Dual therapy for third-line Helicobacter pylori eradication and urea breath test prediction

Abstract

We evaluated the efficacy and tolerability of a dual therapy with rabeprazole and amoxicillin (AMX) as an empiric third-line rescue therapy. In patients with failure of first-line treatment with a proton pump inhibitor (PPI)-AMX-clarithromycin regimen and second-line treatment with the PPI-AMX-metronidazole regimen, a third-line eradication regimen with rabeprazole (10 mg q.i.d.) and AMX (500 mg q.i.d.) was prescribed for 2 wk. Eradication was confirmed by the results of the ¹³C-urea breath test (UBT) at 12 wk after the therapy. A total of 46 patients were included; however, two were lost to follow-up. The eradication rates as determined by per-protocol and intention-to-treat analyses were 65.9% and 63.0%, respectively. The pretreatment UBT results in the subjects showing eradication failure; those patients showing successful eradication comprised 32.9 ± 28.8 permil and 14.8 ± 12.8 permil, respectively. The pretreatment UBT results in the subjects with eradication failure were significantly higher than those in the patients with successful eradication (P = 0.019). A low pretreatment UBT result (≤ 28.5 permil) predicted the success of the eradication therapy with a positive predictive value of 81.3% and a sensitivity of 89.7%. Adverse effects were reported in 18.2% of the patients, mainly diarrhea and stomatitis. Dual therapy with rabeprazole and AMX appears to serve as a potential empirical third-line strategy for patients with low values on pretreatment UBT.

Full text

LETTERS TO THE EDITOR
Dual therapy for third-line
Helicobacter pylori
eradication
and urea breath test prediction
Toshihiro Nishizawa, Hidekazu Suzuki, Takama Maekawa, Naohiko Harada, Tatsuya Toyokawa, Toshio Kuwai,
Masanori Ohara, Takahiro Suzuki, Masahiro Kawanishi, Kenji Noguchi, Toshiyuki Yoshio, Shinji Katsushima,
Hideo Tsuruta, Eiji Masuda, Munehiro Tanaka, Shunsuke Katayama, Norio Kawamura, Yuko Nishizawa,
Toshifumi Hibi, Masahiko Takahashi
World J Gastroenterol 2012 June 7; 18(21): 2735-2738
ISSN 1007-9327 (print) ISSN 2219-2840 (online)
© 2012 Baishideng. All rights reserved.
Online Submissions: http://www.wjgnet.com/1007-9327ofce
wjg@wjgnet.com
doi:10.3748/wjg.v18.i21.2735
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Toshihiro Nishizawa, Masahiko Takahashi, Division of Gas-
troenterology, National Hospital Organization Tokyo Medical
Center, Tokyo 1528902, Japan
Hidekazu Suzuki, Toshifumi Hibi, Division of Gastroenterology
and Hepatology, Department of Internal Medicine, Keio Univer-
sity School of Medicine, Tokyo 1608582, Japan
Takama Maekawa, Shinji Katsushima, Division of Gastroen-
terology, National Hospital Organization Kyoto Medical Center,
Kyoto 6128555, Japan
Naohiko Harada, Division of Gastroenterology, National Ky-
ushu Medical Center, Fukuoka 8108563, Japan
Tatsuya Toyokawa, Division of Gastroenterology, National
Hospital Organization Fukuyama Medical Center, Fukuyama
7208520, Japan
Toshio Kuwai, Division of Gastroenterology, National Hospital
Organization Kure Medical Center, Kure 7370023, Japan
Masanori Ohara, Division of Gastroenterology, National Hos-
pital Organization Hakodate Medical Center, Hakodate 0418512,
Japan
Takahiro Suzuki, Division of Gastroenterology, National Hos-
pital Organization Maizuru Medical Center, Maizuru 6258502,
Japan
Masahiro Kawanishi, Division of Gastroenterology, National
Hospital Organization Higashihiroshima Medical Center, Hi-
gashihiroshima 7390041, Japan
