Full text of DOI:10.2165/00044011-200222020-00002

Clin Drug Invest 2002; 22 (2): 75-85
1173-2563/02/0002-0075/$25.00/0
ORIGINAL RESEARCH ARTICLE
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Comparison of Three 7-Day
Pantoprazole-Based Helicobacter pylori
Eradication Regimens in a Mexican
Population with High Metronidazole
Resistance
M. Dehesa,1 J. Larisch,1 M. Dibildox,2 M. Di Silvio,2 L.H. Lopez,2 E. Ramirez-Barba3
and J. Torres4
1
2
3
4
Hospital Especialidades, Centro Médico Nacional Siglo XXI IMSS, Mexico
Investigación Clínica, BYK Gulden, Mexico
Unidad de Investigación, Facultad de Medicina, Universidad de Guanajuato, Mexico
Unidad de Investigación en Enfermedades Infecciosas, Centro Médico Nacional Siglo XXI, IMSS,
Hospital de Pediatría, Mexico
Abstract
Objective: To compare the efficacy and tolerability of three 7-day pantoprazole-
based regimens to eradicate Helicobacter pylori in Mexican patients with peptic
ulcer (PU) or non-ulcer dyspepsia (NUD).
Background: Short-term therapeutic regimens based on a proton pump inhibitor
(PPI) and two antibiotics have been recommended for the eradication of H. pylori.
Resistance of H. pylori to metronidazole may adversely affect the efficacy of such
regimens.
Patients and methods: This was a single-centre, randomised, open-label, parallel-
group study in which three groups of H. pylori-positive patients with PU or NUD
were compared (n = 159; intention-to-treat population). Patients were randomised
to receive a 7-day pantoprazole-based triple therapy for eradication of H. pylori.
Patients received pantoprazole (P) 40mg twice daily in combination with either
i) amoxicillin (A) 1000mg twice daily and clarithromycin (C) 500mg three times
daily (PAC regimen, n = 51 patients), or ii) clarithromycin 500mg three times daily
and metronidazole (M) 500mg three times daily (PCM regimen, n = 55 patients), or
iii) amoxicillin 1000mg twice daily and metronidazole 500mg three times daily
(PAM regimen, n = 53 patients). After completing eradication therapy, all
PU patients were further treated with once-daily pantoprazole 40mg, either for
another 3 weeks (patients with duodenal ulcer) or for another 7 weeks (patients
with gastric ulcer), to ensure complete ulcer healing. At baseline examination, all
patients underwent the 14C-urea breath test and endoscopy; biopsy specimens
were taken for histology, CLO-test, H. pylori culture and antibiotic susceptibility
testing (agar dilution E-test). Eradication of H. pylori was assessed after all treat-

76
Dehesa et al.
ment with pantoprazole had been discontinued for at least 4 weeks, using the
14C-urea breath test.
Results: In the per-protocol population (n = 153), eradication was achieved in
81.3% (39/48) of patients receiving PAC, 66.0% (35/53) of PCM recipients, and
48.1% (25/52) of those receiving PAM (p = 0.13 for PAC vs PCM and 0.001 for
PAC vs PAM). In the intention-to-treat population, respective eradication rates
were 76.5 (39/51), 63.6 (35/55) and 47.2% (25/53) [p = 0.22 for PAC vs PCM
and 0.004 for PAC vs PAM]. Patient compliance was very good in all treatment
groups. The main adverse event affecting 40% of all patients was a metallic taste,
assessed as likely related to the antibiotics. Susceptibility to the three study
antibiotics was determined for H. pylori isolates using the pretreatment biopsies
from 103 patients. Resistance to metronidazole was present in 68.2% of patients
and to clarithromycin in 24.3%. In 16.8% of patients, H. pylori isolates were
resistant to both metronidazole and clarithromycin. In patient populations with
H. pylori strains resistant to one or both of the antibiotics used in the respective
treatment regimen, eradication rates were consistently lower than in those with
susceptible H. pylori strains. However, these differences were not statistically
significant, probably due to the small sample size.
Conclusions: The 7-day H. pylori eradication regimen with PAC was superior to
PCM and PAM. This is probably due to the high resistance rate to metronidazole
in the Mexican population. Thus, H. pylori eradication regimens that involve
metronidazole cannot be recommended for Mexican patients. Results from this
study highlight the regional differences in efficacy of some well established
H. pylori eradication regimens, and suggest that culture and susceptibility testing
to define H. pylori resistance patterns in specific geographical areas may be
indicated before recommending any particular eradication schedule.
