Irritable Bowel Syndrome-The Effect of Antibiotics

Mark Pimentel, MD, FRCP(C)Di t GI M tilit PDirector, GI Motility ProgramCedars-Sinai Medical Center

Los Angeles, California

Irritable Bowel SyndromeIrritable Bowel Syndrome

• Irritable bowel syndrome (IBS) is the most y ( )common chronic medical condition worldwide.

• 15-20% of all populations suffer from IBS• The cause has remained unknown• The cause has remained unknown• Accounts for 30% of all health related

t (di t d i di t) icosts (direct and indirect) in gastroenterology

Why Antibiotics in GI?Why Antibiotics in GI?

TREAT AN INFECTION

Clostridium Difficile

TREAT A COLONIZER

Helicobacter pyloriClostridium DifficileAcute Gastroenteritis

DiverticulitisGiardia

Helicobacter pylori

PREVENT INFECTION REDUCE NORMAL FLORA

Prophylaxis for traveller’s Bacterial Overgrowth/IBSBone Marrow Transplant

Inflammatory Bowel Disease

STRATEGY 1: Treat the SymptomsSTRATEGY 1: Treat the Symptoms

Pain

BloatingDiarrhea

Constipation

STRATEGY 1: STRATEGY 1: Treat the CAUSETreat the CAUSE

SEROTONIN

DYSMOTILITY

BRAIN-GUT AXIS

Agonist/Antagonist

ACUTE S

IBSACUTE

GASTROENTERITISSIBOSalmonella, E. coli,

Campylobacter, …

SIBOSIBO-- What is it?What is it?

Small BowelSmall Bowel

~ 0 cfu/mLDuodenum

1011cfu/mLColon

101 cfu/mLCecum

Jejunum

102 cfu/mLIleum

103 cfu/mL

Bacterial Hypothesis in IBSBacterial Hypothesis in IBS

Modified Koch’s Postulates Data

1. Evidence of excessive small-bowel microorganisms is seen in persons suffering with

√

IBS.2. This excess small-bowel flora can be proven by culture techniques

√by culture techniques.

3. Elimination of findings that suggest SIBO results in an improvement of IBS.

√results in an improvement of IBS.

4. The return of the bacteria heralds the return of the IBS symptoms.

√

Pimentel M, Am J Gastro, 2010.

Neomycin in IBSNeomycin in IBS

75%

p<0.000001*

32%

10%

*One-way ANOVAPimentel, et al, Am J Gastro, 2003

Important Factors in Antibiotic Important Factors in Antibiotic Use and SelectionUse and Selection

Antibiotic PropertyAntibiotic Property1. Spectrum2. Efficacy3. Resistance3. Resistance4. Localization5 Absorbability5 Absorbability

Antibiotic Efficacy Antibiotic Efficacy

Antibiotic Efficacy in SIBO

M t id l <20%Metronidazole <20%

Neomycin 25%Neomycin 25%

Augmentin or Doxycycline 30-40%

Rifaximin 70%*

*DiStefano M, Aliment Pharm Ther, 2000.

RifaximinRifaximin in IBSin IBSnt

prov

emen

loba

l Im

pP

erce

nt G

P

Weeks after Rifaximin*P=0.02 Mixed Longitudinal Model for 10-week differencePimentel, et al, Ann Intern Med, 2006

RifaximinRifaximin in IBS/SIBOin IBS/SIBO

Citation Finding

Sharara, et al. AJG, Rifaximin improves IBS symptom, ,2006

p y p

Fanigliulo, et al ActaBiolog 2006

Rifaximin improves IBS symptmomsBiolog, 2006

Cuoco L, et al, Minerva Gastro Diabetol, 2006

Rifaximin improves IBS symptoms

Scarpellini, et alAlim Pharm Ther, 2007

Higher dose rifaximin improves IBS symptoms

RifaximinRifaximin in IBSin IBS-- Phase IIBPhase IIB

Placebo BID

Week 1 Week 2 Week 3 Week 4

Rifaximin 550mg BID Placebo BID

Week 1 Week 2 Week 3 Week 4

2 out of 3 weeks with Adequate Relief of IBS SymptomsAND

2 out of 3 weeks with Adequate Relief of IBS Symptom of Bloating

CO-PRIMARYENDPOINTS

ResultsResults

P=0.0352.4

44.2

P=0.0446.1

39.6

Ringel Y et al. Gastroenterology 2008; 134: 1411 Lembo A et al. Gastroenterology 2008; 134: 1390

Duration of ImprovementDuration of Improvement

P=0.019 P=0.010

Ringel Y et al. Gastroenterology 2008; 134: 1411 Lembo A et al. Gastroenterology 2008; 134: 1390

Primary Endpoint: SGA IBSPrimary Endpoint: SGA IBSPrimary Evaluation Period (ITT)Primary Evaluation Period (ITT)y ( )y ( )

Rifaximin Placebo

spon

ders

age

of R

eP

erce

nt

Responder: Patient responding ‘yes’ to adequate relief of SGA-IBS weeklyquestion for ≥ 2 of the 4 weeks during weeks 3 - 6