Kenji Noguchi, Division of Gastroenterology, National Hospital
Organization Sendai Medical Center, Sendai 9838520, Japan
Toshiyuki Yoshio, Division of Gastroenterology, National Hos-
pital Organization Osaka Medical Center, Osaka 5400006, Japan
Hideo Tsuruta, Division of Gastroenterology, National Hospital
Organization Ureshino Medical Center, Ureshino 8430393, Japan
Eiji Masuda, Division of Gastroenterology, National Hospital
Organization Osaka Minami Medical Center, Kawachinagano
5868521, Japan
Munehiro Tanaka, Division of Gastroenterology, National Hospi-
tal Organization Fukuoka Higashi Medical Center, Koga 8113195,
Japan
Shunsuke Katayama, Division of Gastroenterology, National
Hospital Organization Yonago Medical Center, Yonago 6838518,
Japan
Norio Kawamura, Division of Gastroenterology, National Hos-
pital Organization Disaster Medical Center, Tachikawa 1900014,
Japan
Yuko Nishizawa, Pharmaceutical Department, National Center
for Global Health and Medicine, Tokyo 1658655, Japan
Author contributions: Nishizawa T designed the research project
and originally drafted and revised the article; Suzuki H analyzed
the data and critically drafted and revised the article; Maekawa
T, Harada N, Toyokawa T, Kuwai T, Ohara M, Suzuki T, Kawa-
nishi M, Noguchi K, Yoshio T, Katsushima S, Tsuruta H, Masuda
E, Tanaka M, Katayama S and Kawamura N collected the data;
Nishizawa Y, Hibi T and Takahashi M supervised and approved
the nal publication.
Supported by A grant from the National Hospital Organization,
No. H21-NHO-01
Correspondence to: Hidekazu Suzuki, MD, PhD,Hidekazu Suzuki, MD, PhD, Division of
Gastroenterology and Hepatology, Department of Internal Medi-
cine, Keio University School of Medicine, 35 Shinanomachi,
Shinjuku-ku, Tokyo 1608582, Japan. hsuzuki@a6.keio.jp
Telephone: +81-3-53633914 Fax: +81-3-53633967
Received: December 19, 2011 Revised: February 28, 2012
Accepted: March 29, 2012
Published online: June 7, 2012
Abstract
We evaluated the efcacy and tolerability of a dual the
rapy with rabeprazole and amoxicillin (AMX) as an em
piric thirdline rescue therapy. In patients with failure of
rstline treatment with a proton pump inhibitor (PPI)
AMXclarithromycin regimen and secondline treatment
with the PPIAMXmetronidazole regimen, a thirdline
eradication regimen with rabeprazole (10 mg q.i.d.) and
AMX (500 mg q.i.d.) was prescribed for 2 wk. Eradica
tion was conrmed by the results of the 13Curea breath
test (UBT) at 12 wk after the therapy. A total of 46 pa
tients were included; however, two were lost to follow
up. The eradication rates as determined by perprotocol
and intentiontotreat analyses were 65.9% and 63.0%,

Nishizawa T
et al
. Dual therapy for thirdline
H. pylori
eradication
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respectively. The pretreatment UBT results in the sub
jects showing eradication failure; those patients show
ing successful eradication comprised 32.9 ± 28.8 permil
and 14.8 ± 12.8 permil, respectively. The pretreatment
UBT results in the subjects with eradication failure were
signicantly higher than those in the patients with suc
cessful eradication (
P
= 0.019). A low pretreatment
UBT result (≤ 28.5 permil) predicted the success of the
eradication therapy with a positive predictive value of
81.3% and a sensitivity of 89.7%. Adverse effects were
reported in 18.2% of the patients, mainly diarrhea and
stomatitis. Dual therapy with rabeprazole and AMX ap
pears to serve as a potential empirical thirdline strat
egy for patients with low values on pretreatment UBT.
© 2012 Baishideng. All rights reserved.
