Helicobacter pylori Regimens Combining Pantoprazole with Clarithromycin,

Transcription

Volume 8 • Number 6 • 2003
H E L I C O B AC T E R
Eradication of Helicobacter pylori by 7-Day Triple-Therapy
Regimens Combining Pantoprazole with Clarithromycin,
Metronidazole, or Amoxicillin in Patients with Peptic Ulcer
Disease: Results of Two Double-Blind, Randomized Studies
Blackwell Publishing Ltd.
Wieslaw J. Bochenek,* Suzanne Peters,* Polly D. Fraga,* Wenjin Wang,* Michael E. Mack,* Michael S. Osato,†
Hala M. T. El-Zimaity, ‡ Kelly D. Davis* and David Y. Graham†
*Wyeth
Research, Philadelphia, PA, USA; †Department of Medicine,VA Medical Center and Baylor College of Medicine, Houston,
TX, USA; ‡The Helicobacter pylori Pantoprazole Eradication (HELPPE) Study Group (see Acknowledgements)
ABSTRACT
Aim. To compare the short-term (7-day) safety and
efficacy of two triple-therapy regimens using pantoprazole with those of two dual-therapy regimens (one
with pantoprazole and one without), for Helicobacter
pylori eradication in patients with peptic ulcer disease.
Methods. H. pylori infection was identified by
rapid urease (CLOtest), and confirmed by histology
and culture. Patients were enrolled into one of two
randomized, double-blind, multicenter, parallel-group
studies. In study A, patients received oral pantoprazole 40 mg, clarithromycin 500 mg, and metronidazole 500 mg (PCM); pantoprazole, clarithromycin
and amoxicillin 1000 mg (PCA); or pantoprazole
and clarithromycin (PC). In study B, patients received
PCM, PCA, PC, or clarithromycin and metronidazole
without pantoprazole (CM). Treatments were given
twice daily for 7 days. H. pylori status after therapy
was assessed by histology and culture at 4 weeks after
completing the course of study treatment. Modified
intent-to-treat (MITT; each study: n = 424, n = 512)
and per-protocol (PP; each study: n = 371, n = 454)
populations were analyzed. The MITT population
comprised all patients whose positive H. pylori status
was confirmed by culture and histology; the PP
population comprised patients who also complied
with ≥ 85% of study medication doses.
Results. A total of 1016 patients were enrolled. Cure
rates among patients with clarithromycin-susceptible
H. pylori strains were 82 and 86% for PCM, and 72
and 71% for PCA, in studies A and B, respectively. Cure
rates among patients with metronidazole-susceptible
H. pylori strains were 82 and 87% for PCM, and 71
and 69% for PCA, in studies A and B, respectively.
The combined eradication rates observed with the
PCM regimen were superior to those of all other
regimens tested. Side-effects were infrequent and mild.
Conclusions. PCM had the highest overall eradication rate in these two studies examining 7-day
treatment regimens. All regimens were safe and well
tolerated.
Keywords. Pantoprazole, Helicobacter pylori, eradication, antibiotics, 7-day triple therapy.
H
ulcer disease are now recommended [5]. Many
noninvasive tests are now available to diagnose
H. pylori infection, including urea breath tests,
serologic tests, and stool antigen tests.
Despite more than 500 independent clinical
studies evaluating eradication therapies, there is
no clear consensus on the ideal H. pylori eradication regimen [6]. Although over 100 different
drug combinations have been used in patients, only
nine dual or triple treatment regimens have received
Food and Drug Administration (FDA) approval
for use in patients with H. pylori-associated peptic
ulcer disease in the United States. Rabeprazole
was recently approved by the FDA for 7-day
elicobacter pylori is a major etiologic
factor in peptic ulcer disease and a risk
factor for the development of gastric cancer [1–3].
The benefits of H. pylori eradication include healing of gastritis, enhanced ulcer healing, reduction
or elimination of ulcer recurrence, and prevention of ulcer disease [4].
Evaluation and (if positive for H. pylori) treatment of patients with dyspepsia or known peptic
Reprint requests to: Dr David Y. Graham, Department of
Medicine, VA Medical Center and Baylor College of
Medicine, 2002 Holcombe Blvd., Room 3 A-320 (111D),
Houston, TX 77030, USA.
© 2003 Blackwell Publishing Ltd, Helicobacter, 8, 626 –642
626
H. pylori Eradication with Pantoprazole/Antibiotic 7-day Triple Therapy
H. pylori eradication triple therapy in conjunction with amoxicillin and clarithromycin [7].
Impact of Pretreatment Antibiotic Resistance
The emergence of resistance to clarithromycin
and to nitroimidazoles such as metronidazole is
predictive of lower cure rates [8]. Variation in the
prevalence and specificity patterns of antibioticresistant H. pylori is related to epidemiologic
factors including geography [9], antibiotic use
patterns, and specific mutation mechanisms
[10–31]. Metronidazole resistance has been cited
as not having significant impact on treatment
outcome [32].
Meyer et al. [33] recently published an analysis
of 20 studies conducted in nine regions of the
United States (n = 3624). Predicted resistance to
metronidazole (1.3 to 46.8%) was most significantly associated with Asian ethnicity (46.8%;
p < .001), in addition to female sex and individual
study, but was not associated with geography.
Predicted risk for clarithromycin resistance
by US geographic region ranged from 3.4 to
11.5%; the highest rates were for north-east
and mid-Atlantic locations, at 11.5 and 10.6%,
respectively. Amoxicillin resistance was rare [33].
Meyer et al. [33] identified age ( p < .001), sex
(p < .001), and geographic region (p = .05) as risk
factors for clarithromycin resistance (overall
predicted resistance ranged from 2.8 to 15.8%).
Osato et al. [34], in a prior and more detailed
analysis of the microbiologic aspects of many of
the same studies, showed that the E-test consistently provided a higher estimate of the prevalence of metronidazole resistance than did agar
dilution; both test methods yielded much more
uniform results for clarithromycin resistance in
both analyses [33,34].
Of these two antibiotic resistance scenarios,
both analyses suggest that resistance to clarithromycin poses the more formidable obstacle in the
treatment of H. pylori infection. Meyer et al. cite
earlier meta-analytic work by Dore et al. [35]
that reported an association between clarithromycin resistance and an average reduction of
55.4% in H. pylori treatment efficacy (CI, 33.2
to 77.6%) [33,35]. Of the 12 analyzed studies
that comprised 501 H. pylori-infected patients
tested for clarithromycin susceptibility, only 33
individuals harbored clarithromycin-resistant
strains [35].
Osato et al. [34] also point out that the presence of clarithromycin resistance is predictive of
627
treatment failure (more so than metronidazole
resistance). In addition, the contribution of clarithromycin to a multidrug H. pylori eradication
regimen is typically nullified in the presence of
clarithromycin resistance, whereas increasing the
dose of metronidazole can overcome resistance
to that antibiotic when it is used in a multidrug
regimen [34].
Multidrug Regimens and Recommendations
The addition of a proton pump inhibitor (PPI)
to antibiotic-containing regimens has generally
been demonstrated to boost H. pylori eradication
rates [36–42]. The Maastricht 2–2000 Workshop
Consensus Report has endorsed the combination
of a PPI, clarithromycin, and metronidazole
as first-line therapy [5] and recommended
second-line treatment consisting of quadruple
therapy with a PPI, bismuth, metronidazole,
and tetracycline in the event of triple-therapy
failure [5].
From 1995 to the present, numerous clinical
study results specific to H. pylori eradication
triple therapy with pantoprazole have been
published [43–67]. Most of these studies have
shown consistent success using triple-therapy
regimens with durations shorter than 14 days (some
≤ 10 days). Many of these studies were conducted
outside the United States, where resistance patterns
may be different [45,48,52,53,56,57,60 – 62,64,65].
Pilotto et al. recently reported an H. pylori
eradication rate of 94% with a triple therapy
consisting of 40 mg pantoprazole, 1000 mg amoxicillin, and 250 mg clarithromycin daily for 7 days
among elderly patients with peptic ulcer disease
in Vicenza, Italy [66]. Other analyses have compared pantoprazole-based combination peptic
ulcer disease therapies with others using
omeprazole [68–74], lansoprazole [69,75], or
rabeprazole [69]. Numerous reports of H. pylori
eradication triple therapy with a PPI and two
antibiotics administered for 5, 7, 10, or 14 days
have shown eradication rates ranging from 67 to
99%, depending in part on the combination of
antimicrobials chosen, the duration of therapy,
the geographic region where the study was conducted, and the presence of resistance [76– 82].
The two present studies compared H. pylorieradication triple therapies with dual therapies
(one dual therapy contained pantoprazole, and
the other did not), in two large populations (mean
ages were 47 and 49 years; Table 1). Outcome
variables included H. pylori eradication rates,
628
Bochenek et al.
Table 1 Baseline demographics in studies A and B for all enrolled patients (intent-to-treat; all patients who were enrolled and
received study medication)
Ethnicity
Status of peptic ulcer disease
History (n)
Active (n)
Mean age (years)
(SD) [range]
Female
n (%)
White
n (%)
Black
n (%)
Hispanic
n (%)
Asian
n (%)
DU
GU
PCU
DU
GU
PCU
Study A
Regimen
PCM (n = 146)
PCA (n = 148)
PC (n = 152)
Total (n = 446)
47 (13) [22–81]
47 (14) [21–81]
48 (15) [20–84]
47 (14) [20–84]
58 (40)
55 (37)
57 (38)
170 (38)
58 (40)
74 (50)
74 (49)
206 (46)
45 (31)
35 (24)
30 (20)
110 (25)
38 (26)
31 (21)
38 (25)
107 (24)
4 (3)
3 (2)
7 (5)
14 (3)
34
20
34
88
22
26
18
66
6
8
3
17
62
65
62
189
45
36
48
129
7
12
7
26
Study B
Regimen
PCM (n = 143)
PCA (n = 144)
PC (n = 144)
CM (n = 139)
Total (n = 570)
48 (14) [19–82]
49 (14) [23–83]
50 (14) [18–83]
51 (15) [21–81]
49 (14) [18–83]
52 (36)
58 (40)
56 (39)
46 (33)
212 (37)
68 (48)
78 (54)
76 (53)
80 (58)
302 (53)
28 (20)
23 (16)
22 (15)
15 (11)
88 (15)
39 (27)
35 (24)
37 (26)
36 (26)
147 (26)
7 (5)
5 (3)
6 (4)
5 (4)
23 (4)
27
30
34
21
112
19
20
20
23
82
1
4
2
4
11
63
66
71
59
259
31
32
24
32
119
7
7
11
9
34
SD, standard deviation; DU, duodenal ulcer; GU, gastric ulcer; PCU, pyloric channel ulcer; P, pantoprazole 40 mg b.i.d.; C, clarithromycin 500 mg b.i.d.; A,
amoxicillin 1000 mg b.i.d.; M, metronidazole 500 mg b.i.d.
