- Email: [email protected]
Diagnosis and management of Helicobacter pylori infection
clinical CORNERSTONE
n
UPPER GI DISORDERS
’
W. I NO. 5
Diagnosis and Management of Helicobacter pylori Infection Waqar
A. Qureshi,
MD
Assistant Professor and Chief of Endoscopy Baylor College of Medicine and VAMC Houston,Texas
DavidY.
Graham,
MD
Professor of Medicine and Molecular Virology Division Chief, Gastroenterology Baylor College of Medicine and VAMC Houston,Texas
Helicobacter
pylori
infects more than halfof
th e worWs population,
making
it one of the most
prevalent infections. H pylori is now accepted as the most common cause of histologic gastritis and is responsible for the majority of cases ofpeptic ulcer disease andgastric cancer. Approximately 1 in 6 (17%) persons with H pylori infection will develop peptic ulcer disease, and each year 1% to 2% of these will experience a major or lye-threatening complication, such as bleeding, pdoration, or gastric outlet obstruction. Peptic ulcer disease should no longer be regarded as a chronic, recurring, lzfeelong disease, but rather as a curable infectious disease. The diagnosis and therapy of this common infectious disorder have become increasingly straighgorward. In this articl& we discuss the possible outcomes of long-standing infection, the various diagnostic tests available, in&ding whom and when to test, and the combination drug regimens approved f or cure.
EPIDEMIOLOGY OF Helicobacter INTHE UNITED STATES Helicobacter pylori is typically acquired in child-
pylori
hood. Nevertheless, in most populations, there is an age-related increase in prevalence, which typically represents a cohort phenomenon rather than a continued acquisition pattern (1). That is to say, the high rate of infection in 60-year-old patients today reflects infection acquired in childhood when the standards of living were lower. Overall, there is a continuing decline in the prevalence of H pylori infection. In the United States, approximately 35% of adults are infected. Genetic predisposition may play a role; for example, studies have shown that monozygotic twins reared apart have a higher rate of concordance of infections
than do age-matched dizygotic twins reared apart (2). On the other hand, the frequency of H pylori infections in the black population and white Hispanic population in the United States is approximately twice that of the white population. This difference is not racial but instead is a reflection of the differences in socioeconomic status during childhood.
18
clinical CORNERSTONE
Transmissionof the Disease
n
UPPER GI DISORDERS
m Vol. I No. 5
environment are the critical determinants of which pattern of gastritis develops (6,7). Antrum involvement is common to all patterns. Predominantly antral gastritis is associated with normal or increased acid secretion and duodenal ulcer disease. Whether or not the corpus is inflamed appears to relate largely to dietary factors. Inflammation of the acid-secreting corpus of the stomach is associated with reduced acid secretion and gradual loss of parietal cells (8). Such pangastritis yields an increased risk of development of gastric ulcer disease and gastric cancer. Infections with H pylori that contain the proinflammatory pathogenicity island of tug genes also increase the risk of symptomatic disease (9).
The exact route of transmission remains unclear, but evidence overwhelmingly supports person-toperson transmission. This conclusion is consistent with the fact that the prevalence of Hpylori is increased in conditions characterized by overcrowding and in low socioeconomic status families (3). Many studies suggest a fecal-oral mode of transmission, although oral-oral and gastric-oral routes are also possible. H pylori infection clusters in families with young children, suggesting that
DISEASES CAUSED INFECTION
BY H pylori
H pylori infection is associated with chronic gastri-
tis, peptic ulcer disease, gastric adenocarcinoma, primary B-cell gastric lymphoma, and some cases of pernicious anemia.
Gastritis Infection with H pylori causes mucosal inflammation in virtually every patient (10). Whereas normal gastric mucosa has few or no inflammatory cells, H pylori-infected gastric mucosa shows epithelial cell damage and infiltration with polymorphonuclear and mononuclear inflammatory cells. Lymphoid follicles are another characteristic feature of H pylori infection. The lymphocytic
infants and small children, through vomiting or spitting, may spread the infection within the family (4). Although water is safe in developed countries, transmission through unclean water supplies has also been documented in Peru.