Key words:
Helicobacter pylori
; Amoxicillin; Dual thera
py; Eradication; Urea breath test
Peer reviewers: Ozlem Yilmaz, Professor, Department of
Microbiology and Clinical Microbiology, Faculty of Medicine,
Dokuz Eylül University, izmir 35340, Turkey; Vui Heng Chong,
MRCP, FAMS, Gastroenterolgy Unit, Department of Medicine,
Raja Isteri Pengiran Anak Saleha Hospital, Bandar Seri Begawan
BA 1710, Brunei Darussalam; Dr. Khaled Ali Jadallah, Internal
Medicine, King Abdullah University Hospital, Ramtha Street,
22110 Irbid, Jordan; Seng-Kee Chuah, MD, Department of
Gastroenterology, Kaohsiung Chang Gung Memorial Hospital,
ChangGung University College of Medicine, Kaohsiung 833,
Taiwan, China
Nishizawa T, Suzuki H, Maekawa T, Harada N, Toyokawa T,
Kuwai T, Ohara M, Suzuki T, Kawanishi M, Noguchi K, Yoshio
T, Katsushima S, Tsuruta H, Masuda E, Tanaka M, Katayama S,
Kawamura N, Nishizawa Y, Hibi T, Takahashi M. Dual therapy
for third-line Helicobacter pylori eradication and urea breath
test prediction. World J Gastroenterol 2012; 18(21): 2735-2738
Available from: URL: http://www.wjgnet.com/1007-9327/full/
v18/i21/2735.htm DOI: http://dx.doi.org/10.3748/wjg.v18.
i21.2735
TO THE EDITOR
Eradication of Helicobacter pylori (H. pylori) has been re-
ported as an effective strategy in the treatment of peptic
ulcers and gastric mucosa-associated lymphoid tissue
lymphomas and also prevents the recurrence of gastric
cancer after endoscopic resection[1-7]. The rst-line regi-
men for the treatment of H. pylori infection in Japan is
triple therapy with a proton pump inhibitor (PPI), amoxi-
cillin (AMX) and clarithromycin (CLR) administered
for 7 d. Failure of this rst-line therapy against H. pylori
infection has been reported in approximately 20% of
infected patients[8,9]. With the increase in the frequency
of CLR-resistant H. pylori, there is rising concern about
the potential decline in the eradication rate of this infec-
tion[10]. Although therapy with PPI-AMX-metronidazole
(MNZ) administered for 1 wk has been found to be ef-
fective as a second-line regimen in patients failing the
rst-line regimen, approximately 10% of patients fail to
respond to even second-line treatment, necessitating the
establishment of an alternative third-line strategy for the
effective eradication of H. pylori[3,11].
Although H. pylori bacteria easily develop resistance
to CLR and MNZ, H. pylori has been considered to sel-
dom become resistant to AMX. AMX is the preferred
antibiotic because it is bactericidal and resistance is rare;
therefore, it can be used again after treatment failure[8].
A number of studies have suggested that good success
rates for H. pylori eradication could be obtained with
AMX and PPI dual therapy if the effective PPI dose
and frequency of administration were increased[12]. The
majority of patients who experience two eradication fail-
ures have the rapid metabolizer genotype of CYP2C19.
Because omeprazole and lansoprazole are extensively
metabolized by CYP2C19 in this genotype, their plasma
concentrations will not attain levels sufcient to inhibit
acid secretion, and therefore, antibiotics such as AMX
will be less stable in the stomach, resulting in a lower
eradication rate[13]. The PPI rabeprazole is a substitute
of benzimidazole. CYP2C19 is less involved in the me-
tabolism of rabeprazole than in that of omeprazole and
lansoprazole[14]. Moreover, rabeprazole has a greater and
more rapid acid-inhibitory effect than does omeprazole.
Several reports on the pharmacokinetics and pharma-
codynamic characteristics of PPIs have indicated that a
sufcient plasma concentration of PPIs can be achieved
in patients with the rapid metabolizer genotype of CY-
P2C19 by frequent PPI dosing[12,15]. Furuta et al[16] recently
reported an excellent eradication rate of 87.8% following
dual therapy with rabeprazole 4 times/day and AMX as
a third-line rescue. However, their study was completed
at only one or two centers. Our study was designed as a
prospective, multicenter trial with the participation of 16
Japanese hospitals affiliated with the National Hospital
Organization to investigate the efcacy of dual therapy
with 4 times daily dosing of rabeprazole and AMX as
empiric third-line rescue therapy.
