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
Received 27 October 2012; revised 25 November 2012; accepted 2 December 2012
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
Keywords: Helicobacter pylori; Sequential Therapy;
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  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 . 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 . However, the eradication rates
with the triple therapy has decreased from initial height
of >90% to 80% or even 75% in some areas . 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 . 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-
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.
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  and a recent meta-
analysis of nine studies that compares these two regi-
mens  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 ,
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 .
Moreover, there was evidence of a better eradication rate
with concomitant therapy lasting seven days (93%) .
Therefore concomitant therapy seems to be a valid alter-
native to triple therapy in those areas where bismuth is
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 .
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
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 . 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 .
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 . 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 .
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 . Therapy failure mainly depends on
primary resistance to different antibiotics, especially
clarithromyc in, which is increasing world wide . 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
Copyright © 2013 SciRes. OPEN ACCESS
G. Fiorini et al. / Open Journal of Gastroenterology 3 (2013) 38-41
functions (i.e. chemotaxis, protein folding) . 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.
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.
 Vakil, N. and Megraud, F. (2007) Eradication treatment
for Helicobacter pylori. Gastroenterology, 133, 985-1001.
 Ford, AC., Delaney, BC., Forman, D. et al. (2004)
Eradication therapy in Helicobacter pylori positive peptic
ulcer disease: Systematic review and economic analysis.
American Journal of Gastroenterology, 99, 1833-1855.
 Chen, L.T., Lin, J.T., Tai, J.J., et al. (2005) Long-term
results of anti-Helicobacter pylori therapy in early-stage
gastric high grade transformed MALT lymphoma. Jour-
nal of the National Cancer Institute, 97, 1345-1353.
 Morgner, A., Bayerdorff, E., Neubauer, A., et al. (2000)
Malignant tumors of the stomach. Gastric mucosa-asso-
ciated lymphoid tissue lymphoma and Helicobacter py-
lori. Gastroenterology Clinics of North America, 29, 593-
 Malfertheiner, P., Sipponen, P., Naumann, M., et al.
(2005) Helicobacter pylori eradication has the potential
to prevent gastric cancer: A state-of-the-art critique. Ame-
rican Journal of Gastroenterology, 100, 2100-2115.
 Stasi, R., Sarpatwari, A., Segal, J.B., et al. (2009) Effects
of Helicobacter pylori eradication in patients with im-
mune thrombocytopenic purpura: A systematic review.
Blood, 113, 1231-1240.
 Huang, X., Qu, X., Yan, W., et al. (2010) Iron deficiency
anemia can be improved after eradication of Helicobacter
pylori. Postgraduate Medical Journal, 86, 272-278.
 Malfertheiner, P., Megraud, F., O’Morain, C., et al. (2012)
Current concepts in the Management of Helicobacter py-
lori infection: The Maastricht IV/Florence Consensus
Report. Gut, 61, 646-664.
 Fock, K.M., Katelaris, P., Sugano, K., et al. (2009) Sec-
ond Asia-Pacific consensus guidelines for Helicobacter
pylori infection. Journal of Gastroenterology and Hepa-
tology, 24, 1587-1600.
 Gisbert, J.P. (2010) Sequential or concomitant therapy for
Helicobacter pylori eradication? Journal of Clinical Gas-
troenterology, 44, 313-325.
 Zagari, R.M., Bianchi-Porro, G., et al. (2007) Compari-
son of one and two weeks of Omeprazole, amoxicillin
and Clarithromycin treatment for Helicobacter pylori
eradication: The HYPER study. Gut, 56, 475-479.
 Paoluzi, P., Iacopini, F., Crispino, P., et al. (2006) 2-week
triple therapy for Helicobacter pylori infection is better
than 1-week in clinical practice: A large prospective sin-
gle-center randomized study. Helicobacter, 11, 562-568.
 Rokkas, T., Sechopoulos. P., Robotis, I., et al. (2009)
Cumulative H. pylori eradication rates in clinical practice
by adopting first and second-line regimens proposed by
the Maastricht III consensus and a third line empirical
regimen. American Journal of Gastroenterology, 104, 21-
 Katelaris, P.H., Forbes, G.M., Talley, N.J., et al. (2002)
A randomized comparison of quadruple and triple thera-
pies for Helicobacter pylori eradication: The QUAD-
RATE Study. Gastroenterology, 123, 1763-1769.
