Volume: I: Issue-3: Nov-Dec -2010

ISSN 0976-4550

HELICOBACTER PYLORI: AN INTRODUCTION Arshad Mehmood5, M. Akram1, haha!"#dd$%1, A&'a( Ahmed), *ha% Usma%+ha%$,, A!d#( Ha%%a%,, E. Moh$#dd$%-, M. As$&5, Department of Basic Medical Sciences1, Department of Medicine and Allied Sciences2, Department of Preclinical Sciences3, Department of Surgery and Allied Sciences2 Department of Pre-clinical Sciences4, Faculty of astern Medicine, !amdard "ni#ersity$ Department of %on#entional Medicine&, 'slamia "ni#ersity Ba(a)alpur INTRODUCTION Since t(e introduction of !elico*acter pylori to t(e medical community *y Mars(all and +arren almost t)o decades ago, !elico*acter pylori (as *een t(e focus of *asic *ioc(emical and clinical researc( and de*ate$ 'ts rele#ance to (uman disease, specifically to peptic ulcer disease, gastritis, and gastric malignancy, is indisputa*le$ Many ,uestions, (o)e#er, still remain concerning t(e optimal diagnostic and t(erapeutic regimens )it( )(ic( to approac( t(e organism !elico*acter pylori is a gram negati#e, microaerop(ilic *acterium t(at can in(a*it #arious areas of t(e stomac(, particularly t(e antrum$ 't causes a c(ronic lo)-le#el inflammation of t(e stomac( lining and is strongly lin-ed to t(e de#elopment of duodenal and gastric ulcers and stomac( cancer$ .#er /01 of indi#iduals infected )it( t(e *acteria are asymptomatic$ 2(e *acterium )as initially named %ampylo*acter pyloridis, t(en renamed %$ pylori 3pylori 4 geniti#e of pylorus5 to correct a 6atin grammar error$ +(en 17S r89A gene se,uencing and ot(er researc( s(o)ed in 1:/: t(at t(e *acterium did not *elong in t(e genus %ampylo*acter, it )as placed in its o)n genus, !elico*acter$ 2(e genus deri#ed from t(e ancient ;ree- <spiral< or <coil<$ 2(e specific epit(et pyl=ri means <of t(e pylorus< or pyloric #al#e 3t(e circular opening leading from t(e stomac( into t(e duodenum5, from t(e Ancient ;ree- )ord >?@ABCD, )(ic( means gate-eeper$ More t(an &01 of t(e )orldEs population (ar*or !elico*acter pylori in t(eir upper gastrointestinal tract$ 'nfection is more pre#alent in de#eloping countries, and incidence is decreasing in +estern countries F1G$ M$.ro!$o(o+/ !elico*acter pylori is a (eliH-s(aped 3classified as a cur#ed rod, not spiroc(aete5 ;ramnegati#e *acterium, a*out 3 micrometres long )it( a diameter of a*out 0$& micrometres$ 't is microaerop(ilicI t(at is, it re,uires oHygen, *ut at lo)er concentration t(an is found in t(e atmosp(ere$ 't contains a (ydrogenase )(ic( can *e used to o*tain energy *y oHidiJing molecular (ydrogen 3!25 t(at is produced *y intestinal *acteria$ 't produces oHidase, catalase, and urease$ 't is capa*le of forming *iofilms and can con#ert from spiral to a possi*ly #ia*le *ut non cultural coccoid form, *ot( li-ely to fa#or its sur#i#al and *e factors in t(e epidemiology of t(e *acterium$ 2(e coccoid form can ad(ere to gastric epit(elial cells in #itro International Journal o !""lie# $iolo%& an# '(armaceutical )ec(nolo%& 'a%e:1337 !vaila*le online at +++,i-a*"t,com

!.ram et al

ISSN 0976-4550

0$+#re 1: He($.o!a.1er 2/(or$

!elico*acter pylori possess fi#e maKor outer mem*rane protein 3.MP5 families$ 2(e largest family includes -no)n and putati#e ad(esions$ 2(e ot(er four families include porins, iron transporters, flagellum-associated proteins and proteins of un-no)n function$ 6i-e ot(er typical ;ram-negati#e *acteria, t(e outer mem*rane of !elico*acter pylori consists of p(osp(olipids and lipopolysacc(aride 36PS5$ 2(e . antigen of 6PS may *e fucosylated and mimic 6e)is *lood group antigens found on t(e gastric epit(elium$ 2(e outer mem*rane also contains c(olesterol glucosides, )(ic( are found in fe) ot(er *acteria$ !elico*acter pylori (as 4-7 lop(otric(ous flagellaI all gastric and entero(epatic !elico*acter species are (ig(ly motile due to flagella$ 2(e c(aracteristic s(eat(ed flagellar filaments of !elico*acter are composed of t)o copolymeriJed flagellins, FlaA and FlaBF2G 3e%ome !elico*acter pylori consist of a large di#ersity of strains, and t(e genomes of t(ree (a#e *een completely se,uenced$ 2(e genome of t(e strain <277:&< consists of a*out 1$L million *ase pairs, )it( some 1,&&0 genes$ 2(e t)o se,uenced strains s(o) large genetic differences, )it( up to 71 of t(e nucleotides differing$ Study of t(e !elico*acter pylori genome is centered on attempts to understand pat(ogenesis, t(e a*ility of t(is organism to cause disease$ ApproHimately 2:1 of t(e loci are in t(e <pat(ogenesis< category of t(e genome data*ase$ Bot( se,uenced strains (a#e an approHimately 40 -*-long %ag pat(ogenicity island 3a common gene se,uence *elie#ed responsi*le for pat(ogenesis5 t(at contains o#er 40 genes$ 2(is pat(ogenicity island is usually a*sent from !elico*acter pylori strains isolated from (umans )(o are carriers of !elico*acter pylori *ut remain asymptomatic $ 2(e cagA gene codes for one of t(e maKor !elico*acter pylori #irulence proteins$ Bacterial strains t(at (a#e t(e cagA gene are associated )it( an a*ility to cause ulcers$ 2(e cagA gene codes for a relati#ely long 311/7 amino acid5 protein$ 2(e cag pat(ogenicity island 3PA'5 (as a*out 30 genes, part of )(ic( code for a compleH type 'M secretion system$ 2(e lo) ;%-content of t(e cag PA' relati#e to t(e rest of t(e !elico*acter genome suggests t(at t(e island )as ac,uired *y (oriJontal transfer from anot(er *acterial speciesF3G