Key Secondary Endpoint: Key Secondary Endpoint: BloatingBloatinggg

Rifaximin Placebo

spon

ders

age

of R

eP

erce

nt

Responder: Patient responding ‘yes’ to adequate relief of SGA-IBS weeklyquestion for ≥ 2 of the 4 weeks during weeks 3 - 6

Consistency Across EndpointsConsistency Across EndpointsWeeks 3 Through 6 Weeks 3 Through 6 gg

SGA-IBS Weekly

Efficacy Outcome

0.0008(1.18,1.88)1.49Combined0.0263(1.05,2.01)1.45TARGET 20.0125(1.10,2.12)1.53TARGET 1

p-value(95% CI)Odds RatioStudy

SGA-IBS Weekly

Efficacy Outcome

0.0008(1.18,1.88)1.49Combined0.0263(1.05,2.01)1.45TARGET 20.0125(1.10,2.12)1.53TARGET 1

p-value(95% CI)Odds RatioStudy

Primary

IBS Bloating Weekly 0.0002(1.23,1.96)1.56Combined

0.0167(1.08,2.06)1.49TARGET 20.0045(1.16,2.27)1.62TARGET 1IBS Bloating

Weekly 0.0002(1.23,1.96)1.56Combined0.0167(1.08,2.06)1.49TARGET 20.0045(1.16,2.27)1.62TARGET 1Key

Secondary

0.0009(1.26,2.47)1.76TARGET 1 0.0009(1.26,2.47)1.76TARGET 1Other

IBS Ab Pain

IBS Bloating Daily

SGA-IBS Daily

0.0255(1.05,2.02)1.45TARGET 10.0004(1.21,1.92)1.52Combined0.0008(1.26,2.44)1.76TARGET 20.0486(1.01,1.97)1.41TARGET 1

<0.0001(1.28,2.04)1.61Combined0.0072(1.13,2.24)1.59TARGET 2

( , )

IBS Ab Pain

IBS Bloating Daily

SGA-IBS Daily

0.0255(1.05,2.02)1.45TARGET 10.0004(1.21,1.92)1.52Combined0.0008(1.26,2.44)1.76TARGET 20.0486(1.01,1.97)1.41TARGET 1

<0.0001(1.28,2.04)1.61Combined0.0072(1.13,2.24)1.59TARGET 2

( , )OtherSecondary

( )C0.0077(1.12,2.13)1.55TARGET 20.0401(1.02,1.92)1.40TARGET 1Ab Pain & Stool

Daily (FDA)( )C

0.0077(1.12,2.13)1.55TARGET 20.0401(1.02,1.92)1.40TARGET 1Ab Pain & Stool

Daily (FDA)FDA

Proposed

IBS Ab Pain Daily 0.0028(1.13,1.78)1.42Combined

0.0232(1.05,2.03)1.46TARGET 2IBS Ab Pain Daily 0.0028(1.13,1.78)1.42Combined

0.0232(1.05,2.03)1.46TARGET 2

0.0009(1.17,1.84)1.47CombinedDaily (FDA)

Stool Consist.Daily (FDA)

Ab Pain Daily (FDA)

<0 0001(1 31 2 14)1 67Combined0.0096(1.12,2.21)1.57TARGET 20.0015(1.25,2.59)1.80TARGET 10.0009(1.17,1.83)1.46Combined0.0194(1.06,2.00)1.46TARGET 20.0157(1.08,2.03)1.48TARGET 10.0009(1.17,1.84)1.47Combined

Daily (FDA)

Stool Consist.Daily (FDA)

Ab Pain Daily (FDA)

<0 0001(1 31 2 14)1 67Combined0.0096(1.12,2.21)1.57TARGET 20.0015(1.25,2.59)1.80TARGET 10.0009(1.17,1.83)1.46Combined0.0194(1.06,2.00)1.46TARGET 20.0157(1.08,2.03)1.48TARGET 1

Proposed

Odds Ratio and 95% CI0.0 0.5 1.0 1.5 2.0 2.5

Favors Placebo Favors Rifaximin

y ( ) <0.0001(1.31,2.14)1.67Combinedy ( ) <0.0001(1.31,2.14)1.67Combined

Consistency Across EndpointsConsistency Across EndpointsEntire 3 MonthsEntire 3 Months

p-value(95% CI)Odds RatioStudyEfficacy

Outcome

0 0007(1 17 1 77)1 44Combined0.0053(1.13, 2.03)1.52TARGET 2SGA-IBS

Weekly

0.0477(1.00, 1.82)1.35TARGET 1

p-value(95% CI)Odds RatioStudyEfficacy

Outcome

0 0007(1 17 1 77)1 44Combined0.0053(1.13, 2.03)1.52TARGET 2SGA-IBS

Weekly

0.0477(1.00, 1.82)1.35TARGET 1Primary

IBS Bloating Weekly

0 0025(1 18 2 18)1 60TARGET 1

0.0011(1.15, 1.75)1.42Combined0.0031(1.16, 2.09)1.56TARGET 20.1042(0.95, 1.73)1.28TARGET 1

