Journal of Biomedicine 2017, Vol.

2 45

Ivyspring
International Publisher
Journal of Biomedicine
2017; 2: 45-56. doi: 10.7150/jbm.17612
Review

Helicobacter pylori infection: A recent approach to

diagnosis and management
Ramesh Rana, Sheng Lan Wang, Jing Li, Ying Xin Wang, Qian Wen Rao, Chang Qing Yang
Division of Gastroenterology and Hepatology, Digestive Disease Institute, Tongji hospital, Tongji University School of Medicine, 389 Xincun
road, Shanghai 200065, PR China

 Corresponding author: Chang Qing Yang, MD, PhD, Division of Gastroenterology and Hepatology, Digestive Disease Institute, Tongji
hospital, Tongji University School of Medicine, 389 Xincun road, Shanghai 200065, PR China. cqyang@tongji.edu.cn Telephone:
+86-21-66111604, 13817802801 Fax: +86-21-56050502

© Ivyspring International Publisher. This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license
(https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.

Received: 2016.09.17; Accepted: 2017.01.11; Published: 2017.02.05

Abstract
Helicobacter pylori infection is the most common infection worldwide and is associated with
simple dyspepsia, heartburn and peptic ulcer diseases, most commonly leading to upper
gastrointestinal bleeding and, ultimately, to the severe complication of gastric malignancy. Ninety
percent of duodenal ulcers and 70% of gastric ulcers are associated with helicobacter pylori
infections. Noninvasive methods, such as the urea breath test (UBT-13C or 14C) and fecal antigen
test (FAT), have high sensitivity and specificity for the diagnosis of H. pylori. However, 4-6 weeks
of anti-secretary drugs (proton pump inhibitor) prior to testing can lead to false negative results.
Invasive methods have benefits over noninvasive methods in the case of peptic ulcer diseases by
taking samples for culture to determine their sensitivities and to stage disease progression to
malignant transformation. Initially, standard triple regimen was the choice for treatment
worldwide. However, high antibiotic resistances in various geographical regions have recently
made standard quadruple therapy (bismuth-based) the preferred treatment. Recent studies have
shown the promising benefits of 10-14 days of sequential and concomitant quadruple therapies as
the first line option in high drug resistance areas, in cases of multidrug resistance or in prior
treatment failure cases. Levofloxacin-based triple therapy, furazolidone-based regimens, and
recent hybrid or rescue therapies are also beneficial towards the eradication of H. pylori infection
as a second or third line therapy. Additionally, the use of probiotics and phytomedicines improve
eradication rates when used with triple or quadruple therapies.
Key words: Helicobacter pylori, Diagnosis, Treatment, Antibiotic resistance

Introduction
Helicobacter pylori infection is one of the positive group is 1.7-5.3 times higher than that in a HP
primary causes of upper gastrointestinal diseases, negative group [3, 4]. It is more prevalent in
including dyspepsia, peptic ulcer diseases, heartburn, developing nations compared to developed nations,
gastroesophageal reflux disease and even malignant indicating that socioeconomic status and living
transformation. It is the most common infectious standards may play a major role in the distribution of
human pathogen, infecting more than 50% of the infection. However, recent data showed a declining
populations worldwide (approximately 30% of prevalence of HP infection in adults (individuals aged
children and 60% of adults), and is associated with <40 years) [4, 5]. The global prevalence of HP
70% of benign gastric ulcers and 90% of duodenal infection, according to regions, is the following: 7-30%
ulcers [1, 2]. The relative risk of gastric cancer in a HP in North America, 30-90% in South America (mostly

http://www.jbiomed.com
Journal of Biomedicine 2017, Vol. 2 46

in Chile and Brazil), 1.2-70% in Europe (least in the Additionally, it is a risk factor for mucosa-associated
Netherlands, 1.2%), 13-90% in Asia (mostly in lymphoid tissue (MALT) lymphoma and gastric
Bangladesh and India), 50-94% in the Middle East adenocarcinoma (mostly noncardia) [13]. Recently,
(mostly in Albania, Bulgaria, and Estonia), 15-20% in systematic reviews and a meta-analysis revealed that
Australia, and 48-95% in Africa (mostly in Ethiopia) extra gastric diseases are also associated with H.
[6]. In China, it is more prevalent in those aged >60 pylori infections, such as unexplained iron deficiency
years (86%) and, surprisingly, is more prevalent in anemia, idiopathic thrombocytopenic purpura,
vegetarians [7]. The annual HP re-infection rates in unexplained vitamin B12 deficiency, and the
the West are reported to be 0.5-2.5% compared to association of CagA-positive HP strains with ischemic
4.3%-13% in Asia [4]. heart disease [14]. The pathogenesis of H. pylori
As the eradication of HP infection plays a prime includes the following: (i) bacterial colonization in the
role in reducing the potential risk of complications, gastric epithelium (invasion of gastric epithelium); (ii)
such as peptic ulcer disease, MALT lymphoma, and bacterial virulence factors, including cytotoxin
gastric carcinoma, HP eradication therapy performed associated gene A (CagA), CagL and type IV secretion
before 30 years of age has nearly a 100% chance of system (T4SS), vacuolating cytotoxin A (VacA), and
preventing gastric cancer. However, the chance of Cag pathogenicity island (PAI) strains (associated
preventing gastric cancer decreases to 41% in men and with higher inflammatory response); (iii)
71% in women when eradication is performed after 70 environmental regulations of virulence factors; (iv)
years of age [8, 9]. Therefore, the aim of this review is genetic diversity related to virulence; (v) host factors
to discuss the recent and appropriate diagnosis and implicated in pathogenesis, including VacA and
management that are available for H. pylori infections autophagy, oxidation and antioxidation response,
for reducing the lifetime risk of gastric cancers. apoptosis, and epigenetic changes, genetics or
immune response [15-18]; and (vi) H. pylori
Risk factors colonization in the oral cavity, which significantly
As the volume of drug distribution is higher in correlates with gastroesophageal diseases and could
obese patients with a high BMI, the risk of drug cause re-infection and attenuate the eradication rates
failure is higher, most likely due to the reduced of the disease [19].
concentration of drugs at the gastric mucosal level. By
contrast, lower basal metabolic index (BMI) patients Diagnosis
(especially Asian) will have better outcomes [10]. Patients with HP infection may clinically present
Smoking is another risk factor for failure of therapy. A with dyspepsia, heartburn, abdominal pain, diarrhea,
meta-analysis showed that the summary odds ratio or halitosis. A specific diagnosis can be made by
for eradication failure in smokers versus non-smokers available invasive and non-invasive methods (Table
was 1.95 (95% CI 1.55-2.45), with a corresponding 1). Both methods have good sensitivity and
mean difference of 8.4% in eradication rates. The specificity; however, their applicability may vary
reason for this finding may be due to reduced gastric from country to country.
blood flow or intragastric pH in cases of smoking or
nicotine, which could potentiate the vacuolating toxin Invasive methods
activity of H. pylori in gastric cells [11, 12]. Gastroduodenoscopy is very essential in
symptomatic individuals who are not responding to
Pathogenesis therapy and those aged older than 45 years according
Helicobacter pylori, a Gram-negative, helical, to European guidelines [20]. It is not only diagnostic
rod-shaped bacterium is commonly indwelling in the but also therapeutic in upper gastrointestinal bleeding
luminal surface of the gastric epithelium. Typical (UGIB) cases. Additionally, it is a very important
transmission is via feco-oral or oro-oral routes. Not all procedure in taking biopsies to diagnose H. pylori
infected individuals with H. pylori develop clinical infection using RUT, a histopathological evaluation,
diseases; the reasons for this variation may be culture and sensitivity. These invasive tests have good
bacterial pathogenicity and host susceptibility. Ninety sensitivity and specificity; however, the chance of
to ninety-five percent of patients with duodenal ulcers false negative results is the drawback that decreases
and 70% of those with gastric ulcers are associated the diagnostic accuracy of this method due to an
with H. pylori infections. Therefore, it is the main uneven distribution of H. pylori in the gastric mucosa
cause of peptic ulcer diseases associated with or of the biopsied site and numbers of sampling [4].
without upper gastrointestinal bleeding.