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!.ram et al H$s1or/

ISSN 0976-4550

!elico*acter pylori )as first disco#ered in t(e stomac(s of patients )it( gastritis and stomac( ulcers in 1:/2 *y Dr$ Barry Mars(all and Dr$ 8o*in +arren of Pert(, +estern Australia$ At t(e time t(e con#entional t(in-ing )as t(at no *acterium could li#e in t(e (uman stomac( as t(e stomac( produced eHtensi#e amounts of acid of strengt( to t(e acid found in a car *attery$ Mars(all and +arren re)rote t(e teHt*oo-s )it( reference to )(at causes gastritis and gastric ulcers$ 'n recognition of t(eir disco#ery, t(ey )ere a)arded t(e 200& 9o*el PriJe in P(ysiology or Medicine$ ;erman scientists found spiral-s(aped *acteria in t(e lining of t(e (uman stomac( in 1/L&, *ut t(ey )ere una*le to culture it and t(e results )ere e#entually forgotten$ 2(e 'talian researc(er ;iulio BiJJoJero descri*ed similarly s(aped *acteria li#ing in t(e acidic en#ironment of t(e stomac( of dogs in 1/:3$ Professor +alery Na)ors-i of t(e Nagiellonian "ni#ersity in Ora-P) in#estigated sediments of gastric )as(ings o*tained from (umans in 1/::$ Among some rod-li-e *acteria, (e also found *acteria )it( a c(aracteristic spiral s(ape, )(ic( (e called Mi*rio rugula$ !e )as t(e first to suggest a possi*le role of t(is organism in t(e pat(ogenesis of gastric diseases$ 2(is )or- )as included in t(e !and*oo- of ;astric Diseases, *ut it (ad little impact as it )as )ritten in Polis($ Se#eral small studies conducted in t(e early 1:00s demonstrated t(e presence of cur#ed rods in t(e stomac( of many patients )it( peptic ulcers and stomac( cancer$ !o)e#er interest in t(e *acteria )aned )(en an American study pu*lis(ed in 1:&4 failed to o*ser#e t(e *acteria in 11/0 stomac( *iopsies $ 'nterest in understanding t(e role of *acteria in stomac( diseases )as re-indled in t(e 1:L0s )it( t(e #isualiJation of *acteria in t(e stomac( of gastric ulcer patients$ 2(e *acterium (ad also *een o*ser#ed in 1:L: *y Australian pat(ologist 8o*in +arren, )(o did furt(er researc( on it )it( Australian p(ysician Barry Mars(all *eginning in 1:/1$ After numerous unsuccessful attempts at culturing t(e *acteria from t(e stomac(, t(ey finally succeeded in #isualiJing colonies in 1:/2 )(en t(ey unintentionally left t(eir Petri dis(es incu*ating for & days o#er t(e aster )ee-end$ 'n t(eir original paper, +arren and Mars(all contended t(at most stomac( ulcers and gastritis )ere caused *y infection *y t(is *acterium and not *y stress or spicy food as (ad *een assumed *efore F24, 2&G$ Alt(oug( t(ere )as some s-epticism initially, )it(in se#eral years numerous researc( groups #erified t(e association of !elico*acter pylori )it( gastritis and to a lesser eHtent ulcer$ 2o demonstrate t(at !elico*acter pylori caused gastritis and )as not merely a *ystander, Mars(all dran- a *ea-er of !elico*acter pylori culture$ !e *ecame ill )it( nausea and #omiting se#eral days later$ An endoscopy ten days after inoculation re#ealed signs of gastritis and t(e presence of !elico*acter pylori$ 2(ese results suggested t(at !elico*acter pylori )as t(e causati#e agent of gastritis$ Mars(all and +arren )ent on to demonstrate t(at anti*iotics are effecti#e in t(e treatment of many cases of gastritis$ 'n 1:/L t(e Sydney gastroenterologist 2(omas Borody in#ented t(e first triple t(erapy for t(e treatment of duodenal ulcers$ 'n 1::4, t(e 9ational 'nstitutes of !ealt( 3"SA5 pu*lis(ed an opinion stating t(at most recurrent duodenal and gastric ulcers )ere caused *y !elico*acter pylori and recommended t(at anti*iotics *e included in t(e treatment regimenF4G 8ecent researc( states t(at genetic di#ersity in !elico*acter pylori decreases )it( geograp(ic distance from ast Africa, t(e *irt(place of modern (umans$ "sing t(e genetic di#ersity data, t(e researc(ers (a#e created simulations t(at indicate t(e *acterium seems to (a#e spread from ast Africa around &/,000 years ago$ 2(eir results indicate modern (umans )ere already infected *y !elico*acter pylori *efore t(eir migrations out of Africa, remaining associated )it( (uman (osts since t(at time

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!.ram et al E2$dem$o(o+/

ISSN 0976-4550

At least (alf t(e )orldEs population is infected *y t(e *acterium, ma-ing it t(e most )idespread infection in t(e )orld$ Actual infection rates #ary from nation to nation, t(e people in under de#eloped countries (as muc( (ig(er infection rates t(an t(e de#eloped countries li-e 9ort( America, Australasia etc$ )(ere rates are estimated to *e around 2&1$ 'nfections are usually ac,uired in early c(ild(ood in all countries$ !o)e#er, t(e infection rate of c(ildren in de#eloping nations is (ig(er t(an in industrialiJed nations, pro*a*ly due to poor sanitary conditions$ 'n de#eloped nations it is currently uncommon to find infected c(ildren, *ut t(e percentage of infected people increases )it( age, )it( a*out &01 infected for t(ose o#er t(e age of 70 compared )it( around 101 *et)een 1/ and 30 years$ 2(e (ig(er pre#alence among t(e elderly reflects (ig(er infection rates )(en t(ey )ere c(ildren rat(er t(an infection at later ages$ Pre#alence appears to *e (ig(er in African-American and !ispanic populations, alt(oug( t(is is li-ely related to socioeconomic rat(er t(an racial factors$ 2(e lo)er rate of infection in t(e de#eloped countries is largely attri*uted to (ig(er (ygiene standards and )idespread use of anti*iotics$ Despite (ig( rates of infection in certain areas of t(e )orld, t(e o#erall fre,uency of !elico*acter pylori infection is declining$ !o)e#er, anti*iotic resistance is appearing in !elico*acter pyloriI t(ere are already many metronidaJole and clarit(romycin resistant strains in most parts of t(e )orldF&G$ !elico*acter pylori is contagious, alt(oug( t(e eHact route of transmission is not -no)n$ Personto-person transmission *y eit(er t(e oral-oral or fecal-oral route is most li-ely$ %onsistent )it( t(ese transmission routes, t(e *acteria (a#e *een isolated from feces, sali#a and dental pla,ue of some infected people$ 2ransmission occurs mainly )it(in families in de#eloped nations yet can also *e ac,uired from t(e community in de#eloping countries$ !elico*acter pylori may also *e transmitted orally *y means of fecal matter t(roug( t(e ingestion of )aste-tainted )ater, so a (ygienic en#ironment could (elp decrease t(e ris- of !elico*acter pylori infection

0$+#re ): Pa1ho+e%es$s o& He($.o!a.1er 2/(or$ International Journal o !""lie# $iolo%& an# '(armaceutical )ec(nolo%& 'a%e:1340 !vaila*le online at +++,i-a*"t,com