About 90 to 95% of patients with duodenal ulcer
of 80 to 90%), show good compliance and toler-
ability, and are economical.[6-9]
and 75% of patients with gastric ulcer are positive
for Helicobacter pylori. There is now general
agreement that all patients who are diagnosed with
peptic ulcer and are positive for H. pylori should
have the infection eradicated, because this would
significantly reduce the incidence of recurrent
duodenal or gastric ulcers.[1-5]
Worldwide, the reported resistance to amoxi-
cillin is low,[10] whereas resistance to macrolides,
such as clarithromycin, ranges globally from 0 to
15%.[11-13] The resistance to metronidazole also
shows clear geographical differences with a prev-
alence ranging from 10 to 80%.[14-16]
Numerous regimens are being used for the
eradication of H. pylori, but high eradication rates
claimed in one geographical region are often not
reproduced in another region.[17,18] One reason for
this could be regional differences in H. pylori
strains and their resistance to antibiotics. Indeed,
primary or secondary (acquired) resistance to
clarithromycin and metronidazole is a major ob-
stacle for successful eradication therapy and
thus could have a considerable negative impact on
Over the last decade, numerous eradication
regimens for H. pylori have been evaluated. These
include various combinations of selected drugs
administered at different times, frequencies and
doses, and for varying durations. Eradication
regimens involving two antibiotics and a proton
pump inhibitor (known as ‘triple therapy’) are the
most widely accepted regimens, since they have
proven to be highly efficacious (eradication rates
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Clin Drug Invest 2002; 22 (2)

H. pylori Eradication and Metronidazole Resistance
77
the clinical outcome of diseases aggravated by
H. pylori.[11,12,19-21]
Patients were considered positive for H. pylori if
values were ≥150 dpm. The presence of infection
was confirmed by a positive rapid urease test on
two gastric biopsies obtained from the antrum and
corpus.
At baseline, all patients had endoscopically
confirmed peptic ulcer or non-ulcer dyspepsia.
Another requirement for inclusion was the
presence of dyspepsia symptoms such as epigastric
pain (during day- and/or night-time), vomiting,
nausea, retching, acid regurgitation and/or heart-
burn during the previous 3 days.
Exclusion criteria in patients were previous
H. pylori eradication treatment, a known allergy to
the study drugs (pantoprazole, amoxicillin, metro-
nidazole or clarithromycin), or the presence of
malignant diseases. During the study, patients were
not allowed to take any drugs with pH-dependent
absorption characteristics, glucocorticoids, non-
steroidal anti-inflammatory drugs or drugs that are
known to potentially interact with any of the study
medications.
The study was conducted in accordance with
Good Clinical Practice guidelines based on the
Declaration of Helsinki and subsequent revisions.
The Ethics Committee of the Hospital De Especial-
idades, Centro Médico Nacional Siglo XXI,
Instituto Mexicano del Seguro Social, approved
the study. Informed consent to participate in the
study was documented by signatures obtained
from the treating physician and either the patient
or an independent witness.
Pantoprazole-based H. pylori eradication
schemes involving various combinations of anti-
biotics achieve eradication rates of 85 to 100% in
European and South African patient popula-
tions.[22-24] In Mexico, as well as in the USA,
eradication of H. pylori is recommended in patients
with peptic ulcer. However, data on the eradication
rates of H. pylori in Mexican patients are scarce.
In a previous study involving 74 Mexican patients,
76% of H. pylori strains isolated were resistant to
metronidazole in vitro.[14] In the clinical study
presented here, the efficacy of three pantoprazole-
based 7-day H. pylori eradication regimens was
compared in patients from Mexico to determine
whether the high resistance level in H. pylori
strains has any influence on the efficacy of various
H. pylori eradication regimens.
Patients and Methods
Patients and Study Design
This was a single-centre, randomised, open-
label, parallel-group comparative study. Both male
and female patients, aged 18 to 75 years, were re-
cruited; all patients were positive for H. pylori
infection. This was ascertained by a 14C-urea breath
test, using the commercially available PY test® kit
(capsule of 1μCurie of 14C-UBT and a milliar
balloon; Tri Med Specialties Inc., USA) and
collecting breath samples in the milliar balloon
10 minutes after ingestion of the capsule. Breath
samples were analysed with a liquid scintillation
counter (beta microcounter® mod: 9605; Tri Med
Specialties Inc., USA), with 14CO2 concentrations
expressed as disintegrations per minute (dpm).
Treatment Regimens
The three H. pylori eradication regimens
studied (PAC, PAM and PCM) are summarised in
table I. In all three-treatment groups, patients re-
Table I. Pantoprazole-based eradication regimens used for 7 days to eradicate Helicobacter pylori in patients with peptic ulcers or non-ulcer
dyspepsia
Drug/treatment regimen
Pantoprazole (P)
PAC
PAM
PCM
40mg bid
1000mg bid
500mg tid
NIL
40mg bid
1000mg bid
NIL
40mg bid
NIL
Amoxicillin (A)
Clarithromycin (C)
500mg tid
500mg tid
Metronidazole (M)
500mg tid
bid = twice daily; tid = three times daily.
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Clin Drug Invest 2002; 22 (2)

78
Dehesa et al.
ceived the eradication therapy for 7 days. Clari-
thromycin and metronidazole were taken three
times daily. In keeping with most published triple
therapies involving amoxicillin,[24] and to improve
patient compliance, amoxicillin was taken only
twice daily. To ensure ulcer healing, patients with
peptic ulcers previously diagnosed at baseline re-
ceived an additional treatment course with
pantoprazole 40mg once daily for a further 3 weeks
(patients with duodenal ulcer) or for a further
7 weeks (patients with gastric ulcer) after the end
of the eradication therapy.
Laboratory Parameters
At baseline, blood samples were used to
determine leucocyte, erythrocyte, platelet, haemo-
globin concentrations, and to do a haematocrit;
serum concentrations of total bilirubin, γ-glutamyl
transpeptidase, AST, ALT, urea, alkaline phospha-
tase, creatinine and glucose were also determined.
(The study design did not include any follow-up of
laboratory parameters.)
Statistics
Assessment of Treatment Efficacy
and Safety
Based on a two-sided test at the 5% level of
significance and 80% power, it was estimated that
50 per-protocol patients in each treatment group
would be sufficient to detect a 15% difference in
the eradication of H. pylori (Fisher’s exact test was
used as an approximation of the Cochran-Mantel-
Haenszel test).