No statistically significant differences among treatment groups were detected in either study relative to age, sex, ethnic origin, or baseline ulcer
status.
safety/tolerability, rates of emerging resistance,
and compliance.
Patients and Methods
Objectives
Both studies (A and B) included the following
objectives: (1) to evaluate the safety and efficacy
of a 7-day treatment regimen containing
pantoprazole combined with either clarithromycin plus amoxicillin (PCA) or clarithromycin
plus metronidazole (PCM) in the eradication
of H. pylori infection, and (2) to determine
if either triple therapy provides a benefit
greater than that of a dual therapy consisting of
pantoprazole plus clarithromycin (PC), in patients with peptic ulcer disease who had active
duodenal or gastric ulcers, or a history of such
ulcers.
Study B had the additional objective of
comparing the benefit of PCM with that of
clarithromycin plus metronidazole (CM), i.e.
determining if the addition of pantoprazole
provided a significant, specific advantage over
this dual therapy.
Study Design
Table 1 summarizes baseline demographic parameters for all patients enrolled in both studies.
Both were double-blind, randomized, multicenter,
parallel-group comparisons of 7-day dual thera-
pies with 7-day triple therapies in the eradication
of H. pylori in male and female patients with
peptic ulcer disease.
The studies were conducted at 57 centers (study
A) and 53 centers (study B) in the United States
(excluding Alaska and Hawaii). Both study
protocols were approved by institutional review
boards before the enrollment of patients, and
both studies were conducted in accordance
with the US Code of Federal Regulations and
the Declaration of Helsinki. Each patient was
apprised of all potential risks of study participation, and provided signed informed consent
before enrollment. Each patient participated for
approximately 36 days.
Eligible patients in study A were randomly
assigned to receive pantoprazole 40 mg plus
clarithromycin 500 mg twice daily (PC regimen),
pantoprazole plus clarithromycin plus amoxicillin
1000 mg twice daily (PCA regimen), or pantoprazole plus clarithromycin plus metronidazole
500 mg twice daily (PCM regimen) for 7 days.
Eligible patients in study B were randomly
assigned to receive PC, PCA, PCM, or clarithromycin plus metronidazole twice daily (CM
regimen) for 7 days.
A parallel-group design was used to compare
the safety and efficacy of PCA and PCM to PC
in the eradication of H. pylori infection. The dual
combination of PC provided a control for the
two triple therapies. The CM dual therapy provided a control for the evaluation of PCM only.
The primary endpoint was the eradication rate
of H. pylori in patients with documented infection at baseline. H. pylori infection at baseline
was first determined by positive rapid urease test
and positive histology test results and then
confirmed by positive culture test results. H. pylori
eradication was determined by negative culture
and histology results of tests performed on endoscopic biopsy specimens obtained 4 weeks after
a 7-day course of therapy in patients with either
an active ulcer or a history of gastric, duodenal
or pyloric channel ulcer within the past 5 years,
as defined radiographically or by endoscopy.
Efficacy Assessments and Patient Populations Receiving
Triple and Dual Therapies
Two patient populations, the modified-intentto-treat (MITT) and the evaluable [per-protocol
(PP)] population, were defined to assess primary
efficacy in each study. The intent-to-treat (ITT)
population was defined as all patients who were
randomly assigned to receive treatment and took
any study drug; this population was used to
analyze safety.
The primary efficacy analysis was performed
on the MITT populations, which included all
patients in each study who were randomly
assigned to receive a treatment, had taken at
least one dose of study medication, had only one
active peptic ulcer at baseline or had a history of
peptic ulcer within the last 5 years, and had
H. pylori infection confirmed at baseline by a
positive culture test result (antrum or corpus) or
a positive rapid urease plus ≥ 1 positive histologic test result. This population excluded those
patients who entered the study but whose
H. pylori status was not confirmed by culture
and histology at baseline.
The PP population included patients belonging to the MITT population who, additionally,
did not use prohibited medications, completed
6 or more days of the assigned study regimen
(and took ≥ 85% of the tablets/capsules within
the expected treatment period) or discontinued
for reasons related to study medication, and had
H. pylori status evaluated 4 weeks after the stop
date of the study medication (or had a positive
H. pylori status evaluated after the end of
treatment).
Determination of H. pylori Infection
Each patient considered for enrollment in
either study underwent an endoscopy. Prior to
629
endoscopy, serologic testing by rapid FlexSure
HP whole blood or serum test (EPI Enteric
Products, Inc., Stony Brook, NY) functioned as
a screening method to identify prospective study
patients by probability of positive H. pylori
status.
Endoscopy was performed at the baseline/
screening visit (visit 1). Positive H. pylori status
was determined by any positive culture test
result or by a positive rapid urease test result,
plus any positive histologic test result.
One or two specimens from the antrum of
patients with positive serology results were used
to assess HP status at the site by a rapid urease
test (CLOtest, Tri-Medical Specialties, Inc.,
Ballard Medical/Kimberly Clark, Draper, UT)
at visit 1 (baseline) only. Follow-up eradication
assessment relied on definitive histologic and microbiologic results and did not use rapid urease
testing.
Gastric mucosal biopsies were collected using
large-cup forceps without a needle (Radial Jaw
Large Capacity II, Boston Scientific/ Microvasive,
Natick, MA). Seven or eight gastric mucosal biopsy
specimens were collected at baseline and six gastric
mucosal biopsies were collected at study completion (numbers were based upon a previously
published analysis [83]).
One specimen from the antral lesser curvature,
one specimen from the antral greater curvature,
and two specimens from the corpus were used
for histologic assessment. These specimens were
collected at visit 1 (baseline) and again at visit 3
(4 weeks after treatment).
Histologic specimens were analyzed by the
Gastrointestinal Mucosal Pathology Laboratory
at Baylor College of Medicine, Houston, TX,
using Genta stain and a visual analog scale [84]
to observe and quantify H. pylori infection.
The examining pathologist was unaware of the
patient’s clinical status and of the results of other
tests. The histologic test results were considered
positive if the test grade was ≥ 1 and negative if
the test grade was 0.
For culture, one gastric biopsy specimen was
collected from the antrum 2 cm proximal to the
pylorus, and a second specimen collected from
the middle of the greater curvature (approximately
10 cm distal to the esophagogastric junction).
These specimens were collected at baseline (visit
1) and at the final visit (visit 3). Cultures were
examined to determine the level of non-H. pylori
contamination initially at 1 day, and then daily
after 3 days of incubation.
630
Minimal inhibitory concentration (MIC) values
were determined from agar dilution. Small,
convex, translucent colonies with tiny zones of
β-hemolysis presumptive for H. pylori were
subcultured. H. pylori was identified by positive
reactions for catalase, oxidase, and urease production and by gram stain morphology. MICs
were determined as the lowest concentration of
antibiotic for which there was no visible growth
of a specific isolate. Quality control isolates
(H. pylori ATCC 43504 and ATCC 43579) were
included in each determination. Classification of
the sensitivity status was based on the greater of
the two MIC values obtained from antral and
corpus specimens.
Eradication Criteria
Follow-up endoscopy was performed 4 weeks
after the last dose of study medication. H. pylori
was considered ‘eradicated’ if at least one culture test result and at least one histologic test
result was negative and no other test result was
positive.
The H. pylori status at the 4-week posttreatment follow-up visit (including discontinuations related to study medication) was considered
‘infected’ if it was not ‘eradicated’. For example,
if both culture test results were negative but no
histologic results were available, or if all four
histologic tests were negative but no culture
was available, H. pylori status was considered
infected. Patients whose H. pylori status was
missing at the 4-week post-treatment follow-up
visit or whose test was performed before that
visit were treated as infected.
For the PP population, patients missing an
H. pylori status at the post-treatment follow-up
visit were excluded from the analysis, except for
discontinuations related to the study drug, in
which case the patient’s H. pylori status was considered to be infected. It should be emphasized
that patients with positive results of any H. pylori
diagnostic tests performed before the 4-week
post-treatment follow-up visit were included in
the PP population and were treated as infected.
If a test was performed more than once in the
post-treatment period, the last result was used.
Safety Analyses
Patient safety was monitored through physical
examinations (including performance status and
vital signs), adverse event (AE) surveillance,
Bochenek et al.
laboratory evaluations (complete blood count
with differential, blood chemistry, and urinalysis),
and radiographic and endoscopic assessments.
Safety endpoints were analyzed for the ITT population (all patients who were randomly assigned
to receive any treatment and took any study
medication).
Statistical Analysis
Efficacy for each triple therapy was demonstrated by the superiority of the triple therapy
over the dual therapy in eradication rate, as
shown by the two-sided Fisher exact test at an
alpha level of 0.05.
Approximately 120 patients per treatment
group were planned for each study, to allow for
the completion of approximately 321 patients
(study A) and 428 patients (study B) at approximately 60 centers in each study. Hypothesizing
that the eradication rate was 65% for each of
the dual-therapy groups and 85% for each of
the triple-therapy groups, 107 evaluable patients
per group were needed in order to have 90%
power to show a statistically significant difference between triple therapy and dual therapy at
an alpha level of 0.05 in a two-sided test.
With 107 patients per group and a hypothesized 85% eradication rate, ≥ 95% power would
exist to demonstrate that the lower limit of the
confidence interval (CI) on that rate would
exceed 60%. This would establish a threshold
efficacy level of ≥ 60%.
For safety assessments, the incidences of AEs
were compared among groups using the Fisher
exact test. Mean changes from baseline within
treatment groups for laboratory values and vital
sign measurements were analyzed using the
paired t-test.
Results
Eradication Efficacy of Each 7-Day Regimen
Figures 1 and 2 summarize the eradication rates
observed for each regimen in studies A and B,
respectively. Data are presented in both figures
for the MITT and PP populations. PCM was the
most effective therapy tested in these two studies,
showing consistently and significantly higher
eradication rates than PC or CM.