!.ram et al Pa1ho+e%es$s

ISSN 0976-4550

2(e earliest descriptions of t(e organism classified it as predominately eHtracellular, gramnegati#e, flagellated, and motile$ +it( t(e ad#ancement of *ioc(emical tec(ni,ues, ne) information a*out t(e pat(ogenicity and #irulence factors of !elico*acter pylori (as emerged, indicating t(at infection *y !elico*acter pylori re,uires a compleH interaction of *ot( *acterial and (ost factors$ 'n#estigators (a#e identified se#eral *acterial proteins necessary for coloniJation of t(e gastric mucosa *y !elico*acter pylori, including proteins acti#e in t(e transport of t(e organism to t(e surface of t(e mucosa 3eg, flagellin, )(ic( is encoded on genes flaA and flaB5$ .nce in t(e presence of t(e gastric mucosa, *acteria induce a transient (ypoc(lor(ydria *y an un-no)n mec(anism $ 2(e urease enJyme produced *y t(e *acteria alters t(e microen#ironment of t(e organism to facilitate coloniJation$ Ad(erence t(en occurs #ia interaction *et)een cell-surface glycolipids and ad(esins specific to !elico*acter pylori$ 2(ere also appears to *e a role played *y proteins called cecropins, )(ic( are produced *y !elico*acter pylori and in(i*it t(e gro)t( of competing organisms, as )ell as *y a P-type adenosine trip(osp(atase, )(ic( (elps pre#ent eHcessi#e al-aliniJation of t(e microen#ironment *y urease$ .nce attac(ed to gastric mucosa, !elico*acter pylori causes tissue inKury *y a compleH cascade of e#ents t(at depends on *ot( t(e organism and t(e (ost$ !elico*acter pylori, li-e all gram negati#e *acteria, (as in its cell )all lipopolysacc(aride, )(ic( acts to disrupt mucosal integrity$ Furt(ermore, !elico*acter pylori release se#eral pat(ogenic proteins t(at induce cell inKury$ For eHample, t(e %agA protein, produced *y cytotoHic-associated gene A 3cagA5, is a (ig(ly immunogenic protein t(at may *e associated )it( more se#ere clinical syndromes, suc( as duodenal ulcer and gastric adenocarcinoma 3alt(oug( t(is ,uestion is far from settled5$ 2(ere is increasing e#idence t(at %agA positi#ity is associated )it( an increased ris- for distal, *ut not proHimal, gastric adenocarcinoma$ 'n addition, protein products of t(e #acuolating cytotoHin A gene 3#acA5 and t(e A gene induced *y contact )it( epit(elium 3iceA5 are -no)n to *e associated )it( mucosal inKury$ .nce coloniJation of t(e gastric mucosa (as ta-en place, t(e immunogenic properties of !elico*acter pylori induce an inflammatory reaction )it( neutrop(ilic gastritis t(at ultimately results in t(e clinical manifestations of t(e infection$ 2(is process is mediated *y (ost factors, including interleu-ins 1, 2, 7, /, and 12I interferon gamma, tumor necrosis factor, 2 and B lymp(ocytes and p(agocytic cells$ 2(ese factors mediate inKury t(roug( release of reacti#e oHygen species and inflammatory cyto-ines$ !elico*acter pylori additionally appear to increase t(e rate of mucosal-programmed cell deat( 3also -no)n as apoptosis5 F7G$ E&&e.1s o% +as1r$. 2h/s$o(o+/ 'n addition to producing local inKury of gastric mucosa, !elico*acter pylori alters normal gastric secretion$ 'nterestingly, t(e location and se#erity of t(e infection seem closely associated )it( t(e ultimate clinical outcome, most li-ely *ecause of effects on gastric p(ysiology$ Many studies (a#e s(o)n t(at patients )it( a duodenal ulcer )(o are infected )it( !elico*acter pylori (a#e an increased serum le#el of gastrin, )(ic( in turn leads to increased acid output$ 2(ese patients tend to (a#e a milder p(enotypic eHpression of t(eir gastritis, )it( inflammation mostly in t(e antrum or distal part of t(e stomac($

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!.ram et al

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'n contrast, patients )it( gastric adenocarcinoma, a -no)n complication of !elico*acter pylori infection tend to (a#e pangastritis )it( in#ol#ement of t(e acid secreting *ody of t(e stomac( as )ell as t(e antrum$ 2(is condition leads to atrop(y of parietal cells 3)(ic( are responsi*le for producing acid5 and gastrin-producing cells of t(e antrum 3)(ic( stimulate acid secretion5 and e#entually produces ac(lor(ydria$ Patients )it( gastric adenocarcinoma also (a#e impaired acid secretion in response to stimulation )it( gastrin FLG$ Pa1ho(o+$. &$%d$%+s Alt(oug( eHtensi#e )or- (as *een performed to classify (istopat(ologic c(anges seen )it( !elico*acter pylori infection, t(ere is no consensus on classificationI t(e Sydney system and t(e !ouston ;astritis +or-s(op system (a#e, (o)e#er, *een recogniJed as models$ After coloniJation, t(ere appears to *e an intense neutrop(ilic infiltrate in t(e nec-s of t(e mucosal glands$ pit(elial c(anges are common )(en t(ere is irregularity of t(e surface arc(itecture, and atrop(y of t(e glands is typical of longstanding infection$ Moreo#er, t(ere is usually lymp(ocytic infiltration of t(e stroma and impaired mucus secretion$ Finally, areas of patc(yintestinal metaplasia may *e seen, )(ic( are central to t(e de#elopment of neoplasia F/G$

C($%$.a( ma%$&es1a1$o%s
3as1r$1$s a%d +as1r$. .a%.er .nce infected )it( !elico*acter pylori, most persons remain asymptomatic$ Some infected persons may e#en clear t(e infection, )it( serore#ersion rates commonly reported to *e in t(e range of &1 to 101I it is not -no)n if t(is serore#ersion is spontaneous or results from elimination of t(e organism *y anti*iotic agents used to treat ot(er conditions$ !o)e#er, t(e typical course of disease in infected patients *egins )it( c(ronic superficial gastritis, e#entually progressing to atrop(ic gastritis$ 2(is progression appears to *e a -ey e#ent in t(e cellular cascade t(at results in t(e de#elopment of gastric carcinoma$ Histing data indicate a :0-fold increase in rates of gastric carcinoma in patients )it( se#ere, multifocal atrop(ic gastritis, compared )it( normal controls$ 2(e mec(anism of tumorigenesis appears to in#ol#e D9A damage induced *y different cyto-ines and free radicals released in t(e setting of c(ronic inflammation in suscepti*le persons$ Alt(oug( !elico*acter pylori is associated )it( t(e de#elopment of adenocarcinoma of t(e antrum and *ody of t(e stomac(, it is also clearly lin-ed )it( gastric mucosaQassociated lymp(oid tissue 3MA625 lymp(omas$ !elico*acter pylori stimulates lymp(ocytic infiltration of t(e mucosal stromaI t(is infiltration may act as a focus for cellular alteration and proliferation, ultimately resulting in neoplastic transformation to lymp(oma$ 't appears t(at !elico*acter pylori also produces proteins t(at stimulate gro)t( of lymp(ocytes in t(e early stages of neoplasia$ Most tellingly, it (as *een reported t(at regression of lo)-grade gastric MA62 lymp(oma can *e ac(ie#ed in L01 to :01 of patients )it( eradication of !elico*acter pylori infection$ 8ecent )or- (as s(o)n endoscopic ultrasound eHamination to *e in#alua*le in identifying t(e grade of MA62 lymp(oma and in predicting t(e efficacy of treating t(e !elico*acter pylori infection to o*tain regression of t(e lymp(oma F:G$

