American College of Gastroenterology

Guideline on the Management of H. pylori

Infection (Am J Gastroenterol

2007;102:1808–1825)

Current concepts in management of

H.pylori pylori infection - The Maastricht III

consensus report

Sleisenger and fordtran 9th edition.

Wikepedia

Indian Journal of Gastroenterology 2006 Vol

25 January - February

Campylobacter pyloridis (1983)

C.pylori (1987)

H.pylori (1989)

Gram negative organism with following characteristics:Slow growing

Microaerophilic

Highly motile (multiple unipolarflagella)

Spiral

Urease producing

Urease

C=O(NH2)2 + H+ + 2H2O HCO3- + (NH4

+)

Urea Bicarbonate Ammonium

ions

And then…

HCO3- CO2 + OH-

0.5-0.9μm wide and 2-4μm long

7 flagellae, 12-15nm long, covering continuous with outer membrane of the body, terminal bulbs?function, thick outer glycocalyx

Bacillary to coccoid ; infectious form bacillary

Best known culture medium : oxoid brain heart infusion agar (BHI)

Notable for its high content of urease and alkaline phosphatase; produces catalase and cytochromeoxidase

Single circular molecule, mean size of 1.7Mb

Complete sequence determined in 1997

Codes for about 1500 proteins

Many genes can be switched on and off

Genome changes continuously (DNA

importing)

Nature 388, 539 - 547 (07 August 1997)

The complete genome sequence of the gastric pathogen Helicobacter

pylori

JEAN-F. TOMB*, OWEN WHITE*, ANTHONY R. KERLAVAGE*, REBECCA A. CLAYTON*,

GRANGER G. SUTTON*, ROBERT D. FLEISCHMANN*, KAREN A. KETCHUM*,

HANS PETER KLENK*, STEVEN GILL*, BRIAN A. DOUGHERTY*, KAREN NELSON*,

JOHN QUACKENBUSH*, LIXIN ZHOU*, EWEN F. KIRKNESS*, SCOTT PETERSON*,

BRENDAN LOFTUS*, DELWOOD RICHARDSON*, ROBERT DODSON*, HANIF G. KHALAK*,

ANNA GLODEK*, KEITH MCKENNEY*, LISA M. FITZEGERALD*, NORMAN LEE*,

MARK D. ADAMS*, ERIN K. HICKEY*, DOUGLAS E. BERG†, JEANINE D. GOCAYNE*,

TERESA R. UTTERBACK*, JEREMY D. PETERSON*, JENNY M. KELLEY*,

MATTHEW D. COTTON*, JANICE M. WEIDMAN*, CLAIRE FUJII*, CHERYL BOWMAN*,

LARRY WATTHEY*, ERIK WALLIN‡, WILLIAM S. HAYES§, MARK BORODOVSKY§, *

The Institute for Genomic Research, 9712 Medical Center Drive, Rockville, Maryland 20850,

USA

One of the most common chronic bacterial

pathogen in human

Approximately 50% of the world’s population is

infected.

Developing countries > Developed countries

In developing nations prevalence reaches >80% by

the age of 50.

Earlier age of acquisition.

United States:

30% of total population infected

• Of those, ~1% per year develop duodenal

ulcer

• ~1/3 eventually have peptic ulcer

disease(PUD)

70% gastric ulcer cases colonized with H.

pylori.

Prevalence of H. pylori strongly varies

between developing and developed

countries, where prevalence among adults is

typically around 80–90% and < 40%,

respectively.

Furthermore, Helicobacter pylori is the main

cause of gastritis, responsible for 80% of

gastric and 95% of duodenal ulcers.

90%-95% of Indian subjects with DU are

positive for H. pylori compared to 80% of

asymptomatic healthy individuals in the

community.

Duodenal-to-gastric ulcer ratio was 12:1.

Helicobacter pylori was present in 11/13

(84.6%) subjects with peptic ulcer.(Epidemiology of Helicobacter pylori and peptic ulcer in

India Journal of gastroenterology and

hepatology ISSN 0815-9319 Source / Source

2002, vol. 17, no6, pp. 659-665 (41 ref.))