For the MITT populations, the eradication
rates achieved in the PCM groups were 73%
(95% CI 65–81%) and 81% (95% CI 73–88%)
631
Figure 1 H. pylori eradication rates in study A. The modified intent-to-treat (MITT) population included patients who were
randomly assigned to receive a treatment, had taken at least one dose of the study drug, had only one active peptic ulcer at baseline
or had a history of peptic ulcer ≤ 5 years, and had H. pylori infection confirmed at baseline by a positive culture test result (antrum
or corpus) or a positive rapid urease test result plus at least one positive histologic test result. The per-protocol (PP) population
consisted of MITT population patients who did not use prohibited medications, completed at least 6 days of the assigned study
regimen (at least 85% of the tablets/capsules within the expected treatment period) or were withdrawn for reasons related to
study medication, and had H. pylori status evaluated at 4 weeks after the stop date of the study medication (or had a positive
H. pylori status evaluated after the end of treatment). PCM, pantoprazole 40 mg + clarithromycin 500 mg + metronidazole 500 mg
(all twice daily). PCA, pantoprazole 40 mg + clarithromycin 500 mg + amoxicillin 1000 mg (all twice daily). PC, pantoprazole 40 mg
+ clarithromycin 500 mg (both twice daily). CI, confidence interval (exact binomial method). p-values: compared with PC dual
therapy; two-sided Fisher exact test.
in studies A and B, respectively; those achieved
in the PCA groups were 65% in both studies
(95% CIs 57–73%; 56–73%). These rates were
significantly greater ( p ≤ .001) than those in the
PC groups (46 and 44% [95% CIs 38–54%; 36–
53%]). PCM also eradicated H. pylori at a significantly higher rate than did CM in study B (81
vs. 68% [95% CI 59–76%], p = .02; Fig. 2).
The observed eradication rates were consistently greater with PCM and PCA than with
PC, regardless of the baseline ulcer status. For
patients with only a history of ulcers, eradication
rates achieved with PCM were higher than those
for PCA, though not significantly so. Treatment
with PCA also produced significantly greater
eradication rates than PC dual therapy in the
MITT and the PP populations of both studies
( p ≤ .001).
Efficacy Comparison by Baseline Antibiotic Sensitivity
In general, eradication rates were greater in
patients with isolates demonstrated to be susceptible rather than resistant to specific antibiotics
in vitro. Initial resistance/susceptibility frequencies were similar between the two studies.
Baseline resistance to antibiotics significantly
affected the eradication rate. Baseline resistance
to metronidazole was present in approximately
3 times the number of patients in whom baseline
resistance to clarithromycin was present, and
was associated with low rates of emergence of
metronidazole-resistant H. pylori strains (< 7%).
Hence, even though metronidazole-resistant strains
were more numerous than clarithromycin-resistant
strains at baseline, clarithromycin resistance
emerged in far more patients by the end of the
study, as compared with metronidazole resistance.
Table 2 summarizes treatment outcomes for
each regimen, together with percentages of patients
who at baseline possessed clarithromycin- and
metronidazole-susceptible strains of H. pylori;
Table 3 provides a similar summary for patients who
possessed clarithromycin- and metronidazoleresistant H. pylori strains at baseline.
The development of clarithromycin resistance
was highest in the PC regimen (21 and 22% of
PC patients became resistant in studies A and B,
respectively), whereas clarithromycin and metronidazole resistance in patients who received
the CM regimen developed far less frequently
(7 and 6%, respectively, in study B; eradication
632
Bochenek et al.
Figure 2 H. pylori eradication rates in study B. The modified intent-to-treat (MITT) population included patients who were
randomly assigned to receive a treatment, had taken at least one dose of the study drug, had only one active peptic ulcer at baseline
or had a history of peptic ulcer ≤ 5 years, and had H. pylori infection confirmed at baseline by a positive culture test result (antrum
or corpus) or a positive rapid urease test result plus at least one positive histologic test result. The per-protocol (PP) population
consisted of MITT population patients who did not use prohibited medications, completed at least 6 days of the assigned study
regimen (at least 85% of the tablets/capsules within the expected treatment period) or were withdrawn for reasons related to
study medication, and had H. pylori status evaluated at 4 weeks after the stop date of the study medication (or had a positive
H. pylori status evaluated after the end of treatment). PCM, pantoprazole 40 mg + clarithromycin 500 mg + metronidazole 500 mg
(all twice daily). CM, clarithromycin 500 mg + metronidazole 500 mg (both twice daily). PCA, pantoprazole 40 mg + clarithromycin
500 mg + amoxicillin 1000 mg (all twice daily). PC, pantoprazole 40 mg + clarithromycin 500 mg (both twice daily). CI, confidence
interval (exact binomial method). p-values: acompared with PC dual therapy; two-sided Fisher exact test; bcompared with CM dual
therapy; two-sided Fisher exact test.
Table 2 H. pylori eradication rates among patients with antibiotic-susceptible strains at baseline
Initially
clarithromycin-susceptible HPa
Regimen
PCM
PCA
PC
CM
% HP eradicated
Initially
metronidazole-susceptible HPb
Study A
n
Study B
n
Study A
n (%)
Study B
n (%)
Regimen
101
95
103
84
87
89
86
83 (82)
68 (72)
50 (49)
–
72 (86)
62 (71)
43 (48)
66 (77)
PCM
PCA
PC
CM
% HP eradicated
Study A
n
Study B
n
Study A
n (%)
Study B
n (%)
85
82
78
71
71
76
77
70 (82)
58 (71)
36 (46)
–
62 (87)
49 (69)
34 (45)
57 (74)
HP, Helicobacter pylori; P, pantoprazole 40 mg b.i.d.; C, clarithromycin 500 mg b.i.d.; A, amoxicillin 1 g b.i.d.; M, metronidazole 500 mg b.i.d.
aClarithromycin-susceptible = maximum MIC (minimum inhibitory concentration) ≤ 0.064 µg /ml.
bMetronidazole-susceptible = maximum MIC ≤ 8 µg /ml.
rates of 77 and 74% were still achieved in patients
with initially clarithromycin- and metronidazolesusceptible strains; Table 2). Baseline resistance
to metronidazole had less impact on treatment outcome than did baseline resistance to
clarithromycin.
Although clarithromycin resistance was less
prevalent than metronidazole resistance at baseline,
clarithromycin-resistant H. pylori emerged in 21
and 22% of patients in the MITT population
who had received dual therapy and who tested
as clarithromycin-sensitive at baseline, in study
A and study B, respectively. Emergence of clarithromycin resistance was 7% among CM
patients in study B who tested as clarithromycin
sensitive at baseline.
In contrast, clarithromycin resistance emerged
in ≤ 5% of patients who received any tripletherapy regimen (the highest was 4.8% for PCM,
study B). Eradication rates were much lower
among initially clarithromycin-resistant patients,
ranging from 0 to 50%, as compared with 32 to
73% for the 3-fold larger cohort of initially
metronidazole-resistant patients (Table 3).
633
Table 3 H. pylori eradication rates among patients with antibiotic-resistant strains at baseline
Initially
clarithromycin-susceptible HPa
Regimen
PCM
PCA
PC
CM
% HP eradicated
Initially
metronidazole-susceptible HPb
% HP eradicated
Study A
n
Study B
n
Study A
n (%)
Study B
n (%)
Regimen
Study A
n
Study B
n
Study A
n (%)
Study B
n (%)
11
13
11
–
8
11
12
11
3 (27)
5 (38)
2 (18)
–
4 (50)
2 (18)
0 (0)
2 (18)
PCM
PCA
PC
CM
35
36
40
–
26
33
28
26
22 (63)
21 (58)
17 (43)
–
19 (73)
19 (58)
9 (32)
15 (58)
HP, Helicobacter pylori; P, pantoprazole 40 mg b.i.d.; C, clarithromycin 500 mg b.i.d.; A, amoxicillin 1000 mg b.i.d.; M, metronidazole 500 mg b.i.d.
aClarithromycin-resistant = maximum MIC (minimum inhibitory concentration) > 2 µg /ml.
bMetronidazole-resistant = maximum MIC > 8 µg /ml.
Safety and Tolerability of Each Regimen
AEs observed during treatment were similar in
both studies, and thus the data presented here
from both studies were pooled. Table 4 presents
the most common treatment-emergent adverse
event (TEAEs); (≥ 3% in at least one treatment
group) during the treatment or post-treatment
periods. Overall, without regard to treatment,
the most common TEAEs for both studies combined were taste perversion (13%), diarrhea
(9%), abdominal pain (7%), headache (7%), dyspepsia (6%), and nausea (5%).
There were no clinically relevant changes from
baseline in laboratory values or vital signs during
either study.
Discussion
The results of our studies show the PCM and
PCA combinations to be significantly superior
to PC. PCM was also significantly superior to
CM. These results are consistent with published
reports of triple therapy with a PPI plus clarithromycin and metronidazole or clarithromycin
plus amoxicillin [48,52,54,60,61,85–102].
Meta-analyses evaluating PPI-based H. pylorieradication triple therapies have not reported
any trends toward the superiority of one PPI
over another [103–106], and the choice of PPI is
often based on physician preference. Individual
studies have reported various pantoprazolebased triple-therapy regimens with eradication
rates that are numerically higher [47,52,57,107–
109] or lower [56,110] than those of the present
study. However, the only scientifically valid way
to assess differences among pharmacotherapies
is in a well-designed, head-to-head comparative
study. Recently, such a comparison by Cui et al.
[111] showed numerically (but not statistically)
higher H. pylori eradication rates among small
patient cohorts (n = 26–49) for pantoprazole
than for omeprazole in 1-week and 2-week triple
therapies, all of which contained both amoxicillin
and metronidazole.
Studies comparing pantoprazole with other
PPIs in the healing of duodenal and gastric ulcers
generally have not evaluated H. pylori eradication [69,71,72,74]. In 1995, Rehner et al. compared pantoprazole with omeprazole in the
healing of duodenal ulcers (n = 185 pantoprazole; n = 91 omeprazole), and found the two
agents to be equally effective in healing ulcers
and relieving pain, and to have similar AE
profiles [72]. Previously published results of some
comparative studies show significantly better gastric
ulcer healing at 4 weeks [71] for pantoprazole vs.
omeprazole (each used as monotherapy) [70,71].
The present study demonstrates that pantoprazole is useful as a component of first-line triple
therapy for H. pylori eradication, particularly in
the PCM regimen.
