Journal of Gastroenterology and Hepatology (1991) 6, 131-137

Adonis 081593 199100023Q

V. Helicobacter pylori therapy: Effect on peptic ulcer disease A. T.R . AXON Gastroenterology Unit, The General Infirmary, Leeds, U K

INTRODUCTION Data from many sources confirm that the prevalence of

Helicobacter pylon’ (Hp) in patients with duodenal ulcer is

ological data suggest that reinfection by new strains occurs at approximately 1 % per a n n m in the normal population, so some individuals will become reinfected naturally while others may contract infection as a result of the check endoscopy itself if equipment has not been adequately disinfected.

between 90 and looo&,compared with approximately 40”/, in an unselected Western population.’ Although these figures suggest a causative role for H p in duodenal ulcer this hypothesis remains controversial and is unlikely to be DIFFICULTIES IN SETTING UP generally accepted until controlled studies demonstrate THERAPY TRIALS that the elimination of this organism leads to prolonged remission of the disease. Hp is difficult to eradicate and as yet no long-term and few medium-term studies have been Patient selection and trial design published. Nevertheless, many attempts have been made to Most therapeutic trials have recruited colonized indiidentify an effective and reliable therapeutic combination. viduals who present for endoscopy with non-ulcer This paper reviews these papers together with peptic ulcer dyspepsia. Many have used small numbers of patients. trials which have compared H p status with relapse rates Although small studies arc useful in demonstrating failure following treatment. The potential importance of Hp treatof drug regimens, larger series followed for longer periods ment and the problems experienced with therapy are also are necessary when a potentially effective drug or drug considered. combination is being evaluated. It does not necessarily follow that a regimen which eradicates organisms in patients with non-ulcer dyspepsia will be as effective in those DEFINITIONS with peptic ulcer. Factors which might influence success include the pathology, the age of the patient, the virulence of the organism, and its distribution (e.g. duodenum, Although several treatment regimens suppress Hp infecBarrett’s oesophagus or Meckel’s diverticulum). Patient tion, the stomach usually becomes recolonized with the compliance is important too; those with non-ulcer dyssame strain shortly after cessation of treatmentj2 prepepsia may have less severe symptoms than those with sumably, H p regrows from sanctuary sites. If, however, peptic ulcer and this may’affect compliance, partbdwly tests for Hp are negative 1 month after the end of treatwhen the drugs employed have side effects. Finally, certain ment, patients usually remain uncolonized 12 months populations harbour greater numbers of antibioticlater.3.4 A working definition of ‘eradication’ which has resistant organisms (Table l), which may mirror the use of been accepted by most workers is absence of H p coloniantibiotics in a particular community. zation on testing 1 month after the end of a course of treatment. This definition still causes difficulty because some tests for H p are less sensitive than others and their Choice of drug accuracy is influenced by the experience and skill of the Not only is the choice of drug important, hut the salt and investigators. Tests generally accepted are absence of H p formulation may also influence its effectiveness. This may in 2 antral biopsies stained by the Giemsa or Warthin be particularly important when attempting to eradicate H p Starry method when examined by an experienced histoe&. body parenwhich exists in sanctuesJt W e s ~ u t ~ i dth pathologist, or failure to culture the organism when using a chyma but protected from luminal chemotherapeutic previously validated technique. At present the urease test agents by mucus. The treatment scheduIe may be relperformed on endoscopic biopsies or the urease breath test evant-not only dosage, but frequency and- timing in are not considered sufficiently sensitive to be accepted as respect to food. T h e length of time forwhich it is preevidence of eradication 1 month after treatment, but might scribed may influence effectiveness. It is not always clear be at the end of a more prolonged period. Even experienced whether drugs act locally (i.e. intraluminally) or whether pathologists and microbiologists may occasionally fail to systemic levels are of greater importance. The activity of detect a light infection, so the same strain of organism some drugs may be afFeby the pH of the stomach and will occasionally recur in some patients in whom it has by pharmacological agents which modify gastric secretion. been apparently ‘eradicated’. Furthermore, epidemiCorrespondence: Dr A. T. R. Axon. Gastroenterology Unit, The General Infirmary, Leeds LS1 3EX, UK. Accepted for publication 12 November 1990.

