American Journal of Gastroenterology ISSN 0002-9270


C 2007 by Am. Coll. of Gastroenterology doi: 10.1111/j.1572-0241.2007.01393.x
Published by Blackwell Publishing

American College of Gastroenterology Guideline

on the Management of Helicobacter pylori Infection
William D. Chey, M.D., F.A.C.G., A.G.A.F., F.A.C.P.,1 Benjamin C.Y. Wong, M.D., Ph.D., F.A.C.G., F.A.C.P.2 ,
and the Practice Parameters Committee of the American College of Gastroenterology
1
University of Michigan Medical Center, Ann Arbor, Michigan; and 2 Department of Medicine, University
of Hong Kong, Hong Kong
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Helicobacter pylori (H. pylori) remains a prevalent, worldwide, chronic infection. Though the prevalence of this
infection appears to be decreasing in many parts of the world, H. pylori remains an important factor linked to the
development of peptic ulcer disease, gastric malignanc and dyspeptic symptoms. Whether to test for H. pylori in
patients with functional dyspepsia, gastroesophageal reflux disease (GERD), patients taking nonsteroidal
antiinflammatory drugs, with iron deficiency anemia, or who are at greater risk of developing gastric cancer
remains controversial. H. pylori can be diagnosed by endoscopic or nonendoscopic methods. A variety of factors
including the need for endoscopy, pretest probability of infection, local availability, and an understanding of the
performance characteristics and cost of the individual tests influences choice of evaluation in a given patient.
Testing to prove eradication should be performed in patients who receive treatment of H. pylori for peptic ulcer
disease, individuals with persistent dyspeptic symptoms despite the test-and-treat strategy, those with H.
pylori-associated MALT lymphoma, and individuals who have undergone resection of early gastric cancer. Recent
studies suggest that eradication rates achieved by first-line treatment with a proton pump inhibitor (PPI),
clarithromycin, and amoxicillin have decreased to 70–85%, in part due to increasing clarithromycin resistance.
Eradication rates may also be lower with 7 versus 14-day regimens. Bismuth-containing quadruple regimens for
7–14 days are another first-line treatment option. Sequential therapy for 10 days has shown promise in Europe but
requires validation in North America. The most commonly used salvage regimen in patients with persistent H.
pylori is bismuth quadruple therapy. Recent data suggest that a PPI, levofloxacin, and amoxicillin for 10 days is
more effective and better tolerated than bismuth quadruple therapy for persistent H. pylori infection, though this
needs to be validated in the United States.
(Am J Gastroenterol 2007;102:1808–1825)

INTRODUCTION AND PREAMBLE ican College of Gastroenterology have produced this up-
Helicobacter pylori (H. pylori) remains one of the most com- dated management guideline to assist clinicians caring for
mon worldwide human infections and is associated with a patients with H. pylori infection. To accomplish this task, lit-
number of important upper gastrointestinal (GI) conditions erature searches using Medline, PubMed, and the Cochrane
including chronic gastritis, peptic ulcer disease, and gastric Database were performed as part of the preparation for this
malignancy. The prevalence of H. pylori is closely tied to management guideline. The document makes summary rec-
socioeconomic conditions and accordingly, this infection is ommendations (italicized statements) followed by a more de-
more common in developing countries than in developed tailed description of the supporting evidence and rationale
countries such as the United States (1). Regardless, it has been for arriving at the topline recommendation. As with all guide-
estimated that 30–40% of the U.S. population is infected with lines, this document attempts to provide the preferred, but not
H. pylori (2). The vast majority of individuals acquire this in- the only, means by which to diagnose and treat H. pylori in-
fection during childhood. Based upon this observation and fection. Specific issues, which may or may not be discussed in
the fact that H. pylori infection rates in children are decreas- this document, will always influence the best course of action
ing, it is likely that the population-based prevalence of H. to be taken in an individual patient.
pylori in the United States will continue to fall in the coming
years. WHAT ARE THE CLEAR INDICATIONS FOR DIAGNOSING
Guidelines for the management of H. pylori infection were
AND TREATING H. PYLORI INFECTION?
last published by the American College of Gastroenterol-
ogy in 1998 (3). Since that time, a significant amount of Recommendation
new information regarding the management of this infection • Testing for H. pylori infection is indicated in patients with
has become available. Because of this, the authors, Practice active peptic ulcer disease, a past history of documented
Parameters Committee, and Governing Board of the Amer- peptic ulcer, or gastric MALT lymphoma.

1808
 Guideline on the Management of Helicobacter pylori Infection 1809

• The test-and-treat strategy for H. pylori infection is a pylori eradication reduces the recurrence of PUD and is cost-
proven management strategy for patients with uninvesti- effective (6).
gated dyspepsia who are under the age of 55 yr and have
no “alarm features” (bleeding, anemia, early satiety, unex-
GASTRODUODENAL BLEEDING. Sharma and col-
plained weight loss, progressive dysphagia, odynophagia,
leagues performed a meta-analysis to compare the effective-
recurrent vomiting, family history of GI cancer, previous
ness of eradicating H. pylori infection with other approaches
esophagogastric malignancy).
to prevent recurrent ulcer hemorrhage as well as a cost mini-
Although the majority of those infected remain clinically mization analysis to determine the least costly strategy. They
silent, there are a number of well-established clinical con- found that H. pylori treatment decreased recurrent bleeding
ditions that have been associated with H. pylori infection. by 17% and 4% compared with ulcer healing treatment alone
The indications for the diagnosis and treatment of H. pylori (bismuth 120 mg q.i.d to ulcer healing, ranitidine 300 mg
infection are listed in Table 1. q.h.s. for 16 wk or omeprazole 20 mg q.d. for 2 wk) or ulcer
healing treatment followed by maintenance therapy (raniti-
dine 150–300 mg q.h.s. or omeprazole 20 mg q.d. for 12–
DUODENAL AND GASTRIC ULCER. There is a clear link 24 months), respectively (7). A 5-yr prospective, randomized,
between H. pylori infection and the pathogenesis of peptic controlled study by Liu et al. in 82 Taiwanese patients with
ulcer disease (PUD) (4). Given the overwhelming evidence a history of ulcer bleeding demonstrated that maintenance
supporting this relationship, few would question the clinical acid suppression was not routinely necessary to prevent ulcer
and economic merits of H. pylori eradication in a patient with recurrence after successful H. pylori eradication and ulcer
PUD. A meta-analysis including 24 randomized controlled healing (8). Results from these studies have been confirmed
trials and randomized comparative trials including 2,102 pa- by a recent Cochrane systematic review (9)
tients with PUD revealed that the 12-month ulcer remission
rate was 97% (95% CI 95–99%) for gastric ulcer, and 98%
Gastric MALT Lymphoma
(95% CI 97–99%) for duodenal ulcer in patients success-
A growing body of literature from nonrandomized observa-
fully eradicated of H. pylori infection, compared with 61%
tional trials supports the importance of H. pylori infection
(95% CI 52–70%) for gastric ulcer and 65% (95% CI 50–
in the pathogenesis and natural history of mucosa associated
65%) for duodenal ulcer in those with persistent infection
lymphoid tissue (MALT) lymphoma (10, 11). For localized
(5). Recently, a meta-analysis by Ford et al., including 52 tri-
gastric MALT lymphoma, H. pylori treatment achieves tu-
als, demonstrated that H. pylori eradication therapy yielded
mor regression in 60–90% of patients (11). Several recent
superior healing rates for duodenal ulcer but not gastric ulcer
prospective studies have addressed the long-term outcome of
compared with short courses of ulcer healing medications
gastric MALT lymphoma after eradication of H. pylori infec-
such as histamine-2 receptor antagoinists (H2 RAs) or pro-
tion. These reports suggest that H. pylori eradication provides
ton pump inhibitors (PPIs). This study found that H. pylori
durable remission in patients with low-grade MALT lym-
eradication was superior to no treatment in preventing duo-
phoma with recurrence rates of 3–13% over 5 yr of follow-
denal and gastric ulcer recurrence. H. pylori eradication was
up (12–14). Finally, Chen and colleagues evaluated a trial of
also superior to maintenance therapy with acid suppressive
24 patients with high-grade transformed tumors (diffuse large
medications in preventing gastric ulcer but not duodenal ul-
B-cell with features of MALT, DLBCL [MALT] lymphoma).
cer recurrence (6). In a Markov model analysis, H. pylori
H. pylori eradication led to complete remission in 64% (95%
eradication was cost-effective for duodenal ulcer over 1 yr
CI 42–86%) (14). Amongst patients with complete remission
and gastric ulcer over 2 yr. The authors concluded that H.
following H. pylori cure, relapse rates were 0% for high-grade
MALT lymphoma after a median follow-up of more than 5 yr.
This is one of the first studies to suggest that H. pylori erad-
Table 1. Indications for Diagnosis and Treatment of H. pylori ication may offer a treatment option not only for low grade
Established MALToma but also for early-stage H. pylori-positive gastric
• Active peptic ulcer disease (gastric or duodenal ulcer) DLBCL (MALT).
• Confirmed history of peptic ulcer disease (not previously
treated for H. pylori)
• Gastric MALT lymphoma (low grade) Uninvestigated Dyspepsia
• After endoscopic resection of early gastric cancer The test-and-treat strategy provides an evidence-based man-
• Uninvestigated dyspepsia (depending upon H. pylori agement strategy for patients with uninvestigated dyspepsia
prevalence)
Controversial who are under the age of 55 yr and have no alarm features.
• Nonulcer dyspepsia For a detailed discussion of the role of H. pylori eradication
• Gastroesophageal reflux disease in the management of uninvestigated dyspepsia, the reader is
• Persons using nonsteroidal antiinflammatory drugs referred to the American College of Gastroenterology’s re-
• Unexplained iron deficiency anemia cently published Practice Guideline on the Management of
• Populations at higher risk for gastric cancer
Dyspepsia (15).
1810 Chey and Wong