The primary efficacy variable was eradication
of H. pylori as determined after all treatment with
pantoprazole had been discontinued for at least
4 weeks. To compare eradication rates in the three
different treatment groups, the Cochran-Mantel-
Haenszel test was used. Baseline comparison of
the different treatment groups with regard to the
anthropometric data, such as age, height, body-
weight and body mass index, was undertaken using
the Mann-Whitney U-test. For the comparison of
the dichotomous parameters (gender, smoking
behaviour), Fisher’s exact one-tailed test was used.
Differences at the p < 0.05 level were considered
statistically significant.
Efficacy of the three eradication regimens was
evaluated, using the 14C-urea breath test, after all
treatment with pantoprazole had been discontinued
for at least 4 weeks. Values of <150 dpm were
considered negative, thus indicating successful
eradication of H. pylori. No follow-up endoscopies
were carried out.
Safety of the study medications was assessed
after the eradication treatment, and, if appropriate,
after the antiulcer treatment. Any reported adverse
event was assessed by the investigators as either
‘not related’, ‘unlikely related’, ‘likely related’, or
‘definitely related’ to the antibiotics used in the
treatment regimens or to pantoprazole.
Microbiology
Two antrum and two corpus biopsies were taken
for microbiological culture and antibiotic suscep-
tibility testing during the initial endoscopy at
baseline (before eradication treatment). Both
non-selective and selective culture media were
used.[25] Susceptibility to antibiotics (metronida-
zole, clarithromycin, amoxicillin) was determined
by Epsilometry test (E-Test A-B Biodisc, Sweden)
using Columbia agar plates supplemented with 7%
horse blood and incubated in a microaerophilic
atmosphere for 72 hours.[26]
Both the intention-to-treat and per-protocol
patient populations were evaluated. The intention-
to-treat population included all patients for whom
it could not be excluded that they ingested at least
one dose of the study medication. This population
was used for the statistical analysis of demographic
data, baseline comparisons, tolerability and safety.
The per-protocol population included all patients
who: i) completed the entire treatment regimen
according to the protocol, or ii) discontinued from
the study due to adverse events that were assessed
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Clin Drug Invest 2002; 22 (2)

H. pylori Eradication and Metronidazole Resistance
79
to be ‘likely’ or ‘definitely’ related to the study
medication.
Intention-to-treat
population
n = 159
Protocol violators were defined as patients:
i) whose findings from the initial examination
later suggested the presence of a serious disease;
ii) whose breath test (subsequent to a positive rapid
urease test) revealed that they were H. pylori
negative; iii) who were prematurely withdrawn
from the study, either due to adverse events that
the investigator considered unrelated to the study
medication or for any other reason apparently un-
related to the test medication; iv) who deviated
considerably from the protocol (e.g. low com-
pliance, that is, intake of less than 6 days of triple
therapy, deviated from scheduled visits or did not
present at the scheduled control examinations);
v) with premature termination for other reasons
apparently not causally related to the study medi-
cation.
Per-protocol
population
n = 153
(NUD = 113)
(PU = 40)
PAC
n = 51
PAM
n = 53
PCM
n = 55
Protocol
violator
n = 3
Protocol
violator
n = 1
Protocol
violator
n = 2
Fig. 1. Disposition of patients enrolled in the Helicobacter pylori
eradication study.
P = pantoprazole; A = amoxicillin; C = clarithromycin; M = metro-
nidazole; NUD = non-ulcer dyspepsia; PU = peptic ulcer.
Results
A total of 159 patients were enrolled,
randomised and treated (intention-to-treat popula-
tion). Of these, 153 patients completed the study
according to protocol (per-protocol population).
Endoscopic examination at baseline revealed that
113/153 (74%) of patients had non-ulcer dyspepsia
(NUD) and 40/153 (26%) had peptic ulcer (PU).
There was a total of six protocol violators who
left the study prematurely for personal reasons
(figure 1).
the reference ranges and no differences were seen
among the three treatment groups. Compliance
with treatment was better than 90% in all three
groups.
Baseline Assessment of Antibiotic
Susceptibility
The treatment groups were comparable at
baseline with respect to demographic and anthro-
pometric data (table II). The median values of the
tested laboratory parameters, determined at the
beginning of the study, showed no deviation from
H. pylori was successfully cultured from
the pretreatment biopsies of 107 patients and
recultured for antibiotic susceptibility testing.
In four patients, the resistance status could not be
determined because of the inability to reculture the
Table II. Demographic and anthropometric data for the patients treated with PAC, PCM or PAM (intention-to-treat population)
Parameter/treatment regimen
No. of patients (F/M)
PAC
51 (25/26)
PAM
53 (28/25)
PCM
55 (25/30)
48 [20-74]
162 [146-185]
70 [42-96]
25.7 [16-38.5]
Median age (years) [range]
Median height (cm) [range]
Median weight (kg) [range]
Median body mass index (kg/m2) [range]
49 [22-78]
162 [134-178]
68.5 [45-101]
25.5 [18.6-37.9]
50 [ 20-75]
162 [134-178]
68 [40-98]
25.6 [17.1-36.8]
P = pantoprazole; A = amoxicillin; C = clarithromycin; M = metronidazole.