A . T. R. Axon


Drug combinations are, in general, more effective than single agents. Combinations, however, have more side effects and represent a serious drawback to some regimens. A worrying finding is the emergence of resistant strains (Table 2). Treatment with nitroirnidazoles alone induces a high incidence of resistance (7O?J6 which is only partially improved (2S0;,)' when combined with amoxycillin. Combination with colloidal bismuth subcitrate (CBS) reduces resistance to approximately 10%.618r9 Table

1 Primary

resistance 1 ~ 5-nitro-imidazoles* ) Resistance rate to imidazoles (%)

Origin of population


17 8 10



Australiab Austria'n

11 20 25-30

UK2* UK" Belp,ium2'



North Africans Other Wfntries' Central Africa (Zaire, R~anda)~'

50 56 80-90

* Glupczynski, 1990.25 '(Spain, Italy. Greece). Table 2 Acquired resistance tn Tihtibiotics and other agents in Helicobacter pylori after clinicid use* ~~



Not x l c c ~ i n gresistance


Amoxvcillin and other heta-hetams Bismuth salts

Fluoroquinolones (ofloxacin, ciprofloxacin, norfloxacin. . .,. Nitroimidazoles (metronidazole, tinidazole). h\acrolidc> I crythromycin. azythromycin, clindamycin).

' l ' c ~ad~? r clinch


Nitrofurans (?)

* Glupczynski, 1990.Lb

THERAPY REGIMENS Monotherapy H p is sensitive to a wide range of antibiotics in vitro, but most are ineffective in oivo (Table 3). Bismuth preparations, metronidazole, tinidazole, and ofloxacin are partially effective as monotherapies but are not recommended, because of disappointing results and the emergence of resistant organisms. CBS and bismuth subsalicylate (BS S) have both been studied. More data is available for CBS, which has been widely used in the treatment of peptic ulcer for several years. CBS has been formulated as a liquid, as a chewing tablet and as a swallowing tablet and, although these preparations are equally effective in healing peptic ulcer, their antibacterial activity in vivo has not been directly compared. Few studies comparing dosage schedules have been undertaken. A 4 times a day dosage may be more effective than twice daily,'O 8 weeks' treatment no better than 4 weeks', and a 2-week course gives less satisfactory results. Amalgamated data from different studies (Table 3) shows that a 4-week course of CBS one tablet ( 1 20 mg), 4 times a day for a month eradicates H p in 20°/b of individuals. Although fewer data are available for BSS, results are broadly similar. Side effects from bismuth salts are uncommon, but prolonged therapy in high dosage has led to neurological side effects't and, as a result, bismuth preparations are not available in all countries. The low level of Hp eradication, using monotherapy with bismuth mlts, confirms that with the presently available preparations and dosage schedules these drugs are not satisfactory. Nevertheless, they are extremely useful in combination with antibiotics, not only by increasing eradication rates, but also by reducing the emergence of antibiotic-resistant organisms.

Dual therapy 'l'he results of combining two antimicrobial therapies are shown in Table 4. Amalgamated results show that, in adults, a combination of amoxycillin with tinidazole eradicates Helicobacter in only 43% of individuals. This result is not a great improvement on the use of amoxycillin alone

Table 3 Eradication of .Helicobacter pylori (amalgamated data): Monotherapy




3, 10, 12, 27-32

RSS Amoxycillin


Metronidazole Furazolidone

3, 28, 29, 36, 38-40


338 87


3, 28, 41


43, 70

Eradication (Yo) Range ( y o ) 20 16 17 6

Ofl~ixacin Nitrofurantoin


39 11


Josamycin Clindamycin Xzyt hromycin





0 0 0

'l'ctrac) c lint

Spiramycin Omeprazole 9ucralfate



47 3. 28 3, 28

11 7

44 3, 28

8 25


7-43 0-23 0-30





20-33 0-0

0 0 0 0

H. pylori therapy effect on ulcer


Table 4 Eradication of Helicobacter pylori (amalgamated data): dual therapy


+ +

CBS amoxycillin BSS amoxycillin CBS + metronidazole


BSS metronidazole BSS +erythromycin BSS + nitrofurantoin BS S ofloxacin Amoxycillin + tinidazole Amoxycillin +metronidazole ( + H2RA)

3, 27-29, 32, 48, 49 34, 36, 50 8,27, 51 12,48 50 50 35 52 24,53-56 57

Amoxycillin ofloxacin Amoxycillin + nitrofurantoin

56 54, 55

CBS + tinidazole



+ Doxycycline+tinidazole Furazolidone + tinidazole Omeprazole+amoxycillin

24 42 40,58,59

(Table 3) and is associated with the emergence of acquired nitroimidazole resistance in 2 5 O , , . Better results are obtained when CBS or BSS are combined with a nitroimidazole. Of 194 patients treated, Hp was eradicated in 130 patients (6700).This figure is probably higher than the simple additive effects of the two drugs, suggesting synergism, and there is considerable reduction of acquired nitroimidazole resistance with this combination (Table 5). It is unclear for how long and in what dosage the two drugs should be given. Treatment periods of less than 2 weeks have been advocated, but more data is needed. The combination of CBS or BSS with amoxycillin is disappointing, with an eradication rate of only 42%, suggesting that in this case the effect is merely additive. Some preliminary studies using an omeprazole and amoxycillin Combination have shown interesting results, with an eradication rate of approximately 56%. More work is needed to confirm these results. It is unclear why the effect of amoxycillin should be enhanced in this way. The three possibilities are that: Hp poorly tolerates a neutral gastric pH; amoxycillin is more effective at neutral pH; or omepra-,. zole has a direct toxic effect on the organism.