WHAT ARE THE AREAS OF CONTROVERSY FOR WHICH Gastroesophageal Reflux Disease (GERD)
THERE MIGHT BE BENEFIT OF ERADICATING H. PYLORI Despite a large number of studies that have addressed this is-
INFECTION? sue, the relationship between H. pylori infection and GERD
remains incompletely defined. It is known that H. pylori in-
• There is evidence to suggest that a small but significant fection results in different levels of severity and patterns of
subgroup of patients with functional dyspepsia will expe- gastric inflammation in different individuals. This in turn can
rience clinical benefit following H. pylori eradication. lead to varied effects on gastric acid secretion. For exam-
• There is no clear evidence to support that eradicating ple, it has been proposed that patients with antral predom-
H. pylori consistently worsens or improves GERD symp- inant gastritis, the phenotype most commonly encountered
toms. Treatment of H. pylori should not be withheld related in the United States, exhibit increased acid secretion and
to concerns of creating or worsening GERD. are at increased risk of developing duodenal ulcer. On the
• H. pylori and NSAIDs are independent risk factors for the other hand, those with corpus-predominant or pangastritis
development of PUD. Therefore, regardless of whether or tend toward decreased acid secretion and a greater risk of
not a patient is taking an NSAID, all patients with a peptic developing gastric cancer (30). As such, eradication of this
ulcer should be tested and when infected, treated for H. infection can be associated with a wide spectrum of effects on
pylori. gastric acid secretion. Whether a patient has abnormal lower
• The available data support an association between H. esophageal sphincter function or esophageal clearance mech-
pylori infection and iron deficiency but do not prove cause anisms, which would predispose to a greater risk of GERD,
and effect. undoubtedly also affects outcomes. In this way, one can envi-
• Though there is some evidence to suggest that curing H. sion scenarios where eradication of H. pylori infection could
pylori may prevent progression of intestinal metaplasia to be associated with worsening, no change, or improvement in
gastric adenocarcinoma, there is no definitive population- GERD. A recent study found that antral predominant gas-
based data to suggest that H. pylori eradication reduces tritis was the most common H. pylori associated phenotype
the incidence of gastric adenocarcinoma. Pursuing H. in functional dyspepsia patients from western countries and
pylori in patients at increased risk for gastric cancer that eradication therapy in this subgroup of patients led to
should be individualized taking into consideration co- overall improvements in heartburn and regurgitation at 1 yr
morbid illness, which might have bearing on the benefits of follow-up (31).
offered by treatment, and patient preferences. Some investigators have suggested that H. pylori status is
inversely related to the likelihood of suffering with GERD
Functional Dyspepsia (FD) (32). Unfortunately, the heterogeneity of the available data
Whether eradicating H. pylori infection is of clinical and eco- makes it difficult to arrive at a confident conclusion on this
nomic benefit in patients with dyspeptic symptoms who have matter. A recent systematic review pointed out that geograph-
undergone a negative structural evaluation remains contro- ical location of the studies contributes to the confusion, as
versial. Whereas some studies observed a beneficial effect GERD patients from the Far East tended to have a lower
(16–19), others have failed to confirm such benefits (20–24). prevalence of H. pylori than patients from Europe or North
The most recent meta-analyses and systematic reviews have America (33).
reported that eradication of H. pylori infection offers a small Regarding the issue of whether eradication of H. pylori
but statistically significant clinical benefit (therapeutic gain infection may provoke or worsen GERD, a recent system-
of H. pylori eradication over placebo = 8%, NNT = 15, RR of atic review by Raghunath et al. including 27 studies con-
remaining symptomatic 0.91 [95% CI 0.86–0.95]) and may cluded that the available evidence does not support an as-
be cost-effective in FD (25, 26). sociation between H. pylori eradication and the develop-
Eradicating H. pylori in patients with FD may offer ben- ment of reflux esophagitis or worsening of heartburn in
efits beyond symptom improvement. Studies have reported patients with a duodenal ulcer (34). Perhaps more rele-
that peptic ulcers develop in 1–14% of patients with FD vant to North America, Laine and colleagues performed a
when followed over extended periods (16, 27–29). A placebo- post hoc analysis of 8 double-blind, prospective U.S. trials
controlled study from Taiwan found that H. pylori eradica- of H. pylori therapy for patients with active DU or a his-
tion reduced the 1 yr incidence of peptic ulcer in patients tory of DU to quantify the development of GERD symp-
with ulcer-like functional dyspepsia but not in those with toms in patients without a prior history of symptomatic
dysmotility-like or unclassifiable FD (28). No such data from GERD or esophagitis (35). They assessed whether GERD
the United States are currently available. symptoms worsened in patients with prior symptomatic
With these thoughts in mind, the decision of whether to test GERD. Their analysis found no difference in the likeli-
for and treat H. pylori in FD should be individualized taking hood of developing new GERD symptoms or esophagitis in
into consideration patient concerns as well as the presence individuals cured of H. pylori infection compared to those
of risk factors for PUD (age, NSAID use) (29) and gastric with persistent infection. Further, they found that H. pylori
malignancy (ethnic background, family history of gastric ma- eradication was not associated with a worsening of symp-
lignancy). toms in those with preexisting GERD. Recent evidence from
 Guideline on the Management of Helicobacter pylori Infection 1811