Pantoprazole has recently been studied as part
of second-line H. pylori eradication regimens; it
has been used successfully in European populations in combination with rifabutin as part of
a rescue triple therapy after failure of standard
PPI triple therapy [112]. Interestingly, in a second study [113], these authors also compared the
results they achieved using pantoprazole-based
Maastricht standard second-line quadruple therapy [5] with this experimental triple therapy
containing rifabutin, pantoprazole, and amoxicillin after failure of first-line triple therapy. This
experimental triple therapy produced significantly
superior H. pylori eradication [86.6% (95% CI
76–96%) vs. 66.6% (95% CI 53–80%); p < .025]
and significantly fewer side-effects [9 and 11%
for the two rifabutin-pantoprazole-amoxicillin
triple therapies, vs. 47% for the standard quadruple
634
Bochenek et al.
Table 4 Treatment-emergent adverse events observed in ≥3% of patients in both studies
Treatment regimen
Treatment-emergent
adverse event (TEAE)
PCM
n = 289 (%)
Any TEAE
158 (55)
Abdominal pain
Drug-related
Headache
Drug-related
Constipation
Diarrhea
Drug-related
Dyspepsia
Flatulence
Nauseaa
Drug-related
Duodenal ulcera
Stomach ulcera
LFTs abnormalb
Hyperlipemiaa
Vomiting
Dizziness
Pruritusa
Taste perversion
Drug-related
Urine abnormalitya
20 (7)
15 (5.2)
26 (9)
15 (5.2)
4 (1)
22 (8)
22 (7.6)
17 (6)
4 (1)
15 (5)
10 (3.5)
0
3 (1)
4 (1)
3 (1)
6 (2)
6 (2)
5 (2)
40 (14)
38 (13.1)
5 (2)
PCA
n = 292 (%)
156 (53)
23 (8)
15 (5.1)
18 (6)
9 (3.1)
6 (2)
28 (10)
23 (7.9)
13 (4)
5 (2)
19 (7)
18 (6.2)
7 (2)
11 (4)
0
0
4 (1)
4 (1)
1 (< 1)
30 (10)
28 (9.6)
2 (< 1)
PC
n = 296 (%)
148 (50)
17 (6)
7 (2.4)
17 (6)
11 (3.7)
8 (3)
20 (7)
17 (5.7)
25 (8)
11 (4)
6 (2)
5 (1.7)
7 (2)
4 (1)
0
0
4 (1)
6 (2)
0
39 (13)
39 (13.2)
0
CM
n = 139 (%)
p-valuec
72 (52)
15 (11)
8 (5.8)
15 (11)
7 (5.0)
5 (4)
17 (12)
15 (10.8)
10 (7)
5 (4)
14 (10)
11 (7.9)
0.013
3 (2)
0.012
0.036
6 (4)
6 (4)
0.012
20 (14)
20 (14.4)
0.029
NS
NS
NS
NS
NS
NS
NS
NS
NS
.021
NS
.047
NS
NS
NS
NS
P, pantoprazole 40 mg b.i.d.; C, clarithromycin 500 mg b.i.d.; A, amoxicillin 1000 mg b.i.d.; M, metronidazole 500 mg b.i.d.; LFT, liver function test; NS, not
significantly different.
aSignificantly different in frequency (p < .05, Fisher exact test) among the treatment groups that included P.
bOnly 1 patient, however, had LFT values that were of potential clinical importance (3× upper limit of normal); 6 of 8 patients with elevated LFT values had
them at baseline or had a history of elevated values; of the other 2 patients, the elevated LFT value for 1 resolved without treatment and the other case
was considered by the investigator to be due to a muscle injury.
cThe CM regimen was not included in the statistical analysis because it was only used in study B.
TEAEs significantly different during the treatment period only were nausea, pruritus, and urine abnormality. Abnormal urine color was reported by 5 patients
in the PCM group. Four of the 5 had negative urinalyses. One patient reported a red tint to her urine on treatment day 2. Urinalyses at screening and posttreatment were negative, although trace blood was present at follow-up. Darkened urine has been reported with the use of metronidazole.
therapy (pantoprazole 40 mg twice daily, metronidazole 250 mg 3 times daily, bismuth citrate
240 mg twice daily, and tetracycline 500 mg 4 times
daily); p < .0001] [113]. The success of this
regimen offers a simpler second-line alternative
with fewer pills to ingest [5,113].
Pantoprazole-based quadruple therapy (pantoprazole 40 mg twice daily, colloidal bismuth
subcitrate 120 mg four times daily, tetracycline
500 mg four times daily, and metronidazole 500 mg
three times daily) has also achieved favorable
H. pylori eradication rates when used as standard
second-line therapy (82% by intention-to-treat;
95% CI 75–88%) [114].
Hence, pantoprazole remains a useful alternative in a variety of regimens after the failure of
other PPIs; in combination with rifabutin it also
offers utility in eradicating H. pylori strains that
are resistant to clarithromycin and metronidazole, and has been shown to eradicate H. pylori
strains that survive standard triple therapy
[112,113,115,116].
Not surprisingly, the overall eradication rates
in our study were greater for patients with H. pylori
that was susceptible to the antibiotics at baseline
than for those with specifically resistant H. pylori
at baseline.
Metronidazole resistance emerged at lower rates
in our study than in other studies; consistent with
previous reports [48,56,117,118], metronidazoleresistant H. pylori did not pose a treatment
obstacle, even though it was present in our
study. However, clarithromycin-resistant H. pylori
emerged at much higher rates (consistently 21 to
22% of our MITT population) among patients
with initially clarithromycin-susceptible strains
who received PC, and hampered eradication to
a much greater degree.
Pilotto et al. reported overall secondary resistance rates of 35 and 68% to metronidazole
and clarithromycin, respectively, following 7-day
H. pylori-eradication triple therapy with pantoprazole or omeprazole (and also noted no differences in results between the two PPIs). These
authors expressed the critical need for more
durable antimicrobial H. pylori therapies, to
combat the seemingly relentless development of
antimicrobial resistance in H. pylori [119]. These
results argue in favor of extending the treatment
period beyond 7 days to compensate for the
emergence of clarithromycin resistance, which
occurred at a higher rate than metronidazole
resistance, as it did in our study.
Treatment with PCM was observed to be
significantly superior to PC and CM. Thus, the
addition of pantoprazole to the CM regimen
significantly improved the H. pylori eradication
rate over that seen without pantoprazole (85 vs.
73%; p = .033).
Treatment with PCA was also significantly
superior to PC (p ≤ .001). Baseline sensitivity
from isolate testing was predictive of eradication
outcome in all regimens in both studies, most
strongly so with those containing metronidazole.
The presence of clarithromycin resistance at baseline
appeared to pose a greater overall treatment obstacle
than did resistance to metronidazole. In fact, 73%
(in the PCM group) and 58% (in the CM group)
of isolates from patients with strains initially
resistant to metronidazole showed complete
H. pylori eradication (see Table 3).
Given the rising incidence of antibiotic
resistance in the United States, especially to
clarithromycin, maintaining aggressive and
adequately sustained triple therapy is essential
in all attempts at H. pylori eradication. Tripletherapy duration of 10 to 14 days with pantoprazole has been shown to achieve this objective
[54,57,61,120,121]. Some studies [44,64,66,122–
124] have indicated that pantoprazole 40 mg
twice daily for 7 days is efficacious in eradicating
H. pylori. Interpretation of these results in light
of the resistance issues raised in recent analyses
[33,35], however, suggests that a 10-day to 2-week
regimen using pantoprazole is a more prudent
first-line therapy in US patients with peptic ulcer
disease. The need for highly specific susceptibility testing before starting H. pylori eradication
therapy, especially with clarithromycin, has
also been emphasized [125–128], and is probably
a desirable adjunct to H. pylori eradication
therapy, especially among patients in the United
States.
Acknowledgements
The clinical studies presented in this article were
funded by Wyeth Research, Philadelphia, PA, USA.
635
The authors acknowledge the assistance of Dr Scott
Saunders in the preparation of the manuscript.
Clinical investigators for the HELPPE Study Group
were as follows. Study A: Hector Allende, MD, Sun
Research Associates, San Antonio, TX; Steven Lawrence, MD, Denver VA Medical Center, Denver, CO;
Charles Barish, MD, Wake Research Associates,
Raleigh, NC; Emmet W. Lee, MD, Palomar Medical
Group, Inc., Escondido, CA; Malcolm Berenson,
MD, University of Utah Health Services, Salt
Lake City, UT; Brian L. Bleau, MD, and John D.
Long, MD, University of Cincinnati Medical
Center, Cincinnati, OH; Malcolm Brown, MD, Drug
Research and Analysis Corp., Montgomery, AL;
Peter Meier, MD, VA Medical Center, Gastroenterology Section, Minneapolis, MN; Gustavo A. Calleja,
MD, Gastroenterology Care Center, Miami, FL; Thomas
E. Meister, MD, Division of Gastroenterology,
University of Kentucky Medical Center, Lexington,
KY; Donald Campbell, MD, Kansas City VA Medical
Center, Kansas City, MO; David C. Metz, MD, University of Pennsylvania Medical Center, Gastroenterology Division, Philadelphia, PA; Antonio Caos,
MD, Ocoee, FL; David P. Miller, MD, Birmingham
Gastroenterology Associates, P.C., Birmingham, AL;
Stuart T. S. Chen, MD, Truman Medical Center,
Kansas City, MO; Robert B. Nett, MD, The Institute
for Clinical Research, Inc., San Antonio, TX; Edward
Cheng, MD, Northport VAMC Hospital, Northport,
NY; Ronald Payne, MD, Logan, UT; Gene Chiao,
MD, Indianapolis, IN; David A. Peura, MD, University of Virginia Health Sciences Center, Division of
GI, Charlottesville, VA; Rafal Chojnacki, MD, Saint
Mary of Nazareth Hospital Center, Chicago, IL;
Vijayalakshmi S. V. Pratha, MD, Clinical Applications Laboratories, Inc., San Diego, CA; Delbert L.
Chumley, MD, San Antonio, TX; J. Mark Provenza,
MD, Gastrointestinal Specialists, A.M.C., Shreveport, LA; Dale Collins, MD, Arvada, CO; Robert
Raicht, MD, Veterans Affairs Medical Center, New
York, NY; Jack A. DiPalma, MD, Division of Gastroenterology, University of South Alabama College of
Medicine, Mobile, AL; John Robbins, MD, UC Davis
General Medicine Research Group, Sacramento, CA;
Steven Duckor, MD, Associated Gastroenterology
Medical Group, Clinical Research, Orange, CA;
Jeffrey B. Rosen, MD, Clinical Research of South
Florida, Coral Gables, FL; Charles Duckworth, MD,
Division of Digestive Diseases, Emory University,
Atlanta, GA; Mario Z. Rosenberg, MD, Research
Foundation of America, Los Angeles, CA; Michael S.