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Clin Drug Invest 2002; 22 (2)

80
Dehesa et al.
isolate. In the remaining 103 patients, pretreatment
resistance to metronidazole occurred in 68.2% and
to clarithromycin in 24.3%. In 16.8% of patients,
H. pylori isolates were actually resistant to both
metronidazole and clarithromycin. There was no
resistance to amoxicillin. Only 20.6% of patients
had H. pylori isolates susceptible to all three anti-
biotics. [Three patients were later excluded from
the study due to a negative 14C-urea breath test (one
case) or the presence of malignancies.]
tested for the presence of the infection using the
14C-urea breath test. Eradication rates and 95%
confidence intervals (CI) for the per-protocol and
intention-to-treat populations are summarised in
table III. In both populations, the best eradication
results were achieved with the PAC regimen. While
these eradication rates were considerably higher
than those achieved with the other two regimens,
only the comparison with the PAM results was
statistically significant (p < 0.005, in both the
per-protocol and intention-to-treat populations).
Subgroup analysis according to the initial
diagnosis of peptic ulcer or non-ulcer dyspepsia
revealed that eradication rates tended to be higher
Efficacy of H. Pylori Eradication Regimens
After all treatment with pantoprazole had been
discontinued for at least 4 weeks, patients were
Table III. Eradication rates in the per-protocol and intention-to-treat populations of the three treatment groupsa
Treatment regimen
n
Helicobacter pylori eradication (%) 95% confidence interval
Per-protocol population
PAC
PAM
PCM
48
52
53
81.3
48.1
66.0
70.2-92.2
34.4-61.7
53.2-78.7
Intention-to-treat population
PAC
PAM
PCM
51
53
55
76.5
47.2
63.6
64.8-88.1
33.7-60.6
50.9-76.3
a
For the per-protocol population, PAC vs PCM, the odds ratio was 0.45 [95% confidence interval (CI) 0.18 to 1.13], Mantel-Haenszel
chi-square test was 2.25 p = 0.13. In the comparison of PAC vs PAM, the odds ratio was 0.21 (95%CI 0.09 to 0.54) Mantel-Haenszel
chi-square test 10.52 p = 0.001. For the intention-to-treat population: PAC vs PCM, the odds ratio was 0.54 (95% CI 0.23 to 1.26),
Mantel-Haenszel chi-square 1.50 p = 0.22); PAC vs PAM, odds ratio 0.27 (95% CI 0.12 to 0.65), Mantel-Haenszel chi-square 8.23
p = 0.004.
P = pantoprazole; A = amoxicillin; C = clarithromycin; M = metronidazole.
Table IV. Eradication rates of Helicobacter pylori, according to diagnosis and treatment regimen, for the per-protocol population
Regimen (no. of patients)
Eradication rate (%) [95% CI] in patients with
NUD
peptic ulcer
PAC (n = 48)
PAM (n = 52)
PCM (n = 53)
Total (n = 153)
74 [59-90] (n = 31)
45 [29-62] (n = 38)
66 [52-80] (n = 44)
61 [52-70] (n = 113)
p-Value
94 [71-100] (n = 17)
57 [29-82] (n = 14)
67 [29-93] (n = 9)
75 [62-88] (n = 40)
NUD
peptic ulcer
0.044
PAC vs PAM
0.026
PAC vs PCM
0.61
0.20
NUD vs peptic ulcer
PAC vs PAC
0.19
Total vs Total
0.16
CI = confidence interval; NUD = non-peptic ulcer; P = pantoprazole; A = amoxicillin; C = clarithromycin; M = metronidazole.
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Clin Drug Invest 2002; 22 (2)

H. pylori Eradication and Metronidazole Resistance
81
Table V. Eradication rates according to the antibiotic susceptibility of Helicobacter pylori isolates
Regimen
(no. of patients)
Eradication rate (%) [95% CI] in patients with H. pylori strains
resistant to metronidazole resistant to metronidazole and resistant to clarithromycin susceptible to all study
clarithromycin
antibiotics
Per-protocol population
PAC (n = 32)
84 [60-97] (n = 16/19)
42 [15-72] (n = 5/12)
50 [27-73] (n = 10/20)
61 [46-74] (n = 31/51)
p-Value
80 [28-100] (n = 4/5)
43 [10-82] (n = 3/7)
50 [6.8-93] (n = 2/4)
61[30-80] (n = 9/16)
67 [9.4-99] (n = 2/3)
67 [9.4-99] (n = 2/3)
100 [16-100]) (n = 2/2)
75 [35-97] (n = 6/8)
80 [28-100] (n = 4/5)
56 [21-86] (n = 5/9)
83 [36-100] (n = 5/6)
70 [43-88] (n = 14/20)
PAM (n = 31)
PCM (n = 32)
Total (n = 95)
resistant to metronidazole resistant to metronidazole and resistant to clarithromycin susceptible to all study
clarithromycin
antibiotics
PAC vs PAM
PAC vs PCM
0.038
0.054
0.49
0.39
0.81
0.74
0.81
0.52
Resistant vs susceptible
PAC vs PAC
PAM vs PAM
PCM vs PCM
Total vs Total
0.65
0.43
1.0
0.67
0.74
0.54
0.84
0.85
0.33
0.65
0.67
0.61
Regimen
(no. of patients)
Eradication rate (%) [95% CI] in patients with H. pylori strains
resistant to metronidazole resistant to metronidazole and resistant to clarithromycin susceptible to all study
clarithromycin
antibiotics
Intention-to-treat population
PAC (n = 35)
PAM (n = 32)
PCM (n = 33)
Total (n = 100)
73 [50-90] (n = 16/22)
80 [28-100] (n = 4/5)
43 [8.5-76] (n = 3/8)
50 [0.8-93] (n = 2/4)
53 [28-77] (n = 9/17)
67 [9.4-99] (n = 2/3)
67 [9.4-99] (n = 2/3)
100 [16-100] (n = 2/2)
75 [35-97] (n = 6/8)
80 [28-100] (n = 4/5)
56 [21-86] (n = 5/9)
71 [29-96] (n = 5/7)
67 [43-85] (n = 14/21)
42 [15-72] (n = 5/12)
50 [27-73] (n = 10/20)
57 [43-71] (n = 31/51)
p-Value
resistant to metronidazole resistant to metronidazole and resistant to clarithromycin susceptible to all study
clarithromycin
antibiotics
PAC vs PAM
PAC vs PCM
0.23
0.16
0.36
0.39
0.81
0.74
0.81
0.74
Resistant vs susceptible
PAC vs PAC
PAM vs PAM
PCM vs PCM
Total vs Total
0.82
0.43
0.80
0.95
0.60
0.67
0.74
0.54
0.84
0.85
0.59
0.64
CI = confidence interval; P = pantoprazole; A = amoxicillin; C = clarithromycin; M = metronidazole.