North America and Europe suggests that esophageal acid ex- P = 0.005). On the other hand, there is evidence to suggest
posure, the severity of erosive esophagitis, and efficacy of that recurrent ulcer bleeding in persons using low-dose as-
proton pump inhibitor therapy is similar in GERD patients pirin is similar 6 months after H. pylori eradication or with
with and without H. pylori infection (36–38). PPI therapy (6 month rate of recurrent bleeding 1.9% for H.
There is no clear evidence to support that a test-and-treat pylori therapy vs 0.9% for PPI therapy, P = NS) (46). For
strategy for H. pylori consistently worsens or improves GERD patients with a history of an ulcer complication who require
symptoms. Therefore, it is reasonable to conclude that ther- subsequent therapy with an NSAID or aspirin, H. pylori erad-
apy for H. pylori should not be withheld related to concerns ication alone may not be a sufficient risk reduction strategy.
of creating or worsening GERD. Co-therapy with a PPI in such patients at high risk for re-
currence of an ulcer complication has been recommended
(44).
Persons Using Nonsteroidal Antiinflammatory Drugs
(NSAIDs) or Aspirin
The interaction between H. pylori infection and NSAIDs in Iron Deficiency Anemia
the pathogenesis of PUD remains controversial. Studies at- A number of studies have suggested a potential association
tempting to clarify this interaction have yielded conflicting between unexplained iron deficiency anemia and H. pylori
results (39–44). The discordant results can, in part, be ex- infection. The explanation most commonly offered for this
plained by differences in study methodology, outcome mea- relationship is based upon the development of H. pylori-
sures, definitions of ulcer, and patient populations. It is also associated chronic pangastritis with resultant achlorhydria
important to realize that there may be differences in clini- and reduced ascorbic acid secretion leading to reduced in-
cal outcomes based upon whether a patient has or has not testinal iron absorption. Other potential explanations for an
previously taken NSAIDs and whether one is contemplating association between iron deficiency and H. pylori include oc-
primary or secondary prophylaxis (40). cult blood loss from erosive gastritis and sequestration and
From a practical standpoint, the clinician is interested in utilization of iron by the organism (47).
knowing whether testing for and treating H. pylori in pa- Recent large studies from North America have reported
tients taking an NSAID will reduce the risk of developing H. pylori infection was an independent risk factor for iron
ulcers or more importantly, ulcer complications. A meta- deficiency anemia in 688 school-aged children from Alaska
analysis, which included data from 25 observational stud- (48) and 7,462 children, adolescents, and adults from the
ies, demonstrated that both H. pylori infection and nonse- United States (49). In the study by Cardenas and colleagues,
lective NSAID use are independent risk factors for the de- H. pylori infection was associated with an increased risk of
velopment of peptic ulcer and ulcer bleeding. Moreover, this iron deficiency anemia (OR 2.6, 95% CI 1.5–4.6). There is
meta-analysis also suggested that these risk factors are at emerging evidence to suggest that eradication of H. pylori can
least additive and possibly synergistic for the development improve iron deficiency anemia (50–52) though this remains
of peptic ulcer and ulcer bleeding (41). In another recent controversial. A recent unblinded study in 219 H. pylori-
meta-analysis of five studies including 939 patients, H. py- infected children (7–11 yr) with pretreatment iron deficiency
lori eradication was associated with a reduced incidence from Alaska found no difference in the likelihood of iron
of peptic ulcer in patients taking NSAIDs (OR 0.43, 95% deficiency or anemia at 2 months or 14 months following a
CI 0.20–0.93). Subanalyses demonstrated that risk reduc- 6-wk course of oral iron and antibiotics or no antibiotics (53).
tion was evident in NSAID-naı̈ve individuals (OR 0.26, 95% The available data support an association between H.
CI 0.14–0.49) but not for those previously taking NSAIDs pylori infection and iron deficiency but do not prove cause
(OR 0.95, 95% CI 0.53–1.72) (42). While H. pylori eradica- and effect. Further properly designed, adequately powered
tion may reduce the risk of PUD, it does not eliminate the randomized trials are needed to assess whether H. pylori
risk of ulcer development or complications in those using an eradication offers benefit to patients with unexplained iron
NSAID. deficiency anemia.
At present, it seems reasonable to recommend that any pa-
tient with an ulcer should be tested for H. pylori regardless Prevention of Gastric Cancer
of whether or not he/she is taking an NSAID or aspirin (44). Whether curing H. pylori infection can reduce the risk of
There are some data to support the identification and treat- developing gastric adenocarcinoma remains unknown (54).
ment of H. pylori in NSAID-naı̈ve patients who are to be However, there have been a number of recent studies that have
treated with an NSAID (45). To date, similar data demon- evaluated the effect of H. pylori eradication on surrogate out-
strating the utility of H. pylori eradication in aspirin-naı̈ve comes such as the severity and distribution of gastritis and
patients starting aspirin are not available. In patients already gastric preneoplastic lesions (multifocal atrophic gastritis,
taking an NSAID, H. pylori eradication appears to be less intestinal metaplasia, or dysplasia) (55–58). In a random-
effective than PPI therapy in reducing the risk of peptic ul- ized, placebo-controlled trial, Leung et al. followed 435 H.
cer recurrence or ulcer bleeding (6 month rate of recurrent pylori-infected patients for 5 yr after a course of anti-H. pylori
bleeding 18.8% for H. pylori therapy vs 4.4% for PPI therapy, therapy or placebo. In a multiple logistic regression analysis,
1812 Chey and Wong

they observed that persistent H. pylori infection (OR 2.13, populations (58). No such evidence is available from regions
95% CI 1.41–3.24), age >45 yr (OR 1.92, 95% CI 1.18– of the world where gastric cancer is rare, such as the United
3.11), alcohol consumption (OR 1.67, 95% CI 1.07–2.62), States.
and drinking local well water (OR 1.74, 95% CI 1.13–2.67) A recent international working group reviewed the litera-
were independent risk factors associated with intestinal meta- ture addressing this topic. The majority of the scientific task
plasia progression. They concluded that H. pylori eradication force favored testing and treating H. pylori in first-degree rel-
was protective against progression of premalignant gastric le- atives of gastric cancer patients. The task force also endorsed
sions in their Chinese population study (55). In a study from the evaluation of the chemopreventive benefits for gastric
Columbia, 795 adults with preneoplastic gastric lesions were malignancy with a more general screen and treat strategy
randomized to anti-H. pylori therapy or antioxidants and were in populations with a high incidence of H. pylori-associated
followed with serial endoscopies over 12 yr. Multivariate diseases (54).
analysis revealed a significant regression in histopathology
score as a function of the square of time without H. pylori
infection. Further, patients treated for H. pylori were 13.7% DIAGNOSIS OF H. PYLORI INFECTION
less likely to experience progression of preneoplastic gas-
• Testing for H. pylori should only be performed if the clin-
tric lesions (57). Wong et al. recruited 1,630 asymptomatic
ician plans to offer treatment for positive results.
H. pylori-infected subjects in a high-risk region of China,
• Deciding which test to use in which situation relies heav-
and randomly allocated them to H. pylori therapy or placebo,
ily upon whether a patient requires evaluation with upper
after which they were followed for 7.5 yr. They reported that
endoscopy and an understanding of the strengths, weak-
gastric cancer developed in 18 cases. There was an abso-
nesses, and costs of the individual tests.
lute reduction in gastric cancer incidence in subjects who
received H. pylori eradication therapy when compared with The methods of diagnostic testing for H. pylori can be
placebo, which was not statistically significant (37% reduc- divided into those that do and those that do not require en-
tion, P = 0.33). However, in a subgroup of H. pylori carriers doscopy. Table 2 provides a list of the available diagnostic
without precancerous lesions at index endoscopy, the inci- tests for H. pylori. There is no single test that can be consid-
dence of gastric cancer was significantly lower in subjects ered the gold standard for the diagnosis of H. pylori. Rather,
receiving eradication therapy than in those receiving placebo the most appropriate test for any specific situation will be
(P = 0.02). This study supports the possibility that H. pylori influenced by the clinical circumstances, the pretest proba-
eradication may reduce the risk of developing gastric cancer bility of infection, as well as the availability and costs of the
in individuals without precancerous lesions from high-risk individual diagnostic tests.