A total of 46 patients (26 males, 20 females; age 60.7
± 12.9 years, mean ± SD) referred to us between January
2009 and January 2012 were enrolled. Endoscopic exami-
nations were conducted before treatment in all patients,
and H. pylori positivity was conrmed by histology, stool
antigen test, H. pylori-specic IgG antibodies or the 13C-
urea breath test. All patients had a history of two treat-
ment failures (rst-line treatment used: triple therapy with
PPI- AMX-CLR for 7 d; second-line treatment used; tri-
ple therapy with PPI-AMX-MNZ for 7 d). The exclusion
criteria in this study were (1) age < 18 years; (2) presence
of clinically signicant underlying disease (hepatic or renal
disease, diabetes mellitus); (3) history of gastric surgery;
and (4) allergy to any of the drugs used in the study. H.
pylori eradication failure was dened as a positive 13C-urea
breath test (UBT) at the end of 12 wk after completion
of treatment. The 13C-urea used was 100 mg 13C-labelled
urea, produced by Otsuka pharmaceutical Co., LTD, Ja-
pan. The procedure was modified from the European
standard protocol for the detection of H. pylori[17]. We

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chose 2.5 permil for cut-off level of the rise in the delta
value of 13CO2 at 15 min after the ingestion of 13C-urea.
The treatment regimen was rabeprazole 10 mg q.i.d.
and AMX 500 mg q.i.d. administered for 2 wk. Partici-
pants were requested to return at the conclusion of the
therapy for an interview regarding any adverse events.
Successful H. pylori eradication was defined as a nega-
tive UBT at the end of 12 wk after completion of treat-
ment. Statistical analyses were performed using the chi-
square, Fisher’s exact and Student’s t tests, as appropriate.
P values of less than 0.05 were accepted as representing
statistical signicance. The study was conducted with the
approval of the Ethics Committee of the National Hos-
pital Organization Tokyo Medical Center, and informed
consent was obtained from all patients prior to the ex-
aminations. The clinical trial registration number of the
University Hospital Medical Information Network was
R000003204.
Of the 46 patients enrolled, 2 dropped out of the
study, leaving 44 patients in the per protocol (PP) set.
H. pylori eradication was confirmed in 29 patients, rep-
resenting an eradication rate of 63.0% [95% condence
intervals (CI): 47.6%-76.8%] by intention-to-treat (ITT)
analysis and 65.9% (95% CI: 50.1%-79.5%) by PP analysis
(Table 1). Patient compliance with the prescribed treat-
ment was excellent. Adverse events were recorded in 8
patients (18.2%; 95% CI: 8.2%-32.7%). Six patients had
mild diarrhea or soft stools but went on to complete the
study. Two patients developed stomatitis.
Because the numerical results of the UBT are a func-
tion of the total urease activity within the stomach, they
represent a quantitative index of the density of gastric
H. pylori colonization[18]. As a low pretreatment UBT val-
ue could be one of the predictive factors for eradication
success, the pretreatment UBT value was analyzed. The
pretreatment UBT results in the subjects with eradication
failure and in those with successful eradication were 32.9
± 28.8 and 14.8 ± 12.8 (permil, mean ± SD), respectively.
The results of the statistical analysis showed that the pre-
treatment UBT results in the subjects with eradication
failure were signicantly higher than those in the patients
with successful eradication (P = 0.019, effect size 0.81).
We plotted original receiver operator characteristic (ROC)
curves for the pretreatment UBT results to establish the
appropriate cutoff value. According to the ROC curves,
the optimal cutoff value in our population was 28.5.
When patients were assigned to two groups (UBT results
≤ 28.5 permil and > 28.5 permil), the eradication rates
were 81.3% (26/32) and 25.0% (3/12), respectively (P =
0.001). A low pre-treatment UBT value (≤ 28.5 permil)
predicted the success of the eradication therapy with
a sensitivity of 89.7 %, specificity of 60.0 %, positive
predictive value of 81.3%, negative predictive value of
75.0% and accuracy of 79.5%.