http://www.jbiomed.com
Journal of Biomedicine 2017, Vol. 2 47

Table 1. Various diagnostic methods for diagnosis of H. pylori infection

Tests Sensitivity Specificity Diagnosis Advantages Limitation
Pre-treatment Post-treatment
Non-invasive method:
13 C-UBT[21, 22, 45, 46] 95-100% 90-100% Yes Yes Widely available, reliable, Special equipment required
simple, rapid
14C-UBT 92% 100% Yes Yes May have risk in pregnancy
PPV-100% Accuracy 94%
NPV-84%
Monoclonal stool antigen 90-95% 90-95% Yes Yes Simple, reliable, rapid Low compliance
test (SAT) [21, 22]
IgG serology 8-14 85% 80% Yes No Widely available, simple Positive in post eradication
Invasive method:
Rapid urease test [21, 22] 90-95% 91-100% Yes Yes Simple, rapid High bacterial load
Histology [21, 22, 27] 90-100% 93-99% Yes Yes Sensitive, secondary diagnostic Time consuming
Immuno-histochemistry Yes Yes Excellent sensitivity Expansive, limited use
Culture and sensitivity [31] 96%(MCM) 80%(MCM) No Yes Show antibiotic sensitivity Limited availability, low
54%(CC) 100%(CC) compliance
PCR [38] 97% 91% Yes Yes Quick, antibiotic sensitivity Expansive, limited availability
13/14 C-UBT- 13/14 carbon urease breath test, SAT- stool antigen test, PPV- positive predictive value, NPV- negative predictive value, IgG- immunoglobulin G, MCM-
microcapillary culture method, CC- classical culture, PCR- polymerase chain reaction

Rapid urease test (RUT) malignancy) [28]. A biopsy sample from the body of
the stomach is preferred compared to one from the
RUT is a biopsy based on a characteristic urease
antrum in patients taking acid suppressing drugs, or
reaction. It is simple and rapid, with very good
it can be performed after 2 weeks after drug
sensitivity and specificity, even in post-treatment
discontinuation [5, 20]. The availability of
eradication cases. The sensitivity and specificity varies
immunohistochemistry is limited; however, it has
from 90-95% and 91-100%, respectively [21, 22].
advantages in diagnosing HP infection in RUT
However, the number of bacteria present in the
negative cases and HP CagA genotypes [29, 30].
biopsy sample mainly affects the sensitivity of the test
[23], and non-helicobacter urease producing Culture and sensitivity
organisms (Proteus mirabilis, Citrobacter freundii, The role of culture and sensitivity plays a prime
Klebsiella pneumonia, Staphylococcus aureus, and role in increasing H. pylori eradication rates as it not
Enterobacter cloacae) may cause false-positive results only diagnoses H. pylori infection but also guides
in patients with achlorhydria. Therefore, positive test clinicians on using the appropriate treatment regimen
results after 24 hours should be discarded to rule out according to the sensitivities of drugs in particular
false positive test findings [24, 25]. The accuracy of geographical regions where antibiotic resistance is
RUT is low, especially in the presence of a gastric high. The classical culture method has a lower
hemorrhage compared to SAT. However, sensitivity of 65% compared to the newer
gastroduodenoscopy is diagnostic and therapeutic in microcapillary cultivation method, which has a
upper gastrointestinal bleeding, although RUT may sensitivity and specificity of 96% and 80%,
not be accurate in the diagnosis of HP-associated respectively [31]. This test is not a common choice in
upper GI bleeding [4]. areas where there are lower drug resistances because
Histology it is time consuming and expensive, and the
availability of the test is limited.
Histology remains the gold standard for
diagnosis of HP gastritis and detection of H. pylori Polymerase chain reactions
organisms, with a sensitivity and specificity >95% [6, Polymerase chain reaction (PCR) is a recent
21]. Giemsa staining is a widely used technique, and method of HP diagnosis and targets HP
immunostaining would increase the sensitivity and species-specific gene samples taken from blood,
specificity to 100% and 98-99%, respectively [5, 12, saliva, feces or biopsy tissues [32, 33]. The advantages
26-28]. Furthermore, it is very informative regarding of PCR are genotyping of HP and detecting antibiotic
the degree of inflammation and even for categorizing resistance genes and gene mutations [34-37]. The
post helicobacter infective gastric mucosal changes sensitivity and specificity of this method is 97% and
(atrophic gastritis, intestinal metaplasia, mucosa 91.8%, respectively, even in peptic ulcer disease
associated lymphoid tissue (MALT) lymphoma, compared to RUT (47.7%) and histology (71.6%) [38].

http://www.jbiomed.com
Journal of Biomedicine 2017, Vol. 2 48

Therefore, it can be diagnostic as well as investigative the monoclonal technique was comparatively better
regarding the choice for appropriate therapeutic than the polyclonal technique in post-treatment 4-8
drugs. However, the inability to distinguish dead and weeks after anti-secretary therapy. The sensitivity of
living HP organisms is the main limitation of this SAT declined from 98% at baseline to 87% at 7 days
method for confirming eradication. Furthermore, it and to 83% at 14 days after PPI treatment [4].
may give false-positive results by detecting cDNA However, monoclonal stool tests are not as reliable as
from non-HP organisms [39, 40]. RUT, UBT, and histopathology for diagnosis of H.
pylori infections [21].
Non-invasive methods
IgG serology: Serum antigen marker
Urease breath test: (13C and 14C)
IgG antibodies serology is a very simple, widely
At present, the urease breath test (UBT) is
available test for diagnosis of H. pylori infection.
considered the gold standard method of diagnosing
However, its persistence in post-eradicated cases calls
HP infection in both pre- and post-eradicated cases
into question its use in differentiating acute or past
[2]. There are two carbon isotopes used for UBT: 13C-
infections or performing post-treatment evaluation.
non-radioactive and 14C- radioactive. Both methods
The geographical variation in H. pylori strains can
are non-invasive, simple, highly accurate, and
further decrease the reliabilities of the test, although
comparably expensive, and the 13C UBT is usually not
using antigens pooled with different strains would
portable. However, the 14C UBT “Heliprobe” is
increase its reliability [47, 48]. It may give a false
portable and simple, and diagnosis can be made in 20
positive test result in a low prevalence population due
minutes [41, 42]. Although 13C UBT is a very reliable
its low specificity, which has to be confirmed by other
diagnostic test in children older than 6 years of age, it
reliable tests (SAT or UBT). However, it does not give
is unreliable in children below 6 years of age as well
false negative results in patients taking PPIs or
as in those who have taken antibiotics or acid
antibiotics or in other clinical circumstances, such as
suppressing drugs for 2-4 weeks prior to the test [43].
atrophic gastritis, extensive intestinal metaplasia, and
In partial gastrectomy patients, the lateral
MALT. Additionally, particular virulence factors in H.
recombinant position provides a better test result of
13C UBT [44]. The pretreatment 13C UBT dose (15, 25,
pylori, such as CagA and VacA, can be identified by
using specific antibodies serology. As the H. pylori
50, 100 mg) has a sensitivity of 96-100% and specificity
antibody concentrations in saliva and urine are lower
of 100%. Furthermore, in post-treatment cases, 15 mg
than that in serum, these sampling methods are
of 13C UBT has a sensitivity and specificity of 100%
questionable despite being easily obtainable [12, 49].
and 98.9%, respectively. Therefore, a low dose of 15
The serology test is not recommended in children
mg of 13C UBT is as equally reliable as 100 mg [45, 46].
14C UBT is also the most reliable method of
because infected children may not achieve maximal
H. pylori specific antibody levels until 7/8 years of
diagnosing HP infection in pre- and post-eradicated
age [43].
cases. The “Heliprobe”, a 14C UBT, has a sensitivity,
specificity, positive predictive value, negative Management
predictive value, and accuracy of 92%, 100%, 100%,
The aim of treatment is to eradicate the H. pylori
84%, and 94%, respectively [42]. As 13C UBT is
infection; reduce HP related complications, such as
non-radioactive, it has no radiation hazard, even in
atrophic gastritis, peptic ulcer disease, and MALT
pregnancy. However, its non-portability is the main
lymphoma; and reduce the lifetime risk of gastric
limitation. By contrast, 14C is a radioactive isotope and
cancer in individuals with or without a family history,
has little risk of radiation hazard. Therefore, it is not
which is the major cause of mortality worldwide. The
usually recommended during pregnancy.
major indications for eradication in patients with HP
Fecal/stool antigen test (SAT) positive tests are peptic ulcer disease with or without
The stool antigen test has very good diagnostic complications; low-grade gastric mucosa associated
accuracy in pre- and post-treatment cases of H. pylori lymphoid tissue lymphoma, following resection of
infections. A 4-8 week post-treatment evaluation has gastric cancer; dyspepsia; and patients with
excellent results; however, an evaluation <4 weeks first-degree relatives of gastric cancer (Table 2) [4, 6].
post-treatment after PPI is contradicted [4]. The Because antibiotic resistance is increasing day by day
pre-treatment monoclonal antigen technique due to genetic variations or HP strains, the
performed better than the polyclonal technique in 8 appropriate choice of multidrug regimens plays a
studies (1399 patients), with a sensitivity of 96% vs prime role in the eradication rates. The factors that are
90%, specificity of 97% vs 94%, PPV of 96% vs 91% included in choosing appropriate regimens are the
and NPV of 97% vs 85%, respectively. Additionally, prevalence of HP and gastric cancer, antibiotic