Table 2. Diagnostic Testing for Helicobacter pylori

Endoscopic Testing Advantages Disadvantages
∗
1. Histology Excellent sensitivity and specificity Expensive and requires infrastructure and
trained personnel
∗
2. Rapid urease testing Inexpensive and provides rapid results. Excellent Sensitivity significantly reduced in the
specificity and very good sensitivity in properly posttreatment setting
selected patients
∗
3. Culture Excellent specificity. Allows determination of Expensive, difficult to perform, and not widely
antibiotic sensitivities available. Only marginal sensitivity
∗
4. Polymerase chain reaction Excellent sensitivity and specificity. Allows Methodology not standardized across
determination of antibiotic sensitivities laboratories and not widely available

Nonendoscopic Testing Advantages Disadvantages

1. Antibody testing (quantitative Inexpensive, widely available, very good NPV PPV dependent upon background H. pylori
and qualitative) prevalence. Not recommended after H. pylori
therapy
∗
2. Urea breath tests (13 C and Identifies active H. pylori infection. Excellent PPV Reimbursement and availability remain
14
C) and NPV regardless of H. pylori prevalence. inconsistent
Useful before and after
H. pylori therapy
∗
3. Fecal antigen test Identifies active H. pylori infection. Excellent Polyclonal test less well validated than the UBT
positive and negative predictive values regardless in the posttreatment setting. Monoclonal test
of H. pylori prevalence. Useful before and after H. appears reliable before and after antibiotic
pylori therapy therapy. Unpleasantness associated with
collecting stool
∗
The sensitivity of all endoscopic and nonendoscopic tests that identify active H. pylori infection is reduced by the recent use of PPIs, bismuth, or antibiotics
PPI = proton pump inhibitor; PPV = positive predictive value; NPV = negative predictive value; UBT = urea breath test.
 Guideline on the Management of Helicobacter pylori Infection 1813

Endoscopic Diagnostic Tests been performed to define the duration of a PPI’s deleterious
• In patients who have not been on a PPI within 1–2 wk effects on the sensitivity of the RUT. Data with the urea breath
or an antibiotic or bismuth within 4 wk of endoscopy, the test (UBT) suggest that PPI therapy can cause false-negative
rapid urease test (RUT) provides an accurate, inexpensive test results for 1–2 wk (68, 69). As the UBT and RUT rely
means of identifying H. pylori. upon the identification of H. pylori’s urease activity, it is rea-
• For patients who have been taking a PPI, antibiotics, or sonable to suggest that PPIs should be withheld for 1–2 wk
bismuth, endoscopic testing for H. pylori should include before performance of the RUT. In situations where a patient
biopsies from the gastric body and antrum for histology has not taken a PPI for a period of 1–2 wk before their proce-
with or without rapid urease testing. dure, the sensitivity of the RUT is likely sufficient to justify
• Though culture or polymerase chain reaction (PCR) are its use as a single test for H. pylori.
the primary means by which antibiotic sensitivities can
be determined, neither is widely available for clinical use
Histology
in the United States and therefore, cannot be routinely
Histology has been considered by some to be the gold stan-
recommended.
dard for detection of H. pylori (70). Unfortunately, histology
There are presently four biopsy-based diagnostic methods is an imperfect gold standard as the detection of H. pylori
for H. pylori infection. These include the RUT, histology, relies upon a number of issues including the site, number,
culture, and PCR. and size of gastric biopsies, method of staining, and the level
of experience of the examining pathologist (70). A signifi-
cant advantage of histology over other diagnostic methods is
Rapid Urease Testing
the ability to evaluate for pathologic changes associated with
The RUT identifies active H. pylori infection through the or-
H. pylori infection such as inflammation, atrophy, intestinal
ganism’s urease activity. Gastric biopsies are obtained and
metaplasia, and malignancy (71). In fact, some have argued
placed into an agar gel or on a reaction strip containing urea,
that type B chronic gastritis (nonatrophic diffuse antral gastri-
a buffer, and a pH-sensitive indicator. In the presence of
tis or atrophic pangastritis) can be used as a surrogate marker
H. pylori’s urease, urea is metabolized to ammonia and bicar-
for the infection when organisms are not identified (72). Cer-
bonate leading to a pH increase in the microenvironment of
tainly the absence of chronic gastritis is a potent negative
the organism. A change in color of the pH sensitive indica-
predictor for the presence of H. pylori infection.
tor signifies the presence of active infection. Commercially
As the prevalence and density of H. pylori varies through-
available kits yield results in 1–24 h.
out the stomach, particularly in the face of medications that
There are a number of commercially available RUT kits in
may reduce the density of H. pylori, multiple biopsies are
the United States including the CLOtest, HpFast, HUT-test,
needed for accurate diagnosis. It is therefore recommended
Pronto Dry, and Pyloritek with overall pretreatment sensitiv-
that a minimum of three biopsies be obtained, one from the
ities of >90% and specificities of >95% (59, 60). Though
anglularis, one from the greater curvature of the corpus, and
the overall performance of the different tests is comparable,
one from the greater curvature of the antrum, to maximize the
there are some practical differences between the individual
diagnostic yield of histology (70). A recent study found that
tests (61).
the addition of corpus biopsies to antral biopsies increased
Medications that reduce the density and/or urease activity
the detection of H. pylori infection by ∼10% when com-
of H. pylori, such as bismuth-containing compounds, antibi-
pared with antral biopsies alone (73). Similar to the RUT,
otics, or PPIs, can decrease the sensitivity of the RUT by up to
the sensitivity of histology is significantly affected by the use
25% (59). Though controversial, acute ulcer bleeding at the
of medications such as bismuth, antibiotics, and PPIs (67).
time of testing may decrease the sensitivity and negative pre-
Although widely available and capable of achieving sensitiv-
dictive value of the RUT (62–66). As a result of the patchy
ity and specificity of >95%, the cost and need for properly
distribution of H. pylori infection after antibiotics or PPIs,
trained personnel are limitations of histology in clinical prac-
it is recommended that biopsies for the RUT be obtained
tice.
from two sites, the body at the gastric anglularis and greater
curvature of the antrum (67). The simplicity, low cost, and
relatively rapid results make the RUT a practical and cost- Culture
effective means of testing for H. pylori in patients not taking Culture is another highly specific method for identifying ac-
antibiotics, bismuth, or PPIs who require upper endoscopy. tive H. pylori infection. Conceptually, culture is attractive
Unfortunately, the usefulness of the RUT in routine clinical because it not only provides a means by which to identify
practice has been compromised by the widespread use of PPIs infection, but also allows characterization of antimicrobial
as an empiric treatment for upper GI symptoms. As such, sensitivities (74). Unfortunately, culture is not as sensitive
the RUT can rarely be used as a sole means of identifying as RUT or histology (75, 76). Furthermore, culturing tech-
H. pylori infection. More commonly, the RUT is combined niques for H. pylori are demanding and costly and as a con-
with other endoscopic or nonendoscopic modalities to estab- sequence, only available in a limited number of clinical lab-
lish the presence or absence of this infection. No studies have oratories. Nonculture-based means of determining antibiotic
1814 Chey and Wong

resistance are being developed but have not been adequately

standardized and are not widely available.