Epstein, MD, Annapolis, MD; Sanford Roth, MD,
Arizona Research and Education, Phoenix, AZ; Vincent Stephen Fierro, Jr, DO, Erie, PA; Seymour M.
Sabesin, MD, Rush Presbyterian-St. Luke’s Medical
Center, Chicago, IL; Alvan E. Fisher, MD, Omega
Medical Research, Providence, RI; Atul Shah, MD,
FACG, Prince Frederick, MD; Fred C. Fowler,
MD, Charlotte, NC; Reza Shaker, MD, Froedtert
636
Memorial Lutheran Hospital, Milwaukee, WI; Syam
P. Gaddam, MD, Garden Grove, CA; Thomas J.
Sobieski, MD, McGuire Medical Group, Richmond,
VA; Thomas Gavigan, MD, Presbyterian Hospital
Research and Technology, Charlotte, NC; Stephen
Sontag, MD, Veterans Administration Hospital,
Hines, IL; William V. Harford, Jr, MD, Department
of Veteran Affairs, VA–North Texas Healthcare System, Dallas, TX; David B. Stanton, MD, Community
Clinical Trials, Orange, CA; Wieslaw Ignatowicz, MD,
FACS, Clifton, NJ; Thomas G. Tietjen, MD, Internal
Medicine Group, P.C., Cheyenne, WY; Peter James
Kahrilas, MD, North-western University Medical
School, Chicago, IL; Krishna Tripuraneni, MD,
MBA, FACG, Loxahatchee, FL; Peter N. Kaufman,
MD, Rx Trials, Inc., Silver Spring, MD; Richard
Truesdale, Jr, MD, MediQuest Research Group, Inc.,
Ocala, FL; Thomas Kovacs, MD, CURE Clinic,
VAMC West Los Angeles, Los Angeles, CA; James
D. Wolosin, MD, FACP, Digestive Disease Clinic,
P.C., Jackson, TN; Jay Alan Ladenheim, MD, Sunnyvale, CA; Salam F. Zakko, MD, University of Connecticut Health Center, Farmington, CT; Mark
Lamet, MD, Center for Gastrointestinal Disorders,
Hollywood, FL.
Study B: Richard Albery, MD, Phoenix, AZ; John
Person, MD, Sharp Rees-Stealy Medical Center, San
Diego, CA; Dennis Avner, MD, Salt Lake City, UT;
Vijayalakshmi S. Pratha, MD, Clinical Applications
Laboratories, Inc., San Diego, CA; Thomas Bianchi,
MD, Southern Drug Research Network, Community
Medical Arts Center, Tallassee, AL; Waqar Qureshi,
MD, VA Medical Center/Baylor College of Medicine
GI Service, Houston, TX; Brian L. Bleau, MD,
Tacoma Digestive Disease Center, Tacoma, WA;
Anirudh Rai, MD, Tulane University Medical
Center Section of Gastroenterology, New Orleans,
LA; Antonio Caos, MD, Ocoee, FL; Francisco C.
Ramirez, MD; Carl T. Hayden VA Medical Center,
Phoenix, AZ; Roberto Chiprut, MD, Beverly Hills,
CA; Satish S.C. Rao, MD, University of Iowa Hospitals and Clinics, Iowa City, IA; David C. Chua, MD,
Summit Digestive and Liver Disease Specialists,
Oakbrook Terrace, IL; Adisesha B. Reddy, MD,
Gastroenterology Research and Development Center,
Tuscaloosa, AL; Alan F. Cutler, MD, Sinai Hospital,
Detroit, MI; Dennis S. Riff, MD, Associated Gastroenterology Medical Group, Anaheim, CA; Caroline
T. Diamant, MD, Specialty Medical Clinic, Inc., La
Jolla, CA; Herbert Rubin, MD, Beverly Hills Gastroenterology Institute, Beverly Hills, CA; William
Thomas Dickey, MD, Baylor Medical Center at
Irving (Irving Health Care System), Irving, TX; Lance
Rudolph, MD, Albuquerque, NM; Stephen Fitzgerald, MD, Piedmont Medical Research Associates,
Winston-Salem, NC; Alan V. Safdi, MD, Consultants
for Clinical Research Inc., Cincinnati, OH; Gumaro
Garza, MD, McAllen, TX; Mark Schiele, MD, Health
First Medical Group, P.C., Tigard, OR; Harry I.
Bochenek et al.
Geisberg, MD, MedQuest Inc., Centers for Research,
Greer, SC; Howard I. Schwartz, MD, Miami, FL;
Vernon Hee, MD, The Vancouver Clinic Inc.,
Vancouver, WA; Jerrold Schwartz, MD, North-west
Gastroenterologists, S.C., Arlington Heights, IL;
Thomas P. Hughes, MD, Piedmont Digestive Disease
Associates, Winston-Salem, NC; Nayan R. Shah, MD,
Philip Bean Medical Center, Hollywood, MD; Wieslaw
Ignatowicz, MD, FACS, Clifton NJ; Howard K.
Siegel, MD, Eastside Comprehensive Medical Services, New York, NY; Tom C. Klein, MD, Wichita, KS;
William J. Snape, MD, Long Beach Gastroenterology
Associates, Long Beach, CA; George Koval, MD,
West Hills Gastroenterology Associates, P.C., Portland OR; Eric Alan Steckler, MD, Clinical Research
of West Florida, Clearwater, FL; Richard A. Krause,
MD, Center for Digestive Disorders and Clinical
Research, Chattanooga, TN; Z. Reno Vlahcevic, MD,
McGuire Department of Veterans Affairs Medical
Center, Richmond, VA; Loren Laine, MD, Professor
of Medicine, Division of Gastrointestinal and Liver
Diseases, Keck School of Medicine, University of
Southern California, Los Angeles, CA; James B. Wagonfeld, MD, Digestive Health Specialists, Tacoma,
WA; Mark Lamet, MD, Hollywood, FL; Duane D.
Webb, MD, Duke University Medical Center, Durham, NC; Curtis J. Larson, MD, The Portland Clinic,
LLP, Portland, OR; Stuart M. Weisman, MD, Peninsula GI Medical Group, Redwood City, CA; Michael
S. LeVine, MD, and David Finkelman, MD, Southeast Research Associates, Inc., Austell, GA; L.
Michael Weiss, MD, Clearwater, FL; Paul N. Maton,
MD, Oklahoma City, OK; Barry D. Winston, MD,
Houston, TX; Richard W. McCallum, MD, Division
of Gastroenterology, University of Kansas Medical
Center, Kansas City, KS; Lawrence D. Wruble, MD,
Memphis Gastroenterology Group, P.C., Memphis,
TN; Rao Movva, MD, Moline, IL; Marc J. Zuckerman, MD, Texas Tech University Health Sciences
Center, Department of Medicine, El Paso, TX; Daniel
Pambianco, MD, Charlottesville, VA.
Additional investigators for the HELPPE Study
Group were as follows. Study A: Scott P. Henry, MD,
Erie, PA; Simmy Bank, MD, Long Island Jewish
Medical Center, New Hyde Park, NY; John W. Heaton,
Jr, MD, Veterans Affairs Medical Center, Reno, NV;
Donald Bruns, MD, Fairview Red Wing Clinic, Red
Wing, MN; Paul King, MD, University of Missouri
Hospital and Clinics, Columbia, MO; Florian M.
Cortese, MD, Mercury Street Medical Group, PLLC,
Butte, MT; Michael D. Kurtz, MD, Oceanside, CA;
Kenneth R. DeVault, MD, Mayo Clinic Jacksonville,
Jacksonville, FL; Henry N. Maimon, MD, Dayton
Area Research Associates, Kettering, OH; Steven
Edmundowicz, MD, Allegheny University-Graduate,
Philadelphia, PA; Dale E. Merrell, MD, BorelandGroover Clinic, Jacksonville, FL. Study B: Joel David
Levinson, MD, FACP, FACG, Clifton, NJ; Shameem
M. Ahmed, MD, Summit Gastroenterology Associates,
Inc., Barberton, OH; Richard Redinger, MD, University of Louisville Department of Medicine, Louisville,
KY; William Berry, MD, Longmont, CO; Michael A.
Samach, MD, Affiliates in Gastroenterology, P.A.,
Morristown, NJ; John Orchard, MD, The Mercy
Hospital of Pittsburgh, Pittsburgh, PA; Lewis Strong,
MD, Big Thompson Medical Group, P.C., D/B/A
Aspen Medical Center, Loveland, CO; Ronald E.
Pruitt, MD, Nashville Medical Research Institute,
West Nashville, TN; George Triadafilopoulos, MD,
VA Palo Alto Health Care System, Palo Alto, CA.
References
1 Shiotani A, Nurgalieva ZZ, Yamaoka Y, Graham
DY. Helicobacter pylori. Med Clin North Am
2000;84:1125–36.
2 Welin M, Holmgren NM, Nilsson P, Enroth H.
Statistical model of the interactions between
Helicobacter pylori infection and gastric cancer
development. Helicobacter 2003;8:72–8.
3 Peterson WL. Helicobacter pylori and peptic
ulcer disease. N Engl J Med 1991;324:1043–8.
4 NIH Consensus Conference. Helicobacter pylori
in peptic ulcer disease. NIH Consensus Development Panel on Helicobacter pylori in Peptic
Ulcer Disease. J Am Med Assoc 1994;272:65–9.
5 Malfertheiner P, Megraud F, O’Morain C, et al.
Current concepts in the management of Helicobacter pylori infection – the Maastricht 2–2000
Consensus Report. Aliment Pharmacol Ther
2002;16:167–80.
6 Unge P, Berstad A. Pooled analysis of antiHelicobacter pylori treatment regimens. Scand J
Gastroenterol Suppl 1996;220:27–40.
7 Food and Drug Administration (CDER). Approved
labeling, Application Number 21-456 20-973/S013. Rockville, MD: United States Department
of Health and Human Services, Public Health
Service, FDA, 2003;17 [revised (NEW)].