in patients with peptic ulcer. This was particu-
larly evident in the PAC and PAM treatment
groups. However, neither between group nor sub-
group analyses indicated that these differences
were statistically significant (table IV).
were evaluated for efficacy according to the anti-
biotic susceptibility of the isolated H. pylori
strains. This subgroup analysis is summarised in
table V. With the PAC regimen, the lowest eradica-
tion rate was seen in patients harbouring H. pylori
strains resistant to clarithromycin. With the PAM
and PCM regimens, the lowest eradication rates
A total of 95 patients in the per-protocol and
100 patients in the intention-to-treat population
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Clin Drug Invest 2002; 22 (2)

82
Dehesa et al.
Table VI. Summary of adverse events with the three eradication regimens
Parameter/treatment regimen
PAC
51
PAM
53
PCM
55
No. of patients
No. (%) of patients with adverse event
No. of adverse events
47 (92.1)
58
37 (69.8)
59
51 (92.7)
63
Causality assessment to [no. (%)]:
Not related
pantoprazole
antibiotics
1 (1.8)
pantoprazole
antibiotics
1 (1.7)
pantoprazole
antibiotics
1 (1.6)
57 (98.2)
58 (98.3)
62 (98.4)
Unlikely related
0
4 (6.9)
0
9 (15.2)
21 (35.6)
28 (47.5)
0
1 (1.6)
Likely related
1 (1.8)
0
7 (12.0)
46 (79.3)
1 (1.7)
0
1 (1.6)
0
11 (17.5)
50 (79.3)
Definitely related
P = pantoprazole; A = amoxicillin; C = clarithromycin; M = metronidazole.
were seen in patients harbouring H. pylori strains
resistant to metronidazole alone or to both metro-
nidazole and clarithromycin. However, none of the
observed differences between the subgroup eradi-
cation rates were statistically significant.
geographical region or population may not neces-
sarily be extrapolated to another.
In the present study in 159 Mexican patients
(intention-to-treat population), 68% of the pre-
treatment H. pylori isolates were resistant to metro-
nidazole in vitro. This is in good agreement with
the 76% resistance rate found earlier in a similar
patient population.[14] In light of the high level of
in vitro metronidazole resistance, the aim of the
present study was to compare the efficacy of three
7-day pantoprazole-based H. pylori eradication
regimens (PAC, PAM and PCM) in a Mexican
population. Patients received twice-daily (2000
mg/day) rather than three times daily (2250 or 3000
mg/day) amoxicillin, as the former regimen is
frequently used in clinical practice, has the poten-
tial to improve patient compliance and avoids the
use of dosages higher than those required to
achieve H. pylori eradication.[24] Patients were
randomised prospectively into the open-design
study, representing a common everyday setting of
clinical practice.
Our results show that the H. pylori eradication
rate was substantially lower in the treatment re-
gimens involving metronidazole compared with
those involving alternative antibiotics. Thus, the
best overall results were achieved with the PAC
regimen (eradication rate 81.3%, per-protocol
population), whereas regimens containing metro-
nidazole, i.e. PCM and PAM, achieved eradication
rates of only 66% and 48%, respectively. In an
analysis of subgroups of patients based on the
Tolerability
In this study, 135 (80.8%) patients reported
180 adverse events. As shown in table VI, there was
little difference in the incidence of adverse events
between the three eradication regimens. Adverse
events were of only mild or moderate intensity and
did not require withdrawal from treatment. In most
cases (98.3%), adverse events were assessed by the
investigator to be causally related to the antibiotic
agent (7.9% unlikely, 21.7% likely and 68.7%
definitive). The most frequent adverse event was
taste disturbance, experienced as a bitter taste in
the mouth and assessed by investigators to be due
to antibiotics. No serious adverse events were re-
ported. All three treatment regimens used in the
present study were met with high patient com-
pliance and were well tolerated and safe.