Pe21$. #(.er d$sease

2(e relations(ip *et)een !elico*acter pylori infection and peptic ulcer disease (as *een studied eH(austi#ely, and it is no) accepted t(at t(e organism is t(e maKor cause, *ut not t(e only cause, of peptic ulcer disease )orld)ide$ radicating t(e infection can alter t(e natural course of peptic ulcer disease *y dramatically reducing its recurrence rate in treated patients, compared )it( untreated patients$ 2(is reduction occurs in patients )it( duodenal and gastric ulcers t(at (a#e no (istory of nonsteroidal anti-inflammatory drug use$

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2(e mec(anism *y )(ic( !elico*acter pylori induces peptic ulcer disease is incompletely understood *ut most li-ely in#ol#es a com*ination of genetic predisposition of t(e (ost, #irulence factors of t(e organism 3eg, MacA and %agA proteins5, mec(anical damage to t(e mucosa, and alterations of gastric and duodenal secretions

No%"#(.er d/s2e2s$a
9on-ulcer dyspepsia comprises a constellation of #aried symptoms, including dysmotility-li-e, ulcer-li-e, and refluH-li-e symptoms$ Many possi*le causes (a#e *een suggested for non-ulcer dyspepsia, including lifestyle factors, stress, altered #isceral sensation, increased serotonin sensiti#ity, alterations in gastric acid secretion and gastric emptying, and !elico*acter pylori infection$ A recent study also (ig(lig(ted t(e role played *y psyc(osocial impairment 3eg, depression, somatiJation, anHiety5 in patients )it( non-ulcer dyspepsia$ 'n a study lin-ing !elico*acter pylori infection to non-ulcer dyspepsia, patients )it( t(e latter condition )ere t)ice as li-ely to *e positi#e for t(e organism$ !o)e#er, despite suc( epidemiologic e#idence, treatment studies (a#e failed to consistently s(o) t(at eradication of !elico*acter pylori results in impro#ement of non-ulcer dyspepsia symptoms$ %onse,uently, eradication of t(e organism can not *e considered t(e standard of care in all patients )it( non-ulcer dyspepsia, *ecause !elico*acter pylori infection is only a single part of t(e multi-factorial etiology of t(e disease F10G

3as1roeso2ha+ea( re&(#4 d$sease

Muc( attention (as *een focused on t(e possi*le relations(ip *et)een infection )it( !elico*acter pylori and gastroesop(ageal refluH disease 3; 8D5 in its #arious manifestations 3eg, esop(agitis, BarrettRs esop(agus5$ Some in#estigators (a#e suggested a lin- *et)een t(e presence of !elico*acter pylori and a decreased ris- for de#eloping esop(agitis and BarrettRs esop(agusI alt(oug( t(is in#erse association is supported *y many pre#alence studies, ot(ers fail to s(o) it$ Studies (a#e also indicated t(at certain strains of !elico*acter pylori, nota*ly t(e %agA- positi#e strain, may *e protecti#e against t(e de#elopment of BarrettRs esop(agus$ Moreo#er, 6a*enJ and colleagues (a#e s(o)n t(at t(e incidence of esop(agitis may in fact, increase after eradication of t(e organism$ 2reatment of !elico*acter pylori infection can lead to eHacer*ation of ; 8D in many patients, prompting many gastroenterologists to defer endoscopic antral *iopsies in patients )it( significant ; 8D and a*sent ulcer$ %on#ersely, ot(er studies using endoscopic findings, p! pro*e measurements, and (istology to determine t(e presence of !elico*acter pylori did not find any association *et)een ; 8D 3in any of its manifestations5 and infection )it( !elico*acter pylori$ %learly, more definiti#e studies are necessary to define t(e relations(ip, if any, *et)een t(ese 2 entities F11G$

O1her d$sease asso.$a1$o%s

'n#estigators (a#e furt(er postulated a relations(ip *et)een !elico*acter pylori infection and cardio#ascular disease and iron-deficiency anemia$ 2(ese associations, (o)e#er, re,uire muc( more study *efore a causal relations(ips is esta*lis(ed F12G$

D$a+%os1$. 1es1$%+
%urrently, t(ere are se#eral popular met(ods for detecting t(e presence of !elico*acter pylori infection, eac( (a#ing its o)n ad#antages, disad#antages, and limitations$ Basically, t(e tests a#aila*le for diagnosis can *e separated according to )(et(er or not endoscopic *iopsy is necessary$ !istological e#aluation, culture, polymerase c(ain reaction 3P%85, and rapid urease tests are typically performed on tissue o*tained at endoscopy$ Alternati#ely, simple *reat( tests, serology, and stool assays are sometimes used, and trials in#estigating P%8 amplification of sali#a, feces, and dental pla,ue to detect t(e presence of !elico*acter pylori are ongoing

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!istologic e#aluation (as traditionally *een t(e gold standard met(od for diagnosing !elico*acter pylori infection$ 2(e disad#antage of t(is tec(ni,ue is t(e need for endoscopy to o*tain tissue$ 6imitations also arise at times *ecause of an inade,uate num*er of *iopsy specimens o*tained or failure to o*tain specimens from different areas of t(e stomac($ 'n some cases, different staining tec(ni,ues may *e necessary, )(ic( can in#ol#e longer processing times and (ig(er costs$ !o)e#er, (istologic sampling does allo) for definiti#e diagnosis of infection, as )ell as of t(e degree of inflammation or metaplasia and t(e presenceSa*sence of MA62 lymp(oma or ot(er gastric cancers in (ig(-ris- patients$

C#(1#re
Because !elico*acter pylori is difficult to gro) on culture media, t(e role of culture in diagnosis of t(e infection is limited mostly to researc( and epidemiologic considerations$ Alt(oug( costly, time-consuming, and la*or intensi#e, culture does (a#e a role in anti*iotic suscepti*ility studies and studies of gro)t( factors and meta*olism $

Po(/merase .ha$% rea.1$o%

+it( t(e ad#ent of P%8, many eHciting possi*ilities emerged for diagnosing and classifying !elico*acter pylori infection$ P%8 allo)s identification of t(e organism in small samples )it( fe) *acteria present and entails no special re,uirements in processing and transport$ Moreo#er, P%8 can *e performed rapidly and cost- effecti#ely, and it can *e used to identify different strains of *acteria for pat(ogenic and epidemiologic studies$ As suggested earlier, P%8 also is *eing e#aluated for its utility in identifying !elico*acter pylori in samples of dental pla,ue, sali#a, and ot(er easily sampled tissues$ 2(e maKor limitation of P%8 is t(at relati#ely fe) la*oratories currently (a#e t(e capa*ility to run t(e assay$ 'n addition, *ecause P%8 can detect segments of !elico*acter pylori D9A in t(e gastric mucosa of pre#iously treated patients, false-positi#e results can occur, and errors in (uman interpretation of *ands on electrop(oretic gels can li-e)ise lead to false-negati#e results