THE ORGANISM AND ITS EFFECTS ON NORMAL PHYSIOLOGY H pylori is a microaerophilic
gram-negative rod. It is a spiral-shaped, highly motile organism with a unipolar flagellum that lives within and beneath the mucous layer of the stomach, often attached to gastric mucous cells. Various virulence factors enable H pylori to colonize and cause tissue injury (5). Some of these putative virulence factors are shown in Table I. Histologic examination of H pylori-infected gastric mucosa shows large numbers of acute and chronic inflammatory cells, especially phagocytes and plasma cells. H pylori infection is associated with different patterns of gastritis; the host and the
component of the inflammatory response is known as mucosa-associated lymphoid tissue, or MALT. Inflammation tends to spread upwards from the gastric antrum to involve the corpus, thereby causing a reduction in acid secretion and eventual
19
clinical CORNERSTONE
n
UPPER GI DISORDERS
- Vol. I No. 5
I+omotes Co&?&ation Motility
Allows pathogen to escape harmful effects of acid and swim to mucosa
Urease
Production of ammonia by pathogen protects against acid
Adherence
Allows close mucosal contact and improves chances for pathogen survival and residency
Promotes lbsue Injury Cati
The pathogenicity
island of tag genes increases the mucosal inflammatory
Soluble factors
Chemotactic to leukocytes
loss of parietal cells, leading to gastric atrophy. Chronic gastritis is the precursor lesion for the development of gastric atrophy, which in turn can progress to gastric carcinoma.
response
patients with atrophic pangastritis, the risk is much higher. The mechanism for development of gastric carcinoma is most likely multifactorial. Following H pylori infection, some patients may develop autoantibodies that cross-react with gastric antigens. Patients with these autoantibodies have a higher frequency of glandular atypia and neoplastic transformation, which may explain progression of gastritis to atrophy and metaplastic changes in some patients. Once the precursor lesion has developed (atrophic pangastritis), the risk of gastric cancer appears to be relatively constant across age-groups and populations. Thus, the incidence of gastric cancer in any population reflects the proportion of the population with the precursor lesion and the average age
Peptic Ulcer Disease Hpylori infection is responsible for nearly all duodenal ulcers and approximately 70% of gastric ulcers. Most of the remaining gastric ulcers are related to nonsteroidal anti-inflammatory drug (NSAID) use. Patients who have H pylori infection and take NSAIDs have a higher risk of developing peptic ulcer disease than those with either etiologic factor alone. The evidence that H pylori causes peptic ulcer disease is now widely accepted (10). The combination of H pylori infection and a high duodenal acid load produces conditions ripe for development of duodenal ulcer disease. This lowering of the pH in the duodenum, below the pK, for glycine-conjugated bile acids, removes bile acids that normally inhibit growth of H pylori in the small intestine, allowing H pylori to colonize and inflame the duodenal mucosa and possibly reduce its ability to withstand the acid.
Gastric Cancer The risk for developing gastric cancer is most closely related to the degree of damage that the infection causes. The risk is highest in pangastritis with intestinal metaplasia and hypochlorhydria and lowest in predominantly antral gastritis. Overall, the lifetime risk of developing gastric cancer in the United States is in the range of 1% to 3%. This reflects the relatively low incidence of H pylori infection in the United States and the fact that pangastritis with intestinal metaplasia is uncommon. For those
at which it develops. For example, in Korea, both H pylori infection and its sequela, atrophic pangastritis, are common by age 30. Korea has one of the highest rates of gastric cancer in the world.
Gastric (MALT) Lymphoma The normal stomach lacks organized lymphoid tissue. Following prolonged antigen stimulation
20
chid
from chronic H pylori infection, MALT forms from lymphocytes that aggregate following H pylori infection. Over time, MALT can develop into lymphoma (10). Gastric MALT lymphomas are typically low-grade, T-cell-dependent, B-cell lymphomas whose antigenic stimulus is thought to be H pylori. Complete resolution of MALT lymphomas usually occurs following cure of the H pylori infection, provided that the lymphoma is localized to the stomach. These patients generally need careful endoscopic and clinical follow-up. We tend to follow up our patients every 3 months for the first year and then every 6 months for the second year and then yearly, possibly for life. MALT lymphomas may exist in apparently normal mucosa and therefore require histologic examination.
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special requirements for storage and processing. Ideally, the specimen should be placed in a transport medium and immediately taken to the laboratory. Saline will suffice if the sample can be processed within an hour or two. Otherwise, a glycerol-containing medium should be used. The specimen in a glycerol-containing transport medium can be stored in a standard refrigerator at 4°C until it can be taken to the laboratory. As antibiotic resistance becomes more widespread, culturing of H pylori to determine sensitivity patterns will become more common.
Rapid Urease Tests H pylori contains a large amount of urease. When
a biopsy containing this organism is placed in a urea-containing medium, the urea is split into ammonia and carbon dioxide. The ammonia causes an increase in pH, which results in color change of a pH indicator. The 3 tests most commonly used in the United States are: the CLOtest (TriMed Specialties, Lexena, Kan), hpfast (GI Supply, Camp Hill, Pa), and PyloriTek (Serim Research, Elkhart, Ind). The hpfast test has the potential advantage of superior specificity, as it starts with a lower pH and takes advantage of the fact that possible contaminants with urease activity will not react, whereas H pylori will. Nevertheless, in clinical practice, the sensitivity and specificity is in the range of 95% for all 3 tests. False-negative results may occur if the patient has recently taken antibiotics or bismuth-containing compounds or proton pump inhibitors (PPIs), as these transiently lower the bacterial density. Rapid urease testing also provides a check on the pathology laboratory. If frequent discrepancies are found, especially positive rapid urease tests and negative histology, one should question the techniques and stains used by the laboratory.