http://www.jbiomed.com
Journal of Biomedicine 2017, Vol. 2 49

resistance, drug allergies and tolerances, previous Table 2. Indication for HP eradication
history of treatment and outcomes, cost level, General recommendation Strong recommendation
availability of bismuth, adverse effects and patient Functional dyspepsia Peptic ulcer disease
compliances [6]. The available treatment regimens Chronic gastritis with dyspepsia Low grade gastric MALT
and their eradication rates are based on lymphoma or Gastric MALT
lymphoma
intention-to-treat (ITT) and per-protocol (PP) analysis
Chronic atrophic gastritis with erosion or
and are given in Table 3. intestinal metaplasia
Long term use of proton pump inhibitor
General measures Family history of gastric cancer (first degree
H. pylori infection is more prevalent in lower relatives with gastric cancer)
socioeconomic or developing nations and is After resection of early gastric cancer*

transmitted by gut-oral or feco-oral routes. Long term aspirin/ NSAID medication history
with peptic ulcer disease
Maintaining good public health measures can play a
Idiopathic thrombocytopenic purpura
major role in decreasing its prevalence. Washing HP related diseases (gastritis, lymphocytic
hands thoroughly and consuming clean foods and gastritis, gastric hyperplastic polyps, Menetrier
disease, etc.)
water are additional general measures that should be
Iron deficiency anemia of unknown cause#
followed. Eating particular foods, such as broccoli,
Patients’ wishes
green tea, and ginger, may have a beneficial effect.
HP- Helicobacter pylori, MALT- Mucosa associated lymphoid tissue, NSAIDs-
Additionally, these general measures only decrease its Nonsteroidal anti-inflammatory drugs
prevalence, and anti-H. pylori medications are *In Korea, post resection of early gastric cancer is a strong recommendation for HP
eradication.
necessary to eradicate infections. #In China, iron deficiency anemia of unknown cause is also an indication for HP

eradication

Table 3. Treatment regimens and their eradication rates for Helicobacter pylori infections
Drugs Treatment Eradication rates Advantages Limitation
option ITT (%) PP (%)
Standard therapy Standard Widely available Failure in high resistance
LAC7-14 [61] 85 91
LAL [63, 91] 2nd -3rd line 86-96 Alternative if failure of LAC Not used in levofloxacin
resistance area
MAE 7-14 days [50] 2nd line 68-75.6 79.9-83.8 Alternative if Standard therapy failure Higher resistances
Sequential therapy
LA5+LCM5[61] 87 91.6
EA5+ELM5 [47] 2nd line 95.1 96.4 No effect of CYP2C19 polymorphism Less effective in cases of
50(+MR) 97.7(-MR) resistance
84(+GM) 95.1(GM)
RA7+RMM7 [64] 1st line 91.3 93.6 If bismuth unavailable
RA7+RMC7 [64] 71.6 75.3
OA5+OCT5 2nd line 90 94.2 High resistance area 19%S/E
PA5+PMC5 [65] 89.2 High resistance area
Concomitant therapy
OACT5-14 [62] 2nd line 85 95 Alternative to triple therapy 26.3% S/E
EBTL10[67] 2nd line 78.9 87 Amoxicillin allergic cases
EBTM10[67] 2nd line 79.7 90.8 Second line in high resistance areas
RRMB10 [73] 2nd line 77.7 84 Used in treatment failure cases
PAMC7 [65] 2nd line 94.1 Alternative to ST, high resistance area
EACM10 [66] 2nd line 89.1 93.4 Alternative to ST.
OA7+OCT7 [58] 2nd line 82.7 95.7
Rescue therapy alternative to triple therapy failure
ELA14 [70] 3rd line 75 85.7
OBAD7 [72] 3rd line 91 92 High drug resistance area
RABF7-14 [73] 3rd line 89-90 85-90
VAC7 Optional 89-92 91 P-CAB response better than PPI Limited clinical trial
VAM7 [52, 53] 98
ITT- intention-to-treat; PP- per protocol; ST- Sequential therapy; LAM14- lansoprazole, amoxicillin, and metronidazole for 14 days; LA5+LCM5- lansoprazole and amoxicillin
for 5 days followed by lanzoprazole, clarithromycin, and metronidazole for another 5 days; EA5+ELM5- esomeprazole and amoxicillin for 5 days followed by esomeprazole,
levofloxacin, and metronidazole for another 5 days; (+/-)MR- with/without metronidazole resistance; (+/-) GM- with/without gyrA mutations; OACT- omeprazole,
amoxicillin, clarithromycin, tinidazole; EBTL10- esomeprazole, bismuth subcitrate, tetracycline, and levofloxacin for 10 days; EBTM10- esomeprazole, bismuth subcitrate,
tetracycline, and metronidazole for 10 days; RRMB10- rebeprazole, rifabutin, minocycline, and bismuth subcitrate for 10 days; ELA- ecabet sodium, lansoprazole, amoxicillin
bid for 2 weeks; OBAD7- omeprazole, bismuth subcitrate, amoxicillin, doxycycline for 7 days; RABF7-14- rebeprazole, amoxicillin, bismuth subcitrate, furazolidone; VAC7-
vonoprazan, amoxicillin, clarithromycin for 7 days; VAM7- vonoprazan, amoxicillin, metronidazole for 7 days

http://www.jbiomed.com
Journal of Biomedicine 2017, Vol. 2 50

Sequential therapy
Antibiotic therapy (Specific therapy)
Sequential therapy has significant benefits in
Standard therapy eradicating H. pylori infections. There are various
Standard triple therapy (PPI+ amoxicillin+ regimens that are used for 10-14 days. Commonly
clarithromycin) for 7 days is the worldwide followed used sequential therapies and their eradication rates
first line treatment regimen. However, the PPI- based are presented in Table 3. The eradication rates with
standard therapy fails in up to 30% of cases due to these therapies vary from 85-100%. The 10 day
increased resistance to clarithromycin, subsequently therapy has fewer side effects compared to the 14 day
reducing the eradication rate with standard therapy. therapy, and there are no significant differences in
Therefore, this therapy is usually recommended in eradication rates [57, 60]. Clarithromycin-based
low clarithromycin resistant regions. Azithromycin, a sequential therapy (lansoprazole, amoxicillin bid*5d,
worldwide available macrolide, can be used instead; followed by lansoprazole, clarithromycin,
however, cross-resistance decreases the eradication metronidazole bid*5d) is not superior to 14 days of
rate. Increasing the duration of therapy to 10 or 14 standard triple therapy in low clarithromycin
days is suggested; however, 10 or 14 day use has resistance areas [61]. However, sequential therapy
controversial results and may increase antibiotic (omeprazole 20 mg, amoxicillin 1 gm bid*5d, followed
resistance [50]. To overcome this issue, sequential, by omeprazole 20 mg, clarithromycin 500 mg,
concomitant or quadruple approaches have been tinidazole 500 mg bid* 5d) demonstrated eradication
alternatively used as a first line therapy [6, 51]. rates of 91.1% and 92.1% according to ITT and PP
Recently, studies on a triple therapy containing a analyses, respectively, which was significantly better
potassium-competitive acid blocker (P-CAB) compared to the eradication rates with metronidazole
(vonoprazan 20 mg+amoxicillin 750 [62]. In a multicenter trial on failed standard triple
mg+clarithromycin 200 mg/ metronidazole 200 mg therapy, sequential therapy (esomeprazole 40 mg+
bid*7d) compared to a PPI-based low dose amoxicillin 1 mg bid*5d followed by esomeprazole 40
clarithromycin triple therapy showed promising mg+ levofloxacin 240 mg+ metronidazole 500 mg
eradications rates of 89-98% [52, 53]. Therefore, P-CAB bid*5d) showed a higher eradication rate of >95%. The
may be able to replace PPIs as an acid suppressing eradication rates were significantly higher in the
drug in the future. non-metronidazole resistance group (>97%) and
Based on published clinical trials, non-gyrA mutation group (95.1% vs 84.6%).
quinolone-containing triple therapy is effective as a Additionally, the CYP2C19 polymorphism did not
first line therapy and can be considered in affect the eradication rates [63]. In comparing
populations with a clarithromycin resistance >15% moxifloxacin-based (Rebeprazole 20 mg+ amoxicillin
and quinolone resistance <10%. 1 gm bid*7d followed by Rebeprazole 20 mg+
Levofloxacin-containing triple therapy has metronidazole 500 mg+ moxifloxacin 400 mg bid*7d)
eradication rates ranging from 86-96%, even in versus clarithromycin-based sequential therapy, there
retreatment of clarithromycin-based triple therapy were significant eradication rates of 91.3/93.6%
non-responders. Although the risk of quinolone (ITT/PP) with moxifloxacin-based therapy. Therefore,
resistance with urinary tract infections and it can be very effective as a first line therapy with
respiratory infections is high [54-56], as a second line excellent patient compliance and safety compared to
or third line option, PPI+ amoxicillin and levofloxacin clarithromycin-based sequential therapy (eradication
for 10-14 days has significant benefits in eradicating rates of 71.6/75.3%) [64].
H. pylori infection [57, 58].
Concomitant therapy
Standard quadruple therapy is the regimen of
choice in the case of standard triple therapy failure Concomitant therapy is another option for
and availability of a bismuth subcitrate drug. eradicating H. pylori infections in addition to
Quadruple therapy has better eradication rates standard therapy and sequential therapy. In these
compared to triple therapy [12, 14]. The combination therapies, normally all four drugs are concomitantly
of ampicillin-sulbactum (ampicillin 225 mg and given for 7-14 days. They have significant beneficial
sulbactum 150 mg bid.) has equal or higher efficacy in effects in eradication rates, although the side effects
quadruple therapy, so ampicillin-sulbactum can be may occur for a longer duration [60]. The various
considered in cases of amoxicillin resistant H. pylori regimens and their efficacies are presented in Table 3.
strains [59]. In a multicenter prospective RCT conducted in a high
clarithromycin resistant area, concomitant therapy
(esomeprazole, 40 mg; amoxicillin, 1 mg;

