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‘Rescue’ Therapies for the Management of Helicobacter pylori Infection

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 Review Article
Dig Dis 2006;24:113–130
DOI: 10.1159/000090315
‘Rescue’ Therapies for the Management
of Helicobacter pylori Infection
Francesco Di Mario a Lucas G. Cavallaro a Carmelo Scarpignato b
a
Section of Gastroenterology, Department of Clinical Sciences, and b Laboratory of Clinical Pharmacology,
Department of Anatomy, Pharmacology and Forensic Sciences, School of Medicine and Dentistry,
University of Parma, Parma, Italy
Key Words
Helicobacter pylori infection
Helicobacter pylori
eradication
Eradication failure
Failed eradication
attempts
Rescue therapies
Abstract
Helicobacter pylori infection is the main cause of gastri-
tis, gastroduodenal ulcer and gastric cancer and should
be considered as a major public health issue. According
to several international guidelines, first-line therapy for
treating H. pylori infection consists of proton pump in-
hibitor (PPI) or ranitidine bismuth citrate (RBC) with any
two antibiotics of amoxicillin, clarithromycin or metroni-
dazole given for 7–14 days. However, even with the rec-
ommended treatment regimens, approximately 20% of
patients will fail to obtain H. pylori eradication. The pro-
portion of patients with first-line H. pylori therapy failure
may be higher in clinical practice and it may increase
thanks to diffusion of H. pylori treatment. The recom-
mended second-line therapy is the quadruple regimen
composed by tetracycline, metronidazole, bismuth salts
and a PPI. However, the efficacy of this regimen is lim-
ited by poor patient’s compliance due to its side effects,
number of tablets per day, and long duration. Moreover,
bismuth and metronidazole are not available in all coun-
tries. Alternatively, a longer-lasting (i.e. 10–14 days) PPI
or RBC triple therapy with two antibiotics has generally
been used. In an empirical strategy, the choice of second
© 2006 S. Karger AG, Basel
0257–2753/06/0242–0113$23.50/0
Fax +41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
www.karger.com www.karger.com/ddi
line depends on the treatment initially used. If a clarithro-
mycin-based regimen was administered in first line, a
quadruple regimen or PPI (or RBC) triple therapy with
metronidazole and amoxicillin (or tetracycline) should
be suggested as a second line. In case of second-line
treatment failure, the patient should be evaluated by a
case-by-case approach. A susceptibility-guided strategy,
if available, is recommended in order to choose the best
third-line treatment. Culture can reveal the presence of
H. pylori-sensitive strains to clarithromycin (the best ef-
fective) or other antimicrobials (such as amoxicillin, met-
ronidazole and tetracycline). Conversely, in an empirical
strategy, a third-line not yet used therapy, can reach a
high success rate. PPI or RBC, amoxicillin and a new an-
timicrobial (e.g. rifabutin, levofloxacin or furazolidone)
could be used. Several studies have obtained relatively
good results with triple therapy combining PPI, rifabutin,
and amoxicillin, although a reversible myelotoxicity as
leukopenia and thrombocytopenia has been described.
Preliminary good results were also achieved with triples
PPI regimens combining levofloxacin and amoxicillin
without important adverse effects. Furazolidone has also
shown efficacy for H. pylori eradication, although unto-
ward reactions could limit its use, especially when high
doses are employed. Finally, in more than one H. pylori
treatment failure, non-antimicrobial add-on medications
(such as lactoferrin, probiotics and others) could be used
with the aim either to improve the eradication rate or to
minimize side effects.
Copyright © 2006 S. Karger AG, Basel
Prof. Francesco Di Mario, MD
Section of Gastroenterology, Department of Clinical Sciences
Maggiore University Hospital, Via Gramsci, 14
IT–43100 Parma (Italy)
Tel. +39 0521 702 772, Fax +39 0521 291 582, E-Mail francesco.dimario@unipr.it
 Introduction
Helicobacter pylori infection represents the main
cause of gastritis, gastroduodenal ulcer and gastric cancer
and should be considered as a major public health issue.
It is one of the most common bacterial infections, affect-
ing at least half the World population. Its prevalence de-
pends on age, socioeconomic class and country of origin
[1, 2].
First-line therapy for treating H. pylori infection con-
sists of proton pump inhibitor (PPI) or ranitidine bis-
muth citrate (RBC) with any two antibiotics of clarithro-
mycin, amoxicillin or metronidazole given for 7–14 days
(table 1) as recommended by several international con-
sensus conferences [3–6]. However, according to a num-
ber of recent meta-analysis [7, 8], even with the recom-
mended regimens, approximately 20% of patients will fail
to achieve eradication of the H. pylori infection and re-
main H. pylori positive. The percentage of patients with
first-line H. pylori therapy failure may actually be higher
in clinical practice [9, 10]. This issue is assuming an in-
creasing importance because of the wide diffusion of
H. pylori therapy prescription. The choice of best rescue
therapy is always difficult due to development of second-
ary bacterial resistance [11–13] to antibiotics used as first-
line treatment. On the other hand, retreatment is often
limited by patient’s compliance, especially if the pre-
Table 1. Conventional doses of PPIs,
bismuth compounds and antimicrobial Drug
agents commonly used in the H. pylori
eradication regimens Proton pump inhibitors
Omeprazole
Esomeprazole
Lansoprazole
Rabeprazole
Pantoprazole
Bismuth compounds
Bismuth subcitrate (BSC)
Bismuth subsalicylate (BSS)
Ranitidine bismuth citrate (RBC)
Antimicrobial agents
Amoxicillin
Clarithromycin
Metronidazole
Tinidazole
Tetracycline
Rifabutine
Levofloxacin
Furazolidone
114 Dig Dis 2006;24:113–130
scribed second-line therapy lasts longer and employs
higher drug dosage.
In this paper, we will discuss the possible causes of
H. pylori treatment failure and review the current litera-
ture on the several retreatment options available for pa-
tients with H. pylori infection resistant to one or more
eradication attempts.
Indications to Perform More than One
Attempt to Eradicate
More than one eradication attempts should be consid-
ered in all the conditions where this approach is strongly
recommended [6] (table 2). In H. pylori-positive patients
with peptic ulcer disease including both active, inactive
and complicated disease as well as in those with low- and
high-grade mucosa-associated lymphoid tissue lympho-
ma [14], H. pylori eradication is mandatory. In all these
clinical conditions, the benefit of eradication largely out-
weighs any potential risk.
H. pylori treatment therapy is also suggested in pa-
tients with atrophic gastritis, following gastric cancer and
in first-degree relatives of patients with gastric cancer,
taking into account the close association between H. py-
lori, atrophic changes in the gastric mucosa, genetic fac-
tors and gastric cancer [15–17].
Daily dose
20 mg twice daily
40 mg once or 20 mg twice daily
30 mg once or twice daily
20 mg once or twice daily
40 mg once or twice daily
120 mg four times daily
524 mg four times daily
400 mg twice daily
1,000 mg twice daily
250 mg or 500 mg twice daily
500 mg twice or 250 mg four times daily
500 mg twice daily
500 mg four times daily
300 mg once or 150 mg twice daily
250 mg or 500 mg once or twice daily
200 mg twice daily
Di Mario /Cavallaro /Scarpignato
 Reasons for Unsuccessful Eradication
Several factors could be responsible for H. pylori erad-
ication failure and they are usually related to the micro-
organism, to the host or the regimens adopted.
Bacterial Resistance
H. pylori resistance is an important factor leading to
treatment failure [18]. Prevalence of H. pylori resistance
to clarithromycin in European adults displays relevant
regional differences: it is higher in southern (more than
20%) than in northern (about 3%) Europe [19–28]. In
Canada and USA, it is estimated to be close to 4% [29]
and 12%, respectively [30]. In Israel and Iran, it ranges
from about 5% [31] to 17% [32]. In Japan, clarithromycin
resistance is higher (13%) [33] than in Hong Kong (4.5%)
[34] and Korea (5.4%) [35] (fig. 1).
The prevalence of H. pylori resistance to metronida-
zole ranges from 15 to 40% in Europe and USA, which is
higher than in Japan (9–12%) [33, 36]. This prevalence is
much higher in developing countries, ranging from 50 to
80% [37, 38] (fig. 2). However, the impact of resistance
to clarithromycin or metronidazole on H. pylori treat-
ment success is very different. Indeed, while a good cor-
relation between bacterial resistance to clarithromycin
and eradication failure does exist, this is not the case for
metronidazole. As a matter of fact, a recent review [28]
evaluating 20 studies from 1999 to 2003 pointed out a
drop in the efficacy of the PPI-amoxicillin-clarithromycin
regimen from 88 to 18% in the case of clarithromycin-re-
sistant strains. In the case of metronidazole-resistant
strains, however, success of the PPI-clarithromycin-met-
ronidazole regimen decreased from 97 to 73%. Further-
more, the mean loss of efficacy of the metronidazole-
based regimen could be less than 10% if this drug is pre-
scribed in a quadruple 1-week therapy together with PPI,
bismuth and tetracycline [39].
The majority of patients in whom first-line therapy
failed developed secondary resistance to the prescribed
antibiotics. An Italian study [23] enrolled 87 H. pylori-