DIAGNOSTIC TESTS REQUIRING ENDOSCOPY Histology The gold standard for detection of Hpylori is histologic examination of multiple endoscopic mucosal biopsy specimens, using special stains, performed by an expert pathologist. The hematoxylin-eosin (H & E) stain used by many pathologists lacks sufficient sensitivity to detect the organism reliably; for this reason, a special stain is required. The commonly used Giemsa stain has lower specificity and sensitivity than the Diff-Quik@, Genta, or El-Zimaity stains. The Genta stain is a combination of H & E, alcian blue, and the Steiner silver stain and allows for easy recognition of H pylori and assessment of gastric morphology (11). The El-Zimaity stain is another triple stain, with the advantage of being applicable to an autostainer (12). At a minimum, we recommend utilizing a triple stain. The alternative is to ask for 2 stains, an H & E and a DiffQuik- stained slide (13). Four biopsies should be taken: one each from the greater and lesser curvatures of the antrum and corpus. Avoid handling biopsies in order to prevent loss of H pylori, which are found predominantly in the mucus.
TESTS NOT REQUIRING ENDOSCOPY Noninvasive testing includes serologic tests and urea breath tests. Laboratory-based immunoglobulin (1g)G antibody tests against H pylori are generally enzyme-linked immunosorbent assays (ELISA), which have a sensitivity and specificity
Culture It is sometimes necessary to culture the organism, especially when antibiotic susceptibility testing is needed. H pylori is a fastidious organism and has
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clinical CORNERSTONE
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UPPER Cl DISORDERS
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Vol. I No.5
approaching 95%. In a previously untreated patient, a positive test generally denotes an active infection. However, these tests remain positive after treatment and cannot be used to confirm cure. Testing of IgA and IgM antibodies to Hpylori are unreliable, are not US Food and Drug Administration (FDA) approved, and should be avoided. A laboratory report that gives IgM or IgA serologic
before and 30 minutes after urea ingestion. The breath samples are collected in a special plastic bag that contains a stylet to enable transfer of the gas into a standard “red top” blood tube, which is sent to a central laboratory for processing. The 13C urea breath test is more convenient to perform because no radiation is involved and therefore special handling or clearance is not necessary (14). The sensitivity of these tests is about 95%, with specificity of 95% to 100%. A further advantage of urea breath testing is that it assessesthe H pylon’ content of the entire stomach in an overall quantitative manner and is not subject to the sampling errors that occur when biopsy specimens are taken. False-negative results may occur if patients have recently used PPIs, bismuthcontaining compounds, or antibiotics. The 14C urea breath test result may be false-positive when H,receptor antagonists are used. The urea breath test remains the test of choice to con&m eradication of infection after therapy. The 13C urea breath test is approved for initial diagnosis and for confirmation of cure. The 14C urea breath test is approved only for initial diagnosis.
results signifies that the laboratory is using nonapproved tests with unknown (and usually poor) sensitivities and specificities. IgG results that accompany IgM or IgA findings are likely also to be derived from an unproved test. Clinicians should demand that the laboratory use FDAapproved tests with known sensitivities and specificities. The main drawback of serologic testing is the inability to distinguish active infection from cured infection. Several rapid in-office tests are available that provide reliable results with only slightly lower specificity and sensitivity than the send-out ELISA tests.
Stool Tests H pylori is very difficult to culture from stool. Recently, a test for H pylori antigens in stool was introduced. Preliminary data suggest that it is approximately as accurate as serology and urea breath testing for initial diagnosis and only slightly less accurate than the urea breath test for conlirmation of cure. There are still very few data from the United States, but this test will bear watching.