8 Peterson WL, Graham DY, Marshall B, et al.
Clarithromycin as monotherapy for eradication
of Helicobacter pylori: a randomized, doubleblind trial. Am J Gastroenterol 1993;88:1860–4.
9 Katelaris PH, Nguyen TV, Robertson GJ,
Bradbury R, Ngu MC. Prevalence and demographic determinants of metronidazole resistance
by Helicobacter pylori in a large cosmopolitan
cohort of Australian dyspeptic patients. Austr
NZ J Med 1998;28:633–8.
10 Alarcon T, Domingo D, Prieto N, Lopez-Brea
M. Clarithromycin resistance stability in Helicobacter pylori: influence of the MIC and type of
mutation in the 23S rRNA. J Antimicrob Chemother 2000;46:613–6.
11 Debets-Ossenkopp YJ, Sparrius M, Kusters JG,
Kolkman JJ, Vandenbroucke-Grauls CM. Mechanism of clarithromycin resistance in clinical
12
13
14
15
16
17
18
19
20
21
22
23
637
isolates of Helicobacter pylori. FEMS Microbiol
Lett 1996;142:37–42.
Debets-Ossenkopp YJ, Brinkman AB, Kuipers
EJ, Vandenbroucke-Grauls CM, Kusters JG.
Explaining the bias in the 23S rRNA gene mutations associated with clarithromycin resistance
in clinical isolates of Helicobacter pylori. Antimicrob Agents Chemother 1998;42:2749–51.
Dzierzanowska-Fangrat K, Rozynek E,
Jozwiak P, Celinska-Cedro D, Madalinski K,
Dzierzanowska D. Primary resistance to clarithromycin in clinical strains of Helicobacter
pylori isolated from children in Poland. Int J
Antimicrob Agents 2001;18:387–90.
Goodwin A, Kersulyte D, Sisson G, Veldhuyzen
van Zanten SJ, Berg DE, Hoffman PS. Metronidazole resistance in Helicobacter pylori is due to
null mutations in a gene (rdxA) that encodes an
oxygen-insensitive NADPH nitroreductase.
Mol Microbiol 1998;28:383–93.
Hoffman PS. Antibiotic resistance mechanisms
of Helicobacter pylori. Can J Gastroenterol
1999;13:243–9.
Jenks PJ, Edwards DI. Metronidazole resistance
in Helicobacter pylori. Int J Antimicrob Agents
2002;19:1–7.
Maeda S, Yoshida H. [Detection of Helicobacter
pylori 23S rRNA gene mutation associated with
clarithromycin resistance and its clinical applicability]. Jpn J Clin Med 1999;57:87–92 [in Japanese].
Matsuoka M, Yoshida Y, Hayakawa K, Fukuchi S,
Sugano K. Simultaneous colonisation of Helicobacter pylori with and without mutations in the
23S rRNA gene in patients with no history of
clarithromycin exposure. Gut 1999;45:503–7.
Miwa H, Misawa H, Yamada T, Nagahara A,
Ohtaka K, Sato N. Clarithromycin resistance,
but not CYP2C-19 polymorphism, has a major
impact on treatment success in 7-day treatment
regimen for cure of H. pylori infection: a multiple logistic regression analysis. Dig Dis Sci
2001;46:2445–50.
Occhialini A, Urdaci M, Doucet-Populaire F,
Bebear CM, Lamouliatte H, Megraud F.
Macrolide resistance in Helicobacter pylori: rapid
detection of point mutations and assays of macrolide binding to ribosomes. Antimicrob Agents
Chemother 1997;41:2724–8.
Piana A, Are BM, Maida I, et al. Genotypic
characterization of clarithromycin-resistant
Helicobacter pylori strains. New Microbiol
2002;25:123–30.
Ryan KA, van Doorn LJ, Moran AP, Glennon M,
Smith T, Maher M. Evaluation of clarithromycin
resistance and cagA and vacA genotyping of
Helicobacter pylori strains from the west of
Ireland using line probe assays. J Clin Microbiol
2001;39:1978–80.
Stone GG, Shortridge D, Versalovic J, et al. A
638
24
25
26
27
28
29
30
31
32
33
34
Bochenek et al.
PCR-oligonucleotide ligation assay to determine
the prevalence of 23S rRNA gene mutations
in clarithromycin-resistant Helicobacter pylori.
Antimicrob Agents Chemother 1997;41:712–4.
Szczebara F, Dhaenens L, Vincent P, Husson MO.
Evaluation of rapid molecular methods for
detection of clarithromycin resistance in Helicobacter pylori. Eur J Clin Microbiol Infect Dis
1997;16:162–4.
Taylor DE. Pathophysiology of antibiotic resistance: clarithromycin. Can J Gastroenterol
2000;14:891–4.
Umegaki N, Shimoyama T, Nishiya D, Suto T,
Fukuda S, Munakata A. Clarithromycin-resistance
and point mutations in the 23S rRNA gene in
Helicobacter pylori isolates from Japan. J Gastroenterol Hepatol 2000;15:906–9.
Wang G, Jiang Q, Taylor DE. Genotypic characterization of clarithromycin-resistant and –
susceptible Helicobacter pylori strains from
the same patient demonstrates existence of
two unrelated isolates. J Clin Microbiol
1998;36:2730–1.
Wang G, Taylor DE. Site-specific mutations in
the 23S rRNA gene of Helicobacter pylori confer
two types of resistance to macrolide-lincosamidestreptogramin B antibiotics. Antimicrob Agents
Chemother 1998;42:1952–8.
Versalovic J, Osato MS, Spakovsky K, et al. Point
mutations in the 23S rRNA gene of Helicobacter
pylori associated with different levels of clarithromycin resistance. J Antimicrob Chemother
1997;40:283–6.
van Doorn LJ, Glupczynski Y, Kusters JG, et al.
Accurate prediction of macrolide resistance in
Helicobacter pylori by a PCR line probe assay
for detection of mutations in the 23S rRNA gene:
multicenter validation study. Antimicrob Agents
Chemother 2001;45:1500–4.
van der Ende A, van Doorn LJ, Rooijakkers S,
Feller M, Tytgat GN, Dankert J. Clarithromycinsusceptible and -resistant Helicobacter pylori
isolates with identical randomly amplified polymorphic DNA-PCR genotypes cultured from
single gastric biopsy specimens prior to antibiotic therapy. J Clin Microbiol 2001;39:2648–51.
Graham DY, de Boer WA, Tytgat GN. Choosing
the best anti-Helicobacter pylori therapy: effect
of antimicrobial resistance. Am J Gastroenterol
1996;91:1072–6.
Meyer JM, Silliman NP, Wang W, et al. Risk
factors for Helicobacter pylori resistance in
the United States: the surveillance of H. pylori
antimicrobial resistance partnership (SHARP)
study, 1993–99 [summary for patients in Ann
Intern Med 2002 January 1;136: I-39; PMID.
11797613]. Ann Intern Med 2002;136:13–24.
Osato MS, Reddy R, Reddy SG, Penland RL,
Malaty HM, Graham DY. Pattern of primary
35
36
37
38
39
40
41
42
43
44
45
46
resistance of Helicobacter pylori to metronidazole or clarithromycin in the United States. Arch
Intern Med 2001;161:1217–20.
Dore MP, Leandro G, Realdi G, Sepulveda AR,
Graham DY. Effect of pretreatment antibiotic
resistance to metronidazole and clarithromycin
on outcome of Helicobacter pylori therapy: a metaanalytical approach. Dig Dis Sci 2000;45:68–76.
Schwartz H, Krause R, Sahba B, et al. Triple
versus dual therapy for eradicating Helicobacter
pylori and preventing ulcer recurrence: a randomized, double-blind, multicenter study of
lansoprazole, clarithromycin, and/or amoxicillin
in different dosing regimens. Am J Gastroenterol
1998;93:584–90.
Xiao SD, Liu WZ, Hu PJ, et al. A multicentre
study on eradication of Helicobacter pylori using
four 1-week triple therapies in China. Aliment
Pharmacol Ther 2001;15:81–6.
Andersen LP, Colding H, Kristiansen JE.
Potentiation of the action of metronidazole on
Helicobacter pylori by omeprazole and bismuth
subcitrate. Int J Antimicrob Agents 2000;14:231–
4.
De Francesco V, Zullo A, Hassan C, et al. Two
new treatment regimens for Helicobacter pylori
eradication: a randomised study. Dig Liver Dis
2001;33:676–9.
Goenka MK, Das K, Vaiphei K, Nijhawan R,
Kocbhar R. Helicobacter pylori eradication –
evaluation of triple therapy containing omeprazole. Indian J Gastroenterol 1996;15:1–3.
Grimley CE, Penny A, O’Sullivan M, et al.
Comparison of two 3-day Helicobacter pylori
eradication regimens with a standard 1-week
regimen. Aliment Pharmacol Ther 1999;13:869–
73.
Huang J, Hunt RH. The importance of clarithromycin dose in the management of Helicobacter
pylori infection: a meta-analysis of triple therapies with a proton pump inhibitor, clarithromycin and amoxycillin or metronidazole. Aliment
Vcev A, Vceva A, Kurbel S, et al. Amoxycillin,
clarithromycin and either sucralfate or pantoprazole for eradication of Helicobacter pylori in
duodenal ulcer (a randomized controlled trial).
Wiener Klinische Wochenschrift 2001;113:939–
41.
Bardhan KD, Dillon J, Axon AT, et al. Triple
therapy for Helicobacter pylori eradication: a
comparison of pantoprazole once versus twice
daily. Aliment Pharmacol Ther 2000;14:59–67.
Calabrese C, Di Febo G, Areni A, Scialpi C,
Biasco G, Miglioli M. Pantoprazole, azithromycin and tinidazole: short duration triple therapy
for eradication of Helicobacter pylori infection.
Aliment Pharmacol Ther 2000;14:1613–7.
Catalano F, Catanzaro R, Branciforte G, et al.
47
48
49
50
51
52
53
54
55
56
57
58
Five-day triple therapy in Helicobacter pyloripositive duodenal ulcer: an eighteen-month
follow-up. J Clin Gastroenterol 2000;31:130–
6.
Dammann HG, Folsch UR, Hahn EG, et al.
Eradication of H. pylori with pantoprazole,
clarithromycin, and metronidazole in duodenal
ulcer patients: a head-to-head comparison between
two regimens of different duration. Helicobacter
2000;5:41–51.