Ra2$d #rease 1es1$%+

8apid urease testing ta-es ad#antage of t(e fact t(at !elico*acter pylori is a urease producing organism$ Samples o*tained on endoscopy are placed in urea-containing mediumI if urease is present, t(e urea )ill *e *ro-en do)n to car*on dioHide and ammonia, )it( a resultant increase in t(e p! of t(e medium and a su*se,uent color c(ange in t(e p! dependent indicator$ 2(is test (as t(e ad#antages of *eing ineHpensi#e, fast, and )idely a#aila*le$ 't is limited, (o)e#er, *y t(e possi*ility of false positi#e resultsI decreased urease acti#ity, caused eit(er *y recent ingestion of anti*iotic agents, *ismut( compounds, proton pump in(i*itors, or sucralfate or *y *ile refluH, can contri*ute to t(ese false-positi#e results

Urea !rea1h 1es1

A urea *reat( test similarly relies on t(e urease acti#ity of !elico*acter pylori to detect t(e presence of acti#e infection$ 'n t(is test, a patient )it( suspected infection ingests eit(er14%la*eled or 13%- la*eled ureaI 13%- la*eled urea (as t(e ad#antage of *eing non radioacti#e and t(us safer 3t(eoretically5 for c(ildren and )omen of c(ild*earing age$ "rease, if present, splits t(e urea into ammonia and isotope-la*eled car*on dioHideI t(e car*on dioHide is a*sor*ed and e#entually eHpired in t(e *reat(, )(ere it is detected$

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Besides *eing eHcellent for documenting acti#e infection, t(is test is also #alua*le for esta*lis(ing a*sence of infection after treatment, an important consideration in patients )it( a (istory of complicated ulcer disease )it( *leeding or perforation$ 'n addition, a urea *reat( testis relati#ely ineHpensi#e 3)(ic(e#er isotope is used5, is easy to perform, and does not re,uire endoscopy$ !o)e#er, if t(e patient (as recently ingested proton pump in(i*itors, anti*iotic agents, or *ismut( compounds, a urea *reat( test can *e of limited #alue$ 2(erefore, at least 1 )ee- s(ould separate t(e discontinuing of antisecretory medications and testing for acti#e infection, and 4 )ee-s s(ould separate treatment of !elico*acter pylori infection and testing for eradication of t(e organism$ Moreo#er, eHcept for maKor medical centers or tertiary referral centers )(ere results are usually a#aila*le in fe)er t(an 24 (ours, a urea *reat( test may *e furt(er limited *y a turnaround time of se#eral days 3or longer5 re,uired for transport of samples and analysis *y specialiJed la*oratories not present in many community settings F13G$

ero(o+$. 1es1s
'n response to !elico*acter pylori infection, t(e immune system typically mounts a response t(roug( production of immunoglo*ulins to organism-specific antigens$ 2(ese anti*odies can *e detected in serum or )(ole-*lood samples easily o*tained in a p(ysicianRs office$ 2(e presence of 'g; anti*odies to !elico*acter pylori can *e detected *y use of a *ioc(emical assay, and many different ones are a#aila*le$ Serologic tests offer a fast, easy, and relati#ely ineHpensi#e means of identifying patients )(o (a#e *een infected )it( t(e organism$ !o)e#er, t(is met(od is not a useful means of confirming eradication of !elico*acter pyloriI se#eral different samples and c(anges in titers of specified amounts o#er time )ould *e needed$ 'n addition, fe) patients *ecome truly seronegati#e, e#en after eradication of t(e organism$ 'n lo)-pre#alence populations, serologic tests s(ould *e a second-line met(odology *ecause of lo) positi#e predicti#e #alue and a tendency to)ard false-positi#e results$ Serologic tests may *e useful in identifying certain strains of more #irulent !elico*acter pylori *y detecting anti*odies to #irulence factors associated )it( more se#ere disease and complicated ulcers, gastric cancer, and lymp(oma F14G$

1oo( a%1$+e% 1es1$%+

Stool antigen testing is a relati#ely ne) met(odology t(at uses an enJyme immunoassay to detect t(e presence of !elico*acter pylori antigen in stool specimens$ A cost effecti#e and relia*le means of diagnosing acti#e infection and confirming cure, suc( testing (as a sensiti#ity and specificity compara*le to t(ose of ot(er nonin#asi#e tests$ Tuestions remain regarding possi*le cross reacti#ity )it( ot(er !elico*acter species present in t(e intestines, *ut definiti#e studies are lac-ing F1&G$

3e%era( d$a+%os1$. 2r$%.$2(es

2(e ,uestion, of )(ic( patients to test, )(en to test t(em and )(at test to use is still a trou*ling one for many p(ysicians$ "ltimately, t(e ans)er to t(ese ,uestions must *e *ased on patient preference, cost, a#aila*ility of different tests, and positi#e and negati#e predicti#e #alues of different tests 3)(ic( depend on t(e indi#idual patient population, including t(e pre#alence of disorders caused *y !elico*acter pylori infection in t(e community5$ 9e#ert(eless, certain principles of testing seem uni#ersal$ First, endoscopic met(ods of diagnosis s(ould *e used only if t(e procedure is necessary to detect some ot(er condition *esides !elico*acter pylori infection$ Second, only t(ose patients in )(om treatment )ill ma-e a difference s(ould *e tested$ %onclusi#e e#idence does not eHist t(at eradication of t(e infection in patients )it( simple dyspepsia )ill relie#e symptoms, and testing of asymptomatic patients )it(out a (istory of documented peptic ulcer disease is not )arranted$ 2esting can *e considered on a case *y case *asis in patients )it( symptoms suggesti#e of peptic ulcer disease$

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Because treatment of !elico*acter pylori infection is definitely indicated in patients )it( acti#e or pre#iously documented peptic ulcer disease, gastric MA62 lymp(oma, or family (istory of gastric cancer, t(eir !elico*acter pylori status must *e clarified$ "rea *reat( and stool antigen tests are t(e most cost-efficient tests to identify acti#e infection, *ut t(eir limitations must *e considered$ Alt(oug( serology is an eHcellent, ineHpensi#e test to ascertain if someone )it( a (istory of peptic ulcer disease and un-no)n !elico*acter pylori status )arrants treatment, endoscopy )it( tissue sampling in patients )it( a (istory of peptic ulcer disease can pro#ide more definiti#e diagnosis of !elico*acter pylori infection, as )ell as information a*out t(e acti#ity of peptic ulcer disease and possi*ly ot(er factors at play 3including gastric carcinoma5$ Follo)-up testing )it( urea *reat( or stool antigen tests *ot( of )(ic( (a#e sensiti#ities and specificities greater t(an :01 is necessary to document cure in patients )it( complicated peptic ulcer disease e$g$ perforation, (emorr(age, o*struction or recurrent symptoms and s(ould *e performed 4 )ee-s after completion of treatment F17G$