Risk factors: Age, Socio-economic status,

Overcrowding, lack of hot or running water.

In developed countries, age related increase

in prevalence – just a birth cohort

phenomenon.

Genetic factors :

Monozygotic twins reared apart had a

higher rate of concordance of infection than

did age-matched dizygotic twins.

Reservoir:

Humans – major

Domestic cats, sheep – minor

Transmission: MODES

fecal-oral,

oral-oral,

gastro-oral

Helicobacter pylori is the main cause of

gastritis, responsible for 80% of gastric and

95% of duodenal ulcers.

Ingestion Evasion + Entrance of Mucus

1 Layer (Motility + Ure I)

2 Binding(Leb R,MHC,TFF1,PAMPS)

3 Insertion(Cag E)

4 Intra cellular pathway

TFF1:gastric trefoil protein(found in mucosa & mucus)

PAMPS: pathogen associated molecular receptors(TLRs 4 & 2)

Type IV secretions apparatus(1) (translocate cagA)

Possible insertion by needle like organelle coated with a sheath (Cag 7 protein) [Rohde et al]

Cag A translocates into the host cell cytoplasm & tyrosine phosphorylated by Src kinase and through the interaction mantains epithelial morphology

Cytokine Production Growth Factor

IL- 8+ chemokines Like cellular response

Polymorphisms in the regions controlling IL-

1β : gastric cancer and reduced incidence of

DU, Reduced acid secretion

Genes that regulate magnitude of

inflammation:

IL-10,

IL-1B

Tumor necrosis factor-α (TNF-α), and

IL-8

Oip A: outer inflammatory protein A

Increased bacterial density,

Mucosal IL-8 levels, and

Neutrophil infiltration,

More severe clinical consequences

Type IV secretion system – peptidoglycan--

NOD 1 – activation of NF-kB – IL-8

The Helicobacter pylori virulence factor

CagA is implicated in the pathogenesis of

gastric disorders such as chronic gastritis,

peptic ulcers and gastric cancer. CagA is

translocated into H. pylori-infected cells,

where it interacts with cellular scaffolding

and signalling proteins, causing host-cell

elongation and dispersal, and giving rise to

the so-called 'scattering/hummingbird'

phenotype

Role of oxidative stress:

Regultes gene expression

Redox factor-1(apurinic-apyrimidinic

endonuclease-1): involved in redox sensitive

signaling and contibuting to activation of NF-

kB & AP-1.

Chronic active gastritis

Precursor lesions of gastric adenocarcinoma

are atrophic gastritis , intestinal metaplasia,

and dysplasia.

CagA positive strains are associated with

reduced frequency of Barrett’s esophagus

and esophgeal adenocarcinoma.

WEAK ASSOCIATION BETTER LEVEL OF EVIDENCE

Raynaud’s

Phenomenon

Sclerodema

ITP

Acne rosacea

Migraines

Thyroiditis

GBS

CAD

ITP

IDA

Antral gastritis

Increased gastrin

release

Stimulation of parietal cell

Increased acid

Increased duodenal

acid load

Gastric metaplasia

HP colonization

Duodenal

ulcer

Established• Active peptic ulcer disease (gastric or duodenal ulcer)

• Confirmed history of peptic ulcer disease (not previously treated for H. pylori)

• Gastric MALT lymphoma (low grade)

• After endoscopic resection of early gastric cancer

• Uninvestigated dyspepsia (depending upon H. Pylori prevalence)

Controversial• Nonulcer dyspepsia

• Gastroesophageal reflux disease

• Persons using nonsteroidal antiinflammatory drugs

• Unexplained iron deficiency anemia

• Populations at higher risk for gastric cancer

For patients with uninvestigated dyspepsia who are <55 yr and have no “alarm features”

ALARM FEATURES

Bleeding,

Anemia,

Early satiety,

Unexplained weight loss,

Progressive dysphagia,

Odynophagia,

Recurrent vomiting,

Family history of GI cancer,

Previous esophagogastric malignancy

Patients with

Peptic ulcer disease and

low grade MALT lymphoma;

Atrophic gastritis;

First degree relatives of patients with gastric

cancer;

Patients with unexplained IDA;