Polymerase Chain Reaction

PCR is a DNA amplification technique that utilizes the rapid
production of multiple copies of a target DNA sequence to
identify H. pylori. This testing method is highly specific and
may be more sensitive than other biopsy-based diagnostic
techniques. A recent study found that PCR was able to de-
tect H. pylori in approximately 20% of gastric biopsies with Figure 1. Effect of H. pylori prevalence on the positive predictive
chronic gastritis but no identifiable organisms by histology value (PPV) of antibody testing (where sensitivity = 85% and speci-
(77). PCR also provides a means of identifying mutations ficity = 79%) (144).
associated with antimicrobial resistance (78–80). Although
presently restricted to the research arena, this method may
some day provide a practical, reproducible method for an- (83). Three of the qualitative whole blood antibody kits were
tibiotic sensitivity testing, organism typing, and organism directly compared in another study demonstrating sensitivi-
virulence testing (81). ties ranging from 76% to 84% and specificities of 79–90%
(84). In general, performance characteristics for the quali-
Nonendoscopic Diagnostic Tests tative office-based tests have been more variable than those
• Antibody testing is inexpensive and widely available but yielded by the quantitative tests. It is very important to under-
poor PPV in populations with a low prevalence of H. pylori stand that the PPV of antibody testing is greatly influenced by
infection limits its usefulness in clinical practice. the prevalence of H. pylori infection (85) (Fig. 1). This issue
• The UBTs and fecal antigen tests provide reliable means will be further discussed in the section addressing the use of
of identifying active H. pylori infection before antibiotic diagnostic testing in clinical practice. Further, antibody tests
therapy. developed using antigens from one region of the world may
• The UBT is the most reliable nonendoscopic test to docu- not perform well when applied to patients in another part of
ment eradication of H. pylori infection. the world suggesting that local validation may be necessary
• The monclonal fecal antigen test provides another nonen- (75, 86). Finally, antibody tests are of little benefit in docu-
doscopic means of establishing H. pylori cure after antibi- menting eradication as results can remain positive for years
otic treatment. following successful cure of the infection (82).
• Testing to prove H. pylori eradication appears to be most
accurate if performed at least 4 wk after the completion of Urea Breath Tests
antibiotic therapy. The UBT, like the RUT, identifies active H. pylori infection
by way of the organism’s urease activity. In the presence of
There are currently three nonendoscopic diagnostic testing H. pylori, the ingestion of urea, labeled with either the non-
methods for H. pylori infection. Antibody testing identifies an radioactive isotope 13 C or the radioactive isotope 14 C, results
immunological reaction to the infection while the nonendo- in production of labeled CO2 , which can be quantitated in
scopic urease tests and fecal antigen test identify the presence expired breath (87–90). Although the amount of radiation in
of active H. pylori infection. the 14 C UBT is less than daily background radiation expo-
sure (88), the 13 C test is preferred in children and pregnant
Antibody Tests females (87). Overall, the performance characteristics of both
Antibody testing relies upon the detection of IgG antibodies tests are similar with sensitivity and specificity typically ex-
specific to H. pylori in serum, whole blood, or urine. IgG an- ceeding 95% in most studies (87, 88). Test reproducibility has
tibodies to H. pylori typically become present approximately been found to be excellent (89). The UBT also provides an
21 days after infection and can remain present long after accurate means of posttreatment testing (90–93). Most tests
eradication (82). Antibodies to H. pylori can be quantita- utilize a citrate test meal (50–75 mg), which is administered
tively assessed using enzyme-linked immunosorbent assay before the labeled urea (87). A urease blood test, which relies
(ELISA) and latex agglutination techniques or qualitatively upon the detection of labeled bicarbonate in a blood sam-
assessed using office-based kits. The advantages of the an- ple, also reliably identifies active H. pylori infection before
tibody tests are their low cost, widespread availability, and and after treatment (94, 95). As the nonendoscopic urease
rapid results. Unfortunately, several factors limit the useful- tests rely upon the identification of H. pylori’s robust urease
ness of antibody testing in clinical practice. A meta-analysis activity, test sensitivity is decreased by medications that re-
evaluated the performance characteristics of several commer- duce organism density or urease activity, including bismuth
cially available quantitative serological assays and found their containing compounds, antibiotics, and PPIs. It is currently
overall sensitivity and specificity to be 85% and 79%, re- recommended that bismuth and antibiotics be withheld for at
spectively, with no differences between the different assays least 28 days and a PPI for 7–14 days prior to the UBT (68,
 Guideline on the Management of Helicobacter pylori Infection 1815

Table 3. Performance Characteristics of the Fecal Antigen Test (95) When testing for H. pylori in populations with a low pretest
# Studies / probability of infection, the FAT provides greater accuracy
# Patients Sensitivity Specificity PPV NPV than serologic testing with only a modest increase in incre-
mental costs (107). Similar to the UBT, the sensitivity of the
Pretreatment
Polyclonol 89/10,858 91 93 92 87 FAT is affected by the recent use of bismuth compounds, an-
Monoclonol 8/1,399 96 97 96 97 tibiotics, and PPIs (108, 109). Recent studies also suggest
Posttreatment that the specificity of the FAT is reduced in the setting of
Polyclonol 39/3,147 86 92 76 93 bleeding PUD and, for this reason, should not be the sole
Monoclonol 6/418 95 97 91 98 diagnostic test employed in this setting (110–113). Although
PPV = positive predictive value; NPV = negative predictive value. the FAT is simple to administer and perform, issues slowing
its widespread use include the unpleasantness of handling
69, 96). It is controversial whether H2 RAs affect the sensi- and storing stool, limited availability, and variable state-to-
tivity of the UBT (97–99) though many laboratories recom- state reimbursement. The development of in-office stool tests
mend withholding these drugs for 24–48 h before the UBT. is under way and may improve upon some of the practical
Antacids do not appear to affect the accuracy of the UBT limitations of the currently available tests (102). At present,
(100). Aside from the issues just discussed, other factors af- in-office tests have not been adequately validated in clinical
fecting the acceptance of the UBT in clinical practice include trials.
the need for infrastructure to perform the test, the need for Based upon the available data, it is reasonable to conclude
a patient to attend an additional outpatient visit to undergo that the FAT can be used interchangeably with the UBT to
the test, and cost. At current levels of reimbursement in the identify H. pylori before antibiotic therapy. The polyclonal
United States, the UBT is more costly than the antibody tests FAT has been less well validated than the UBT in the post-
or fecal antigen test. The expense of the UBT is largely driven treatment setting. Compared with the polyclonal test, the
by equipment costs and the cost of labeled urea. UBTs using monoclonal FAT appears to provide a more reliable means
lower dose 13 C, which have recently been found to yield ex- of proving H. pylori eradication.
cellent performance characteristics, may in part address this
issue (101).
H. PYLORI TESTING IN CLINICAL PRACTICE
Fecal Antigen Test Testing When There Is a Need for Endoscopy
The fecal antigen test (FAT) identifies H. pylori antigen in If endoscopy is necessary based upon the patient’s clinical
the stool by enzyme immunoassay with the use of polyclonal presentation, biopsy-based endoscopic tests are most appro-
anti-H. pylori antibody. Recently, a stool test utilizing a mon- priate. Provided the patient has not been on recent bismuth,
oclonal anti-H. pylori antibody has been evaluated (102, 103). antibiotics, or a PPI, the RUT offers the desirable combination
As both tests detect bacterial antigen(s) suggestive of ongo- of accuracy and low cost. If there are mucosal abnormalities
ing infection, they can be used to screen for infection and identified at the time of endoscopy, which require further his-
as a means of establishing cure following therapy. A recent tologic evaluation, biopsies should be obtained for histology.
systematic review (102) reported performance characteris- Unfortunately, most patients referred for upper endoscopy
tics of the FAT before and after eradication therapy (Table 3). are taking acid-suppressive agents such as a PPI or H2 RA
While this analysis demonstrated excellent sensitivity, speci- or have recently received drugs that can suppress H. pylori
ficity, positive and negative predictive values for the poly- (antibiotics or bismuth). In such patients, it is appropriate to
clonal test before treatment, sensitivity and PPV were less obtain biopsies for histology with or without RUT or plan
satisfactory after treatment. On the other hand, the mono- testing with a UBT or FAT at a later date after withholding
clonal test yielded sensitivity, specificity, and predictive val- the offending agents for an appropriate period of time.
ues greater than 90% before and after treatment. The precise In the setting of an active ulcer bleed, there are case se-
explanations for the differences in accuracy between the poly- ries and cohort studies that suggest that the sensitivity of the
clonal and monoclonal tests remain unclear but may have to RUT and, to a lesser extent, histology may be reduced (62,
do with the need for intraperitoneal injection of H. pylori 63, 114, 115). These studies suggest that although positive
antigens into rabbits to produce antibodies for the polyclonal results reliably identify the presence of H. pylori infection,
assay (102). The FAT has been approved by the U.S. Food and the likelihood of false-negative results may be increased in
Drug Administration and endorsed by the European “Maas- the setting of acute upper gastrointestinal bleeding. A recent
tricht 2–2000 Consensus Report” as an alternative means of prospective cohort study from the United States did not con-
establishing H. pylori cure to urea breath testing (104). Recent firm findings from previous studies (65). In this study, 61
studies indicate that the FAT may be effective in confirming patients with variceal hemorrhage underwent biopsy-based
eradication as early as 14 days after treatment (105, 106). H. pylori testing during an initial endoscopy for acute bleed-
However, there is evidence to suggest that the FAT should be ing and again 1 month later. The sensitivities of RUT and
done more than 4 wk and perhaps as long as 8–12 wk after histology performed during acute bleeding and 1 month later
treatment of H. pylori (102). were not significantly different. However, it is notable that
1816 Chey and Wong