Triple therapy The amalgamated results of triple therapy are shown in Table 6. The combination of CBS or BSS with a nitroimidazole and either tetracycline or amoxycillin eradicates Hp in 80-90°/0 of individuals. As with dual therapy, it is unclear how long triple therapy should be given. Combinations cause significant side effects which include general malaise, diarrhoea, sore mouth, fungal infections and pseudamembranous colitis. The addition of amoxycillin or tetracycline to the bismuth/nitroimidazole combination increases eradication from approximately 65 to 85 ' : o .

Other combinations Several other combinations have been assessed. H, receptor antagonistsin combination with antibiotics have not been effective.l2-l4


Eradication (9,)

Range ( 0 ; )

267 57 141 106 19 20

44 33 73 62 79 25 0 33 43 67 20 25

047 25-58 57-85 53-80


9 134 12 15 30 11 4


18 50 56



EFFECT OF Hp ERADICATION ON DUODENAL ULBER RELAPSE Individuals infected with Hp are twenty times more likely to develop duodenal ulcer than those who are uninfected. However, approximately 40°;,of the normal population in the vber age group but without duodenal ulcers a e also mfeclta. It follows tha? Hp does not occur as a result of dpodenal ulceration and ,he, ,sssociation can be explained onlpon the basis of either-hp,being a component cause of duodenal ulcer or, alternatively, both duodenal ulcer and HD infection arising from a third commcn factor. If the first of these two alternatives is correct&he organism must be responsible for more than 90°/, of duodenal ulcers and its eradication should lead to permanent remission in these. Recent trials habe studied patients whose ulcers have been healed by a variety -.f medicaxrnts and have then been followed for both Hp status and duodenal ulcer recurrence (Table 7). Six studies assessed H p status 1 month after the end of treatment. When Hp was still subsequently relapsed, present, 96 of 114 pacznts (11"I) where it had compared with only 20 of been eradicated. Ten stubeg have assessed Hp status at the time of relapse. The combined data from the eight studies, which followe$ patients for longer than 9 months, shows that ulcers recurred in only 6 of 217 patients (3%) when Hp was absent, compared with 116 of 155 patients (74",,) where it was identified. These data confirm that, even in a group of individuals known to have duodenal ulcef disease,qelapseis more than 20 times higher in infected patients than in those who remain free from Hp following treatment. Of greater importance, however, is the observation that the e l i i a tion of Hp alters the 'natural history' of duodenal ulcer disease. The relapse rate of 119, followire eradication is considerably less t h a ~either the 82% found after treatment with H, receptor antagonists or the 53% fok!owing treatment with CBS.I5Where ulcesyo r e w t may be due either to recrudescence of infection where eradication' was incomplete or misdiagnosed, or to reinfection with Hp from mot- hurce. The 11O{, who Taur may also include the small number of patients with duodenal ulc ::in whom

A. T. R. Axon


Table 5 Effect of nitroimidazole compounds on H. pylori colonization in patients with gastritis or DU Therapy



Eradication rate

Time after therapy


Burette' Dekoster9 hiarllai"

10 29 28 52 17 27 33

214 416 19/27 2/22 12/52 1/11 4/60


20 20 3 75 54 47 88 90


Metronidazole ( +H,-blocker) Metronidazole Tinidazole (H,-blocker) Tinidazole (+ CBS) Tinidazole (+ amoxycillin) Tinidazole + CBS) hlctronidazole (+CBS) Metronidazole ( + CBS and amoxycillin)

Hirschl') Stebbingzz Goodwinb

Acquired resistance 0 No. "

12 m 12m

4-6W 4-6W


50 67 70 9 25 10 7


Table 6 Eradication of Helicobacter pylon': Triple therapy 'l'rcarmcnt


CBS + amoxycillin+metronidazole

3, 8, 27, 28, 32, 60 61, 62 63-65 24, 64 66 42

BSS + amoxycillin+ metronidazole CRS + tetracycline+ metronidazole

CBS + doxycycline+metronidazole BSS +tetracycline +metronidazole Furazolidone+ amoxycillin + metronidazole

Table 7


Eradication (9,)

Range ( O i l )

124 196 165 37 25 6

81 85 89 65 88 83

74-90 80-90 65-94 65-76

Duodcnal ulcer rrlapw rate? 7-



FoIIow-u~ (months)

Cogfllan6v I .amhcrt6* MarshalPa Smith'O

1987 1987

1988 1988

39 45 70 44

12 6 12 18

I\, m dy'"




B~rody~~ Rauwst6 Blum" George"

1989 1990 1990 1990


9-37 12

192 62






12-48 I2

DU relapse

start of follow-up HP + HP No. Yo No. 19/24



n.d. 84





n.d. n.d.