Patients with chronic ITP

For localized gastric MALT lymphoma, H.

pylori treatment achieves tumor regression

in 60–90% of patients

H. pylori eradication may offer a treatment

option not only for low grade MALToma but

also for early-stage H. pylori-positive gastric

DLBCL (MALT)

test

s

Endoscopic

testing

Advantage disadvantage

1 Histology Excellent sensitivity (>95%) and

specificity(>95%)

Expensive and requires

infrastructure and trained

personnel

2 Rapid Urease

Test

Inexpensive and provides rapid

results.

specificity(>95%)

sensitivity(>90%)

Sensitivity significantly

reduced in the

posttreatment setting

3 Culture Excellent specificity. Allows

determination of

antibiotic sensitivities

Expensive, difficult to

perform, and not widely

available. Only marginal

sensitivity

4 PCR Excellent sensitivity and

specificity. Allows

determination of antibiotic

sensitivities

Methodology not

standardized across

laboratories and not

widely available

To maximize the diagnostic yield of histology a

minimum of three biopsies be obtained.

One from the anglularis,

One from the greater curvature of the

corpus,

One from the greater curvature of the

antrum.

A recent study found that PCR was able to

detect H. pylori in approximately 20% of

gastric biopsies with chronic gastritis but no

identifiable organisms by histology

PCR also provides a means of identifying

mutations associated with antimicrobial

resistance

Non-endoscopic

testing

Advantage disadvantage

1 Antibody testing

(quantitative

and qualitative) (Sn

>80/ Sp >90)

Inexpensive, widely available,

very good NPV

PPV dependent upon

background H. pylori

prevalence. Not

recommended after

H. Pylori therapy

2 Urea breath tests (13C

and 14 C) (Sn

>95/Sp>95)

Identifies active H. pylori

infection. Excellent PPV

and NPV regardless of H. pylori

prevalence.

Useful before and after

H. pylori therapy

Availability remain

inconsistent

3 Fecal antigen test

(Sn >90/Sp>90)

Identifies active H. pylori

infection. Excellent PPV and

NPV regardless

of H. pylori prevalence. Useful

before and after H.pylori

therapy.

Polyclonal test less

well validated than

the UBT

in the posttreatment

setting. Monoclonal

test

appears reliable

before and after

antibiotic

The UBTs and fecal antigen tests provide reliable

means of identifying active H. pylori infection

before antibiotic therapy.

The UBT is the most reliable nonendoscopic test to

document eradication of H. pylori infection.

The monclonal fecal antigen test provides another

nonendoscopic means of establishing H. pylori cure

after antibiotic treatment.

Testing to prove H. pylori eradication: should

performed at least 4 wk after the completion of

antibiotic therapy.

Any treatment regimen should achieve

eradication rate of >= 80%

Quadruple therapies are alternative first

choice treatment.

Bismuth based quadruple therapies remain

the second chice treatment, if not, a PPI,

amoxycillin or tetracycline and

metronidazole are recommended.

Initial treatment fails in up to 25% of

patients.

Reasons for that

• Antibiotic resistant organism,

• Poor compliance,

• Prior antibiotic use,

REGIMEN DURATION ERADICATION RATE COMMENTS

Bismuth

subsalicylate

525 mg, Metro

500mg,Tetra

500mg(each 4

times per day)

+ PPI bd

14 days 70% Inexpensive but

complicated,

less effective

as retreatment

than as primary

Rx,

PPI, Amoxy

1000mg,

Levofloxacin

250mg (each

twice daily)

10 days 57-91% Limited data

PPI, Amoxy

1000mg,

Rifabutin

150mg (each

bd)

14 days 60-80% Expensive,

hematological

events, limited

data

PPIs : headache and diarrhea, occurring in up to 10% of patients.

Macrolide (clarithromycin): GI upset, diarrhea, and altered taste.

Penicillin(amoxicillin): GI upset, headache & diarrhea.

Metronidazole: Dose related and include a metallic taste in the mouth, dyspepsia, and a disulfiram-like reaction with alcohol consumption.

Tetracycline: GI upset and photosensitivity. This antibiotic should not be used in children <8 yr of age.