the sensitivity of the RUT in this study was relatively low • Any patient with an H. pylori-associated ulcer.
at both time points (initial RUT = 79%, follow-up RUT = • Individuals with persistent dyspeptic symptoms despite
71%). Regardless of which results one chooses to believe, it the test-and-treat strategy.
is important to emphasize that a positive RUT indicates the • Those with H. pylori-associated MALT lymphoma.
presence of active H. pylori infection. On the other hand, a • Individuals who have undergone resection of early gastric
negative RUT and/or histology in the setting of acute upper cancer.
GI bleeding should be confirmed with another test. An anti-
body test provides a reasonably sensitive nonendoscopic test- When confirmation of eradication is necessary, testing
ing option. In this setting, because the pretest probability of should generally be performed no sooner than 4 wk after
H. pylori infection is high in a patient with an ulcer, the PPV the completion of treatment. Because of its high cost, endo-
of an antibody test is reasonably high (Fig. 1). Alternatively, scopic tests should only be used if endoscopy is clinically
a patient can undergo a UBT or FAT at a later date after indicated for other reasons. If testing to prove eradication
withholding medications that can negatively affect the sensi- were performed in the setting of endoscopy, most would ad-
tivity of these tests for an appropriate period of time. Recent vocate using histology or the combination of histology and
work suggests that engaging in such a practice significantly RUT as RUT alone has reduced sensitivity in the posttreat-
increases the detection of H. pylori infection in patients with ment setting (119). When endoscopic follow-up is unneces-
recent ulcer bleeding. A recent retrospective study from Spain sary, testing to prove eradication of H. pylori infection is best
found that 57 of 72 (79%) patients with ulcer bleeding and no accomplished with the UBT. The FAT provides an alterna-
evidence of H. pylori on emergency endoscopy had a positive tive means of establishing eradication though, as has already
“delayed” UBT (116). been discussed, the timing and reliability of this test have
not been as clearly demonstrated as for the UBT. Because
Testing in Patients With Uninvestigated Dyspepsia antibody tests can remain positive for prolonged periods fol-
Primary care providers are frequently asked to evaluate lowing successful cure of H. pylori infection, they should be
avoided in the posttreatment setting. If antibody testing is
and treat patients with uninvestigated dyspepsia. The test-
performed in the posttreatment setting, only a negative re-
and-treat strategy for H. pylori has been endorsed for the
sult is reliable. A positive result should be confirmed with a
management of uninvestigated dyspepsia by a number of
UBT or FAT before offering antibiotic therapy for presumed
organizations, including the American Gastroenterological
persistent infection.
Association (117) and the American College of Gastroen-
terology (15). For a detailed discussion regarding H. pylori
testing in patients with uninvestigated dyspepsia, the reader
TREATMENT OF H. PYLORI INFECTION
is referred to these recent publications (15, 117). Both docu-
ments emphasize that in regions where the prevalence of H. Primary Treatment of H. pylori Infection
pylori infection is high, such as urban areas or communities • In the United States, the recommended primary therapies
with large immigrant populations, the PPV of antibody test- for H. pylori infection include: a PPI, clarithromycin, and
ing is reasonably good and therefore provides an acceptable amoxicillin, or metronidazole (clarithromycin-based triple
means of screening for H. pylori infection. However, in re- therapy) for 14 days or a PPI or H 2 RA, bismuth, metron-
gions where H. pylori prevalence is low, the PPV of antibody idazole, and tetracycline (bismuth quadruple therapy) for
testing is poor (85). From a pragmatic standpoint, this means 10–14 days.
that if a physician practices in a community with an H. pylori • Sequential therapy consisting of a PPI and amoxicillin for
prevalence of less than ∼20%, as is the case in much of the 5 days followed by a PPI, clarithromycin, and tinidazole
United States, though a negative antibody test suggests the for an additional 5 days may provide an alternative to
absence of infection, a positive test is no better than a coin clarithromycin-based triple or bismuth quadruple therapy
toss in predicting the presence of active infection (Fig. 1). As but requires validation within the United States before it
such, in low prevalence populations, antibody tests should can be recommended as a first-line therapy.
be avoided altogether or positive results should be confirmed The first course of therapy offers the greatest likelihood of
with a test that identifies active infection such as the UBT or eradicating H. pylori infection. Subsequent treatment trials,
FAT prior to initiating eradication therapy (117, 118). particularly if the same antibiotics are utilized or if the patient
has been previously exposed to any antibiotics contained in
Testing to Prove Eradication After Antibiotic Therapy the treatment regimen, are less likely to achieve a success-
In an ideal world, all patients treated for H. pylori infection ful outcome. As such, it is important to only use treatment
would undergo testing to prove eradication of the infection. regimens for which there is evidence of proven effectiveness
Unfortunately, universal posttreatment testing is neither prac- (120).
tical nor cost-effective. Since publication of the last ACG In the United States, the recommended primary therapies
guideline on H. pylori infection (3), the accepted indications for H. pylori infection include: a PPI, clarithromycin, and
for testing to prove eradication after antibiotic therapy, largely amoxicillin or metronidazole (clarithromycin-based triple
based upon expert consensus, have broadened to include: therapy) or a PPI or H2 RA, bismuth, metronidazole, and tetra-
 Guideline on the Management of Helicobacter pylori Infection 1817

Table 4. First-Line Regimens for Helicobacter pylori Eradication

Regimen Duration Eradication Rates Comments
Standard dose PPI b.i.d. (esomeprazole is q.d.), 10–14 70–85% Consider in nonpenicillin allergic patients who
clarithromycin 500 mg b.i.d., amoxicillin 1,000 mg b.i.d. have not previously received a macrolide
Standard dose PPI b.i.d., clarithromycin 500 mg b.i.d. 10–14 70–85% Consider in penicillin allergic patients who
metronidazole 500 mg b.i.d. have not previously received a macrolide or
are unable to tolerate bismuth quadruple
therapy
Bismuth subsalicylate 525 mg p.o. q.i.d. metronidazole 10–14 75–90% Consider in penicillin allergic patients
250 mg p.o. q.i.d., tetracycline 500 mg p.o. q.i.d.,
ranitidine 150 mg p.o. b.i.d. or standard dose
PPI q.d. to b.i.d.
PPI + amoxicillin 1 g b.i.d. followed by: 5 >90% Requires validation in North America
PPI, clarithromycin 500 mg, tinidazole 500 mg b.i.d. 5
PPI = proton pump inhibitor; pcn = penicillin; p.o. = orally; q.d. = daily; b.i.d. = twice daily; t.i.d. = three times daily; q.i.d. = four times daily.
∗
Standard dosages for PPIs are as follows:
lansoprazole 30 mg p.o., omeprazole 20 mg p.o., pantoprazole 40 mg p.o., rabeprazole 20 mg p.o., esomeprazole 40 mg p.o.
Note: the above recommended treatments are not all FDA approved. The FDA approved regimens are as follows:
1. Bismuth 525 mg q.i.d. + metronidazole 250 mg q.i.d. + tetracycline 500 mg q.i.d. × 2 wk + H2 RA as directed × 4 wk.
2. Lansoprazole 30 mg b.i.d. + clarithromycin 500 mg b.i.d. + amoxicillin 1 g b.i.d. × 10 days.
3. Omeprazole 20 mg b.i.d. + clarithromycin 500 mg b.i.d. + amoxicillin 1 g b.i.d. × 10 days.
4. esomeprazole 40 mg q.d. + clarithromycin 500 mg b.i.d. + amoxicillin 1 g b.i.d. × 10 days.
5. Rabeprazole 20 mg b.i.d. + clarithromycin 500 mg b.i.d. + amoxicillin 1 g b.i.d. × 7 days.