 Luther, J., Higgins, P.D., Schoenfeld, P.S., et al. (2010)
Empiric quadruple vs. triple therapy for primary treat-
ment of Helicobacter pylori infection: Systematic review
and meta-analysis of efficacy and tolerability. American
Journal of Gastroenterology, 105, 65-73.
 Malfertheiner, P., Bazzoli, F., Delchier, J.C., et al. (2011)
Helicobacter pylori eradication with a capsule containing
bismuth subcitrate potassium, metronidazole, and tetra-
cycline given with omeprazole versus clarithromycin-
based triple therapy: A randomised, open-label, non-in-
feriority, phase 3 trial. Lancet, 377, 905-913.
 Gisbert, J.P. and Calvet, X. (2012) Update on non bis-
muth quadruple (concomitant) therapy for eradication of
Helicobacter pylori. Clinical and Experimental Gastro-
enterology, 5, 23-34. doi:10.2147/CEG.S25419
 Gisbert, J.P. and Calvet, X. (2011) Review article: Non-
bismuth quadruple (concomitant) therapy for eradication
of Helicobacter pylori. Alimentary Pharmacology &
Therapeutics, 34, 604-617.
 Zullo, A., Rinaldi, V., Winn, S., et al. (2000) A new
highly effective short-term therapy schedule for Helico-
bacter pylori eradication. Alimentary Pharmacology &
Therapeutics, 14, 715-718.
 Gatta, L., Vakil, N., Leandro, G., et al. (2009) Sequential
therapy or triple therapy for Helicobacter pylori infection:
Copyright © 2013 SciRes. OPEN ACCESS
G. Fiorini et al. / Open Journal of Gastroenterology 3 (2013) 38-41
Copyright © 2013 SciRes.
Systematic review and meta-analysis of randomized con-
trolled trials in adults and children. American Journal of
Gastroenterology, 104, 3069-3079.
 Zullo, A., De Francesco, V., Hassan, C., et al. (2007) The
sequential therapy regimen for Helicobacter pylori
eradication: A pooled-data analysis. Gut, 56, 1353-1357.
 Murakami, K., Fujioka, T., Okimoto, T., et al. (2002)
Drug ccombinations with amoxicillin reduces selection of
clarithromycin resistance during Helicobacter pylori era-
dication therapy. International Journal of Antimicrobial
Agents, 19, 67-70. doi:10.1016/S0924-8579(01)00456-3
 Houben, M., Van de Beek, D., Hensen, E., et al. (1999) A
systematic review of helicobacter eradication therapy—
The impact of antimicrobial resistance on eradication rates.
Alimentary Pharmacology & Therapeutics, 13, 1047-1055.
 Cockburn, J., Gibberd, R.W., Reid, A.L., et al. (1987)
Determinants of non-compliance with short term antibi-
otic regimens. British Medical Journal, 295, 814-818.
 Labenz, J., Stolte, M., Blum, A.L., et al. (1995) Intragas-
tric acidity as a predictor of the success of Helicobacter
pylori eradication: A study in peptic ulcer patients with
omeprazole and amoxicillin. Gut, 37, 39-43.
 De Francesco, V., Giorgio, F., Hassan, C., et al. (2010)
Worldwide H. pylori antibiotic resistance: A systematic
review. Journal of Gastrointestinal and Liver Disease, 19,
 Salama, N.R., She pherd, B. a nd Falkow, S. (2004) Global
transposon mutagenesis and essential gene analysis of H.
pylori. Journal of Bacteriology, 186, 7926-7935.
 Chalker, A.F., Minehart, H.W., Hughes, N.J., et al. (2001)
Systematic identification of selective essential genes in H.
pylori by genome prioritization and allelic replacement
mutagenesis. Journal of Bacteriology, 183, 1259-1268.
 Baldwin, D.N., Shepherd, B., Kraemer, P., et al. (2006)
Identification of H. pylori genes contributing to stomach
colonization. Infection and Immunity, 75, 1005-1016.