Therapy for <i>H.</i> <i>pylori</i>: Current concepts

doi:10.4236/ojgas.2013.31006

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Open Journal of Gastroenterology, 2013, 3, 38-41 OJGas

http://dx.doi.org/10.4236/ojgas.2013.31006 Published Online February 2013 (http://www.scirp.org/journal/ojgas/)

Therapy for H. pylori: Current concepts

Giulia Fiorini1, Angelo Zullo2, Valentina Castelli1, Chiara Ricci3, Giovanna Lo Re1, Ilaria Saracino1,

Cristina Zaccaro1, Federico Maria Verardi4, Alessandra Reggi4, Dino Vaira1*

1Department of Clinical and Surgical Science, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy

2Gastroenterology and Digestive Endos copy, “Nuovo Regina Margherita” Hospital, Rome, Italy

3Gastroenterology Unit, University of Brescia, Brescia, Italy

4Department of Internal Medicine, Aging and Kidney Disease, Alma Mater Studiorum, University of Bologna, Bologna, Italy

Email: *[email protected]

Received 27 October 2012; revised 25 November 2012; accepted 2 December 2012

ABSTRACT

Helicobacter pylori plays an important role in the

pathogenesis of chronic active gastritis, peptic ulcer

and gastric mucosa-associated lymphoid tissue-lym-

phoma, and is also involved in carcinogenesis of the

stomach. Since now no current first-line therapy is

able to cure the infection in all treated patients. We

evaluated data on the most successful therapy regi-

mens—sequential, concomitant and quadruple thera-

pies—and on the standard therapy available for H.

pylori eradication. When therapy fails several factors

may be involved: we reviewed both bacterial a nd host

factors that can affect the eradication and that can be

involved in therapeutic management of the H. pylori

infection.

Keywords: Helicobacter pylori; Sequential Therapy;

Eradication

1. INTRODUCTION

Helicobacter pylori infection is a major cause of gastro-

intestinal-related morbidity and mortality worldwide. It

is the principal cause of peptic ulcer disease (PUD) and

low-grade, B-cell gastric lymphoma [1] and it has been

associated to the pathogenesis of gastric adenocarcinoma

[2-5]. Indeed, bacterial eradication prevents peptic ulcer

disease recurrence and it is able to cure near 80% of lo-

calized low-grade gastric lymphomas. Among extra-di-

gestive diseases, there is a significant association be-

tween H. pylori infection and both idiopathic thrombo-

cytopenic purpura and idiopathic iron deficiency anemia

[6,7]. Recent management guidelines from the Maas-

tricht IV consensus conference still recommend a com-

bination of PPI, clarithromycin, and amoxicillin for 7 -

14 days as first-line treatment of H. pylori infection in

areas of low clarithromycin resistance or the combination

of a proton pump inhibitor (PPI), bismuth, metronidazole,

and tetracycline (bismuth quadruple therapy) for 10 - 14

days where there is a high clarithromycin resistance.

However, due to an increased H. pylori resistance to dif-

ferent antibiotics, new strategies are required for the

treatment of the infection [8]. Different antibiotics com-

binations, administered together with a proton pump in-

hibitor, have been proposed in the last decades. Unfortu-

nately, there are still no available therapies able to eradi-

cate H. pylori in all treated patients.

2. CURRENT THERAPIES

The most used first-line therapy regimen for H. pylori

eradication is the triple therapy, which include the com-

bination of two antibiotics (clarithromycin plus amox-

icillin or metronidazole) with a proton pump inhibitors

for at least seven days [9]. However, the eradication rates

with the triple therapy has decreased from initial height

of >90% to 80% or even 75% in some areas [10]. Cur-

rent European guidelines confirmed the use of a standard

7-day triple therapy only in those areas where primary

clarithromycin resistance is lower than 15% - 20%,

whilst a prolonged 14-day regimen or quadruple bismuth

therapy should be considered when bacterial resistance

rate is higher [8]. Recent data found that following the

prolonged 14-day triple therapy the eradication rate was

still very poor (70%) in patients with non ulcer dyspepsia

and in patients with peptic ulcer (81.7%) [11,12]. Indeed

the eradication of the infection after a failed initial triple

therapy is particularly difficult to achieve. In a recent

study, the cumulative eradication rate was 89.6% by us-

in g t hr e e con secutive stand ard therap ies in pati ents treated

in clinical practice, being only 70.3%, 69.1% and 70%

following first-, second-, and third-line regimens, resp ec-

tively [13].

Quadruple therapy (PPI + Bismuth + Metronidazole +

Tetracycline administered for 7 - 10 days) is a useful

treatment in areas where metronidazole resistance is low

and clarithromycin resistance is high. One large, ran-

*Corresponding a uthor.

OPEN ACCESS

G. Fiorini et al. / Open Journal of Gastroenterology 3 (2013) 38-41 39

domized, controlled trial compared 7-day quadruple ther-

apy with 7-day triple therapy [14] and a recent meta-

analysis of nine studies that compares these two regi-

mens [15] showed similar eradication rates (78% triple

therapy vs 82% quadruple therapy). However, many of

these comparative studies were performed before the

emergence of high rates of clarithromycin resistance, so

the results need to be interpreted with caution. A recent

randomized controlled trial in Europe showed that quad-

ruple therapy using a single capsule containing 3 antibi-

otics was superior to triple therapy, with an eradication

rate of 93% compared to 68% with triple therapy [16],

suggesting that this therapy could be a valid alternative

to triple therapy. However, patients compliance to this

therapy needs to be confirmed in further studies.