U/ 0

OO '




17/21 n.d. 010

End of follow-up HPHP +

23 26


n.d. 81




0162 5/40

0 13

No. 22129 25/33 38/47 28/35 313 314 17/21 731179 010 5/16



76 76 81 80 100 75 81 41 0 31

No. 1/10 0112 5/23 019 0118 0154 0117 1/13 0162 0124

10 0 22 0 0 0 0

8 0 0

*First author given. n.d.: no data.

Hp is never found and where an alternative aetiology such as treatment with NSAIDs may b e responsible. It might be argued that the lower relapse rate in patients without Hp is not the result of Hp eradication, but the use of bismuth as one of the treatment modalities. This is unlikely r0 be the case because, in one study, 38 individuals with resistant ulcer were randomized to either CRS o r CRS plus antibiotics.16 Of the ulcers which healed, 17 became H p negative and 21 remained positive. After 1 year none of the first group had relapsed, compared with 81';" of those H p positive. As both groups had received CBS it follows that the exhibitid"6f this drug could not have been responsible for the difference.

Larger trials, followed over longer periods, are needed to

confirm these results, but the data suggesting that H p eradication prevents duodenal ulcer relapse are very persuasive.

STRATEGY FOR TREATMENT I t is tempting to advocate the general use of anti-Hp therapy in all patients with duodenal ulcer disease. However, the indiscriminate use of antibiotics is to be discouraged. It is essential t o recognize the drawbacks which attend Hp therapy.

H. pylori therapy effect on ulcer

The most effective anti-Hp regimens include CBS or BSS plus a nitroimidazole and another antibiotic in addition. The use of a nitroimidazole is critical if high levels of eradication are to be achieved. However, most studies have been carried out in countries where nitroimidazoles are not widely prescribed for other diseases and primary resistance to the drug is low (Table 1). Unfortunately, in many parts of the world, especially areas where giardiasis and amoebiasis are endemic, these drugs are used very frequently and primary resistance is common. It follows that a considerable number of patients harbouring Helicobacter will not respond, but are nevertheless at risk of side effects. Even in communities where resistance is relatively low, triple therapy fails in up to 20% and in these an organism resistant to nitroimidazoles will usually be found either because of primary resistance or resistance acquired during medication. Very effective alternative treatments for peptic ulcer are available. These do not carry the side effects of antibiotic combinations and do not cause the emergence of resistant organisms. Anti-helicobacter therapy, therefore, should be undertaken only after due consideration of all the factors involved. For these reasons the working party considers that, for the time being, Hp therapy should be reserved for those groups of patients where it has been shown unequivocally to have an advantage over the currently available cytoprotective and acid suppressive drugs. (1) At present the value of Hp therapy in non-ulcer dyspepsia and gastric ulcer remains unproven and the working party recommends that it should not be used in these groups except as a research tool. (2) Where duodenal ulcer is thought to result from NSAID treatment or other pathology (such as Crohn’s disease) H p therapy should not be used. (3) Where there is no history of NSAID therapy and the duodenal ulcer is Hp related, eradication therapy should be considered. (4) In patients with mild disease which can be managed easily by intermittent therapy with acid suppression or cytoprotective drugs, the working party believes that at present Hp eradication should not be employed generally. ( 5 ) In individuals where duodenal ulcer is a serious management problem requiring either continuous medication or consideration of surgery, or where complications such as bleeding or perforation have occurredJ Hp eradication should be attempted. (6) Finally, there is a group of patients with H p associated duodenal ulcer in whom there is doubt as to the underlying aetiology. For example, it may be difficult in elderly patients to know whether they have been taking NSAIDs. I n these, a more circumspect approach must be taken and it may be desirable to treat with acid suppression instead of, or as well as, Hp eradication. If Hp therapy is undertaken, the most effective treatment regimen should be employed. The working party recommends a triple combination of either CBS or BSS 1 tablet q.d.s., tetracycline hydrochloride 500 mg q.d.s. and metronidazole 400mg t.d.s. given for 2 weeks. This has been shown to eradicate H p infection in 91% of an Australia dyspeptic population.” Amoxycillin 500 mg q.d.s. may be substituted for tetracycline, but more patients are intolerant of this drug. It must be emphasized that the major therapeutic drawback at present is metronidazole resistance. This is Usual


following metronidazole monotherapy and common after dual therapy. It is for this reason that the working party has recommended triple therapy. Other combinations should at present be used only in a research setting.


v. cam-

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Helicobacter pylori therapy: effect on peptic ulcer disease.

Journal of Gastroenterology and Hepatology (1991) 6, 131-137 Adonis 081593 199100023Q V. Helicobacter pylori therapy: Effect on peptic ulcer disease...
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