Ma%a+eme%1 3e%era( 1rea1me%1 2r$%.$2(es

Determining t(e optimum treatment of !elico*acter pylori infection is difficult, *ecause t(e organism li#es in an en#ironment not easily accessi*le to many medications and *ecause emerging *acterial resistance presents an added c(allenge$ Moreo#er, many of t(e recommended regimens are difficult for patients to ta-e, leading to pro*lems )it( complianceI specifically, (a#ing to ta-e a large num*er of pills at least t)ice daily and coping )it( unpleasant ad#erse effects do little to encourage patient cooperation$ Despite t(ese o*stacles, current regimens can o*tain cure rates in eHcess of /&1 in most patient populations F1LG$

Pa1$e%1 ma%a+eme%1 $% 2r$mar/ .are

2(e maKority of patients infected )it( !elico*acter pylori present initially in primary care, suffering from dyspeptic symptoms )it( or )it(out alarm symptoms$ 2(is is )(ere many of t(em can and s(ould *e treated for t(e infection, e#en t(oug(, in t(e a*sence of endoscopy, t(e primary care p(ysician may not (a#e an accurate diagnosis of t(e underlying disease pat(ology$ A furt(er consideration is t(e increasing media, and (ence patient, a)areness of !elico*acter pylori, and its relations(ip to diseases suc( as gastric cancer$ 'n t(is en#ironment, primary care p(ysicians need to (a#e a clear understanding of t(e maKor role t(at t(ey play in t(e management of t(e infection$ 2(e recommendations gi#en (ere are particularly rele#ant to management in primary care, *ut many of t(em apply across clinical practice$ 2)o strongly recommended indications )(ic( s(ould *e noted (ere as particularly rele#ant in primary care are patients )(o are first-degree relati#es of gastric cancer patients and eradication t(erapy in response to patientsE )is(es after full consultation$ As recommended in t(e original Maastric(t %onsensus 8eport, a Utest and treatE approac( s(ould *e offered to adult patients under t(e age of 4& years 3t(e age cut-off may #ary locally according to t(e mean age of gastric cancer onset5 presenting in primary care )it( persistent dyspepsia$ Se#eral studies (a#e since *een pu*lis(ed )(ic( support t(is recommendation F1/G$

A%1$!$o1$. a+e%1s
%urrently, anti*iotic agents used to treat !elico*acter pylori infection are administered in com*ination, )it( no single agent e#er used as monot(erapy *ecause of a lac- of efficacy and t(e potential de#elopment of resistance$ MetronidaJole (as acti#ity independent of p!, *ut resistance to t(e drug is common in many parts of t(e )orld$

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2(is pro*lem )it( resistance is ameliorated some)(at, (o)e#er, )(en t(e drug is used )it( clarit(romycin$ MetronidaJole can (a#e unpleasant ad#erse effects 3e$g$ nausea5 and a disulfiramli-e reaction to alco(ol ingestion is possi*le, alt(oug( eHceedingly rare$ %larit(romycin (as lo)er rates of resistance 3approHimately L1Q1115 *ut is not acid sta*le, may cause dysgeusia and is more eHpensi#e t(an ot(er anti*iotic agents$ 8esistance to amoHicillin is rare, *ut t(is drug usually re,uires t(e co-administration of a proton pump in(i*itor *ecause its acti#ity is p!dependent$ Finally, tetracycline (as t(e ad#antage of lo) cost and lo) occurrence of resistance *ut can cause discoloration of t(e teet( in c(ildren and p(otosensiti#ity reactions F1:G$

Ad5#%.1$6e a+e%1s
2(e most popular agents currently used in com*ination )it( anti*iotic agents to eradicate !elico*acter pylori infection are t(e proton pump in(i*itors i-e omepraJole *eing t(e most )idely studied drug$ .mepraJole acts not only *y directly in(i*iting *acterial microsomal enJymes *ut also *y raising intra-gastric p!, t(us facilitating t(e action of anti*iotic agents, reducing gastric secretions, and increasing anti*iotic concentrations in t(e stomac($ .t(er adKuncti#e agents include (istamine receptor antagonists and ranitidine *ismut( citrate, )(ic( (as anti-secretory properties in addition to t(e anti*acterial action of *ismut( 3i$e$ interruption of t(e *acterial cell )all5$ 8anitidine *ismut( citrate is no longer a#aila*le F20G$

C#rre%1 re+$me%s
Presently, t(e most efficacious regimens include 2 anti*iotic agents and at least 1 adKuncti#e agent for 14 days$ 'n literature citation study carried out (as claimed ade,uate cure rates )it( a Lday course of ,uadruple t(erapy 32 anti*iotics, 2 adKuncti#e agents5, *ut ot(er studies (a#e not confirmed t(is finding$ Most clinicians treat !elico*acter pylori infection )it( a triple drug or e#en ,uadruple-drug approac($ 2(e 1::/ guidelines suggested t(e follo)ing 3 regimens to *e optimal F21G$ 315 Administration of a proton pump in(i*itor, clarit(romycin and eit(er metronidaJole or amoHicillin for 2 )ee-s 325 Administration of ranitidine *ismut( citrate 3t(is guideline preceded t(e drugRs )it(dra)al in t(e "nited States5, clarit(romycin and eit(er metronidaJole, amoHicillin, or tetracycline for 2 )ee-s 335 A proton pump in(i*itor, *ismut(, metronidaJole and tetracycline for 2 )ee-s$ More recent recommendations outlined in a postgraduate course offered *y t(e American ;astroenterology Association propose t(e use of ne)er proton pump in(i*itors$ For patients )(o fail initial triple-drug t(erapy, according to follo)-up testing, su*se,uent t(erapy s(ould in#ol#e using a different com*ination of a#aila*le anti*iotic agents, increasing t(e duration of treatment, or incorporating a course of ,uadruple t(erapy$ %ulture )it( sensiti#ity testing s(ould *e performed after 2 treatment failures F22G$

Emer+$%+ 1hera2$es A%1$!$o1$.s a%d o1her a+e%1s

As emerging drug resistance continues to plague efforts to eradicate !elico*acter pylori infection, ne) t(erapeutic regimens incorporating eHisting anti*iotic agents and ne)ly de#eloped compounds are essential$ 9itaJoHanide (as promise as an effecti#e agent )(en used in com*ination )it( omepraJole, and furt(er studies are ongoing$ 'n addition, macrolides ot(er t(an clarit(romycin may play a role in future t(erapies$ 2(e mapping of t(e complete genome of !elico*acter pylori (as opened t(e door for a ne) era in c(emot(erapeutic drugs$ 't )ill no) *e possi*le to de#elop agents t(at act on specific -ey protein products #ital to sur#i#al of t(e *acterium F23G$