Discussion
Resistance of H. pylori to individual antibiotics
can hamper the success of a particular eradication
regimen.[12,13] Resistance to metronidazole and
clarithromycin, especially, varies between geo-
graphical regions. This suggests that high eradica-
tion rates achieved with a particular regimen in one
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Clin Drug Invest 2002; 22 (2)

H. pylori Eradication and Metronidazole Resistance
83
susceptibility of H. pylori isolates to each antibi-
otic agent, the lowest eradication rates were con-
sistently achieved in patients harbouring H. pylori
strains resistant to one or both of the antibiotic
agents used in the respective treatment regimens.
This was true for all three treatment regimens. In
patients with H. pylori strains resistant to metroni-
dazole alone or metronidazole and clarithromycin,
the PAM regimen yielded eradication rates of 42 to
43%. Even in patients with H. pylori strains
susceptible to all the antibiotics used in this study,
the PAM regimen achieved an eradication rate of
only 56%. However, because of the small sample
size, the 95% confidence intervals were very wide
and none of the differences in eradication rates
observed in the subgroup analysis attained statisti-
cal significance.
It is well known that in vitro resistance to metro-
nidazole does not always correlate with in vivo
resistance.[19,20,27-29] However, our results suggest
that the widespread incidence of in vitro resistance
to metronidazole in the Mexican population may
indeed be responsible for the poor eradication out-
come in regimens containing metronidazole. It is
interesting to note that in spite of the high pretreat-
ment level of metronidazole resistance and rela-
tively high pretreatment level of clarithromycin
resistance (24%), the PCM regimen achieved in-
termediate results. Thus, the impact of metroni-
dazole resistance on clarithromycin-containing
regimens appears to be lower than on those
containing amoxicillin, which has also been
observed by others.[21] Our results lend further
support to the notion that the extent to which
metronidazole resistance reduces the efficacy of
eradication regimens generally depends on the
associated components of the regimen and prob-
ably also on the duration of the treatment.[11,30]
Our data suggest that H. pylori resistance to
clarithromycin has increased during the last two
years from 14%[14] initially to 24% in the present
study. A similar trend of increasing resistance to
macrolides has also been observed in Europe and
in the USA where rates of up to 14% (primary
resistance) and up to 60% (secondary resistance)
have been reported in association with treatment
failures.[11,12] If this trend continues, it may impede
the success of clarithromycin-containing eradica-
tion regimens in the future.
The benefit of H. pylori eradication in patients
with undiagnosed dyspepsia or with non-ulcer dys-
pepsia remains controversial as any such benefits
may depend on the virulence of the bacterial strains
involved.[31-36] In our study, subgroup analysis
showed that patients diagnosed initially with
peptic ulcer achieved an overall higher H. pylori
eradication rate compared with those diagnosed
with non-ulcer dyspepsia (table IV), although this
was not statistically significant.
In Europe, a 7-day course of therapy appears to
be adequate to achieve eradication rates of between
80% and 90%.[13,30,37] In the present study, even
the highest result of 81.3% achieved with the 7-day
PAC regimen fell short of the target eradication
rate of >90%. However, we have shown previously
that such a target can be attained in Mexican
patients using a 14-day PAC regimen; in this study
the eradication rate was 94%.[14]
The question of how long eradication treatment
should be given to achieve maximum eradication
rates is still a matter of controversy. Current guide-
lines for H. pylori eradication recommend that
triple therapy be applied for at least 7 days.[4] In a
German study, there was no statistically significant
difference between the eradication rates achieved
with a 7-day and a modified 14-day PCM regi-
men.[38] However, in the United States, extended
eradication regimens of 10 to 14 days are currently
being considered and many studies provide evi-
dence that eradication rates increase with the dose
and length of treatment.[24,35,39-42] Other recent
studies show that eradication rates achieved with
14-day regimens were significantly higher than
those with 7-day regimens.[43,44] Extending the
triple therapy to 14 days may be beneficial, espe-
cially in patients with a high level of intragastric
H. pylori colonisation.[45] Furthermore, it appears
that the adverse impact of metronidazole resistance
decreases with increases in the length of treat-
ment.[21] Thus, suggestions to extend the length of
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Clin Drug Invest 2002; 22 (2)

84
Dehesa et al.
eradication regimens may well point the right way.
Regimens such as PAC used in the present study
could benefit any population with a high incidence
of strains resistant to metronidazole.
References
1. NIH Consensus Conference. Helicobacter pylori in peptic ulcer
disease. NIH Consensus Development Panel on Helicobacter
pylori in Peptic Ulcer Disease. JAMA 1994; 272: 65-9
2. Olbe L, Hamlet A, Dalenback J, et al. A mechanism by which
Helicobacter pylori infection of the antrum contributes to the
development of duodenal ulcer. Gastroenterology 1996; 110:
1386-94
The final choice of the most suitable regimen
should be based on the local prevalence of resis-
tance of H. pylori strains to antibiotics, principally
clarithromycin and metronidazole. The high
prevalence of metronidazole resistance urges the
view that in affected areas metronidazole should be
avoided and substituted with other drugs in combi-
nation therapy.[21,46] Until new treatment options
are available and established, 10- to 14-day eradi-
cation regimens such as PAC may be a compromise
to achieve H. pylori eradication rates of ≥90% in
the Mexican population. This proposal, in turn,
would have to be weighed against compliance, as
well as the safety and tolerability of the regimen.
In addition, it may be warranted in specific geo-
graphical areas to perform culture and suscepti-
bility testing to define H. pylori resistance patterns
before any eradication regimen is adopted for
general use.[11,21,35,47,48]
3. Dehesa M, Robles G, Aguirre J, et al. Consenso Mexicano sobre
Helicobacter pylori. Rev Gastroenterol Mex 1997; 62: 41-5
4. Malfertheiner P. European Helicobacter pylori study group.
Current concepts in the management of Helicobacter pylori
infection. The Maastricht 2-2000 Consensus report [online].