http://www.jbiomed.com
Journal of Biomedicine 2017, Vol. 2 51

clarithromycin, 500 mg; metronidazole, 500 mg LOAD10. This result demonstrated that the LOAD
bid*10d) had significantly higher eradication rates of regimen is highly active in cases of treatment-naïve
89% and 93.4% (versus 78.7%/82.8% of sequential patients with HP infections. However, further large
therapy) according to ITT and PP analyses, randomized controlled trials are needed to evaluate
respectively, despite drug resistances (metronidazole, the efficacy of this regimen [69]. A meta-analysis
34%; clarithromycin, 27%; and dual drugs ,7.9%) on showed treatment compared with doxycycline and
culture [9]. In another study, 7 days of concomitant tetracycline only, and there was no difference in
therapy (pantoprazole, 40 mg; amoxicillin, 1 mg; eradication rates; however, compared with other
clarithromycin, 500 mg; metronidazole, 500 mg bid) regimens, there were higher eradication rates with
showed eradication rates of 94.1%, which was doxycycline [70].
significantly higher compared to that of 7-day
standard triple therapy (81.6%) and 10-day sequential Hybrid therapy
therapy (89.2%) [65]. Additionally, 7-day concomitant A prospective randomized study with hybrid
therapy (Rebeprazole, amoxicillin, clarithromycin, therapy of omeprazole, 20 mg, and amoxicillin, 1 gm
metronidazole) showed eradication rates of 90.3% twice daily for 7 days, followed by omeprazole, 20
[57]. In another study with omeprazole, 20 mg; mg; clarithromycin, 500 mg; and tinidazole, 500 mg
amoxicillin, 1 gm; clarithromycin, 500 mg; and twice daily for another 7 days, showed eradication
tinidazole, 500 mg for 14 day, the eradication rates rates of 82.7% and 95.7% according to ITT and PP
were 86.3% and 95% according to ITT and PP analyses, respectively. The side effects were
analyses, respectively [60], whereas the 5-day comparably less than those of 14-day concomitant
treatment showed eradication rates of 85.5% and therapy (22.7% vs. 26.3%) [60]. Another multicenter
91.6% according to ITT and PP analyses, respectively pilot study with a hybrid therapy of esomeprazole, 40
[62]. Therefore, these therapies with 7-14 day mg, and amoxicillin, 1 gm, twice daily for 10, 12 or 14
durations can be an alternative to sequential therapy days plus clarithromycin, 500 mg, and metronidazole,
in high drug resistance areas and also in settings 500 mg, twice daily for the final 7 days showed
where bismuth is not available [9, 57, 62, 65, 66]. eradication rates of 95%, 95.1%, and 93.4% for the 10,
Ten-day bismuth-based second line quadruple 12, and 14 day therapies, respectively. This study
therapies have comparably lower eradication rates. concluded that in moderate to low clarithromycin or
The study with EBTL (esomeprazole, 40 mg bid; metronidazole resistance areas, therapy can be
bismuth subcitrate, 300 mg qid; tetracycline, 500 mg shortened to 10 or 12 days. However, further study is
qid; levofloxacin, 500 mg OD* 10 d) showed essential in moderate to high clarithromycin,
eradication rates of 78.9% and 87% according to ITT metronidazole or dual resistance regions [71].
and PP analyses, respectively [67]. In a high dose
Rescue therapy
metronidazole study, EBTM (esomeprazole, 40 mg
bid; bismuth subcitrate, 300 mg qid; tetracycline, 500 A study (n=74) was performed in patients with
mg qid; metronidazole, 500 mg qid*10d) showed failed eradication of HP triple therapy (lansoprazole,
eradication rates of 79.7% and 90.8% according to ITT 30 mg; amoxicillin, 750 mg; clarithromycin, 200 mg
and PP analyses, respectively. Metronidazole-based bid) in a Japanese population with rescue therapy
quadruple therapy is cheap, safe and well tolerated. (ecabet sodium, 2 gm; lansoprazole, 30 mg;
Therefore, this treatment could be an option for amoxicillin, 750 mg bid) for 2 weeks. The study
second line therapy for H. pylori infections in high demonstrated eradication rates of 75% and 85.7%
resistance areas [67]. A bismuth-based PARB regimen according to ITT and PP analyses, respectively [72].
(pantoprazole, amoxicillin, rifabutin, bismuth The anti-HP effect of ecabet sodium has beneficial
subcitrate) is the third line quadruple therapy in H. effects and can be an option for rescue therapy in
pylori eradication. A study with a PARB regimen standard clarithromycin-based triple therapy failure
(pantoprazole, 20 mg; amoxicillin, 1 gm; rifabutin, 150 cases.
mg; bismuth subcitrate, 240 mg bid) for 10 days A rescue quadruple therapy that is
demonstrated a significant therapeutic gain, with tetracycline-based, RRMB (Rebeprazole, rifabutin,
eradication rates of 96.6% compared to triple therapy minocycline, bismuth subcitrate), in first line triple or
without bismuth subcitrate (66.7%) [68]. sequential therapy and successive levofloxacin-based
A randomized trial of levofloxacin, 250 mg; triple regimen failure cases showed an eradication of
omeprazole, 20 mg; nitazoxanide, 500 mg bid; and 77.7% and 84% according to ITT and PP analyses,
doxycycline, 100 mg qd (LOAD) for 7 or 10 days had respectively. This study concluded that a RRMB
eradication rates of 88.9% on LOAD7 and 90% on regimen can be an option in those who have failed at