11–12% 1.7–23.4%

5.5% 12%
8.2% 4.5%
25% 17%

9.8%

6.8%

Fig. 1. Primary resistance of H. pylori to

clarithromycin in different world regions.

Table 2. Strongly recommended

indications for H. pylori eradication Indication Strength of the
therapy and the strength of the supporting supporting evidence
evidence
Peptic ulcer disease (active or not, including complicated ulcer) 1
Mucosa-associated lymphoid tissue (MALT) lymphoma 2
Atrophic gastritis 2
Post-gastric cancer resection 3
Patients who are first-degree relatives of gastric cancer patients 3
Patients’ wishes (after full consultation with their physician) 4
Iron deficiency anemia 2
Idiopathic thrombocitopenia 2

Rescue Therapies for Helicobacter pylori Dig Dis 2006;24:113–130 115

Eradication
 22–34%
76%
Fig. 2. Primary resistance of H. pylori to
metronidazole in different world regions.
Fig. 3. Patient-related factors for unsuc-
cessful H. pylori eradication therapy.
positive patients neither harboring clarithromycin- nor
metronidazole-resistant strains. 70% of the patients who
failed first-line therapy got secondary antibiotic resis-
tance, with resistance rates to clarithromycin and metro-
nidazole of 64 and 35%, respectively. In another study,
performed in Ireland, after failure of first-line therapy,
the clarithromycin resistance rate increased from 3.4 to
58%. Even more importantly, resistance to both clarithro-
mycin and metronidazole dramatically affected the effi-
cacy of treatment [40].
Patient-Related Factors (fig. 3)
Factors related to the patients such as compliance, up-
per gastrointestinal diseases (e.g. functional dyspepsia or
116 Dig Dis 2006;24:113–130
15– 40%
41%
38% 29% 9–12%
32– 63%
53%
32%
duodenal ulcer) and gastric acid secretion could influence
the success of H. pylori eradication.
Poor compliance is one of the most important issues
in treatment failure [41, 42]. The occurrences of adverse
effects such as taste disturbance, nausea and loose stools
discourage patients from completing a course of therapy
[43]. Moreover, a treatment schedule consisting of many
tablets per day and long duration, could also affect pa-
tient’s compliance [44]. On the other hand, a clear expla-
nation that nearly all side effects are self-limiting and a
strong encouragement to complete the treatment has dra-
matically reduced the discontinuation rates [45–47]. In a
study of eradication failure, 30 H. pylori-positive outpa-
tients were treated with a 7-day PPI triple therapy. Pa-
Di Mario /Cavallaro /Scarpignato
tient compliance was assessed by particular containers
endowed with an electronic device recording the time of
opening. In patients who took more than 60% of the es-
tablished medications, the cure rate was significant high-
er (72%) than in those who took less than 60% of the pre-
scribed pills [48].
Another important factor influencing the success of
eradication is the clinical characteristics of the patients.
In particular, patients affected by functional dyspepsia
(FD) have been reported to have lower eradication rates
than those with peptic ulcer disease (PUD), as already
observed in the original meta-analysis by Huang and Hunt
[49]. This was confirmed in a French study analyzing in-
dividual data of 2,751 H. pylori-positive patients included
in 11 multicenter clinical trials given eradication treat-
ment [50]. The reasons for this difference are not clear. It
could be due to the different status of gastric mucosa or
to the difference of infecting H. pylori strains, i.e. antibi-
otic resistance or Cag status. For instance, in patients with
FD a resistance to clarithromycin higher than that ob-
served in DU patients has been described [51]. Along the
same lines, patients harboring Cag-A-positive strains,
more frequent amongst DU patients, have a lower failure
than those harboring Cag-A-negative strains [52].
Finally, the increase in gastric pH induced by antise-
cretory drugs is crucial in order to allow antibiotics exert-
ing the best activity against H. pylori [53, 54]. PPIs dis-
play several pharmacological actions that give them a
place in the eradication regimens (for review, see Scar-
pignato and Pelosini [54]), that is:
1 they exert an antibacterial action against H. pylori;
2 by increasing intragastric pH, they allow the microor-
ganism to reach the growth phase and become more
sensitive to antibiotics such as amoxicillin and clar-
ithromycin;
3 they increase antibiotic stability and efficacy, and
4 by reducing gastric emptying and mucus viscosity,
they increase the gastric residence time and mucus
penetration of antimicrobials.
However, not all the subjects have the same basal and
stimulated gastric acid output or the same response to
PPI. A small part of individuals may be acid hypersecre-
tors with a large parietal cell mass. On the other hand, a
genetic variation on hepatic metabolism of PPIs may also
play a role [55, 56]. This class of drugs is indeed metabo-
lized by cytochrome P450 isoenzyme 2C19 (CYP2C19)
in the liver. There are genetic differences that affect the
activity of this enzyme. The genotypes of CYP2C19 are
classified into three groups: homozygous extensive me-
tabolizer (homEM), heterozygous extensive metabolizer
Rescue Therapies for Helicobacter pylori
Eradication
(hetEM) and poor metabolizer (PM). The pharmacoki-
netics and pharmacodynamics of PPIs differ among the
different CYP2C19 genotype groups. Plasma PPI and in-
tragastric pH levels during PPI treatment are the lowest
in the homEM group and the highest in the PM group.
These CYP2C19 genotype-dependent differences in
pharmacokinetics and pharmacodynamics of PPIs are re-
flected in the cure rates for H. pylori infection with PPI-
based therapies [57].
Recent evidence suggests that not only the increase in
intragastric pH but also the duration of the antisecretory
action could influence the eradication rate achieved with
PPI-based regimens [58]. In addition, the duration of
nocturnal acid breakthrough (NAB), frequently observed
even with twice daily PPIs, can also affect the success of
therapy [59].
Finally, smoking could have a negative impact on
H. pylori eradication for reasons (such as increasing acid
secretion or altering gastric mucus) not yet completely
understood [60].
Treatment-Related Factors
The components, the dosage and the duration of a
treatment play an important role in H. pylori eradication.
PPI triple therapy is significantly more effective than dual
therapy with two antibiotics or only one antibiotic com-
bined with a PPI [61]. Twice daily PPIs are more effective
than once daily administration. Two-week PPI-based tri-
ple therapy achieves better eradication rates than those
observed after 1 week of treatment [62] (table 3).
‘Rescue’ Therapies
Rescue Therapy Options after First-Line Failure
(Second-Line Treatments)
H. pylori eradication after first-line therapy failure is
considered more difficult, mainly due to selection of bac-
terial strains resistant to antibiotics used in the previous
eradication attempt [63, 64]. For this reason, the best H.
pylori rescue treatment is actually the right first-line ther-
apy. As a general rule, geographical prevalence of antimi-
crobial resistance should influence the first-line regimen.
If clarithromycin resistance rate is below 15–20%, treat-
ment can start with a clarithromycin-based regimen [65].
Clarithromycin, in fact, with its high capacity to diffuse
through gastric mucosa, represents the most effective bac-
tericidal antibiotic against H. pylori [66]. However, after
failure of a clarithromycin-based regimen, secondary re-
sistance to this antibiotic is very frequent; range about
Dig Dis 2006;24:113–130 117
 Table 3. Meta-analysis of the studies with PPI-based eradication regimens of 1 or 2 week duration. Forrest’s plot
comparing the intention-to-treat eradication rates obtained with the two kinds of therapies (from Calvet et al.,
[62])