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Per(aps t(e most eHciting )or- in t(e ,uest to eradicate !elico*acter pylori as a significant (uman pat(ogen is in t(e area of #accine de#elopment$ 2(e fact t(at t(e organism is pre#alent )orld)ide, is responsi*le for significant mor*idity and mortality, and is difficult and eHpensi#e to eradicate ma-es it a prime target for #accine t(erapy$ Pioneering )or- in t(e early 1::0s pro#ided e#idence t(at #accination against !elico*acter pylori infection )as possi*le, *ased on murine models$ 't )as later learned t(at t(e -ey mec(anism of protecti#e immunity against t(e organism occurred #ia stimulation of 2-(elper type 2 p(enotype cells, )(ic( are induced *y t(e production of interleu-ins 4 and 10 and not *y anti*ody production$ Se#eral issues remain in regard to a safe and effecti#e #accine against !elico*acter pylori infection$ 'n t(e first place, a safe mucosal adKu#ant or #ector to stimulate an immune response must *e identified$ Different agents, including c(olera toHin and an sc(eric(ia coli (eat la*ile toHin, (a#e *een used in conKunction )it( specific !elico*acter pylori antigens 3e$g$ urease5 )it( #arying success$ Attenuated li#e #accines, including strains of Salmonella, used in com*ination )it( !elico*acter pylori antigens (a#e s(o)n promise$ Secondly, t(e optimal route of administration needs to *e definedI studies in mice s(o) promise )it( nasal and rectal routes, )(ic( )ould a#oid t(e possi*le post immuniJation gastritis li-ely )it( an oral route$ 'n addition, different regimens need to *e de#eloped to ensure complete steriliJation of t(e gastric mucosaI t(e latter step (as not generally *een attempted in murine models F24G$ Pre6e%1$o% !elico*acter pylori is a maKor cause of diseases of t(e upper gastrointestinal tract$ radication of t(e infection in indi#iduals )ill impro#e symptoms including dyspepsia, gastritis and peptic ulcers, and may pre#ent gastric cancer$ 8ising antimicro*ial resistance increases t(e need for a pre#ention strategy for t(e *acteria$ 2(ere (a#e *een eHtensi#e #accine studies in mouse models, )(ic( (a#e s(o)n promising results$ 8esearc(ers are studying different adKu#ants, antigens and routes of immuniJation to ascertain t(e most appropriate system of immune protection, )it( most of t(e researc( only recently mo#ing from animal to (uman trials F2&G$ An intramuscular #accine against !elico*acter pylori infection is undergoing P(ase ' clinical trials and (as s(o)n an anti*ody response against t(e *acterium$ 'ts clinical usefulness re,uires furt(er study F27G$ Studies (a#e recently *een pu*lis(ed suggesting t(at !elico*acter pylori acti#ity could *e suppressed #ia dietary met(ods$ A 200: Napanese study in %ancer Pre#ention 8esearc( found t(at eating as little as L0 g 32$& ounces5 of *roccoli sprouts daily for t)o mont(s reduces t(e num*er of colonies of !elico*acter pylori *acteria in t(e stomac( *y 401 in mice and (umans$ 2(is treatment also seems to (elp *y en(ancing t(e protection of t(e gastric mucosa against !elico*acter pylori *ut is relati#ely ineffecti#e on related gastric cancers$ 2(e pre#ious infection returned )it(in t)o mont(s after *roccoli sprouts )ere remo#ed from t(e diet, so an ongoing inclusion in t(e diet is *est for continued protection from !elico*acter pylori F2LG$ A 200/ study pu*lis(ed in Oorean Nournal of Micro*iology and Biotec(nology found t(at -imc(i 3fermented ca**age5 contains a *acterium strain <s(o)ing strong antagonistic acti#ity against !elico*acter pylori$<

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2(e *acterium strain isolated from -imc(i, designated 6*$ plantarum 9.1, )as found to reduce t(e urease acti#ity of !elico*acter pylori *y 40-701 and suppress t(e latter *acteriaEs *inding to (uman gastric cancer cell line *y more t(an 331$ A 200: study (as found t(at green tea can pre#ent inflammation if ingested prior to eHposure to !elico*acter infection F2/G$

Her!a( 1rea1me%1 o& He($.o!a.1er 2/(or$ $%&e.1$o%

Many (undreds of plants )orld)ide are used in traditional medicine as treatment for *acterial infections$ Some of t(ese (a#e also *een su*Kected to in #itro screening *ut t(e efficacy of suc( (er*al medicines (as seldom *een rigorously tested in controlled clinical trials$ %on#entional drugs usually pro#ide effecti#e anti*iotic t(erapy for *acterial infections *ut t(ere is an increasing pro*lem of anti*iotic resistance and a continuing need for ne) solutions$ Alt(oug( natural products are not necessarily safer t(an synt(etic anti*iotics, some patients prefer to use (er*al medicines$ 2(us (ealt(care professionals s(ould *e a)are of t(e a#aila*le e#idence for (er*al anti*iotics$ 2(is re#ie) )as underta-en to assess critically t(ose anti*acterial (er*al medicines t(at *een (a#e su*Kected to controlled clinical trials$ 'n a recent study, anti-!elico*acter pylori acti#ity of &0 commonly used "nani 3traditional5 medicine plants from Pa-istan t(at are eHtensi#ely utiliJed for t(e cure of gastrointestinal disorders to eHplore t(e natural source for pilot compounds against !elico*acter pylori$ F2:G$ %urcumin is t(e su*stance t(at gi#es t(e spice turmeric its yello) color$ %urry po)der, )(ic( is used eHtensi#ely in 'ndian cuisine, is largely made of turmeric and ot(er spices$ %urcumin contains many po)erful antioHidants and anti-inflammatory compounds, )(ic( (a#e *een s(o)n to support colon (ealt(, a (ealt(y cardio#ascular system, and most recently *rain (ealt($ DoJens of studies (a#e s(o)n t(at it is a c(emo-pre#entati#e, and more recently it (as *een s(o)n to eHert a strong anti*acterial effect against !elico*acter pylori$ Studies carried furnis(ed results s(o)ing a significant in #itro effect of its eHtracts against !elico*acter pylori, leading researc(ers to conclude t(at curcumin could *e considered a #alua*le support in t(e treatment of t(e infection F30G$ 'n a recent study, researc(ers found t(at licorice eHtract produced a potent effect against strains of !elico*acter pylori t(at are resistant against clarit(romycin, one of t(e anti*iotics typically used in t(e t(ree anti*iotic treatment regimens$ 2(e aut(ors concluded t(at t(is study pro#ides (ope t(at licorice eHtract can form t(e *asis for an alternati#e t(erapeutic agent against !elico*acter pylori$ 8esearc( study *ased communication found t(at licorice eHtracts are also effecti#e against !elico*acter pylori strains t(at are resistant to *ot( amoHicillin and clarit(romycin, ma-ing t(em #ia*le as c(emo pre#enti#e agents for peptic ulcer or gastric cancer in !elico*acter pylori infected indi#iduals F31G$