Non-bismuth quadruple therapy or “concomitant” ther-

apy is the combination of proton pump inhibitor-clarithro-

mycin-amoxicillin-nitroimidazole administered together.

A recent meta-analysis of randomized trials showed that

the eradication rate with non bismuth quadruple therapy

was 90% compared to 78% with triple therapy [17].

Moreover, there was evidence of a better eradication rate

with concomitant therapy lasting seven days (93%) [18].

Therefore concomitant therapy seems to be a valid alter-

native to triple therapy in those areas where bismuth is

not available.

Sequential therapy is a novel treatment method that

was firstly introduced in Italy in 2000 [19 ]. It is a 10 -day

treatment consisting of a PPI and amoxicillin 1 gr (both

twice daily) administered for the first 5 days followed by

triple therapy consisting of a PPI, clarithromycin 500 mg,

and tinidazole 500 mg (all twice daily) for the remaining

5 days. A recent systematic review and meta-analysis

showed a high eradication rate (>90%) of standard se-

quential therapy [20].

The efficacy of sequential therapy towards standard

triple therapy has been proved in several randomized

trials and the success rate of the sequential regimen was

distinctly higher, in all studies were a “head-to-head”

comparison was performed the sequential regimen was

significantly superior to either 7-day or 10-day standard

triple therapies [21 ].

3. FACTORS THAT AFFECT

TREATMENT RESPONSE

1) Resistance

One of the main reasons for the poor performance of

treatments is the increasing number of H. pylori strains

resistant to antibiotics especially clarithromycin and

metronidazole. Ind eed antimicrobial resistance is respon -

sible for the declining rates of H. pylori eradication seen

in many countries. Clarithromycin acts interrupting bac-

terial protein synthesis and the resistance is caused by a

mutation in the organism that prevents binding of the

antibiotic to the ribosome of H. pylori. A rapid efflux

pathway may also develop in H. pylori when exposed to

anti-microbial agents. The drug is rapidly pumped ou t of

the organism preventing the anti-microbial effect. It has

been suggested that sequential therapy may be more ef-

fective than triple therapy because the initial treatment

with a proton pump inhibito r and amoxicillin poiso ns the

cell wall of the organism preventing the development of

efflux channels [22]. A systematic review of H. pylori

therapy found that when clarithromycin w as the key drug

in a regimen, eradication rates fell by 56% if clarithro-

mycin resistant strains were present. Furthermore nitro-

imidazole resistance causes a reduction in efficacy of

50% with triple and quadruple therapies [23].

2) Patient’s adherence to treatment

Patients taking less than 80% of their treatment regi-

men have a high rate of treatment failure, and failed

treatment is associated with the emergence of anti-mi-

crobial resistance [24]. It should always be emphasized

to the patient that successful eradication depends on full

compliance with the treatment. A least a short time

should be taken to counsel the patient, explaining the

procedures involv ed in tak ing complicated drug th erapies

and describing the side-effects to improve the outcome.

3) Side-effects and smoking habit

Up to 50% of patients have mild side-effects while

taking H. pylori treatment and less than 10% of patients

stop treatment because of side-effects. Some of the most

common side-effects are metallic taste, especially by

using metronidazole or clarithromycin, constipation while

taking bismuth based treatments, and diarrhea or stom-

ach cramps. However there is no significant difference in

side effects among the different treatments available.

Smoking reduces the success rate of standard triple

therapy mainly altering antibiotics delivering into the

gastric mucosa. Indeed, reduction in gastric blood flow

and mucus secretion or an increased acid hypersecretion

can reduce the antibiotic activity [25].

4. FUTURE THERAPIES

According to current European Guidelines, if first line

therapy fails with triple therapy either a bismuth-based

quadruple therapy or a levofloxacin-based triple regimen

should be used, while treatment should be guided by

antimicrobial susceptibility testing after failure of sec-

ond-line therapy [8]. Therapy failure mainly depends on

primary resistance to different antibiotics, especially

clarithromyc in, which is increasing world wide [26]. Ma ny

studies have addressed the identification of novel thera-

peutic target either genes (i.e. genes required for H. py-

lori in vitro survival or for mucosal colonization, genes

involved in cellular motility, etc.) [27,28] or cellular

G. Fiorini et al. / Open Journal of Gastroenterology 3 (2013) 38-41

functions (i.e. chemotaxis, protein folding) [29]. Indeed,

some molecules have shown a very high bactericidal

level of activity against H. pylori in vitro and some

molecules preserve antibacterial activity even at low pH

values as needed in the presence of gastric acid.

5. CONCLUSION

The best treatment for the eradication of H. pylori is still

lacking. It is well known that standard triple therapy has

a poor efficacy to cure the infection because of the in-

creased resistance to clarithromycin which is the key

antibiotic. Nevertheless current guidelines still recom-

mend this treatment in areas with low clarithromycin

resistance (less than 15% - 20%). In those areas where

the resistance is higher sequential, quadruple or con-

comitant therapies are recommended for first-line em-

pirical treatment. New therapeutic targets are now under

consideration but currently there is still no answer to the

question about what is the best replacement for Helico-

bacter pylori eradication therapy.

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