Bismuth compounds: Darkening of the tongue and stool, nausea, and GI upset.

In United states

Metronidazole resistance: 40% strains

Clrithromycin strains: 11%

Teracyclin, Amoxycillin: <15%

INDIAN SCENARIO:

Due to antibiotic use or misuse widely

prevalent; high frequency of antibiotic

resistance.

several fixed-dose combinations of proton-pump

inhibitor with amoxicillin and tinidazole is the

most widely prescribed.

Fixed-dose combinations available: the dose of

amoxicillin is suboptimal, being 750 mg BID

rather than 1 g BID as recommended.

Form Packing/Price Photo PANTOCID-HP kit

1's (IRP: rupee 118) Related PANTOCID-HP

kit information Contents amoxycillin 750

mg, clarithromycin 600 mg, pantoprazole 40

mg CIMS Class Antacids, Antireflux Agents &

Antiulcerants Packing/Presentation

In multi-center study from India, 259 isolates

of H. pylori were tested for in vitro

susceptibility to antibiotics; of these,

77.9% -- metronidazole,

44.7% -- clarithromycin, and

32.8% -- amoxicillin.

In another study of 67 clinical isolates of H.

pylori from Kolkata,

85% -- metronidazole and

7.5% -- tetracycline,

but most were sensitive to clarithromycin,

furazolidone and amoxicillin.

Rates of recurrence of H. pylori infection

may be expected to be high in India.

H. pylori reinfection rates are very low in

Western populations,being less than 0.5 per

patient-year.

In one Indian study of 45 patients followed

up following eradication of H. pylori,

recurrence of infection was detected in only

one patient (2.4%) after one year.

The only other full publication on re-

infection in the Indian literature suggests

that recurrence of infection occurs in around

60% of patients.

REF: Nanivadekar SA, Sawant PD, Patel HD,

Shroff CP, Popat UR, Bhatt PP. Association or

peptic ulcer with Helicobacter pylori and the

recurrence rate. A three year follow up

study. J Assoc Physicians India 1990;38 (Suppl

1):703-6

Studies from India suggest that between

75%-90% of DU in India heal with antibiotic

therapy aimed at H. pylori eradication.9,10

Ulcer relapse rates after antibiotic therapy

may be slightly higher in India than those

reported in the Western literature.

For instance, after an 11-month follow up, 5

of 31 (16%) patients who became H. pylori

negative had DU relapse compared to 8 of 12

patients (67%) who remained H. pylori

positive.9

Nanivadekar et al reported that among 66

cases with healed DU under follow up and

undergoing 152 endoscopic examinations,

ulcer relapse was seen in 6 of 61 (10%)

examinations without recurrence of H.

pylori infection and in 58 of 91 (63%)

examinations with recurrence of H. pylori

infection.11

Overall H. pylori resistance rate was

77.9% to metronidazole,

44.7% to clarithromycin and

32.8% to amoxycillin.

Multiple resistance was seen in 112/259

isolates (43.2%) and these were two/three

and four drug resistance pattern to

metronidazole, clarithromycin, amoxycillin

observed (13.2, 32 and 2.56%, respectively).

Metronidazole resistance was high in

Lucknow, Chennai and Hyderabad (68, 88.2

and 100%, respectively) and moderate in

Delhi (37.5%) and Chandigarh (38.2%).

Ciprofloxacin and tetracycline resistance was

the least, ranging from 1.0 to 4%.

The prevalence of resistance of H. pylori is

very high to metronidazole,

moderate to clarithromycin and amoxycillin and

low to ciprofloxacin and tetracycline.

The rate of resistance was higher in southern

India than in northern India.

Prevalence of the

CagA gene -- in 96% (90/94) of patients, and

VacA m2 -- 60% (56/94),

VacA m1 -- 32% (30/94).

A significant association between the cagA

and vacA m2 region (chi2 = 5.556; p < 0.01)

was found in ulcer patients.

The vacA m2 genotype showed a near-

significant value (chi2 = 3.943; p < 0.047) in

ulcer patients when compared with vacA m1.

These findings suggest that H. pylori strains

with the vacA m2 region were predominant

in South India, especially in and around

Chennai