Goh K, Parasakthi N, Cheah P, et al. Efficacy of
a 1-week pantoprazole triple therapy in eradicating Helicobacter pylori in Asian patients. J
Gastroenterol Hepatol 2000;15:910–4.
Vcev A, Stimac D, Ivandic A, Vceva A, Takac B,
Pezerovic D. Pantoprazole, amoxycillin and
either azithromycin or clarithromycin for eradication of Helicobacter pylori in duodenal ulcer.
Adamek RJ, Szymanski C, Pfaffenbach B.
Pantoprazole suppresses Helicobacter pylori
without affecting cure. Helicobacter 1999;4:266–
71.
Catalano F, Branciforte G, Catanzaro R, et al.
Comparative treatment of Helicobacter pyloripositive duodenal ulcer using pantoprazole at
low and high doses versus omeprazole in triple
therapy. Helicobacter 1999;4:178–84.
Dajani AI, Awad S, Ukabam S, et al. One-week
triple regime therapy consisting of pantoprazole,
amoxicillin and clarithromycin for cure of Helicobacter pylori-associated upper gastrointestinal
diseases. Digestion 1999;60:298–304.
Lamouliatte H, Samoyeau R, De Mascarel A,
Megraud F. Double vs. single dose of pantoprazole in combination with clarithromycin and
amoxycillin for 7 days, in eradication of Helicobacter pylori in patients with non-ulcer dyspepsia. Aliment Pharmacol Ther 1999;13:1523–30.
Pilotto A, Leandro G, Franceschi M, et al. Rapid
improvement of symptomatology with pantoprazole, amoxycillin and metronidazole in Helicobacter pylori-positive duodenal ulcer patients.
Hepatogastroenterology 1999;46:245–51.
Adamek RJ, Bethke TD. Cure of Helicobacter
pylori infection and healing of duodenal ulcer:
comparison of pantoprazole-based one-week
modified triple therapy versus two-week dual
therapy. The International Pantoprazole HP Study
Group. Am J Gastroenterol 1998;93:1919–24.
Adamek RJ, Pfaffenbach B, Szymanski C. Cure
of H. pylori infection using a 7-day triple therapy
combining pantoprazole with two antibiotics.
Helicobacter 1998;3:206–11.
Bardhan KD, Morton D, Slater DN, et al.
Pantoprazole-based 10-day triple therapy is
effective in Helicobacter pylori eradication.
Dehesa M, Larisch J, Dibildox M, et al. [Com-
59
60
61
62
63
64
65
66
67
68
639
parison of two schedules based on pantoprazole
for eradication of Helicobacter pylori in patients
with active duodenal ulcer]. Revista Gastroenterologia Mexico 1998;63:66–71 [in Spanish].
Ellenrieder V, Fensterer H, Waurick M, Adler G,
Glasbrenner B. Influence of clarithromycin
dosage on pantoprazole combined triple therapy
for eradication of Helicobacter pylori. Aliment
Glaser J, Hein J, Daikeler R, et al. [Short-term
triple therapy with pantoprazole, amoxicillin and
metronidazole in Helicobacter pylori infection].
Med Klinik 1998;93:65–9 [in German].
Louw JA, van Rensburg CJ, Hanslo D,
Grundlings HD, Girdwood AH, Marks IN. Twoweek course of pantoprazole combined with 1
week of amoxycillin and clarithromycin is
effective in Helicobacter pylori eradication and
duodenal ulcer healing. Aliment Pharmacol Ther
1998;12:545–50.
Pazzi P, Scagliarini R, Gamberini S, Matarese V,
Rizzo C, Gullini S. Short-term low-dose
pantoprazole-based triple therapy for cure of
Helicobacter pylori infection in duodenal ulcer
patients. Aliment Pharmacol Ther 1998;12:731–4.
Svoboda P, Kantorova I, Ochmann J, Doubek J,
Kozumplik L, Marsova J. Pantoprazole-based
dual and triple therapy for the eradication of
Helicobacter pylori infection: a randomized controlled trial. Hepatogastroenterology 1997;44:886–
90.
Adamek RJ, Szymanski C, Pfaffenbach B,
Opferkuch W, Ricken D, Wegener M. [Shortterm triple therapy with pantoprazole, clarithromycin and metronidazole for the healing of
Helicobacter pylori infection]. Deutsche Med
Wochenschrift 1995;120:358–60 [in German].
Labenz J, Peitz U, Tillenburg B, Becker T,
Borsch G, Stolte M. [Short-term triple therapy
with pantoprazole, clarithromycin and metronidazole in eradication of Helicobacter pylori].
Leber Magen Darm 1995;25:125–7 [in German].
Pilotto A, Franceschi M, Leandro G, et al. Cure
of Helicobacter pylori infection in elderly
patients: comparison of low versus high doses of
clarithromycin in combination with amoxicillin
and pantoprazole. Aliment Pharmacol Ther
2001;15:1031–6.
Pilotto A, Di Mario F, Franceschi M, et al.
Pantoprazole versus one-week Helicobacter
pylori eradication therapy for the prevention of
acute NSAID-related gastroduodenal damage
in elderly subjects. Aliment Pharmacol Ther
2000;14:1077–82.
Rinaldi V, Zullo A, De Francesco V, et al.
Helicobacter pylori eradication with proton pump
inhibitor-based triple therapies and re-treatment
with ranitidine bismuth citrate-based triple therapy. Aliment Pharmacol Ther 1999;13:163–8.
640
69 Welage LS, Berardi RR. Evaluation of omeprazole,
lansoprazole, pantoprazole, and rabeprazole
in the treatment of acid-related diseases. J Am
Pharmaceut Assoc 2000;40:52–62 [quiz 121–3].
70 Schepp W, Rehner M, Witzel L. A review of
treatment of duodenal and gastric ulcers – pantoprazole vs. omeprazole. Aliment Pharmacol Ther
1994;8:53–7.
71 Witzel L, Gutz H, Huttemann W, Schepp W.
Pantoprazole versus omeprazole in the treatment of acute gastric ulcers. Aliment Pharmacol
Ther 1995;9:19–24.
72 Rehner M, Rohner HG, Schepp W. Comparison
of pantoprazole versus omeprazole in the treatment of acute duodenal ulceration – a multicentre
study. Aliment Pharmacol Ther 1995;9:411–6.
73 Beker JA, Bianchi Porro G, Bigard MA, et al.
Double-blind comparison of pantoprazole and
omeprazole for the treatment of acute duodenal
ulcer. Eur J Gastroenterol Hepatol 1995;7:407–
10.
74 Adamek RJ, Szymanski C, Pfaffenbach B.
Pantoprazole versus omeprazole in one-week
low-dose triple therapy for curve of H. pylori
infection. Am J Gastroenterol 1997;92:1949–50.
75 Cammarota G, Papa A, Cianci R, et al. Threeday antibiotic therapy with azithromycin and
tinidazole plus lansoprazole or pantoprazole to
cure Helicobacter pylori infection: a pilot study.
Eur J Gastroenterol Hepatol 1999;11:247–50.
76 Wurzer H, Rodrigo L, Stamler D, et al. Shortcourse therapy with amoxycillin-clarithromycin
triple therapy for 10 days (ACT-10) eradicates
Helicobacter pylori and heals duodenal ulcer.
ACT-10 Study Group. Aliment Pharmacol Ther
1997;11:943 –52.
77 Yokota H, Kimura T, Kashimura H, Nakahara A,
Tanaka N, Fukutomi H. High dose clarithromycin
in the eradication of Helicobacter pylori infection
[Abstract]. Gastroenterology 1997;112:A279.
78 Schwartz H, Krause R, Siepman N, et al. Seven-day
triple therapy with lansoprazole, clarithromycin,
and metronidazole for the cure of Helicobacter
pylori infection: a short report. Helicobacter
1996;1:251–5.
79 Laine L, Frantz JE, Baker A, Neil GA. A United
States multicentre trial of dual and proton pump
inhibitor-based triple therapies for Helicobacter
pylori. Aliment Pharmacol Ther 1997;11:913–7.
80 O’Connor HJ, McLoughlin R, Kelly S, Laundon J,
Cunnane K. Lansoprazole triple therapy for
Helicobacter pylori – is 5 days enough? Aliment
81 Bazzoli F, Zagari M, Pozzato P, et al. Evaluation
of short-term low-dose triple therapy for the
eradication of Helicobacter pylori by factorial
design in a randomized, double-blind, controlled
study. Aliment Pharmacol Ther 1998;12:439–45.
82 Williamson R, Pipkin GA, Wood JR. New
Bochenek et al.
83
84
85
86
87
88
89
90
91
92
93
options in Helicobacter pylori eradication:
efficacy, resistance and synergy. Scand J Gastroenterol Suppl 1998;225:36–40.
el-Zimaity HM, al-Assi MT, Genta RM,
Graham DY. Confirmation of successful therapy
of Helicobacter pylori infection: number and site
of biopsies or a rapid urease test. Am J Gastroenterol 1995;90:1962–4.
el-Zimaity HM, Graham DY, al-Assi MT, et al.
Interobserver variation in the histopathological
assessment of Helicobacter pylori gastritis. Hum
Pathol 1996;27:35–41.
Vukobrat-Bijedic Z, Lacevic N, Bratovic I,
Gribajcevic M, Gogov B, Radovic S. [Effect of
pantoprazole, amoxicillin and metronidazole
treatment on the level of H. pylori eradication
and the histological image of antral gastritis in
patients with duodenal ulcer]. Med Arhiv
2000;54:21–4 [in Serbo-Croatian].
Frevel M, Daake H, Janisch HD, et al. Eradication of Helicobacter pylori with pantoprazole
and two antibiotics: a comparison of two
short-term regimens. Aliment Pharmacol Ther
2000;14:1151–7.
Treiber G, Ammon S, Schneider E, Klotz U.
Amoxicillin/metronidazole/omeprazole/clarithromycin: a new, short quadruple therapy for
Helicobacter pylori eradication. Helicobacter
1998;3:54–8.
Asaka M, Sugiyama T, Kato M, et al. A multicenter, double-blind study on triple therapy with
lansoprazole, amoxicillin and clarithromycin for
eradication of Helicobacter pylori in Japanese
peptic ulcer patients. Helicobacter 2001;6:254–
61.
Bell GD, Powell KU, Burridge SM, et al. Helicobacter pylori eradication: efficacy and side effect
profile of a combination of omeprazole, amoxycillin and metronidazole compared with four
alternative regimens. Q J Med 1993;86:743–50.