http://www.jbiomed.com
Journal of Biomedicine 2017, Vol. 2 52

least two previous regimens; however, a trial needs to supplementation for two weeks pre- and
be performed in a larger population [73]. A post-treatment with standard triple therapy
culture-guided rescue quadruple therapy using (omeprazole+ clarithromycin+ amoxicillin bid) for 7
omeprazole, bismuth, doxycycline and amoxicillin for days demonstrated significantly higher eradication
1 week demonstrated eradication rates of 91% (ITT) rates at pre-treatment (79.5%) and post-treatment
and 92% (PP) despite high drug resistances (79.2%) than without probiotics (60.8%) [79].
(metronidazole, 100%; clarithromycin, 95%; Additionally, meta-analyses on supplementation with
levofloxacin, 31%; and tetracycline, 5%). Therefore, probiotics demonstrated comparably higher rates of
this amoxicillin and doxycycline-based quadruple H. pylori eradication in patients who supplemented
regimen can be a good third line rescue treatment with probiotics, and the total side effects (especially
option [74]. Another rescue trial with furazolidone diarrhea) were also comparably less with probiotics
based quadruple therapy (rebeprazole, 20 mg; [80, 81].
amoxicillin, 1 gm; bismuth subcitrate, 220 mg;
furazolidone, 100 mg bid*14 days or furazolidone, 100 Antibiotic resistance
mg tid *7 days) had eradications rates of 89%/85% In the present context, increasing antibiotic
according to ITT/PP analysis at 14 days and 90% at 7 resistance rates and decreasing eradication rates are
days [75]. the major problems in treating H. pylori infections.
The higher rates of clarithromycin resistance in many
Alternative therapies
countries have contradicted its empirical use in
Probiotics and phytomedicines in Helicobacter pylori standard anti-H. pylori regimens. The overall
infections worldwide resistance rates of metronidazole and
Probiotics and phytomedicines are alternative clarithromycin are significantly higher followed by
therapies and can reduce antibiotic resistance and levofloxacin compared to other drugs (Table 4) [6, 82].
increase eradication rates. The most commonly used Therefore, the culture-guided therapy for H. pylori is
probiotics are lactic acid producing micro-organisms, currently essential, especially in high antibiotic
such as Lactobacillus spp. and Bifidobacterium spp. resistance regions. Based on a European Medicine
Phytomedicines include plant extracts or herbs, Agency evaluation of medicinal products that are
ginseng, green tea, red wine, flavonoids, broccoli indicated for the treatment of bacterial infections, 3
sprouts, and garlic. The mechanisms of alternative categories were defined according to susceptibility to
therapies include (i) modulating the host immune the given antibiotic agents: 0-10% resistant- usually
response and normal gut microbiota, promoting host susceptible, 10-50% resistant- inconsistently
health; (ii) decreasing antibiotic associated susceptible, and >50% resistant- usually resistant. H.
side-effects; (iii) competing for nutrition and adhesion pylori falls into the second category [12]. In European
of cell receptors, leading to reduced colonization of countries, resistance to metronidazole (34.9%) was
HP; (iv) stimulating mucin production and stabilizing higher, followed by 17.5% with clarithromycin and
the gut mucosal barrier; and (v) inhibiting the urease 14.1% with levofloxacin. The clarithromycin and
enzyme [1, 76-78]. Lactobacillus acidophilus daily levofloxacin resistance rates were significantly higher
(> 20%) in Western, Central and Southern European
countries compared to
Table 4. Antibiotic resistances according to geographical regions Northern European
Regions Metronidazole Clarithromycin Amoxicillin Quinolones Tetracycline Furazolidine countries (<10%) [83]. In
Asia[6] [57,58] 27-100% 3-45% 0-33% 3- 38% 4-7% 1-5% (China) Asian countries, the
Least (India) metronidazole resistances
High Taiwan 27% Thailand 3% Taiwan 0% India 3% China1-5%
SEA 100% India 45% India 33% China are predominantly higher
30-38% in Southeast Asian regions
Europe [56] 34.9% 17.5% 0% 14.1% - - (100%) and coastal regions
North America 44.1% 29.3% 2.2% - 2.7% -
of China (>90%).
South America 53-82% 4-24% 2% - - -
Amoxicillin (33%) and
Columbia 82% Argentina 24% clarithromycin (45%)
Africa [6, 82] 55-90% 29.3% 65.6% - 43.9% - resistances are high in
(Senegal 90%)
India, levofloxacin
Middle East [6] 73-100% 0-9% 0-21% 2-5% 0-5% 9% (Iran)
Egypt 100% Iran 9% Iran 21% resistance (30-38%) is high
SEA- Southeast Asia in China [6, 84, 85] and
gatifloxacin resistance

http://www.jbiomed.com
Journal of Biomedicine 2017, Vol. 2 53

(47.9%) is high in Japan [86]. In African nations, drug resistant cases; therefore, these treatments can be
metronidazole resistances are predominantly high recommended in standard triple therapy failure or if
(92%), followed by amoxicillin (65%), tetracycline there is a contraindication to bismuth containing
(43%), and clarithromycin (29%). In contrast to other quadruple therapy. Additionally, probiotics and
geographical regions, amoxicillin and tetracycline phytomedicines in addition to triple or
resistances are significantly high in African nations quadruple/sequential/concomitant therapies would
[82]. In North American nations, the drug resistance not only improve the eradication rates but also
rates were 44% with metronidazole, followed by decrease the antibiotic resistance rates.
clarithromycin (29%) and multidrug resistance (15%)
[82]. In South American nations, metronidazole Abbreviations
resistances (Columbia- 82%) predominated, followed HP: Helicobacter pylori; RUT: Rapid urease test;
by clarithromycin (Argentina- 24%) [6]. In Middle UBT: Urease breath test; SAT: Stool antigen test; RUT:
Eastern nations, metronidazole resistances (70-100%) Rapid urease test; IgG: Immunoglobulin G; BMI: Basal
were significantly higher in many countries, followed metabolic index; CagA: Cytotoxin-associated antigen
by amoxicillin (21%). In contrast, clarithromycin A, T4SS: type IV secretion system; VacA: Vacuolating
resistances were lower in these nations (0-9%) [6]. cytotoxin A; PAI: Cag pathogenicity island (PAI)
There were no reports found on the resistances of strains; MALT: Mucosa associated lymphoid tissue
PPIs, ranitidine, and bismuth [82, 87]. lymphoma; PCR: Polymerase chain reaction; ITT:
Intention-to-treat; PP: Per-protocol; vs: versus; CI:
Future advances confidence interval; UGIB: Upper gastrointestinal
In recent years, researchers have improved the bleeding; cDNA: circulating deoxyribonucleic acid; 13
understanding of the innate and adaptive immune C: 13 carbon isotope; 14C: 14 carbon isotope; PPIs:
responses against H. pylori. However, the Proton pump inhibitors; P-CAB: Potassium
development of a successful vaccine producing competitive acid blocker; CYP2C19: Cytochrome P450
immunity against H. pylori is still uncertain [88]. Anti 2C19; RCT: Randomized control trial; EBTL:
IL-22 antibody injection efficiently killed H. pylori in Esomeprazole, bismuth subcitrate, tetracycline,
an in-vitro mice model. IL-22 played a critical role in levofloxacin; EBTM: Esomeprazole, bismuth
vaccine-induced protection by promoting the subcitrate, tetracycline, metronidazole; PARB:
expression of anti-microbial peptides, including Pantoprazole, amoxicillin, rifabutin, bismuth
RegIIIB. In conclusion, urease-specific memory subcitrate; LOAD 7 or 10: Levofloxacin, omeprazole,
Th17/Th22 cells could constitute immune correlates nitazoxanide, doxycycline for 7 or 10 days; RRMB:
of vaccine protection in humans [89]. In another Rebeprazole, rifabutin, minocycline, bismuth
mouse model, conjugating antigen vaccines with subcitrate; GEM: non-genetically modified
GEM (non-genetically modified Lactococcus lactis) Lactococcus lactis.
particles could lead to promising oral therapeutic
vaccine formulations against H. pylori [90]. Acknowledgements
Funding: This study was supported by grants
Conclusion from the National Natural Science Foundation of
As the eradication of H. pylori infection is China (No. 81370559), Shanghai major joint project for
essential to prevent its ultimate complication, gastric important diseases (2014ZYJB0201), and Shanghai
carcinoma, a proper diagnosis can be performed using joint project with advanced technology
simple, non-invasive methods, such as UBT and FAT. (SHDC12014122).
Eradication can be further improved by testing for
drug sensitivities, especially in high drug resistance Competing Interests
regions, with the help of invasively biopsied samples The authors have declared that no competing
for culture and sensitivity. Therefore, appropriate interest exists.
treatment regimens can be conducted according to the
geographical regions, even in high drug resistant References
areas. Recently, clarithromycin-based standard triple 1. Vítor JM, Vale FF. Alternative therapies for Helicobacter pylori:
probiotics and phytomedicine. FEMS Immunology & Medical
therapy has become not recommended in high drug Microbiology. 2011; 63: 153-64. doi:10.1111/j.1574-695X.2011.00865.x.
resistant regions; instead, bismuth containing 2. Choi YJ. Specific Conditions: Diagnosis of H. pylori Infection in Case of
quadruple therapy is preferred. Currently, sequential Upper Gastrointestinal Bleeding. Helicobacter pylori: Springer; 2016:
157-62.
or concomitant quadruple therapies have significant
higher eradication rates even in single or multiple