0.0007(1.17, 1.77)1.44Combinedy

IBS Bloating Weekly

0 0025(1 18 2 18)1 60TARGET 1

0.0011(1.15, 1.75)1.42Combined0.0031(1.16, 2.09)1.56TARGET 20.1042(0.95, 1.73)1.28TARGET 1

0.0007(1.17, 1.77)1.44Combinedy

Key Secondary

<0.0001(1.24, 1.89)1.53Combined0.0008(1.24, 2.25)1.67TARGET 20.0103(1.10, 2.04)1.50TARGET 1IBS Bloating

Daily

0.0003(1.20, 1.83)1.48Combined0.0127(1.09, 1.99)1.47TARGET 2SGA-IBS Daily0.0025(1.18, 2.18)1.60TARGET 1

<0.0001(1.24, 1.89)1.53Combined0.0008(1.24, 2.25)1.67TARGET 20.0103(1.10, 2.04)1.50TARGET 1IBS Bloating

Daily

0.0003(1.20, 1.83)1.48Combined0.0127(1.09, 1.99)1.47TARGET 2SGA-IBS Daily0.0025(1.18, 2.18)1.60TARGET 1Other

Secondary

0.0141(1.08, 1.92)1.44TARGET 20.0396(1.01, 1.83)1.36TARGET 1Ab Pain & Stool

Daily (FDA)

0.0118(1.06, 1.61)1.31Combined0.0435(1.01, 1.81)1.35TARGET 2IBS Ab Pain

Daily

0.0495(1.00, 1.83)1.35TARGET 1

0.0141(1.08, 1.92)1.44TARGET 20.0396(1.01, 1.83)1.36TARGET 1Ab Pain & Stool

Daily (FDA)

0.0118(1.06, 1.61)1.31Combined0.0435(1.01, 1.81)1.35TARGET 2IBS Ab Pain

Daily

0.0495(1.00, 1.83)1.35TARGET 1

FDA Proposed 0.0014(1.14, 1.72)1.40CombinedDaily (FDA)

0.0114(1.09, 2.00)1.48TARGET 2Stool Consist. Daily (FDA)

0.0009(1.24, 2.33)1.70TARGET 10.0058(1.09, 1.64)1.33Combined0.0298(1.03, 1.83)1.37TARGET 20.0725(0.98, 1.75)1.31TARGET 1Ab Pain Daily

(FDA)

0.0014(1.14, 1.72)1.40CombinedDaily (FDA)

0.0114(1.09, 2.00)1.48TARGET 2Stool Consist. Daily (FDA)

0.0009(1.24, 2.33)1.70TARGET 10.0058(1.09, 1.64)1.33Combined0.0298(1.03, 1.83)1.37TARGET 20.0725(0.98, 1.75)1.31TARGET 1Ab Pain Daily

(FDA)

Proposed

Favors Placebo Favors RifaximinOdds Ratio and 95% CI

<0.0001(1.27, 1.97)1.58Combined( )Daily (FDA) <0.0001(1.27, 1.97)1.58Combined( )Daily (FDA)

0.0 0.5 1.0 1.5 2.0 2.5

Antibiotic ResistanceAntibiotic Resistance

ConventionalConventional Antibiotics Recurrence

SIBO40% Eradicated 25% Eradicated

Rifaximin Recurrence

70% Eradicated 100% Eradicated

Yang, et al. Dig Dis Sci, 2007.

Antibiotic in IBS/SIBO: ChecklistAntibiotic in IBS/SIBO: Checklist

Resistance ClinicalResistance

Efficacy>50%

Non-absorbed

LocalizedDelivery

Gen Pl Yes No No Yes No Yes No Yes

Ciprofloxacin

Metronidazole

A i illi /Ampicillin/ClavulanateTetracycline/DoxycyclineNeomycin

Rifaximin

Methane as a Diagnostic TestMethane as a Diagnostic Test

C-IBS Not C-IBS

Methane 22 6 28

No Methane 2 26 28

24 3224 32

Sensitivity=0.92, Specificity=0.81, y yPositive Predictive Value=0.79, Negative Predictive Value=0.93

Pimentel, et al Dig Dis Sci. epub, 2009.

Methane is Important in CMethane is Important in C--IBS TreatmentIBS Treatment

Pimentel, et al. Dig Dis Sci, 2006.

Treating MethaneTreating Methane

CH4 Eradication Clinical Response

80

90

100

80

90

onse

P=0.001 P=0.01

60

70

80

catin

g C

H4

50

60

70

nica

l Res

po30

40

50

rcen

t era

dic

30

40

50

nt w

ith C

lin

0

10

20Per

0

10

20Pe

rce

0Neomycin Rifaximin Neo+Rifax

0Neomycin Rifaximin Neo+Rifax

Low et al. ACG. P1074

ConclusionsConclusions

• Antibiotics significantly improve global IBS tIBS symptoms.

• In addition, abdominal pain, bloating and stool consistency are significantly impacted.

• This effect is durable suggesting an effect on a true pathophysiologic p p y gprocess in IBS.

• Selection of antibiotic type isSelection of antibiotic type is important.