Study Exp, n/N Ctr, n/N Peto OR (95% CI fixed) Weight Peto OR
(95% CI fixed)

Dal Bó, 1998 45/66 25/33 11.7 0.70 (0.28, 1.74)

Dammann, 1997 81/125 91/129 35.5 0.77 (0.46, 1.30)
Katicic, 1996 40/55 43/52 12.0 0.57 (0.23, 1.40)
Laine, 1996 43/50 46/50 6.3 0.55 (0.16, 1.90)
Louw, 1998 26/33 31/34 5.5 0.38 (0.10, 1.45)
Moayeddi, 1996 30/33 32/37 4.6 1.54 (0.36, 6.65)
Paoluzi, 1998 74/108 85/101 24.3 0.43 (0.23, 0.80)

Total (95% CI) 339/470 353/436 100.00 0.62 (0.45, 0.84)

2 4.13 (d.f. = 6) Z = 3.03

60–70% [23]. As a consequence, a significant decrease in
clarithromycin efficacy is observed [28] when it is re-
administrated in a PPI triple second-line therapy, even
prolonging the treatment to 14 days [67]. Thus, after fail-
ure of first-line clarithromycin-based regimens, a second-
line therapy based on metronidazole should be adopted.
The European Consensus Report [6] recommends a qua-
druple therapy for second-line treatment composed of:
PPI b.i.d., bismuth salts (120 mg q.i.d.), metronidazole
(500 mg three times daily) and tetracycline (500 mg
q.i.d.). Many studies have reported good results with this
quadruple schedule for 7–14 days with a mean eradica-
tion rate of 77% [68]. A pooled analysis on the efficacy of
second-line therapies regimens, including 75 treatment
arms, confirmed the efficacy of this regimen. In fact, the
pooled eradication rates by PPI dual therapy, PPI triple
therapy, RBC triple therapy and quadruple therapy were
45, 69, 80 and 75%, respectively [69], showing the supe-
riority of both RBC triple and quadruple therapy. Qua-
druple therapy, however, could af-fect patient’s compli-
ance due to the high incidence of adverse effects (up to
60%, although serious events are rare), and the great num-
ber of tablets per day (14 for 7–14 days) [64]. Further-
more, bismuth compounds are not available anywhere (as
it is the case in the Asia-Pacific region and in some Euro-
pean countries such as France). In this case, the second-
line treatment should use a PPI and two antibiotics (PPI
triple therapy), the choice of which depends on the treat-
ment initially used (see above).
Treatment Options for Nonresponders to First-Line
Treatment with Clarithromycin-Amoxicillin-Based
Regimens (fig. 4; table 4)
After failure of a combination treatment with a PPI,
clarithromycin and amoxicillin, taking into account the
very low secondary resistance rate to amoxicillin [28], the
first antibiotic should be replaced with a nitroimidazolic
compound (metronidazole or tinidazole). The recom-
mended treatment is the ‘classic’ quadruple therapy
which reaches an eradication rate of 75–95% [9, 69–73].
However, a simpler PPI triple therapy with amoxicillin-
metronidazole can achieve high success rates. Indeed,
Nagahara et al. [67] obtained an eradication rate of 81%
with a PPI schedule for 14 days in patients who failed
first-line PPI-clarithromycin-amoxicillin therapy. More
recently, other Japanese studies confirmed the good effi-
cacy of PPI triple therapy with amoxicillin and metroni-
dazole as second-line treatment. The eradication rate was
higher than 80% when either rabeprazole (20 mg b.i.d.)
or lansoprazole (30 mg b.i.d) were administered for 7–
10 days with metronidazole (250 mg b.i.d.) and amoxicil-
lin (750 mg b.i.d.). Similar results were also obtained in
patients harboring metronidazole-resistant strains [74–
76]. European trials, using doses of metronidazole higher
than those employed in Japanese studies, confirmed the
satisfactory eradication rate with this treatment for 7–
14 days, although the efficacy dropped to about 60% in
presence of metronidazole-resistant strains [77–79]. Fur-
thermore, a French randomized open study compared the

118 Dig Dis 2006;24:113–130 Di Mario /Cavallaro /Scarpignato

Fig. 4. Rescue regimens after PPI-clarithro-
mycin-amoxicillin failure. PP = Per proto-
col analysis; PPI = proton pump inhibitor;
RBC = ranitidine bismuth citrate.