Available from .htm http://helicobacter.org/ehpsg_guide-
lines_ patients_2000.htm [Accessed 2002 ]
5. Tytgat GN. Review article: Helicobacter pylori: where are we
and where are we going? Aliment Pharmacol Ther 2000; 14
Suppl 3: 55-8
6. Walsh JH, Peterson WL. The treatment of Helicobacter pylori
infection in the management of peptic ulcer disease. N Engl
J Med 1995; 333: 984-91
7. DS Boer WA, Tytgat GN. The best therapy for Helicobacter
pylori infection: should efficacy or side-effect profile deter-
mine our choice? Scand J Gastroenterol 1995; 30: 401-7
8. Malfertheiner P, Megraud F, O’Morain C. Current European
concepts in the management of Helicobacter pylori infection.
Eur J Gastroenterol Hepatol 1997; 9: 1-2
9. 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
Pharmacol Ther 1999; 13: 719-29
10. Ferrero M, Ducons JA, Sicilia B, et al. Factors affecting the
variation in antibiotic resistance of Helicobacter pylori over
a 3-year period. Int J Antimicrob Agents 2000; 16: 245-8
11. Megraud F. Epidemiology and mechanism of antibiotic resis-
tance in Helicobacter pylori. Gastroenterology 1998; 115:
1278-82
Conclusions
The 7-day H. pylori eradication regimen with
PAC was superior to PCM and PAM. This is
probably due to the high resistance rate to metroni-
dazole in the Mexican population. Thus, H. pylori
eradication regimens that involve metronidazole
cannot be recommended for Mexican patients. Our
results highlight regional differences in the effi-
cacy of some well established H. pylori eradication
regimens and suggest that culture and susceptibil-
ity testing to define H. pylori resistance patterns in
specific geographical areas may be indicated
before recommending any particular eradication
schedule.[11,21,35,48]
12. O’Morain C, Montague S. Challenges to therapy in the future.
Helicobacter 2000; 5 Suppl 1: S23-6
13. Pilotto A, O’Morain C. Treatment of Helicobacter pylori infec-
tion. Curr Opin Gastroenterol 2000; 16 Suppl 1: S44-51
14. Dehesa M, Larisch J, Dibildox M, et al. Comparison of 2 sched-
ules based on pantoprazole for eradication of Helicobacter
pylori in patients with active duodenal ulcer. Rev Gastro-
enterol Mex 1998; 63: 66-71
15. Okada M, Nishimura H, Kawashima M, et al. A new quadruple
therapy for Helicobacter pylori: influence of resistant strains
on treatment outcome. Aliment Pharmacol Ther 1999; 13:
769-74
16. Rappuoli R, Pizza M, Covacci A. Metronidazole resistance in
Helicobacter pylori. Clin Infect Dis 1999; 28: 937-9
17. Gomollon F, Ducons JA, Gimeno L, et al. The ideal therapy
must be defined in each geographical area: experience with a
quadruple therapy in Spain. Helicobacter 1998; 3: 110-4
18. Katelaris PH, Adamthwaite D, Midolo P, et al. Randomized trial
of omeprazole and metronidazole with amoxycillin or
clarithromycin for Helicobacter pylori eradication, in a region
of high primary metronidazole resistance: the HERO study.
Aliment Pharmacol Ther 2000; 14: 751-8
Acknowledgements
The authors thank Dr Jose-Antonio Vargas (Byk Gulden,
Mexico) and Dr Kathy B. Thomas (Byk Gulden, Konstanz,
Germany) for coordinating thepreparation of themanuscript.
This study was supported in part by a grant from Byk Gulden,
Mexico.
19. Van Zwet AA, Thijs JC, de Graaf B. Explanations for high rates
of eradication with triple therapy using metronidazole in
patients harboring metronidazole-resistant Helicobacter
pylori strains. Antimicrob Agents Chemother 1995; 39: 250-2
© Adis International Limited. All rights reserved.
Clin Drug Invest 2002; 22 (2)

H. pylori Eradication and Metronidazole Resistance
85
20. Van Der Wouden EJ, Thijs JC, Van Zwet AA, et al. The influ-
ence of in vitro nitroimidazole resistance on the efficacy of
nitroimidazole-containing anti-Helicobacter pylori regimens:
a meta-analysis. Am J Gastroenterol 1999; 94: 1751-9
21. Van Der Wouden EJ, Thijs JC, Van Zwet AA, et al. Review
article: nitroimidazole resistance in Helicobacter pylori. Ali-
ment Pharmacol Ther 2000; 14: 7-14
22. Labenz J, Tillenburg B, Weismuller J, et al. Efficacy and toler-
ability of a one-week triple therapy consisting of panto-
prazole, clarithromycin and amoxycillin for cure of
Helicobacter pylori infection in patients with duodenal ulcer.