http://www.jbiomed.com
Journal of Biomedicine 2017, Vol. 2 54

3. Helicobacter, Group CC. Gastric cancer and Helicobacter pylori: a 25. Osaki T, Mabe K, Hanawa T, Kamiya S. Urease-positive bacteria in the
combined analysis of 12 case control studies nested within prospective stomach induce a false-positive reaction in a urea breath test for
cohorts. Gut. 2001; 49: 347-53. diagnosis of Helicobacter pylori infection. Journal of medical
4. Kim SG, Jung HK, Lee HL, Jang JY, Lee H, Kim CG, et al. Guidelines for microbiology. 2008; 57: 814-9. doi: 10.1099/jmm.0.47768-0.
the diagnosis and treatment of Helicobacter pylori infection in Korea. 26. Braden B. Diagnosis of Helicobacter pylori infection. BMJ (Clinical
Journal of gastroenterology and hepatology. 2014; 29: 1371-86. research ed). 2012; 344: e828. doi: 10.1136/bmj.e828.
doi:10.1111/jgh.12607 27. Buharideen S, Wijetunge S, Jayamaha T, Sinnadurei A, Waduge R,
5. Tonkic A, Tonkic M, Lehours P, Mégraud F. Epidemiology and diagnosis Ratnatunga C. Evaluation of histology as a Helicobacter pylori detection
of Helicobacter pylori infection. Helicobacter. 2012; 17: 1-8. doi: method and analysis of associated problems. Journal of Diagnostic
10.1111/j.1523- 5378.2012.00975.x. Pathology. 2016; 10: 2. doi: 10.4038/jdp.v10i2.7676.
6. Hunt R, Xiao S, Megraud F, Leon-Barua R, Bazzoli F, Van Der Merwe S, 28. Lee HS. Histopathologic Diagnosis of H. pylori Infection and Associated
et al. Helicobacter pylori in developing countries. World Gastric Diseases. Helicobacter pylori: Springer; 2016: 119-27.
gastroenterology organisation global guideline. Journal of 29. Eshun JK, Black DD, Casteel HB, Horn H, Beavers-May T, Jetton CA, et
gastrointestinal and liver disease. 2011; 20: 299-304. al. Comparison of immunohistochemistry and silver stain for the
7. Zhang M, Zhou Y-Z, Li X-Y, Tang Z, Zhu H-M, Yang Y, et al. diagnosis of pediatric Helicobacter pylori infection in urease-negative
Seroepidemiology of Helicobacter pylori infection in elderly people in gastric biopsies. Pediatric and Developmental Pathology. 2001; 4: 82-8.
the Beijing region, China. World journal of gastroenterology: WJG. 2014; 30. Uchida T, Kanada R, Tsukamoto Y, Hijiya N, Matsuura K, Yano S, et al.
20: 3635. doi: 10.3748/wjg.v20.i13.3635. Immunohistochemical diagnosis of the cagA‐gene genotype of
8. Kato M, Asaka M. Recent knowledge of the relationship between Helicobacter pylori with anti‐East Asian CagA‐specific antibody. Cancer
Helicobacter pylori and gastric cancer and recent progress of science. 2007; 98: 521-8. doi: 10.1111/j.1349-7006.2007.00415.x.
gastroendoscopic diagnosis and treatment for gastric cancer. Japanese 31. Allahverdiyev AM, Bagirova M, Caliskan R, Tokman HB, Aliyeva H,
journal of clinical oncology. 2010; 40: 828-37. doi: 10.1093/jjco/hyq119. Unal G, et al. Isolation and diagnosis of Helicobacter pylori by a new
9. Lee S-Y. Current progress toward eradicating Helicobacter pylori in East method: microcapillary culture. World J Gastroenterol. 2015; 21:
Asian countries: differences in the 2013 revised guidelines between 2622-8262. doi: 10.3748/wjg.v21.i9.2622.
China, Japan, and South Korea. World journal of gastroenterology. 2014; 32. Nagasawa S, Azuma T, Motani H, Sato Y, Hayakawa M, Yajima D, et al.
20: 1493-502. doi:10.3748/wjg.v20.i6.1493. Detection of Helicobacter pylori (H. pylori) DNA in digestive systems
10. Abdullahi M, Annibale B, Capoccia D, Tari R, Lahner E, Osborn J, et al. from cadavers by real- time PCR. Legal Medicine. 2009; 11: S458-S9.
The eradication of Helicobacter pylori is affected by body mass index doi: 10.1016/j.legalmed.2009.03.001.
(BMI). Obesity surgery. 2008; 18: 1450-4. doi: 10.1007/s11695-008-9477-z. 33. Kabir S. Detection of Helicobacter pylori DNA in feces and saliva by
11. Suzuki T, Matsuo K, Ito H, Sawaki A, Hirose K, Wakai K, et al. Smoking polymerase chain reaction: a review. Helicobacter. 2004; 9: 115-23. doi:
increases the treatment failure for Helicobacter pylori eradication. The 10.1111/j.1083-4389.2004.00207.x.
American journal of medicine. 2006; 119: 217-24. doi: 34. Glocker E, Kist M. Rapid detection of point mutations in the gyrA gene
10.1016/j.amjmed.2005.10.003. of Helicobacter pylori conferring resistance to ciprofloxacin by a
12. Malfertheiner P, Megraud F, O'Morain CA, Atherton J, Axon AT, Bazzoli fluorescence resonance energy transfer-based real-time PCR approach.
F, et al. Management of Helicobacter pylori infection—the Maastricht Journal of clinical microbiology. 2004; 42: 2241-6.
IV/Florence consensus report. Gut. 2012; 61: 646-64. 35. Oleastro M, Ménard A, Santos A, Lamouliatte H, Monteiro L,
doi:10.1136/gutjnl-2012-302084. Barthélémy P, et al. Real-time PCR assay for rapid and accurate detection
13. Ekström AM, Held M, Hansson L-E, Engstrand L, Nyrén O. Helicobacter of point mutations conferring resistance to clarithromycin in
pylori in gastric cancer established by CagA immunoblot as a marker of Helicobacter pylori. Journal of clinical microbiology. 2003; 41: 397-402.
past infection. Gastroenterology. 2001; 121: 784-91. 36. Oleastro M, Gerhard M, Lopes A, Ramalho P, Cabral J, Guerreiro AS, et
14. Zagari RM, Romano M, Ojetti V, Stockbrugger R, Gullini S, Annibale B, al. Helicobacter pylori virulence genotypes in Portuguese children and
et al. Guidelines for the management of Helicobacter pylori infection in adults with gastroduodenal pathology. European Journal of Clinical
Italy: the III Working Group Consensus Report 2015. Digestive and Liver Microbiology and Infectious Diseases. 2003; 22: 85-91. doi:
Disease. 2015; 47: 903- 12. doi: 10.1016/j.dld.2015.06.010. 10.1007/s10096-002-0865-3.
15. Cid TP, Fernández MC, Benito Martínez S, Jones NL. Pathogenesis of 37. Ribeiro ML, Gerrits MM, Benvengo YH, Berning M, Godoy AP, Kuipers
Helicobacter pylori infection. Helicobacter. 2013; 18: 12-7. doi: EJ, et al. Detection of high-level tetracycline resistance in clinical isolates
10.1111/hel.12076. of Helicobacter pylori using PCR-RFLP. FEMS Immunology & Medical
16. Figueiredo C, Machado JC, Yamaoka Y. Pathogenesis of Helicobacter Microbiology. 2004; 40: 57-61.
pylori infection. Helicobacter. 2005; 10: 14-20. doi: 38. Chung WC, Jeon EJ, Oh JH, Park JM, Kim TH, Cheung DY, et al.
10.1111/j.1523-5378.2005.00339.x. Dual-priming oligonucleotide-based multiplex PCR using tissue samples
17. Costa AC, Figueiredo C, Touati E. Pathogenesis of Helicobacter pylori from the rapid urease test kit for the detection of Helicobacter pylori in
infection. Helicobacter. 2009; 14: 15-20. doi: bleeding peptic ulcers. Digestive and Liver Disease. 2016; 48: 899-903.
10.1111/j.1523-5378.2009.00702.x. doi: 10.1016/j.dld.2016.04.012.
18. Backert S, Clyne M. Pathogenesis of Helicobacter pylori infection. 39. Sugimoto M, Wu J-Y, Abudayyeh S, Hoffman J, Brahem H, Al-Khatib K,
Helicobacter. 2011; 16: 19-25. doi:10.1111/j.1523-5378.2011.00876.x. et al. Unreliability of results of PCR detection of Helicobacter pylori in
19. Zou QH, Li RQ. Helicobacter pylori in the oral cavity and gastric clinical or environmental samples. Journal of clinical microbiology. 2009;
mucosa: a meta‐analysis. Journal of Oral Pathology & Medicine. 2011; 40: 47: 738-42. doi: 10.1128/JCM.01563-08.
317-24. doi: 10.1111/j.1600-0714.2011.01006.x. 40. Wang S, Zhang W-M, Reineks E. Breath Tests for Detection of
20. Mentis A, Lehours P, Mégraud F. Epidemiology and Diagnosis of Helicobacter pylori and Aspergillus fumigatus. Advanced Techniques in
Helicobacter pylori infection. Helicobacter. 2015; 20: 1-7. doi: Diagnostic Microbiology: Springer; 2013: 13-30.
10.1111/hel.12250. 41. Parente F, Porro GB. The 13C-urea breath test for non-invasive diagnosis
21. Lario S, Ramirez-Lazaro MJ, Montserrat A, Quilez ME, Junquera F, of Helicobacter pylori infection: which procedure and which measuring
Martinez-Bauer E, et al. Diagnostic accuracy of three monoclonal stool equipment? European journal of gastroenterology & hepatology. 2001;
tests in a large series of untreated Helicobacter pylori infected patients. 13: 803-6.
Clinical biochemistry. 2016; 49: 682-7. 42. Jonaitis LV, Kiudelis G, Kupcinskas L. Evaluation of a novel 14C-urea
doi:10.1016/j.clinbiochem.2016.01.015. breath test" Heliprobe" in diagnosis of Helicobacter pylori infection.
22. Calvet X, Sánchez-Delgado J, Montserrat A, Lario S, Ramírez-Lázaro MJ, Medicina (Kaunas, Lithuania). 2007; 43: 32-5.
Quesada M, et al. Accuracy of diagnostic tests for Helicobacter pylori: a 43. Drumm B, Koletzko S, Oderda G, pylori EPTFoH. Helicobacter pylori
reappraisal. Clinical Infectious Diseases. 2009; 48: 1385-91. doi: infection in children: a consensus statement. Journal of pediatric
10.1086/598198. gastroenterology and nutrition. 2000; 30: 207-13.
23. Vaira D, Gatta L, Ricci C, Miglioli M. Diagnosis of Helicobacter pylori 44. Yin SM, Zhang F, Shi DM, Xiang P, Xiao L, Huang YQ, et al. Effect of
infection. Alimentary pharmacology & therapeutics. 2002; 16: 16-23. posture on C- 13-urea breath test in partial gastrectomy patients.
24. Ferwana M, Abdulmajeed I, Alhajiahmed A, Madani W, Firwana B, World Journal of Gastroenterology. 2015; 21: 12888-95. doi:
Hasan R, et al. Accuracy of urea breath test in Helicobacter pylori 10.3748/wjg.v21.i45.12888.
infection: Meta-analysis. World journal of gastroenterology: WJG. 2015; 45. Gatta L, Ricci C, Tampieri A, Osborn J, Perna F, Bernabucci V, et al.
21: 1305-14. doi: 10.3748/wjg.v21.i4.1305. Accuracy of breath tests using low doses of 13C-urea to diagnose