Table 4. Eradication therapies adopted in patients nonresponders to first-line PPI-clarithromycin-amoxicillin regimens

Authors, year Ref. n Patient Duration Second-line eradication therapy Eradication rate, %
No. population of therapy
days ITT PP
(95% CI) (95% CI)

Michopoulos et al., 2000 73 38 PU, FD 7 PPI-BSC-metronidazole 500 mg t.i.d.-tetracycline 500 mg t.i.d. 76 (62–91) 86 (72–100)
Boixeda et al., 2002 71 140 FD, PU 7 PPI-BSC-tetracycline-metronidazole 500 mg t.i.d. 82 (75–88) 85 (79–91)
Georgopoulos et al., 2002 72 49 FD, PU 7 omeprazole-BSC-metronidazole-tetracycline 84 (70–93) 84 (70–93)
Gomollon et al., 1999 70 21 PU 7 PPI-BSC-tetracycline-metronidazole 500 mg t.i.d. 95 (76–100) 95 (76–100)
Nagahara et al., 2004 67 80 PU, FD 10 omeprazole 20 mg o.d.-amoxicillin 500 mg b.i.d.-metronidazole 81 (71–89) 91 (81–97)
250 mg b.i.d.
Isomoto et al., 2003 74 60 PU, FD 7 rabeprazole 10 mg b.i.d.-amoxicillin 750 mg b.i.d.-metronidazole 82 (72–92) 88 (80–96)
250 mg b.i.d.
Murakami et al., 2003 75 92 PU, FD 7 PPI-amoxicillin 750 mg b.i.d.-metronidazole 250 mg b.i.d. 88 (80–95) 91 (83–98)
Miwa et al., 2003 76 39 PU or FD 10 PPI-amoxicillin 750 mg b.i.d.-metronidazole 250 mg b.i.d. 92 (79–98) 95 (82–99)
Lamouliatte et al., 2003* 78 57 PU, FD 14 PPI-amoxicillin-metronidazole 63 (50–75) 72 (56–84)
Perri et al., 2003 80 59 PU, FD 7 RBC-amoxicillin-tinidazole 85 (76–94) 86 (78–95)
Rinaldi et al., 1999 81 38 PU, FD 14 RBC-tetracycline-tinidazole 82 (75–97) 86 (69–94)
Zullo et al., 2001 82 22 PU, FD 14 RBC-tetracycline-tinidazole 96 (75–100) 96 (75–100)
Gisbert et al., 1999 83 30 PU, FD 7 RBC-tetracycline-metronidazole 83 (69–97) 86 (73–99)

FD = Functional dyspepsia; PU = peptic ulcer; PPI = proton pump inhibitor; BSC = bismuth subcitrate. Unless otherwise specified, PPIs and antimicrobi-
als have been administered at their conventional antisecretory or antibacterial doses, given twice daily (see table 2).
* Included also patients (13% of the total) that failed to other first-line therapy regimens than PPI-clarithromycin-amoxicillin.

eradication rate obtained with second-line therapy based
on antibiotic susceptibility with that achieved by using
empirical regimens. Of the 285 patients evaluated, 116
received different PPI-amoxicillin-clarithromycin regi-
mens, 57 patients were treated with omeprazole (20 mg
b.i.d.), metronidazole (500 mg b.i.d.) and amoxicillin
(1 g b.i.d.) for 2 weeks, and 113 with a regimen based on
susceptibility testing. The eradication rate was unaccept-
ably low in the first subgroup of patients, it was 63% in
the second, while in the group where the choice of treat-
ment was guided by susceptibility testing, the eradication
rate reached 74%; albeit no statistical difference was
achieved between the two latter groups. The overall cure
rate in patients with PPI-amoxicillin-metronidazole ther-
apy was 80% in the metronidazole-sensitive strains and
60% in the metronidazole-resistant strains [78].
Good results were also observed when RBC triple ther-
apy was administered as second-line treatment. Perri et
al. [80] randomized 180 patients who failed first-line PPI-
amoxicillin-clarithromycin, into one of the following 7-
day treatments: (a) RBC (400 mg b.i.d.) with amoxicillin
(1 g b.i.d.) and tinidazole (500 mg b.i.d.); (b) ‘classic’ qua-
druple PPI-bismuth-metronidazole-tetracycline therapy,
and (c) PPI-amoxicillin and levofloxacin (500 mg o.d.).
RBC triple therapy showed an eradication rate (85%)
higher than the levoxacin-based regimen (63%) and sim-
ilar to the quadruple schedule (83%) but with less side
effects. Encouraging results were also obtained with RBC

Rescue Therapies for Helicobacter pylori Dig Dis 2006;24:113–130 119

Eradication
Fig. 5. Rescue regimens after PPI-amoxicil-
lin-nitroimidazole failure. PP = Per proto-
col analysis; PPI = proton pump inhibitor;
RBC = ranitidine bismuth citrate.

Fig. 6. Rescue regimens after PPI-clarithro-

mycin-metronidazole failure. PP = Per pro-
tocol analysis; PPI = proton pump inhibi-
tor; RBC = ranitidine bismuth citrate.

Table 5. Eradication therapies adopted in patients non-responding to first-line PPI-nitroinidazole regimens with clarithromycin or amox-
icillin

Authors, year Ref. n Patient Duration Second-line eradication therapy Eradication rate, %
No. population of therapy
days ITT (95% CI) PP (95% CI)

PPI-nitroinidazole-amoxicillin
Gisbert et al., 1999 83 20 7 PPI-amoxicillin-clarithromycin 85 (62–97) 85 (62–97)
Magaret et al., 2001 85 20 14 PPI-amoxicillin-clarithromycin 75 (56–94) 82 (64–100)
Lerang et al., 1997 84 18 10 PPI-amoxicillin 750 mg b.i.d.-clarithromycin 100 100
Magaret et al., 2001 85 28 14 PPI-BSS-metronidazole-tetracycline 250 mg q.i.d. 71 (54–88) 80 (64–96)
PPI-nitroinidazole-clarithromycin
Gisbert et al., 1999 83 10 7 PPI-BSC-metronidazole 250 mg b.i.d.-tetracycline 80 (44–97) 80 (44–97)
Zullo et al., 2001 82 16 PU, FD 14 RBC-tinidazole-tetracycline 88 (62–97) 88 (62–97)

FD = Functional dyspepsia; PU = peptic ulcer; PPI = proton pump inhibitor; BSS = bismuth subsalicylate; BSC = bismuth subcitrate.

triple therapy where tinidazole and tetracycline were
added to the bismuth compound for 14 days. In fact, in
two Italian studies this regimen, administrated as second-
line therapy, achieved cure rates of 82% [81] and 96%
[82], although 12% of patients complained of mild ad-
verse effects. Moreover, one randomized Spanish study,
including 60 patients, compared the efficacy of RBC
(400 mg b.i.d.), tetracycline (500 mg q.i.d.) and metroni-
dazole (250 mg q.i.d.) therapy to that of quadruple sched-
ule consisting of omeprazole (20 mg b.i.d.), bismuth
(120 mg q.i.d.), tetracycline (500 mg q.i.d.) and metroni-
dazole (250 mg q.i.d.), both for 7 days. The triple RBC-
based treatment achieved a higher eradication rate (86%)
than the quadruple therapy (59%), with the advantage of
being a simpler regimen with a lower number of tablets
per day [83]. It is worth mentioning, however, that in this