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1$ Anant(a-ris(nan 9, Oate M$ !elico*acter pyloriV 2(e rap-idly c(anging scenario$ 'nV %(attopad(yay 2O$ editor$ ;$'$Surgery annual$ Mol$ &$ 9e) Del(iV By)ordI 1::/$ p$ 120$ 2$ %urrent uropean concepts in t(e management of !elico*acter pylori infection$ 2(e Maastric(t %onsensus 8eport ;ut 1::LI-1V/-13$ 3$ Fisc(*ac( +$ Primary gastric lymp(oma of MA62V consid-erations of pat(ogenesis, diagnosis and t(erapy$ %an N ;astroenterol 2000I1-V44D-&0$ 4$ 9'! %onsensus %onference$ !elico*acter pylori and pep-tic ulcer disease$ N Am Med Assoc 1::4I)8)V7&-:$ &$ A*ra(am P, B(atia SN$ First national )or-s(op on !elico*acter pyloriV position paper on !elico*acter pylori in 'ndia$ 'ndian N ;astroenterol 1::LI19VS2:-S33$ 7$ 2andon 8$ Second national )or-s(op on !elico*acter pyloriV %onsensus Statements2reatment of !elico*acter pylori in peptic ulcer disease$ 'ndian N ;astroenterol 2000I L$ 1:VS3L$ /$ %(i*a 9, 8ao BM, 8adema-er N+, !unt 8!$ Meta-analy-sis of t(e efficacy of anti*iotic t(erapy in eradicating !elico*acter pylori$ Am N ;astroenterol 1::2I;8V1L17-2L$ :$ Peterson +6, ;ra(am DW, Mars(all B, Blaser MN, ;enta 8M, Olein PD et al$ %larit(romycin as monot(erapy for eradication of !elico*acter pyloriV a randomiJed, dou*le *lind trial$ Am N ;astroenterol 1::3I;;V1/70-4$ 10$ Bard(an OD, Dallaire %, isold !, Duggan A $ 8anitidine *ismut( citrate )it( clarit(romycin for t(e treatment of duo-denal ulcer$ ;ut 1::LI-1V1/1-7$ 11$ De Boer +A, 2ytgat ;9N$ 2(e *est t(erapy for !elico*acter pylori infection$ S(ould efficacy or side effect profile deter-mine our c(oiceX Scand N ;astroenterol 1::&I,<V401L$ 12$ Anant(aris(nan 9, Oate M$ !elico*acter pylori and its role in disorders of t(e upper gastrointestinal tract$ 'nV ;upta 86, editor$ 8ecent Ad#ances in Surgery$ 9o$ 7$ 9e) Del(iVNaypee Brot(ersI 1::L$ p$ 17/-/:$ 13$ Mars(all BN, Armstrong NA, Francis ;N, 9o-es 92, +ee S!$ Anti*acterial action of *ismut( in relation to %ampylo*acter pyloridis coloniJation and gastritis$ Diges-tion 1:/LI,8V17-30$ 14$ Penston N;$ !elico*acter pylori eradication-understand-a*le caution *ut no eHcuse for inertia$ Aliment P(armacol 2(er 1::4I;V37:-/:$ 1&$ Minay O$ #aluation of s(ort-term c(emot(erapy for !elico*acter pylori using %larit(romycin *ased regimens$ 3Dissertation5$ Pondic(erryV "ni#ersity of Pondic(erryI 17$ 2000$ 1L$ Nanan FAN, A(mad MM, 8o)s(on A!M, !ussain S, !ussain M, 8a(im S et al$ radication of !elico*acter pylori )it( a metronidaJole containing regimen in a metronidaJole a*using population$ 'ndian N ;astroenterol 2001I)<V 3L$ 1/$ ;lupeJyns-i W, Burette A$ Drug t(erapy for !elico*acter pylori infection$ Pro*lems and Pitfalls$ Am N ;astroenterol 1::0I;5V1&4&-:$ 1:$ 8une S$ !elico*acter pylori, peptic ulcer disease and in(i-*ition of gastric acid secretion$ Digestion 1::2I51V11-7$

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20$ !o)den %+, !unt 8!$ ;uidelines for t(e management of !elico*acter pylori infectionfor and on *e(alf of t(e Ad (oc %ommittee on Practice Parameters of t(e American %ollege of ;astroenterology$ Am N ;astroenterol 1::/I:,V2330-L$ 21$ !arris A$ 2reatment of !elico*acter pylori$ Drugs of 2oday 1::LI,,V&:-77$ 22$ DaKani Y, Olamut MN$ 9o#el t(erapeutic approac(es to gastric and duodenal ulcersV an update$ Hpert .pin 'n#estig Drugs 2000I:V1&3L-44$ 23$ !offman PS$ Anti*iotic resistance mec(anisms of !elico*acter pylori$ %an N ;astroenterol 1:::I1,V243-:$ 24$ A(uKa M, D(ar A, Bal %, S(arma MP$ 6ansopraJole and secnidaJole )it( clarit(romycin, amoHicilin or pefloHicin in t(e eradication of !elico*acter pylori in a de#eloping country$ Aliment P(armacol 2(er 1::/I1)V&&1-&$ 2&$ Mersalo#ic N, S(ortridge D, Oli*er O, ;riffy M, Beyer N, Flamm 8O et al$ Mutations in 23 Sr 89A are associated )it( clarit(romycin resistance in !elico*acter pylori$ Antimicro* Agents %(emot(er 1::7I-<V4LL-/0$ 27$ Megraud F$ pidemiology and mec(anism of anti*iotic re-sistance in !elio*acter pylori$ ;astroenterology 1::/I115V12L/-/2$ 2L$ M(as-ar M, Sand(u M, A*ra(am P$ 'n #itro antimicro*ial suscepti*ility of !elico*acter pylori strains in 'ndian pa-tients$ 'ndian N ;astroenterol 1::LI19VS3&$ 2/$ Mc%olm AA, Mclaren A, Olin-ert ;, Francis M8, %onnolly P%, ;rin(am %N et al$ 8anitidine *ismut( citrateV A no#el anti-ulcer agent )it( different p(ysioc(emical c(aracteris-tics and impro#ed *iological acti#ity to a *ismut( citrate-ranitidine admiHture$ Aliment P(armacol 2(er 1::7I1<V241-&0 2:$ !uang NT, %(i*a 9, +il-inson NM, !unt 8!$ Attempt *y meta-analysis to define t(e optimal treatment regimen for eradicating (elico*acter pylori infection$ %an N ;astroenterol 1::LI11V44A$ 30$ %(i*a 9, !unt 8!$ Bismut(, metronidaJole and tetracy-cline and acid suppression in !$ pylori eradicationV a meta-analysis$ ;ut 1::7I,:VA37-L$ 31$ Mcnulty %a, Dent N%, Ford ;A, +il-inson SP$ 'n(i*itory anti-micro*ial concentrations against %ampylo*acter py-lori in t(e gastric mucosa$ N Antimicro* %(emot(er 1://I))IL2:-3/$ 32$ Oate M$ Pre#alence of !elico*acter pylori in normal con-trols and patients )it( upper alimentary disorders )it( special reference to complications of duodenal ulcer-a study in Sout( 'ndia$ 3P($D$ t(esis5$ Pondic(erryV "ni#er-sity of Pondic(erryI 2000$ 33$ ArmuJJi A, %remonini F, BartoloJJi F, %anducci F, %andelli M, .Ketti M et al$ 2(e effect of oral administration of 6acto*acillus ;; on anti*iotic associated gastrointestinal side effects during !elico*acter pylori eradication t(erapy$ Aliment P(armacol 2(er 2001I15V173-7:$

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