• CDI became more serious illness in North America & Europe, even in countries with low incidence of B1/NAP1/027

• Initial approach of treatment is to discontinue the Antibiotic that precipitated the infection

• Standard treatment are Metronidazole (MZD) & Vancomycin

DISCUSSION EVALUATION

• MTZ is efficiently absorbed & small amount reaches the colon Disadvantage in mucosal & luminal

infections

• Systemic SE include:

Nausea– HA – Taste perversion – Peripheral neuropathy

• MTZ is associated with more failure & higher recurrence in severely ill patients as compared to Vancomycin

• Oral MTZ or Vancomycin induces the emergence of Vancomycin resistant enterococcus (VRE)

DISCUSSION EVALUATION

• 20-30% of patients have recurrent course of

illness of CDI

• Retreatment with MTZ or Vancomycin resolves

the condition in most patients, however, 1/3

have >1 recurrence

• Severe illness & deaths are associated with

relapses

DISCUSSION EVALUATION

Narrow antimicrobial

spectrum

Against CD, Staph &

Enterococci

Bactericidal

Low systemic SE

45% reduction in recurrences

Improved Global cure

Poorly absorbed

from intestine

Similar rate of recurrence &

cure for strains B1/NAP1/027

Post-antibiotic effect

Preserves intestinal flora

FDA approved in May 2011 for the treatment of C.

difficile-associated diarrhea in patients aged ≥18 years

Fidaxomicin

DISCUSSION EVALUATION

Strengths:

• Prospective, multicenter, double-blinded,

randomized, parallel group trial

• Well defined dose and dosage form

• Presence of comparable studies supporting

safety & efficacy

• Organized & informative tables & figures

DISCUSSION EVALUATION

• P values, SD & CI are mentioned

• Recurrence monitoring

• Informed Consent

• Inclusion & Exclusion criteria were highly

relevant to CDI

• Primary & secondary end points were clearly

identified

DISCUSSION EVALUATION

Limitations:

• Cannot generalize results to adolescents in case

of Fidaxomicin

• No biostatistic investigators

• Small sample size

CONCLUSION EVALUATION

Author’s conclusion:

Fidaxomicin & Vancomycin have similar

effectiveness with respect to the clinical

resolution of acute diarrheal disease due

to CDI but more sustained/durable

resolution of disease is achieved with

Fidaxomicin

CONCLUSION EVALUATION

Author’s conclusion well correlated

with the study objective

CONCLUSION

The incidence and hospitalizations due to C. difficile infection and disease have grown at an alarming rate

The mainstays of treatment for some time have been metronidazole and vancomycin

Last year, FDA approved a new antibiotic for the treatment of CDI, Fidaxomicin in adults (>18 yo )

It is currently indicated for mild to moderate CDI

It has been shown not to be inferior to vancomycin but it has not been shown to be superior

CONCLUSION

One potential advantage: it does not alter the normal flora of the bowel as much as vancomycindoes, which may explain why the risk of recurrent disease was lower with fidaxomicin

Fidaxomicin can be used instead of Vancomycindue to lower rate of recurrence hence lower costs & improved rate of global cure

But Further studies are required to generalize Fidaxomicin in adolescents & worlwide

OTHER STUDIES

Prospective

Multicenter

Double-blind

Randomised, non-inferiority trial

From 45 sites in Europe & 41 sites in the USA & Canada

Between April 19, 2007, & Dec 11, 2009

Identical in design and procedures to previous study

Aim => To compare the efficacy of fidaxomicin and

vancomycin in Europe, as well as in Canada &

USA

Primary efficacy variable :

Rate of clinical cure in MITT & PP population at the

end of therapy or at the time of early withdrawal

from the study => Resolution of Sx + no need for further Tx

Secondary efficacy variable :

1) Recurrence of CDI during the 4 week period after the end of the course of therapy

2) Global cure in MITT & PP population

MITT

509

PP

451

Vanco, 125mg po

q.6hrs =>

257

Fidaxomicin,

200mg bid po for 10

days =>

252

Vanco

235

Fidaxo

216

223 cured =>

86.8%221 cured =>

87.7%

213 cured =>

90.6%

198 cured =>

%91.7

535 patients were enrolled in this study

A greater proportion of patients were inpatients at the time of enrolment in Europe than in Canada and the USA

Fewer patients in Europe than in Canada & USA had a previous episode of C difficile infection in the preceding 3 months

Treatment of other infections with concomitant antibiotics was more common in Europe than it was in Canada & USA

Fidaxomicin was non-inferior to vancomycin for clinical cure rate

=>These findings match those from a study done in just Canada and the USA

Treatment with fidaxomicin was associated with a lower rate of recurrence in the 4 weeks after completion of treatment than was vancomycin

=> This difference was larger than that in the previous study

Sustained response rates were also higher in subgroups treated with fidaxomicin than in those given vancomycin

Clinical cure with the two drugs was not significantly different for any subgroup with the exception of patients exposed to concomitant antibiotics during treatment

=> Exposure to concomitant antibiotics during

treatment reduced the clinical cure rate of

patients given vancomycin, but had no apparent

effect on those treated with fidaxomicin

=> This could indicate that intestinal microflora have

a role in initial response, and not just resistance

to recurrence

Trends in time to resolution of diarrhea were not

significantly different in treatment groups

However,with patients who received concomitant

antibiotics, longer times to resolution was noticed than

those who did not

Occurrence of treatment-emergent adverse events did

not differ between groups

All strains were susceptible to both fidaxomicin &

vancomycin

In Canada & USA, the most prevalent group was BI,

but in Europe, Y was most common

In summary, fidaxomicin was non-inferior to

vancomycin in initial clinical response

Patients successfully treated with fidaxomicin

were less likely to have recurrence of disease

within 4 weeks after treatment completion

=> superior sustained response for

fidaxomicin.

References

REFERENCES

REFERENCES

The Lancet Infectious Diseases,Volume 12, Issue 4, April 2012, Pages 281–289, Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial

The American Journal of Geriatric Pharmacotherapy Volume 10, Issue 1, February 2012, Pages 14–24 Clostridium Difficile Infection in Older Adults: A Review and Update on its Management

The American Journal of Geriatric Pharmacotherapy Volume 10, Issue 4, August 2012, Pages 258–263. A Year in Review: New Drugs for Older Adults in 2011

REFERENCES

International Journal of Infectious Diseases Volume 15, Issue 7, July 2011, Pages e438e448,Use of alternative or adjuvant pharmacologic treatment strategies in the prevention and treatment of Clostridium Difficile infection

Journal of Infection Available online 24 October 2012, Clostridium difficile: A European perspective

The Journal for Nurse Practitioners Volume 7, Issue 7, July August 2011, Pages 602–603, Clostridium difficile Treatment

First Consult ,Clostridium difficile infection

Clinical Practice Guidelines for Clostridium difficile Infection in Adults:2010 Update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA), May 2010, vol.31, no.5