120 Dig Dis 2006;24:113–130 Di Mario /Cavallaro /Scarpignato

study the eradication rate of the quadruple regimen was
remarkably low, due to unknown reasons (likely different
populations and/or H. pylori strains).
Treatment Therapies for Nonresponders to
Amoxicillin/Nitroimidazole-Based Regimens
(fig. 5; table 5)
After PPI-amoxicillin-nitroimidazole failure, retreat-
ment with PPI-amoxicillin-clarithromycin for 7–10 days
proved to be very effective with eradication rates ranging
from 75% to 100%. [84, 85]. This second-line schedule
appears to be the most logical, since there is often a low
prevalence of clarithromycin resistance rate. On the oth-
er hand, classical quadruple therapy, potentially over-
coming the impact of metronidazole resistance, could be
also suggested. Margaret et al. [85] compared quadruple
with PPI-clarithomycin-amoxicillin therapies in 48 pa-
tients who failed first-line metronidazole-based regimen.
A satisfactory success rate (more than 70%) was found for
both the regimens, without significant difference.
An alternative rescue regimen may be a similar one
using a RBC instead of a PPI. In an observational study,
involving a small number of patients who failed first-line
eradication therapy, Beales [86] has shown an adequate
eradication rate with RBC-amoxicillin-clarithromycin
for 7 days.
Treatment Options for Nonresponders to
Clarithromycin/Nitroimidazole-Based Regimens
(fig. 6; table 5)
After failure of first-line therapy combining a PPI with
clarithromycin and nitroimidazole, the theoretical choice
would be dual therapy consisting of high-dose PPI and
amoxicillin. However, controversial results [69, 87] have
been obtained with this schedule, despite the early en-
couraging cure rate [88]. Thus, the best option remains a
classic quadruple therapy which does not include clar-
ithromycin and it is very effective also against metroni-
dazole-resistant strains [69, 84, 89].
To simplify the latter schedule, Zullo et al. [82] em-
ployed RBC instead of PPI and bismuth and achieved
good results. Indeed, in patients who fail a first H. pylori
treatment with PPI-tinidazole-clarithromycin an eradi-
cation rate of 88% was obtained by using the RBC-tetra-
cycline-tinidazole combination as a second-line treat-
ment. In the countries where bismuth is not available, a
PPI triple therapy with metronidazole and amoxicillin
could be suggested, probably lasted for 14 days [78].
However, the success rate could drop to about 60% in
presence of metronidazole-resistant strains [28].
Rescue Therapies for Helicobacter pylori
Eradication
Alternative Antibiotics in Second-Line Therapy
(table 6, 7)
PPI triple therapies with antimicrobials not specifi-
cally used as components of eradication regimens (ta-
ble 1), such as rifabutin, levofloxacin or furazolidone,
could be administered as second-line treatment when a
double resistance to both clarithromycin and metronida-
zole is suspected (like, for instance, in developing coun-
tries) and bismuth compounds are not available, or as
alternative to quadruple therapy. Several studies have ob-
tained relatively good results with triple therapy combin-
ing PPI, rifabutin, and amoxicillin for 7–14 days with
satisfactory eradication rates [90–94]. Although a case of
reversible myelotoxicity with leukopenia and thrombocy-
topenia has been reported [93], in the above studies the
adverse effects were generally rare. Perri et al. [90] ran-
domized 135 patients, who failed first-line therapy, into
three groups for 10 days: quadruple therapy or PPI-amox-
icillin-rifabutin triple therapy with two different dosage
of rifabutin (150 or 300 mg o.d.). The group with rifabu-
tin at high dosage obtained the highest eradication rate
(86%), with fewer side effects than quadruple therapy.
Toracchio et al. [94] evaluated 104 patients, who had
failed one course of triple therapy. A 10-day triple thera-
py with pantoprazole, amoxicillin and rifabutin was ad-
ministrated as second-line therapy, obtaining an eradica-
tion rate of 78.5% in patients harboring secondary resis-
tance to clarithromycin and tinidazole.
Rifaximin is a synthetic rifamycin derivative that
shares with rifabutin its antibacterial activity against H.
pylori [95–98]. Most importantly, no strain with primary
rifaximin resistance has been reported as yet. This anti-
biotic is however poorly adsorbed and its administration
is associated with very few, if any, side effects [99]. In this
connection, some rifaximin-based eradication regimens
have been attempted [for review, see 100], with a dual
rifaximin-clarithromycin combination achieving a 70%
eradication rate [101]. New antimicrobial combinations
(with and without PPIs) need, of course, to be explored
in well-designed clinical trials including a large cohort of
H. pylori-infected patients before rifaximin be considered
a suitable antibiotic for first- or second-line eradication
therapy.
Preliminary good results were also reported with triple
PPI regimens combining levofloxacin and amoxicillin for
7–10 days [102, 103], with only mild side effects (such as
glossitis [104]). Nista et al. [103], in a randomized trial,
enrolled 280 patients, who failed first-line PPI-amoxicil-
lin-clarithromycin, and randomized them to four groups:
two PPI triple therapies for 10 days with rabeprazole
Dig Dis 2006;24:113–130 121
Table 6. Alternative antimicrobial agents adopted in second-line regimens after first eradication failure

Authors, year Ref. n Patient Duration First-line eradication therapy Second-line eradication Eradication rate, %
No. population of therapy therapy
days ITT PP
(95% CI) (95% CI)

Bock et al., 2000* 91 25 PU, FD 7 predominantly PPI triple therapies PPI-amoxicillin-rifabutin 72 (46–88) 86 (62–97)
with amoxicillin or metronidazole
Toracchio et al., 2005 94 104 PU, FD 10 not specified PPI-amoxicillin-rifabutin 78 (67–90) 82 (71–92)
prevalently
Perri et al., 2001* 90 45 PU, FD 10 various PPI triple therapies PPI-amoxicillin-rifabutin 87 (76–96) 87 (76–96)
Watanabe et al., 2003 102 33 FD, PU 7 PPI-amoxicillin-clarithromycin PPI-amoxicillin-levofloxacin 69 (61–79) 69 (61–79)
prevalently
Bilardi et al., 2004* 105 44 PU, FD 10 various PPI triple therapies PPI-amoxicillin-levofloxacin 70 (53–87) 70 (53–87)
Nista et al., 2003 103 70 FD 10 PPI-amoxicillin-clarithromycin PPI-amoxicillin-levofloxacin 94 (87–99) 94 (87–99)
Nista et al., 2003 103 70 FD 10 PPI-amoxicillin-clarithromycin PPI-levofloxacin-tinidazole 90 (80–96) 90 (80–96)
Wong et al., 2003 106 37 FD, PU 7 various RBC/PPI triple therapies PPI-levofloxacin-rifabutin- 86 (75–97) 86 (75–97)
Isakov et al., 2002 109 35 PU 7 not specified BSC-tetracycline 750 mg 86 (70–95) 91 (76–98)
b.i.d-furazolidone

FD = Functional dyspepsia; PU = peptic ulcer; PPI = proton pump inhibitor; BSC = bismuth subcitrate.
* Mixture of patients who failed one or more eradication regimens.