http://www.jbiomed.com
Journal of Biomedicine 2017, Vol. 2 55

Helicobacter pylori infection: a randomised controlled trial. Gut. 2006; 64. Hwang JJ, Lee DH, Lee AR, Yoon H, Shin CM, Park YS, et al. Efficacy of
55: 457-62. doi: 10.1136/gut.2005.078626. moxifloxacin-based sequential therapy for first-line eradication of
46. Gatta L, Vakil N, Ricci C, Osborn J, Tampieri A, Perna F, et al. A rapid, Helicobacter pylori infection in gastrointestinal disease. World journal of
low‐dose, 13C‐urea tablet for the detection of Helicobacter pylori gastroenterology. 2015; 21: 5032-8. doi: 10.3748/wjg.v21.i16.5032.
infection before and after treatment. Alimentary pharmacology & 65. Hsu P-I, Wu D-C, Chen W-C, Tseng H-H, Yu H-C, Wang H-M, et al.
therapeutics. 2003; 17: 793-8. Randomized controlled trial comparing 7-day triple, 10-day sequential,
47. Marchildon PA, Sugiyama T, Fukada Y, Peacock JS, Asaka M, and 7-day concomitant therapies for Helicobacter pylori infection.
Shimoyama T, et al. Evaluation of the effects of strain-specific antigen Antimicrobial agents and chemotherapy. 2014; 58: 5936-42. doi:
variation on the accuracy of serologic diagnosis of Helicobacter pylori 10.1128/AAC.02922-14.
infection. Journal of clinical microbiology. 2003; 41: 1480-5. 66. Georgopoulos SD, Xirouchakis E, Martinez-Gonzales B, Zampeli E,
48. Atkinson NSS, Braden B. Helicobacter Pylori Infection: Diagnostic Grivas E, Spiliadi C, et al. Randomized clinical trial comparing ten day
Strategies in Primary Diagnosis and After Therapy. Digestive Diseases concomitant and sequential therapies for Helicobacter pylori eradication
and Sciences. 2016; 61: 19- 24. doi: 10.1007/s10620-015-3877-4. in a high clarithromycin resistance area. European journal of internal
49. Leodolter A, Vaira D, Bazzoli F, Schütze K, Hirschl A, Megraud F, et al. medicine. 2016;32:84-90. doi: 10.1016/j.ejim.2016.04.011.
European multicentre validation trial of two new non‐invasive tests for 67. Kuo CH, Hsu PI, Kuo FC, Wang SS, Hu HM, Liu CJ, et al. Comparison of
the detection of Helicobacter pylori antibodies: urine‐based ELISA and 10 day bismuth quadruple therapy with high-dose metronidazole or
rapid urine test. Alimentary pharmacology & therapeutics. 2003; 18: levofloxacin for second- line Helicobacter pylori therapy: a
927-31. randomized controlled trial. The Journal of antimicrobial chemotherapy.
50. Yoon H, Kim N, Lee BH, Hwang TJ, Lee DH, Park YS, et al. 2013; 68: 222-8. doi:10.1093/jac/dks361.
Moxifloxacin‐ Containing Triple Therapy as Second‐Line Treatment for 68. Ciccaglione AF, Tavani R, Grossi L, Cellini L, Manzoli L, Marzio L.
Helicobacter pylori Infection: Effect of Treatment Duration and Rifabutin Containing Triple Therapy and Rifabutin with Bismuth
Antibiotic Resistance on the Eradication Rate. Helicobacter. 2009; 14: Containing Quadruple Therapy for Third‐Line Treatment of
429-37. doi: 10.1111/j.1523-5378.2009.00709.x. Helicobacter pylori Infection: Two Pilot Studies. Helicobacter.
51. Mégraud F. The challenge of Helicobacter pylori resistance to antibiotics: 2016;21:375-81. doi: 10.1111/hel.12296.
the comeback of bismuth-based quadruple therapy. Therapeutic 69. Basu PP, Rayapudi K, Pacana T, Shah NJ, Krishnaswamy N, Flynn M. A
advances in gastroenterology. 2012; 5: 103-9. doi: randomized study comparing levofloxacin, omeprazole, nitazoxanide,
10.1177/1756283X11432492. and doxycycline versus triple therapy for the eradication of Helicobacter
52. Suzuki S, Gotoda T, Kusano C, Iwatsuka K, Moriyama M. The Efficacy pylori. The American journal of gastroenterology. 2011; 106: 1970-5. doi:
and Tolerability of a Triple Therapy Containing a 10.1038/ajg.2011.306.
Potassium-Competitive Acid Blocker Compared With a 7-Day PPI-Based 70. Niv Y. Doxycycline in Eradication Therapy of Helicobacter pylori-A
Low-Dose Clarithromycin Triple Therapy. The American journal of Systematic Review and Meta-Analysis. Digestion. 2016; 93: 167-73. doi:
gastroenterology. 2016; 111: 949-56. doi: 10.1038/ajg.2016.182. 10.1159/000443683.
53. Murakami K, Sakurai Y, Shiino M, Funao N, Nishimura A, Asaka M. 71. Wu JY, Hsu PI, Wu DC, Graham DY, Wang WM. Feasibility of
Vonoprazan, a novel potassium-competitive acid blocker, as a Shortening 14‐day Hybrid Therapy While Maintaining an Excellent
component of first-line and second- line triple therapy for Helicobacter pylori Eradication Rate. Helicobacter. 2014; 19: 207-13. doi:
Helicobacter pylori eradication: a phase III, randomised, double-blind 10.1111/hel.12113.
study. Gut. 2016; doi: 10.1136/gutjnl-2015-311304. 72. Furuta T, Kato M, Sugimoto M, Sasaki M, Kamoshida T, Furukawa K, et
54. Berning M, Krasz S, Miehlke S. Should quinolones come first in al. Triple therapy with ecabet sodium, amoxicillin and lansoprazole for 2
Helicobacter pylori therapy? Therapeutic advances in gastroenterology. weeks as the rescue regimen for H. pylori infection. Internal medicine
2010; 4:103-4. doi: 10.1177/1756283X10384171. (Tokyo, Japan). 2011; 50: 369-74.
55. Federico A, Gravina AG, Miranda A, Loguercio C, Romano M. 73. Ierardi E, Giangaspero A, Losurdo G, Giorgio F, Amoruso A, De
Eradication of Helicobacter pylori infection: which regimen first. World Francesco V, et al. Quadruple rescue therapy after first and second line
journal of gastroenterology. 2014; 20: 665-72. doi: 10.3748/wjg.v20.i3.665. failure for Helicobacter pylori treatment: comparison between two
56. Lee YC, Wu HM, Chen THH, Liu TY, Chiu HM, Chang CC, et al. A tetracycline-based regimens. J Gastrointestin Liver Dis. 2014; 23: 367-70.
Community‐Based Study of Helicobacter pylori Therapy Using the doi: 10.15403/jgld.2014.1121.234.qrth.
Strategy of Test, Treat, Retest, and Re‐treat Initial Treatment Failures. 74. Cammarota G, Martino A, Pirozzi G, Cianci R, Branca G, Nista E, et al.
Helicobacter. 2006; 11: 418-24. doi: 10.1111/j.1523-5378.2006.00432.x. High efficacy of 1‐week doxycycline‐and amoxicillin‐based quadruple
57. Jung SM, Cheung DY, Kim JI, Kim I, Seong H. Comparing the Efficacy of regimen in a culture‐guided, third‐line treatment approach for
Concomitant Therapy with Sequential Therapy as the First-Line Therapy Helicobacter pylori infection. Alimentary pharmacology & therapeutics.
of Helicobacter pylori Eradication. Gastroenterology research and 2004; 19: 789-95. doi: 10.1111/j.1365-2036.2004.01910.x.
practice. 2016: 5. doi: 10.1155/2016/1293649. 75. Cheng H, Hu F-L. Furazolidone, amoxicillin, bismuth and rabeprazole
58. Li BZ, Threapleton DE, Wang JY, Xu JM, Yuan JQ, Zhang C, et al. quadruple rescue therapy for the eradication of Helicobacter pylori.
Comparative effectiveness tolerance of treatments for Helicobacter World Journal of gastroenterology. 2009; 15: 860-4.
pylori: systematic review and network meta-analysis. BMJ (Clinical 76. Vale FF, Vítor JM, Oleastro M. Probiotics as an Alternative Therapy for
research ed). 2015; 351: h4052. doi: 10.1136/bmj.h4052. Helicobacter pylori-Associated Diseases. Helicobacter pylori Research:
59. Mirbagheri SA, Hasibi M, Abouzari M, Rashidi A. Triple, standard Springer; 2016: 543-74.
quadruple and ampicillin-sulbactam-based quadruple therapies for H 77. Hwang SW. Probiotics. Helicobacter pylori: Springer; 2016: 479-85.
pylori eradication: A comparative three-armed randomized clinical trial. 78. de Klerk N, Maudsdotter L, Gebreegziabher H, Saroj SD, Eriksson B,
World journal of gastroenterology. 2006; 12: 4888. Eriksson OS, et al. Lactobacilli reduce Helicobacter pylori attachment to
60. De Francesco V, Hassan C, Ridola L, Giorgio F, Ierardi E, Zullo A. host gastric epithelial cells by inhibiting adhesion gene expression.
Sequential, concomitant and hybrid first-line therapies for Helicobacter Infection and immunity. 2016; 84: 1526-35. doi: 10.1128/IAI.00163-16.
pylori eradication: a prospective randomized study. Journal of medical 79. Du YQ, Su T, Fan JG, Lu YX, Zheng P, Li XH, et al. Adjuvant probiotics
microbiology. 2014; 63: 748-52. doi: 10.1099/jmm.0.072322-0. improve the eradication effect of triple therapy for Helicobacter pylori
61. Liou J-M, Chen C-C, Chen M-J, Chen C-C, Chang C-Y, Fang Y-J, et al. infection. World Journal of Gastroenterology. 2012; 18: 6302-7. doi:
Sequential versus triple therapy for the first-line treatment of 10.3748/wjg.v18.i43.6302.
Helicobacter pylori: a multicentre, open-label, randomised trial. Lancet. 80. Tong J, Ran Z, Shen J, Zhang C, Xiao S. Meta‐analysis: the effect of
2013; 381: 205-13. doi: 10.1016/S0140- 6736(12)61579-7. supplementation with probiotics on eradication rates and adverse events
62. Zullo A, Scaccianoce G, De Francesco V, Ruggiero V, D’Ambrosio P, during Helicobacter pylori eradication therapy. Alimentary
Castorani L, et al. Concomitant, sequential, and hybrid therapy for H. pharmacology & therapeutics. 2007; 25: 155-68. doi:
pylori eradication: a pilot study. Clinics and research in hepatology and 10.1111/j.1365-2036.2006.03179.x.
gastroenterology. 2013; 37: 647-50. doi: 10.1016/j.clinre.2013.04.003. 81. Zou J, Dong J, Yu XF. Meta‐Analysis: The Effect of Supplementation with
63. Liou JM, Chen CC, Chen MJ, Chang CY, Fang YJ, Lee JY, et al. Empirical Lactoferrin on Eradication Rates and Adverse Events During
modified sequential therapy containing levofloxacin and high-dose Helicobacter pylori Eradication Therapy. Helicobacter. 2009; 14: 119-27.
esomeprazole in second-line therapy for Helicobacter pylori infection: a doi: 10.1111/j.1523-5378.2009.00666.x.
multicentre clinical trial. The Journal of antimicrobial chemotherapy. 82. De Francesco V, Giorgio F, Hassan C, Manes G, Vannella L, Panella C, et
2011; 66: 1847-52. doi: 10.1093/jac/dkr217. al. Worldwide H. pylori antibiotic resistance: a systematic review.
Journal of gastrointestinal and liver disease. 2010; 19: 409-14.