Currently, a standard third-line therapy still remains
to be established. H. pylori isolates after two eradication
failures are often resistant to both MNZ and CLR. The
alternative candidates for third-line therapy are fluoro-
quinolones-AMX-PPI, rifabutin-AMX-PPI, and high-
dose PPI/AMX therapy[2,19-21]. Gisbert et al[22] conducted
a prospective multicenter study to evaluate the outcomes
of treatment with a third-line levofloxacin-based regi-
men. The patients were treated for 10 d with a regimen
consisting of omeprazole, levofloxacin and AMX. The
eradication rates as determined by PP and ITT analyses
were 66% and 60%, respectively. However, resistance to
uoroquinolones has been shown to be easily acquired,
and in countries with a high rate of use of these drugs,
the resistance rates are relatively high. González Carro
et al[23] evaluated the efficacy of a third-line rifabutin-
based triple therapy. The patients were treated with PPI,
rifabutin and AMX for 10 d. The eradication rates as de-
termined by PP and ITT analyses were 62.2% and 60.8%,
respectively. However, it has been suggested that the use
of rifabutin be reserved for the treatment of multidrug-
resistant Mycobacterium tuberculosis strains[24].
Our results for the dual therapy with 4 times daily
dosing of rabeprazole and AMX for 14 d, which yielded
eradication rates in the PP and ITT analyses of 65.9%
and 63.0%, were as successful as other empiric third-line
therapy regimens. In particular, a low pretreatment UBT
result (≤ 28.5 permil) predicted the success of the eradi-
cation therapy with a positive predictive value of 81.3%,
sensitivity of 89.7% and specificity of 60.0%, so the
dual therapy appeared to serve as a promising option for
empiric third-line rescue therapy in patients with a low
pretreatment UBT value.
We recently reported the resistant rates of H. pylori to
AMX. The resistance rates to AMX (MIC ≥ 0.06 μg/mL)
in the groups with no history of eradication treatment,
a history of one treatment failure, and a history of two
treatment failures were 13.6%, 26.5% and 49.5%, respec-
tively. The MIC
90
of AMX increased by 2-fold after each
eradication failure
[25]
. Resistance to AMX in H. pylori was
gradually induced after unsuccessful eradication. Because
the AMX resistance rate after two treatment failures was
relatively high, the eradication rate of the present study
was lower than that of previous report by Furuta et al
[16]
.
Therefore, antimicrobial susceptibility testing of H. pylori
is desirable before the selection of a suitable third-line
therapy, although the culture-based antibiotic susceptibil-
Table 1 Demographic characteristics of the patients and the
results of eradication therapy
Characteristics Total
(
n
= 46)
Eradication
success
(
n
= 29)
Eradication
failure
(
n
= 15)
P
value
Age (mean ± SD, yr) 60.7 ± 12.9 59.8 ± 13.4 60.8 ± 12.1 0.813
Sex (male/female) 26/20 15/14 10/5 0.530
Diagnosis (GU/DU/CG) 23/15/8 15/10/4 8/3/4 0.450
Pretreatment UBT 20.4 ± 21.2 14.8 ± 12.8 32.9 ± 28.8 0.019
Eradication rate (ITT) % 63.0
Eradication rate (PP) % 65.9
GU: Gastric ulcer; DU: Duodenal ulcer; CG: Chronic gastritis; UBT: Urea
breath test; ITT: Intention-to-treat; PP: Per protocol.
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et al
. Dual therapy for thirdline
H. pylori
eradication

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ity testing for H. pylori is expensive, time-consuming, and
not always available on a routine basis
[26]
. There are sever-
al limitations to our study. First, our eradication study was
single armed using the dual therapy, and different doses
or superiority over quinolone-based therapy was not
evaluated. Second, we did not examine the in vitro suscep-
tibility in patients treated with the dual therapy. Thus, in
vitro resistance to AMX was not elucidated. These issues
should be re-evaluated in future studies.
Finally, although we did not achieve excellent eradi-
cation success, the dual therapy appeared to serve as a
promising option for empiric third-line rescue therapy
in patients with low pretreatment UBT values. The an-
timicrobial susceptibility testing of H. pylori is desirable
before the selection of a suitable third-line therapy in
patients with high pretreatment UBT values.
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