Table 7. H. pylori eradication therapies after two or more eradication failures

Authors, year Ref. n Patient population Duration Third-line therapy Eradication rate, %
No. of therapy
days ITT PP
(95% CI) (95% CI)

Gomollón et al., 2000 110 29 PU 14 culture guided 48 (29–67) 50 (30–69)

Cammarota et al., 2004 111 94 PU, FD, MALT 7 culture guided 90 (84–96) 91 (83–97)
lymphoma
Beales, 2001 86 16 not specified 14 culture guided 69 (46–88) 69 (46–88)
Dore et al., 2002 113 42 FD or PU 14 omeprazole-BSC-metronidazole-tetracycline 95 (85–99) 98 (89–100)
500 mg b.i.d.
Wong et al., 2003 106 15 FD, PU 7 omeprazole-BSC-metronidazole-tetracycline 87 (62–97) 93 (75–99)
Miehlke et al., 2003 87 41 PU, FD 14 omeprazole 40 mg q.i.d.-amoxicillin 750 mg q.i.d. 76 (60–88) 83 (68–94)
Qasim et al., 2005 107 34 FD 10 PPI-amoxicillin-rifabutin 38 (23–59) 38 (23–59)
Canducci et al., 2001 93 10 not specified 10 PPI-amoxicillin-rifabutin 70 (35–93) 77 (40–95)
Perri et al., 2000 114 41 FD 7 PPI-amoxicillin-rifabutin 71 (57–85) 74 (61–88)
Gisbert et al., 2003 92 14 PU, FD 14 PPI-amoxicillin-rifabutin 79 (49–95) 79 (49–95)
Zullo et al., 2003 104 36 PU, FD 10 PPI-amoxicillin-levofloxacin 83 (71–95) 88 (77–99)
Wong et al., 2003 106 19 FD, PU 7 PPI-levofloxacin-rifabutin 89 (68–99) 89 (68–99)
Treiber et al., 2002 107 10 Not specified 7 PPI-BSC-tetracycline-furazolidone 90 (55–100) 90 (55–100)
Qasim et al., 2005 107 10 PU, FD 7 PPI-amoxicillin-furazolidone 60 (26–88) 60 (26–88)
Gisbert et al., 2004 115 48 Not specified 7–14 empirical therapy based on regimens not previously 71 (57–82) 72 (58–83)
prescribed

FD = Functional dyspepsia; PU = peptic ulcer; PPI = proton pump inhibitor; BSC = bismuth subcitrate.
* 10 patients in second-line treatment.

(20 mg b.i.d.), levofloxacin (500 mg o.d.) and amoxicillin
(1 g b.i.d.) or with levofloxacin (500 mg o.d.) and tinida-
zole (500 mg b.i.d.) and two classic quadruple therapies
for 7 and 14 days. Success eradication was higher in the
levofloxacin (about 90%) than in the quadruple regimens
(ranging from 63 to 69%) with significantly less side ef-
fects. Bilardi et al. [105] randomized 90 patients, who had
failed one or more eradication attempts, into pantopra-
zole (40 mg b.i.d.), amoxicillin (1 g b.i.d.) and levofloxa-
cin (250 mg b.i.d.) regimen for 10 days or omeprazole
(20 mg b.i.d.) for the first 1 week followed by a PPI-tetra-
cycline-metronidazole-bismuth quadruple therapy in the
second week. The former schedule showed a significant
higher success cure (70%) than quadruple regimen (37%).