Aliment Pharmacol Ther 1997; 11: 95-100
23. Adamek RJ, Opferkuch W, Wegener M. Modified short-term
triple therapy –ranitidine, clarithromycin, and metronidazole
–for cure of Helicobacter pylori infection. Am J Gastroenterol
1995; 90: 168-9
24. Bardhan KD. Pantoprazole: A new proton pump inhibitor in
the management of upper gastrointestinal disease. Drugs of
Today 1999; 35: 773-808
37. Adamek RJ, Suerbaum S, Pfaffenbach B, et al. Primary and
acquired Helicobacter pylori resistance to clarithromycin,
metronidazole, and amoxicillin –influence on treatment out-
come. Am J Gastroenterol 1998; 93: 386-9
38. 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 be-
tween two regimens of different duration. Helicobacter 2000;
5: 41-51
39. Lerang F, Moum B, Ragnhildstveit E, et al. Simplified 10-day
bismuth triple therapy for cure of Helicobacter pylori infec-
tion: experience from clinical practice in a population with a
high frequency of metronidazole resistance. Am J Gastro-
enterol 1998; 93: 212-6
40. Bardhan KD, Morton D, Slater DN, et al. Pantoprazole-based
10-day triple therapy is effective in Helicobacter pylori erad-
ication. Aliment Pharmacol Ther 1998; 12: 185-9
41. Sung JJ. Where are we with current therapy? Helicobacter
2000; 5 Suppl 1: S17-21
25. Godwin CS, Blincow ED, Warren JR, et al. Evaluation of cul-
tural techniques for isolating Campylobacter pyloridis from
endoscopic biopsies of gastric mucosa. J Clin Pathol 1985;
38: 1127-31
42. Malfertheiner P, Kirchner T, Kist M. Effect of pantoprazole
based triple therapy on H. pylori eradication and gastric ulcer
healing and relevance of bacterial resistance - Byk advanced
gastric ulcer study (BAGUS). Gut 2000 47 Suppl 3: A127
43. Bhasin DK, Sharma BC, Ray P, et al. Comparison of seven and
fourteen days of lansoprazole, clarithromycin, and amoxi-
cillin therapy for eradication of Helicobacter pylori: a report
from India. Helicobacter 2000; 5: 84-7
44. Calvet X, Garcia N, Lopez T, et al. A meta-analysis of short
versus long therapy with a proton pump inhibitor, clarithro-
mycin and either metronidazole or amoxycillin for treating
Helicobacter pylori infection. Aliment Pharmacol Ther 2000;
14: 603-9
45. Maconi G, Parente F, Russo A, et al. 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
46. Fennerty MB. Should we abandon metronidazole containing
Helicobacter pylori treatment regimens?. The clinical rele-
vance of metronidazole resistance. Am J Gastroenterol 1998;
93: 2-3
26. Glupczynski Y, Labbe M, Hansen W, et al. Evaluation of the E
test for quantitative antimicrobial susceptibility testing of
Helicobacter pylori. J Clin Microbiol 1991; 29: 2072-5
27. Wongkusoltham P, Vilaichone RK, Kullavanijaya P, et al.
Eradication rates of Helicobacter pylori between metronida-
zole-sensitive and metronidazole-resistant strains with
metronidazole containing regimen in Thai patients with pep-
tic ulcer disease. J Med Assoc Thai 2001; 84 Suppl 1: S474-80
28. Graham DY, de Boer WA, Tytgat GNJ. Choosing the best anti-
Helicobacter pylori therapy: effect of antimicrobial resis-
tance. Am J Gastroenterol 1996; 91: 1072-6
29. Hoffman PS. Antibiotic resistance mechanisms of Helicobacter
pylori. Can J Gastroenterol 1999; 13: 243-9
30. Pilotto A, Leandro G, Franceschi M, et al. The effect of anti-
biotic resistance on the outcome of three 1-week triple thera-
pies against Helicobacter pylori. Aliment Pharmacol Ther
1999; 13: 667-3
31. Tytgat G, Hungin AP, Malfertheiner P, et al. Decision-making
in dyspepsia: controversies in primary and secondary care.
Eur J Gastroenterol Hepatol 1999; 11: 223-30
32. McColl K, Murray L, El-Omar E, et al. Symptomatic benefit
from eradicating Helicobacter pylori infection in patients
with nonulcer dyspepsia. N Engl J Med 1998; 339: 1869-74
33. Sachs G, Shin JM, Munson K, et al. Review article: the control
of gastric acid and helicobacter pylori eradication. Aliment
Pharmacol Ther 2000; 14: 1383-401
47. De Boer WA, Tytgat GNJ. How to treat Helicobacter pylori
infection – should treatment strategies be based on testing
bacterial susceptibility? A personal viewpoint. Eur J Gastro-
enterol Hepatol 1996; 8: 709-16
48. Mendonca S, Ecclissato C, Sartori MS, et al. Prevalence of
Helicobacter pylori resistance to metronidazole, clarithro-
mycin, amoxicillin, tetracycline, and furazolidone in Brazil.
Helicobacter 2000; 5: 79-83
34. McColl K, Malfertheiner P. Helicobacter pylori and functional
dyspepsia. Curr Opin Gastroenterol 2000; 16 Suppl 1: S29-32
35. Graham DY. Therapy of Helicobacter pylori: current status and
issues. Gastroenterology 2000; 118 Suppl 1: S2-8
36. Graham DY, Yamaoka Y. Disease-specific Helicobacter pylori
virulence factors: the unfulfilled promise. Helicobacter 2000;
5 Suppl 1: S3-9
Correspondence and offprints: Dr M. Dehesa, Altadena
No. 50, Col. Nápoles, 03810 Mexico City, Mexico.
E-mail: mdehesa@prodigy.net.mx
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Clin Drug Invest 2002; 22 (2)