cycline (bismuth quadruple therapy). Details regarding these associated with reduced eradication rates and are not recom-
regimens can be found in Table 4. When given at the recom- mended. The currently available PPIs perform comparably
mended doses, most recent studies report intention-to-treat when used in these regimens (128, 129). Data from a recent
(ITT) eradication rates in the range of 70–80% (121–124). meta-analysis of 13 studies suggests that b.i.d. dosing of a PPI
Large randomized trials suggest that the inclusion of amoxi- in clarithromycin-based triple regimens is more effective than
cillin or metronidazole yields similar results when combined q.d. dosing (130). Pretreatment with a PPI prior to a course
with a PPI and clarithromycin (125). Though international of H. pylori eradication therapy does not appear to adversely
guidelines have recommended treatment durations of at least influence treatment outcomes (131). Further, it appears that
7 days, treatment durations of 10–14 days have typically been an H2 RA can be substituted if a patient cannot tolerate a PPI
employed in the United States (3). A recent large trial from the (132).
United States, which evaluated the combination of rabepra- Bismuth quadruple therapy has been advocated as a pri-
zole, clarithromycin, and amoxicillin, found that 7 and 10 mary therapy for H. pylori (133). Bismuth quadruple ther-
days of therapy yielded equivalent eradication rates. The ITT apy offers eradication rates that are similar to clarithromycin
eradication rate for 7 days was 77% (95% CI 71–83%) versus triple therapy. A recent meta-analysis including 5 random-
78% (95% CI 72–84%) for the 10-day regimens. This study ized trials reported ITT and per protocol (PP) eradication
also reported an eradication rate of 27% for a 3-day treat- rates of 79% (95% CI 74–81%) and 85% (95% CI 81–
ment regimen (123). A recent meta-analysis of seven studies 88%) for clarithromycin triple therapy and 80% (95% CI
involving more than 900 patients found that a 14-day course 77–84%) and 87% (95% CI 84–91%) for bismuth quadru-
of clarithromycin triple therapy provided better eradication ple therapy, respectively (134). Though this regimen has
rates than a 7-day course of therapy (Peto OR 0.62 favors been evaluated with an H2 RA or PPI, a recent meta-analysis
14 vs 7 days of therapy for eradication of H. pylori infec- found that quadruple therapy with a PPI provides greater
tion [95% CI 0.45–0.84]). There was also a trend towards efficacy in patients with metronidazole-resistant H. pylori
improved efficacy with 10 days of therapy compared with 7 strains (135). A criticism of this regimen involves its com-
days of therapy, which did not reach statistical significance plexity (q.i.d. dosing regimen and high pill count) and per-
(126). The superiority of 14-day versus 7-day treatment du- ceived frequency of side effects. A simplified 14-day b.i.d.-
ration has been confirmed by a recent large randomized sin- dosing regimen recently evaluated by Graham and colleagues
gle center trial from Italy (127). As a result of the falling in the United States achieved an eradication rate of 92% (95%
eradication rates with clarithromycin-based triple therapy, it CI 79–98%) (136). Another recent study reported compara-
is essential to take every opportunity to optimize treatment ble eradication rates with a novel triple antibiotic capsule
success. Given the results of this meta-analysis, it seems pru- given t.i.d. and a PPI b.i.d. for 10 days (137). Although mi-
dent to recommend a 14-day course of clarithromycin triple nor side effects with bismuth-based quadruple therapy occur
therapy, particularly in the United States where eradication commonly, the frequency of moderate or severe side effects
rates have typically been 80% or less with shorter durations is no greater than with clarithromycin-based triple therapy
of therapy. Treatment durations of less than 7 days are clearly (133).
1818 Chey and Wong

It seems reasonable to consider a PPI, clarithromycin, and fects associated with amoxicillin include GI upset, headache,
amoxicillin in patients who have not previously received clar- and diarrhea. Side effects of metronidazole tend to be dose
ithromycin and who are not allergic to penicillin. For patients related and include a metallic taste in the mouth, dyspep-
allergic to penicillin, metronidazole can be substituted for sia, and a disulfiram-like reaction with alcohol consumption.
amoxicillin. Bismuth quadruple therapy should be favored in Common side effects of tetracycline include GI upset and
those allergic to penicillin or in those who have previously photosensitivity. This antibiotic should not be used in chil-
been treated with a macrolide antibiotic. dren under 8 yr of age because of possible tooth discoloration.
Unfortunately, eradication rates yielded by clarithromycin- Finally, bismuth compounds have been associated with dark-
based triple therapy or bismuth-based quadruple therapy are ening of the tongue and stool, nausea, and GI upset (145).
less than 85% and may be decreasing. As such, alternative Informed patients are less likely to be alarmed when side
primary therapies are necessary. Several studies from Italy effects that they are aware of occur and, consequently, less
have reported eradication rates exceeding 90% with a novel likely to needlessly stop their treatment.
sequential therapy consisting of a PPI and amoxicillin for 5 Antibiotic resistance must also be carefully considered
days followed by a PPI, clarithromycin, and tinidazole for when choosing amongst the various anti-H. pylori treatment
an additional 5 days. Whether metronidazole or other imi- regimens. A recent multicenter U.S. study which collected
dazoles can be used in place of tinidazole has not yet been data from 1993 to 1999 reported antibiotic resistance rates
established. This regimen has achieved eradication rates su- amongst H. pylori strains of 37% for metronidazole, 10%
perior to clarithromycin-based triple therapy and was well for clarithromycin, 3.9% for both antibiotics, and 1.4% for
tolerated in children, adults, and elderly patients infected amoxicillin (146). Subsequent data collected from 1998 to
with H. pylori (138–141). Further, sequential therapy may 2002 yielded resistance rates of 25% for metronidazole, 13%
be superior to clarithromycin triple therapy in patients with for clarithromycin, 5% for at least 2 antibiotics, and 0.9%
clarithromycin-resistant H. pylori strains. A post hoc anal- for amoxicillin (147). Though these data sets are difficult to
ysis from a large multicenter trial evaluated the efficacy of directly compare, it appears that metronidazole and amoxi-
sequential therapy versus clarithromycin triple therapy (82% cillin resistance have remained relatively stable while clar-
[18/22] vs 44% [7/16], P < 0.0155) in a subset of patients ithromycin resistance has increased. The increasing back-
with clarithromycin-resistant H. pylori (142). In the available ground rate of clarithromycin resistance provides at least a
studies, the reported compliance with therapy has exceeded partial explanation for the decreasing efficacy of traditional
90% and side effects have been no greater than those expe- clarithromycin-containing regimens. It is quite clear that clar-
rienced with clarithromycin triple therapy. Several important ithromycin resistance, which has been attributed to several
questions remain to be answered regarding this promising different point mutations in the peptidyltransferase region en-
regimen before it can be accepted as a standard first-line ther- coded in domain V of the 23S rRNA gene (142), is associated
apy in the United States. Perhaps most importantly, validation with a high rate of treatment failure when clarithromycin-
of this promising new therapy in North America is necessary. containing regimens are employed (148–150). On the other
In addition, it is not clear that there is any incremental benefit hand, metronidazole resistance appears to be more relative.
to providing antibiotic therapy sequentially rather than as a To some extent, metronidazole resistance can be overcome by
concurrent quadruple regimen. the use of higher doses of metronidazole and/or the addition
of a PPI to bismuth, tetracycline, and metronidazole (143).
Predictors of H. pylori Treatment Outcome An important study found that previous treatment with either
The most important predictors of treatment failure following a macrolide or metronidazole for any reason significantly in-
anti-H. pylori therapy include poor compliance and antibiotic creased the likelihood of H. pylori resistance to these agents
resistance. There is limited evidence to suggest that smoking, (151). As such, clinicians should routinely ask about previ-
alcohol consumption, and diet may also adversely affect the ous macrolide or metronidazole use when deciding upon an
likelihood of successful eradication (143). H. pylori treatment regimen. Further, it seems reasonable to
It is critical for clinicians to stress the importance of tak- consider bismuth quadruple therapy with a PPI or sequential
ing the medications as prescribed to minimize the likelihood therapy in individuals who have previously been treated with
of treatment failure and development of antibiotic resistance. clarithromycin or metronidazole.
Patients should also be informed of the most commonly re- Recent data suggest that bacterial and host factors also in-
ported treatment-related side effects. While mild side effects fluence treatment outcomes. A systematic review and meta-
are very common with any of the recommended H. pylori analysis including 14 studies (1,529 patients) found that
treatment regimens, significant side effects are reported in CagA-negative strains of H. pylori were associated with an
only 5–20% (144). The most commonly reported side effects increased risk of treatment failure compared with CagA-
with the PPIs include headache and diarrhea, occurring in up positive strains (risk ratio of treatment failure 2.0, 95% CI
to 10% of patients. To optimize their effects on gastric acid 1.6–2.4) (152). Another meta-analysis found that CYP2C19
secretion, PPIs should be taken 30–60 minutes before eating. polymorphisms, which influence the clearance of PPIs and
The most frequent side effects reported with clarithromycin thus their effect on gastric acid secretion, could influence
include GI upset, diarrhea, and altered taste. Common side ef- treatment outcomes when regimens containing a PPI are used
 Guideline on the Management of Helicobacter pylori Infection 1819