122 Dig Dis 2006;24:113–130 Di Mario /Cavallaro /Scarpignato

Interestingly enough, Wong et al. [106] compared the ef-
ficacy of PPI-levofloxacin-rifabutin triple therapy with a
classical quadruple therapy in a randomized trial involv-
ing 75 and 34 patients who failed various first-line and
two or more courses of therapies, respectively. A very
high eradication rate (up to 80%) was observed for the
regimens also in patients harboring metronidazole- and/
or clarithromycin-resistant strains.
Finally, furazolidone has also shown a good efficacy in
eradicating H. pylori, although adverse events could lim-
it its use. Potential furazolidone-related side effects in-
clude gastrointestinal symptoms, disulfiram-like reaction
in patients taking alcohol, monoamine oxidase (MAO)
inhibitor properties as well as glucose-6-phosphate dehy-
drogenase (G-6-PD) reduced activity. A detailed list of
food or drugs with potential interactions is therefore man-
datory for patients taking such antimicrobial [107, 108].
Isakov et al. [109] randomized duodenal ulcer patients,
after failure first-line treatment and harboring metroni-
dazole-resistant strains, to receive for 7 days: bismuth
(240 mg b.i.d.), furazolidone (200 mg b.i.d.) and tetracy-
cline (750 mg q.i.d.) or classic quadruple therapy. Eradi-
cation rates were 85 and 74% for the furazolidone-based
regimen and quadruple therapy, respectively, with a sig-
nificant lower rate of adverse events in the first group.
Rescue Therapies after Two or More Failures (table 7)
As recommended by European Guidelines [6], after
failure of second-line regimen, primary care patients
should be referred to a specialist setting and should per-
form third-line therapy according to susceptibility test-
ing, if available. However, the best approach (empirical
or susceptibility-guided) and the best therapy for patients
with more than one failed eradication attempts remain
controversial due to the lack of large randomized cohort
studies and the lack of homogeneity of patients studied.
Beales [86], in a small observational study, treated 16
patients according to metronidazole and/or clarithromy-
cin resistance into the following regimens: omeprazole-
amoxicillin-rifabutin, RBC-clarithromycin-tetracycline
or RBC-tinidazole-tetracycline. Alternatively, 4 patients
with unknown resistance patterns underwent omepra-
zole-amoxicillin-rifabutin therapy. The overall success
rate was higher (68%) in patients managed with suscepti-
bility test strategy than in those treated by the empirical
approach (50%).
Gomollón et al. [110] evaluated, in a small group of
patients, the efficacy of 2-week quadruple, culture-guided
combinations as third-line therapy. Different quadruple
therapies with tetracycline-bismuth-omeprazole plus an
Rescue Therapies for Helicobacter pylori
Eradication
additional antimicrobial (clarithromycin or amoxicillin
or metronidazole or ciprofloxacin according to H. pylori
susceptibility testing and allergy to penicillin) were stud-
ied. Overall eradication rate was unsatisfactory (less than
50%), with successful cure rate of 36% for the clarithro-
mycin-based quadruple regimen and 67% for the amoxi-
cillin-tetracycline-bismuth-omeprazole combination.
Cammarota et al. [111] managed 94 patients with per-
sistent H. pylori infection after two treatment failures by
a culture-guided approach. The majority of patients (89),
harboring tetracycline- and amoxicillin-sensitive strains,
received a 1-week quadruple drug combination consist-
ing of: omeprazole (20 mg b.i.d.), bismuth (120 mg q.i.d.),
amoxicillin (1 g b.i.d.) and doxycycline (100 mg b.i.d.).
Four patients were given 1-week triple therapy with
omeprazole-amoxicillin (1 g b.i.d.) and levofloxacin
(500 mg b.i.d.) because of the presence of resistant strains
to tetracycline but not to levofloxacin; 1 patient with re-
sistant strains to tetracycline and levofloxacin but not to
clarithromycin was treated by a standard PPI-amoxicil-
lin-clarithromycin triple therapy. An overall eradication
rate was obtained in 90%, showing the good efficacy of
this approach and suggesting quadruple therapy with
doxycycline as a possible option for third-line therapy.
Taking into account the low impact of metronidazole
resistance in quadruple therapy [28, 112], this regimen
could be suggested without culture. Dore et al. [113]
reached an excellent success rate when quadruple regi-
men for 14 days was prescribed, in 42 patients, as a third-
line therapy. This very good result was confirmed in a
Chinese randomized controlled study involving a small
number of patients harboring metronidazole- and/or clar-
ithromycin-resistant strains [106].
Alternatively, Miehlke et al. [87] observed in a pro-
spective randomized study a similar and satisfactory suc-
cess rate with both high-dose dual PPI-amoxicillin and
quadruple therapy. A trend for a better compliance was
reported in the previous regimen, although quadruple
therapy consisted of a high metronidazole dose (2 g
o.d.).
In an empirical management of patients who failed
two or more eradication attempts, few prospective but
not randomized or controlled studies have obtained good
results employing PPI triple therapy with amoxicillin and
an antibiotic not included in previous regimens (such as:
rifabutin, levoxacin or furazolidone) for 7–14 days. Perri
et al. [114] evaluated the efficacy of 7-day triple therapy
with pantoprazole (40 mg b.i.d.), amoxicillin (1 g b.i.d.)
and rifabutin (300 mg o.d.) on 41 H. pylori-positive pa-
tients who failed more than two eradication treatments
Dig Dis 2006;24:113–130 123
assuming both clarithromycin and nitroimidazolic com-
pounds. A 71% success rate was obtained without report-
ing important adverse events (only 3% of patients had
mild side effects such as diarrhea or nausea). In a multi-
center Spanish pilot study [92], a similar, albeit longer,
third-line therapy was prescribed to 14 patients in whom
two eradication trials with the classical antibiotics (e.g.
clarithromycin, metronidazole and tetracycline) failed.
An eradication rate of 79% was achieved, although a high-
er percentage of patients complained of mild gastrointes-
tinal side effects (36%) [92]. Alternatively, Zullo et al.
[104] obtained a satisfactory success cure (83.3%) admin-
istering a 10-day schedule combining rabeprazole (20 mg
b.i.d.), amoxicillin (1 g b.i.d.) and levofloxacin (250 mg
b.i.d.) to 36 patients with persisting H. pylori infection.
The authors did not report important side effects, al-
though 2 patients discontinued the treatment due to glos-
sitis. Finally, Treiber et al. [108], in a pilot study, evalu-
ated the efficacy of a 1-week quadruple regimen based on
lansoprazole (30 mg b.i.d.), bismuth 240 mg (b.i.d.), tet-
racycline (1 g b.i.d.) and furazolidone (200 mg b.i.d.) as
a third line. Success was observed in 9 of 10 (90%) pa-
tients who failed different first-line, clarithromycin-based
therapies and a second-line quadruple therapy composed
of PPI-bismuth-metronidazole and tetracycline, showing
the efficacy of a furazolidone-based regimen even after
the failure of ‘classic’ quadruple therapy. On the contrary,
Qasim et al. [107] obtained an unsatisfactory success rate
(13/34, 38%) with a 10-day course of rifabutin (300 mg
o.d.), amoxicillin (1 g b.i.d.) and PPI (b.i.d.), employed
as third-line therapy. On the other hand, a 1-week regi-
men with furazolidone (200 mg b.i.d.), amoxicillin (1 g
b.i.d.) and PPI (b.i.d.) cured the H. pylori infection in 60%
of patients who failed first-, second- and third-line thera-
pies with rifabutin, suggesting that furazolidone-based
regimens could be effective also after failure of rifabutin-
based therapies.
Gisbert et al. [115], in a prospective single-center
study, managed 48 patients who failed two eradication
attempts by an empirical strategy. In no case was the same
schedule repeated (both in second- and third-line thera-
py). A new antibiotic (rifabutin) or the same antibiotic
associated with PPI and bismuth (if with high risk of in-
ducing resistant H. pylori strains) was administered. An
overall eradication rate of 71% was observed, suggesting
that susceptibility testing could be not always necessary.
Novel Agents (table 8)
Eradication therapy with adjunctive nonantimicro-
bial agents could be useful either to increase the effective-
124 Dig Dis 2006;24:113–130
Table 8. Novel non-antimicrobial agents
for H. pylori eradication
Lactoferrin
Probiotics
N-acetylcysteine (NAC)
Pronase
Ecabet sodium
Repamipide
Ginger root
Broccoli sprouts
Propolis
Essential oils
For references, see text.
ness of currently used antibiotics (e.g. altering bacterial
micro-environmental and/or hindering the development
of secondary bacterial resistance) or to reduce adverse
effects.
Lactoferrin is a glycoprotein found in human and bo-
vine milk and in several exocrine secretions (e.g. tears,
bile and saliva) [116] that showed bacteriostatic and bac-
tericidal effects [117, 118]. Human lactoferrin, as a single
agent, does not eradicate H. pylori infection as was dem-