http://www.jbiomed.com
Journal of Biomedicine 2017, Vol. 2 56

83. Megraud F, Coenen S, Versporten A, Kist M, Lopez-Brea M, Hirschl AM, 89. Moyat M, Bouzourene H, Ouyang W, Iovanna J, Renauld J, Velin D.
et al. Helicobacter pylori resistance to antibiotics in Europe and its IL-22-induced antimicrobial peptides are key determinants of mucosal
relationship to antibiotic consumption. Gut. 2013; 62: 34-42. doi: vaccine-induced protection against H. pylori in mice. Mucosal
10.1136/gutjnl-2012-302254. immunology. 2016;4. doi: 10.1038/mi.2016.38.
84. Sun Q-J, Liang X, Zheng Q, Gu W-Q, Liu W-Z, Xiao S-D, et al. Resistance 90. Liu W, Tan Z, Xue J, Luo W, Song H, Lv X, et al. Therapeutic efficacy of
of Helicobacter pylori to antibiotics from 2000 to 2009 in Shanghai. oral immunization with a non-genetically modified Lactococcus
World journal of gastroenterology. 2010; 16: 5118-21. lactis-based vaccine CUE-GEM induces local immunity against
85. Su P, Li Y, Li H, Zhang J, Lin L, Wang Q, et al. Antibiotic resistance of Helicobacter pylori infection. Applied microbiology and biotechnology.
Helicobacter pylori isolated in the Southeast Coastal Region of China. 2016: 1-11. doi: 10.1007/s00253-016-7333-y.
Helicobacter. 2013; 18: 274-9. doi: 10.1111/hel.12046. 91. Liou J-M, Lin J-T, Chang C-Y, Chen M-J, Cheng T-Y, Lee Y-C, et al.
86. Nishizawa T, Suzuki H, Hibi T. Quinolone-based third-line therapy for Levofloxacin- based and clarithromycin-based triple therapies as
Helicobacter pylori eradication. Journal of clinical biochemistry and first-line and second-line treatments for Helicobacter pylori infection: a
nutrition. 2009; 44: 119-24. doi: 10.3164/jcbn.08-220R. randomised comparative trial with crossover design. Gut. 2010; 59:
87. Gerrits MM, van Vliet AH, Kuipers EJ, Kusters JG. Helicobacter pylori 572-8. doi: 10.1136/gut.2009.198309.
and antimicrobial resistance: molecular mechanisms and clinical 92. Kuo CH, Lu CY, Shih HY, Liu CJ, Wu MC, Hu HM, et al. CYP2C19
implications. The Lancet infectious diseases. 2006; 6: 699-709. doi: polymorphism influences Helicobacter pylori eradication. World journal
10.1016/S1473-3099(06)70627-2 of gastroenterology. 2014; 20: 16029-36. doi: 10.3748/wjg.v20.i43.16029.
88. Koch M, Meyer TF, Moss SF. Inflammation, immunity, vaccines for
Helicobacter pylori infection. Helicobacter. 2013; 18: 18-23. doi:
10.1111/hel.12073.

http://www.jbiomed.com