(153). These observations are of greatest importance to far and duration of therapy vary between studies. Further, the
eastern countries where the extensive metobolizer status is available studies often do not clearly report how many times
more common. Further, the inability of the clinician to readily or with which antibiotics a patient has previously been treated.
determine CagA status of H. pylori or the cytochrome P450 As has already been discussed, disadvantages of bismuth-
status of their patients makes these observations unlikely to based quadruple therapy include the large daily pill count
change clinical practice in the immediate future. (potentially exceeding 18 pills), dosing frequency (typically
four times daily), and frequent side effects. In the hopes of
Salvage Therapy for Persistent H. pylori Infection addressing some of these issues, a simplified twice-daily reg-
• In patients with persistent H. pylori infection, every ef- imen was recently evaluated and reported to yield an eradi-
fort should be made to avoid antibiotics that have been cation rate of over 90% in patients who had received at least
previously taken by the patient. 2 previous courses of antibiotic therapy (155). Though most
• Bismuth-based quadruple therapy for 7–14 days is an ac- international studies have utilized this regimen for 7 days
cepted salvage therapy. (104), a 10–14 day course is still most commonly employed
• Levofloxacin-based triple therapy for 10 days is another in the United States.
option in patients with persistent infection, which requires A number of recent studies have evaluated alternatives to
validation in the United States. bismuth-based quadruple salvage therapy. Rifabutin, an an-
tibiotic used in the treatment of tuberculosis, has been uti-
When faced with a patient who has failed an initial course lized as an alternative to clarithromycin in several small stud-
of therapy for H. pylori, the clinician should avoid using an- ies with eradication rates ranging from 38% to 91% (156–
tibiotics employed in previous treatment regimens. Because 159). In a recent study from Australia, 137 patients who had
of the expense and lack of availability, culture and antibiotic failed therapy with omeprazole, clarithromycin, and amoxi-
sensitivity testing are typically not performed unless a patient cillin were treated with a 12-day course of rifabutin 150 mg,
has failed at least 2 courses of therapy. Even in this circum- pantoprazole 80 mg, and amoxicillin 1 g or 1.5 g daily.
stance, the usefulness of such testing is arguable as there is no The overall eradication rate was 91% and the presence of
evidence to suggest that choosing a salvage regimen based clarithromycin or metronidazole resistance did not influ-
upon an understanding of the patient’s previous antibiotic ence the likelihood of treatment success (160). The most
exposure is any less successful than choosing an antibiotic common side effects with rifabutin include rash and gas-
regimen based upon the results of antimicrobial sensitivity trointestinal complaints including nausea, vomiting, dys-
testing. Recommendations regarding salvage therapy regi- pepsia, and diarrhea. Rifabutin has been associated with
mens are provided in Table 5. rare but potentially serious myelotoxicity and ocular toxicity
If a patient with persistent infection has not been previ- (161, 162).
ously treated with clarithromycin, triple therapy with a PPI, Patients should be warned about the possibility of red dis-
clarithromycin, and amoxicillin or metronidazole can be con- coloration of urine while taking rifabutin.
sidered. Furazolidone, an antibiotic commonly used to treat giar-
Unfortunately, most patients are initially treated with a dia, cholera, and bacterial enteritis has been evaluated as an
clarithromycin-containing regimen. In such circumstances, alternative to clarithromycin, metronidazole, or amoxicillin
the most frequently used “rescue” or “salvage” therapy is for persistent H. pylori infection. Available studies utilizing
bismuth quadruple therapy consisting of a PPI, tetracycline, furazolidone have yielded widely variable eradication rates,
metronidazole, and bismuth (104). This salvage regimen ranging from 52% to 90% (163–166). Unfortunately, fura-
is widely available, inexpensive, and relatively effective. A zolidone is not currently marketed in the United States. Side
pooled analysis of 16 studies and 24 abstracts demonstrated effects including nausea, vomiting, headache, and malaise
an average eradication rate of 76% (range 60–100%) for occur in up to a third of patients. Less frequent side effects
quadruple therapy when used as second-line therapy (154). include hypersensitivity, hypotension, a disulfiram-like reac-
Unfortunately, the data on quadruple therapy are difficult to tion to alcohol, and mild, reversible hemolytic anemia (163–
interpret as antibiotic dosing, frequency of administration, 167).

Table 5. Salvage Therapies for Persistent H. pylori Infection (164)

Regimen Duration Eradication Rates Comments
Bismuth quadruple therapy
PPI q.d. tetracycline, Pepto Bismol, metronidazole q.i.d. 7 68% (95% CI 62–74%) Accessible, cheap but high pill count and
frequent mild side effects
Levofloxacin triple therapy
PPI, amoxicillin 1 g b.i.d., levofloxacin 500 mg q.d. 10 87% (95% CI 82–92%) Requires validation in North America
For recommendations regarding rifabutin and furazolidone, please refer to the text.
PPI = proton pump inhibitor; q.d. = daily; q.i.d. = four times daily; b.i.d. = twice daily.
1820 Chey and Wong

Levofloxacin is a fluoroquinolone antibiotic with in vitro

activity against H. pylori. Levofloxacin-based triple therapy
r In populations with a low pretest probability of H. py-
(PPI, levofloxacin, and amoxicillin) has recently been stud- lori infection, nonendoscopic tests such as the urea
ied as second- and third-line therapy in patients with per- breath test and fecal antigen test offer superior posi-
tive predictive value compared with antibody tests.
sistent H. pylori infection. In general, the available clinical
trials have involved relatively small numbers of patients and
r Eradication rates with a PPI, clarithromycin, and amox-
demonstrated variable eradication rates, ranging from 63% icillin are decreasing worldwide. Fourteen-day courses
to 94% (168–170). A recent meta-analysis including four of therapy are more effective than seven-days treatment
regimens.
randomized controlled trials found that a 10-day regimen of
levofloxacin-based triple therapy yielded superior eradication
r Newer treatments such as sequential therapy require
(RR 1.41, 95% CI 1.25–1.59) and was associated with fewer validation in the United States before they can be rec-
ommended as a standard first-line therapy.
side effects (RR 0.51, 95% CI 0.34–0.75) than a 7-day course
of bismuth-based quadruple therapy. Summary eradication
r A PPI, levofloxacin, and amoxicillin for 10 days appear
rates for levofloxacin-based triple therapy and bismuth-based to be more effective and better tolerated than a PPI, bis-
quadruple therapy were 87% (95% CI 82–92%) and 68% muth, tetracycline, and metronidazole in patients with
(95% CI 62–74%), respectively (168). A recent study from persistent H. pylori infection but require validation in
Italy found that using rabeprazole, levofloxacin, and tinida- North America.
zole in place of amoxicillin yielded an ITT eradication rate of
84% (171). Unfortunately, none of the studies that have eval-
uated levofloxacin-based triple therapy, have been conducted Reprint requests and correspondence: William D. Chey, F.A.C.G.,
in the United States. As such, these encouraging results re- A.G.A.F., F.A.C.P., Associate Professor of Internal Medicine, Di-
rector – GI Physiology Laboratory, University of Michigan Medical
quire validation in the United States. The background rate Center, 3912 Taubman Center, -0362 Ann Arbor, MI 48109.
of H. pylori resistance to levofloxacin in the United States Received November 3, 2006; accepted January 11, 2007.
remains largely unknown. However, preliminary data from
Canada, Italy, Belgium, and Japan suggest that such resis-
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negative immunocompetent individuals. Ophthalmology
2001;108:750–2. Guarantor of the article: William D. Chey
163. Graham DY, Osato MS, Hoffman J, et al. Furazolidone Specific author contributions: William D. Chey, manuscript
combination therapies for Helicobacter pylori infection preparation; Benjamin C.Y. Wong, manuscript preparation;
in the United States. Aliment Pharmacol Ther 2000;14: Practice Parameters Committee, manuscript review.
211–5. Financial support:. None.
164. Isakov V, Domareva I, Koudryavtseva L, et al.
Furazolidone-based triple ‘rescue therapy’ vs. quadruple Potential competing interests: None.