onstrated by a recent study performed in vivo in 9 pa-
tients [119]. Conversely, bovine lactoferrin could have
synergistic actions if employed with PPI and antibiotics
as showed in two clinical trials [120, 121]. In a multi-
center prospective study, 119 consecutive patients, after
failure of first-line PPI triple therapy, were enrolled. The
patients were randomized in a 14-day quadruple ther-
apy composed of esomeprazole (20 mg b.i.d.), bis-
muth (120 mg q.i.d.), amoxicillin (1 g b.i.d.) and tinida-
zole (500 mg b.i.d.) with or without bovine lactoferrin
(200 mg b.i.d.). The eradication rate in the group taking
lactoferrin was significantly higher than that of those
who did not use the milk protein (80 vs. 64%) [122]. It
is worth mentioning, however, that when lactoferrin was
added to a standard 7-day regimen combining esoprem-
azole (20 mg) with clarithromycin (500 mg) and amoxicil-
lin (1 g), all twice daily, no increase of eradication rate
over the triple therapy alone has been observed [123].
These disappointing results were of course surprising, but
the reasons for the discrepancy between this and the pre-
vious Italian studies [120, 121] are not clear. Since a dif-
ference in the prevalence of primary bacterial resistance
to clarithromycin could be reasonably ruled out, other
causes must be sought. A possibility is that lactoferrin and
tinidazole may exert a synergistic effect against H. pylori,
Di Mario /Cavallaro /Scarpignato
while lactoferrin and amoxicillin do not. Such a hypoth-
esis is supported by the observation that when lactoferrin
is administered as monotherapy in the week before clar-
ithromycin-tinidazole combination, it does not give any
additive therapeutic effect [124]. Since lactoferrin can
bind and disrupt some bacterial cell membranes [125],
another possible explanation is that the antibacterial ef-
fect of lactoferrin – based on bacterial membrane damage
of gram-negative bacteria – could be marginalized when
amoxicillin is simultaneously administered. Indeed,
amoxicillin too mainly acts interfering with microbial
membrane structure. On the contrary, such an effect of
lactoferrin could be useful when tinidazole is adminis-
tered, a different mechanism being exploited by such an-
timicrobial. Whatever the reason, further studies are
needed before recommending lactoferrin as add-on med-
ication to eradication regimens in clinical practice.
Probiotics could have inhibitory effect to H. pylori ad-
herence [126] as well as antibacterial and immunomodu-
latory properties [127, 128]. However, first-line clinical
trials [129–131] which administered probiotics as add-on
medications to standard-PPI triple therapy have provid-
ed conflicting results. However, probiotic (Lactobacillus
GG and Bifidobacteria) supplementation did achieve a
significant reduction of the incidence of eradication regi-
men-related side effects [129–134].
N-acetylcysteine (NAC), being both a mucolytic and a
thiol-containing antioxidant agent, could affect H. pylori
micro-environment. Huynh et al. [135] demonstrated
that NAC, in a dosage of 120 mg/day for 14 days, reduced
the H. pylori load in mice by almost 1 log compared with
sham treatment, but did not improve the severity of gas-
tritis. Although devoid of in vitro activity against the mi-
croorganism, pronase has an additive effect in curing H.
pylori infection [136]. In the patients who took pronase
before surgery, the surface mucus gel layer was thinner
than in the patients who did not take the proteolytic en-
zyme, and the structure of the mucus layer was markedly
disrupted [136].
Ecabet sodium is a locally nonabsorbable antiulcer
drug developed in Japan. Kim et al. [137] observed as it
altered the inflammatory response in human gastric epi-
thelial cell lines infected with CagA+ H. pylori, inhibiting
the activation of NF-B and in turn blocked both the
transcription and expression of the IL-8 gene. Similarly,
rebamipide which displays anti-inflammatory gastric
properties and stimulates the synthesis of endogenous
prostaglandins in the gastric mucosa [138], was shown to
be capable of reducing mucosal inflammation even in the
absence of H. pylori eradication [139]. Both these drugs
Rescue Therapies for Helicobacter pylori
Eradication
therefore represent potential candidates as add-on medi-
cation to eradication regimens.
Finally, natural substances, like ginger root [140],
broccoli sprouts [141], propolis [142] and essential oils
[143], have all been shown an inhibitory effect on H. py-
lori growth in vitro and/or in vivo. Whether they could
improve the eradication rate of first- and second-line
eradication regimens remains to be established.
Conclusions
The best H. pylori rescue treatment is the right first-
line therapy. Generally, the geographical prevalence of
antimicrobial resistance should influence the first-line
regimen. If the clarithromycin resistance rate is below
15%, treatment can start with a regimen based on clar-
ithromycin. Alternatively, quadruple therapy, which has
a similar success rate to a clarithromycin-based regimen
but is not limited by primary or secondary resistance to
both clarithromycin or metronidazole, could be used
[112].
Whether it is better using a very effective first-line
treatment despite adverse effects and poor compliance or
starting with a simpler and better tolerated triple therapy
is still matter of debate. In the case of first-line therapy
failure with a clarithromycin-based regimen, the best op-
tion is ‘classic’ quadruple therapy adopting a PPI triple
therapy with amoxicillin and metronidazole for 10–14
days where bismuth compounds are not available.
After failure of second-line treatment, the patients, if
in primary care, should be referred to a specialist setting
and should be evaluated, using a case-by-case approach,
taking into account the eradication regimens attempted,
the previous antimicrobial therapy and other comorbidi-
ties. The choice of third-line therapy should preferably be
made according to susceptibility testing, or prescribing
regimens containing new antimicrobials empirically.
In countries with a high resistance to metronidazole,
quadruple therapy using furazolidone instead of metro-
nidazole could be suggested, if available. Similarly, levo-
floxacin or rifabutin triple therapies could be adopted.
Otherwise, if these new antimicrobials are not available
and/or if the patient had previously performed one or
more treatments with them (because of, for instance, re-
spiratory infections), culture could give important infor-
mation about the sensitivity of H. pylori strains to differ-
ent antibiotics. Whether it is worth using add-on medica-
tions to increase the eradication rate or limit side effects
is at present not well established.
Dig Dis 2006;24:113–130 125
 Note Added in Proof
While this review was being submitted, Gisbert and De La
Morena [144] published a meta-analysis outlining the high efficacy
of levofloxacin-based rescue regimens. The eradication rate appears
to be time-dependent since 10-day treatment was more effective
than 7-day therapy. Besides being more effective than standard
quadruple combination, levofloxacin-based regimens were also bet-
ter tolerated, with a significantly lower incidence of adverse events.
Some additional studies [145–147] confirmed the effectiveness of
different levofloxacin combinations as a second- or third-line ther-
apy, a feature shared by other quinolones, like for instance moxi-
floxacin [148]. Interestingly enough, Giannini et al. [147], by using
a high-dose (500 mg b.i.d.) levofloxacin regimen, found no differ-
ence in eradication rate between a short (4-day) and the conven-
tional 7-day treatment. In an attempt to make rifabutin-based reg-
imens more effective and tolerated, Borody et al. [149] evaluated
a high-dose amoxicillin (1.5 g t.i.d.) and pantoprazole (80 mg t.i.d.)
plus a low-dose rifabutin (150 mg o.d.), all for 12 days, in 130 pa-
tients whose Helicobacter pylori infection proved to be resistant to
standard clarithromycin-based triple therapy, achieving 96.6%
eradication rate. Finally, it is worth mentioning that during the past
United European Gastroenterology Week (UEGW), held in Copen-
hagen, October 15–19, 2005, the revised Maastricht Guidelines for
Helicobacter pylori eradication, developed by the European Heli-
cobacter pylori Study Group (EHSG), were presented [150]. Besides
recommending two new indications for eradication, namely iron-
deficiency anemia and idiopathic thrombocytopenia, these guide-
lines emphasized that bismuth-containing quadruple therapy still
remains the best second-line eradication therapy, if available. In
countries where bismuth-containing compounds are not on the
market, the PPI-amoxicillin (or tetracycline)-metronidazole com-
bination is recommended. After further failed eradication attempts,
the treatment is however empiric, mainly based on the previous
therapies and on the availability of microbial susceptibility test-
ing.

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