Georgopoulos SD, Ladas SD, Karatapanis S,
et al. Factors that may affect treatment outcome
of triple Helicobacter pylori eradication therapy
with omeprazole, amoxicillin, and clarithromycin.
Dig Dis Sci 2000;45:63–7.
Gisbert JP, Gonzalez L, Calvet X, et al. Proton
pump inhibitor, clarithromycin and either
amoxycillin or nitroimidazole: a meta-analysis
of eradication of Helicobacter pylori. Aliment
Gisbert JP, Mur M, Boixeda D, et al. [One-week
treatment with omeprazole, clarithromycin and
amoxicillin: high efficacy in the eradication of
Helicobacter pylori and cicatrization of duodenal
ulcer]. Med Clin (Barc) 1997;108:524–9 [in
Spanish].
Goh KL, Parasakthi N, Chuah SY, Cheah PL,
Lo YL, Chin SC. Comparison of two 1-week
low-dose omeprazole triple therapies – optimal
94
95
96
97
98
99
100
101
102
103
104
treatment for Helicobacter pylori infection?
Houben MH, Hensen EF, Rauws EA, et al.
Randomized trial of omeprazole and clarithromycin combined with either metronidazole or
amoxycillin in patients with metronidazoleresistant or -susceptible Helicobacter pylori strains.
Isomoto H, Furusu H, Morikawa T, et al. 5-day
vs. 7-day triple therapy with rabeprazole,
clarithromycin and amoxicillin for Helicobacter
pylori eradication. Aliment Pharmacol Ther
2000;14:1619–23.
Kashimura H, Suzuki K, Hassan M, et al.
Polaprezinc, a mucosal protective agent, in
combination with lansoprazole, amoxycillin and
clarithromycin increases the cure rate of Helicobacter pylori infection. Aliment Pharmacol Ther
1999;13:483–7.
Katelaris PH, Patchett SE, Zhang ZW, Domizio P,
Farthing MJ. A randomized prospective comparison of clarithromycin versus amoxycillin in
combination with omeprazole for eradication of
Helicobacter pylori. Aliment Pharmacol Ther
1995;9:205–8.
Kihira K, Satoh K, Saifuku K, et al. Rabeprazole,
amoxycillin and low- or high-dose clarithromycin
for cure of Helicobacter pylori infection. Aliment
Kiyota K, Habu Y, Sugano Y, et al. Comparison
of 1-week and 2-week triple therapy with
omeprazole, amoxicillin, and clarithromycin in
peptic ulcer patients with Helicobacter pylori
infection: results of a randomized controlled trial.
J Gastroenterol 1999;34:76–9.
Wong BC, Chang FY, Abid S, et al. Triple
therapy with clarithromycin, omeprazole, and
amoxicillin for eradication of Helicobacter pylori
in duodenal ulcer patients in Asia and Africa.
Bhasin DK, Sharma BC, Ray P, Pathak CM,
Singh K. Comparison of seven and fourteen days
of lansoprazole, clarithromycin, and amoxicillin
therapy for eradication of Helicobacter pylori:
a report from India. Helicobacter 2000;5:84–7.
Laine L, Suchower L, Frantz J, Connors A, Neil G.
Twice-daily, 10-day triple therapy with omeprazole, amoxicillin, and clarithromycin for
Helicobacter pylori eradication in duodenal
ulcer disease: results of three multicenter, doubleblind, United States trials. Am J Gastroenterol
1998;93:2106–12.
Vallve M, Vergara M, Gisbert JP, Calvet X. Single
vs. double dose of a proton pump inhibitor in
triple therapy for Helicobacter pylori eradication: a meta-analysis. Aliment Pharmacol Ther
2002;16:1149–56.
Dobrucali A, Canbakan B, Canbakan M, et al.
[Meta-analysis of determining the pathogen
105
106
107
108
109
110
111
112
113
114
115
116
117
641
eradicating efficacy of various therapeutic
regimens in Helicobacter pylori infection].
Wien Med Wochenschr 1998;148:464–8 [in
German].
Chiba N, Rao BV, Rademaker JW, Hunt RH.
Meta-analysis of the efficacy of antibiotic
therapy in eradicating Helicobacter pylori. Am J
Gastroenterol 1992;87:1716–27.
Bazzoli F, Pozzato P, Zagari M, et al. Efficacy
of lansoprazole in eradicating Helicobacter pylori:
a meta-analysis. Helicobacter 1998;3:195–201.
Pilotto A, Leandro G, Franceschi M, et al. The
effect of antibiotic resistance on the outcome of
three 1-week triple therapies against Helicobacter
pylori. Aliment Pharmacol Ther 1999;13:667–73.
Thijs JC, Van Zwet AA, Oey HB. Efficacy and
side effects of a triple drug regimen for the
eradication of Helicobacter pylori. Scand J
Gastroenterol 1993;28:934–8.
Ellenrieder V, Boeck W, Richter C, Marre R,
Adler G, Glasbrenner B. Prevalence of resistance
to clarithromycin and its clinical impact on the
efficacy of Helicobacter pylori eradication. Scand
J Gastroenterol 1999;34:750–6.
Perri F, Villani MR, Festa V, Quitadamo M,
Andriulli A. Predictors of failure of Helicobacter
pylori eradication with the standard ‘Maastricht
triple therapy’. Aliment Pharmacol Ther
2001;15:1023–9.
Cui M, Hu F, Jiang H, Zheng X. Comparison of
pantoprazole and omeprazole-based triple therapy regimens in the treatment of Helicobacter
pylori infection. Chung Hua I Hsueh Tsa Chih
[Chinese Med J] 2002;82:1245–8.
Perri F, Festa V, Clemente R, Quitadamo M,
Andriulli A. Rifabutin-based ‘rescue therapy’
for Helicobacter pylori infected patients after
failure of standard regimens. Aliment Pharmacol
Ther 2000;14:311–6.
Perri F, Festa V, Clemente R, et al. Randomized
study of two ‘rescue’ therapies for Helicobacter
pylori-infected patients after failure of standard
triple therapies. Am J Gastroenterol 2001;96:58–
62.
Boixeda D, Bermejo F, Martin-De-Argila C,
et al. Efficacy of quadruple therapy with
pantoprazole, bismuth, tetracycline and metronidazole as rescue treatment for Helicobacter
pylori infection. Aliment Pharmacol Ther
2002;16:1457–60.
Gisbert JP, Pajares JM. Helicobacter pylori ‘rescue’ regimen when proton pump inhibitor-based
triple therapies fail. Aliment Pharmacol Ther
2002;16:1047–57.
Perri F, Festa V, Andriulli A. Treatment of
antibiotic-resistant Helicobacter pylori. N Engl
J Med 1998;339:53.
Wongkusoltham P, Vilaichone RK, Kullavanijaya P, Phaosawadi K, Mahachai V. Eradication
642
118
119
120
121
122
Bochenek et al.
rates of Helicobacter pylori between metronidazolesensitive and metronidazole-resistant strains with
metronidazole containing regimen in Thai patients
with peptic ulcer disease. J Med Assoc Thai
2001;84:S474–80.
Adamek RJ, Suerbaum S, Pfaffenbach B,
Opferkuch W. Primary and acquired Helicobacter
pylori resistance to clarithromycin, metronidazole,
and amoxicillin – influence on treatment outcome. Am J Gastroenterol 1998;93:386–9.
Pilotto A, Franceschi M, Rassu M, et al. Incidence
of secondary Helicobacter pylori resistance to
antibiotics in treatment failures after 1-week
proton pump inhibitor-based triple therapies: a
prospective study. Dig Liver Dis 2000;32:667–72.
Cilleruelo Pascual ML, Urruzuno Telleria P,
Roman Riechman E, et al. [Triple-therapy treatment during 1 month versus 2 weeks in gastroduodenal disease due to Helicobacter pylori
in children]. An Esp Pediatr 1996;44:456–60 [in
Spanish].
Maconi G, Parente F, Russo A, Vago L, Imbesi V,
Porro GB. Do some patients with Helicobacter
pylori infection benefit from an extension to 2
weeks of a proton pump inhibitor-based triple
eradication therapy? Am J Gastroenterol
2001;96:359–66.
Gisbert JP, Marcos S, Gisbert JL, Pajares JM.
Helicobacter pylori eradication therapy is more
effective in peptic ulcer than in non-ulcer dys-
123
124
125
126
127
128
pepsia.[comment]. Eur J Gastroenterol Hepatol
2001;13:1303–7.
Boixeda D, Martin De Argila C, Bermejo F,
Lopez-Sanroman A, Hernandez Ranz F,
Garcia Plaza A. Seven-day proton pump inhibitor,
amoxicillin and clarithromycin triple therapy.
Factors that influence Helicobacter pylori eradication success. Revista Española Enfermedades
Digestivas 2003;95:202–9.
Malfertheiner P, Kirchner T, Kist M, Leodolter
A, Peitz U, et al. Helicobacter pylori eradication
and gastric ulcer healing – comparison of three
pantoprazole-based triple therapies. Alim Pharmacol Ther 2003;17:1125–35.
Megraud F, Occhialini A, Doermann HP.
Resistance of Helicobacter pylori to macrolides
and nitroimidazole compounds. The current
situation. J Physiol Pharmacol 1997;48:25–38.
Kato S, Fujimura S, Udagawa H, et al. Antibiotic
resistance of Helicobacter pylori strains in
Japanese children. J Clin Microbiol 2002;40:649–
53.
Megraud F, Lehn N, Lind T, et al. Antimicrobial
susceptibility testing of Helicobacter pylori in a
large multicenter trial: the MACH 2 study. Antimicrob Agents Chemother 1999;43:2747–52.
Hoshiya S, Watanabe K, Tokunaga K, et al.
Relationship between eradication therapy and
clarithromycin-resistant Helicobacter pylori in
Japan. J Gastroenterol 2000;35:10–4.

Helicobacter pylori Regimens Combining Pantoprazole with Clarithromycin,

Transcription

Similar documents

Previous macrolide exposure H. pylori success at risk choose PYlera® capsules plus omeprazole

H. pylori

Document 6446742

Dan Kalish - 4.22.16 H. Pylori PPT

G U I D E L I N E S ... ADVISORY COMMITTEE Helicobacter pylori Scope

H. pylori Therapeutic Class Review (TCR) January 21, 2013

Treatment of Helicobacter pylori

HELICOBACTER PYLORI ABDOMINAL PAIN