Urea Breath Testing
WHEN AND WHOM TO TEST FOR H pylori INFECTION
The urea breath test is the most efficient and accurate method to determine Hpylori status. Labeled urea is ingested, and if H pylori is present, its urease splits the labeled urea to release labeled CO,, which can be detected in the breath. Two forms of labeled urea are available: the radioactive isotope of carbon ( 14C) and the stable nonradioactive 13C. In the former test, i4C urea is ingested in a capsule and breath samples are collected for detection of the radioactive isotope carbon dioxide (r4C0,). A small amount of radioactivity is a drawback. The 13C nonradioactive urea is given with a test meal, and exhaled breath is sampled
Indications for testing include upper abdominal discomfort or dyspepsia, the presence or history of peptic ulcer disease, or a family history of gastric cancer. When patients present with a history typical for peptic ulcer disease or have previously been diagnosed with ulcer disease, either by endoscopy or on barium study, noninvasive testing is preferred. Patients presenting with vague upper abdominal symptoms or dyspepsia include those with ulcers, gastroesophageal reflux disease (GERD), or nonulcer dyspepsia. If the patient has “alarm
22
clinical CORNERSTONE
features,” such as anemia, gastrointestinal bleeding, significant vomiting, anorexia, and weight loss, or the suspicion of a malignancy, upper endoscopy should be performed. Patients who clearly have symptoms of GERD do not usually require testing for H pylori infection. Serology or urea breath tests are appropriate to confirm H pylori infection for patients seen in the outpatient setting, in whom endoscopy does not
UPPER GI DISORDERS
. Vol. I No.5
terial activity against H pylori, but they may contribute to successful treatment regimens. PPIs block acid secretion at the H+,K+-ATPase pump on the gastric parietal cell. Both omeprazole (Prilosec@) and lansoprazole (Prevacid@) have antibacterial activity against H pylori.
Antimicrobials Because H pylori is a bacterial infection of a mucosal surface, both topical and systemically acting antimicrobials are helpful. Bismuth is a topical agent that is directly bactericidal to H pylori and leads to bacterial lysis within 2 hours of drug ingestion. H pylori does not seem to develop resistance to the various bismuth salts. Bismuth has an excellent safety record, although it does temporarily discolor the tongue and cause black stools. Bismuth is available as bismuth subsalicylate (Pepto-Bismol@) and as ranitidine bismuth citrate (Trite@‘). The traditional antibiotics that have proven efficacy against H pylori include clarithromycin (Biaxin@), amoxicillin, metronidazole (Flagyl@), and tetracycline hydrochloride.
appear to be necessary. Once active H pylori infection is confirmed, treatment should follow (15,16). As a general rule, one should not test for the presence of H pylori infection unless one is willing to treat the patient for the infection.
TREATMENT INFECTION
n
Claritbromycin Clarithromycin binds to bacterial ribosomes and disrupts protein synthesis, leading to cell death. It is relatively stable in the acid environment, and among the macrolides has the lowest minimum inhibitory concentration (MIC). When given in conjunction with a PPI, its concentration in the mucous layer increases markedly. Clarithromycin should be given with food and is generally well tolerated. Clarithromycin increases theophylline and carbamazepine levels.
OF H pylori
The successful elimination of H pyZori infection not only leads to the relief of symptoms and healing of ulcers but also prevents ulcer complications and possibly other sequelae of long-term H pylori infection. Treatment of H pylori infection consists of antisecretory agents and antimicrobial drugs in combination (TableII). Combination therapy is necessary because of the high rate of development of antibiotic resistance and of treatment failures when single agents are used. Some of the currently used drugs are discussed briefly here, followed by details of FDA-approved combination drug regimens.
Amoxicillin Amoxicillin is a bactericidal, acid-stable, semisynthetic penicillin. Its MIC decreases as the pH increases, which may explain its efficacy when given with a PPI. Resistance to amoxicillin is uncommon but has been reported.
Antisecretory Agents Metronidazole
Antisecretory agents help heal ulcers regardless of etiology. The Hz-receptor antagonists, cimetidine (Tagamet@), ranitidine (Zantac@), famotidine (Pepcid@), and nizatidine (Axid@), have no antibac-
The activity of metronidazole is independent of pH. Unfortunately, H pylori rapidly develops resistance to this drug; in the United States, primary resis-
23
CliniCdCORh’ERSTONE
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UPPER Cl DISORDERS
Dual Therapies (approved
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Vol. I No.5
but not recommended)
A PPI or ranitidine bismuth citrate plus the following amoxicillin or clarithromycin
antibiotic:
-
Triple Therapies A PPI or a bismuth plus 2 of the following Amoxicillin Clarithromycin Metronidazole Tetracycline
antibiotics:
PPI = proton pump inhibitor.
tance ranges from 20% to 50%. Increasing the dose may sometimes overcome resistance.
histology, rapid urease testing, or the 13C urea breath test are used to confirm cure. They must be discontinued if the 14C urea breath test is used. The conditions required for positive fecal H pylori antigen testing are not known but probably are the same as those for 13C urea breath testing. Treatment success rates are high but not 100%; therefore, it is critically important to confirm cure. Both the physician and the patient who completes a course of therapy may be lulled into a false sense of security until the patient presents with recurrent disease or a life-threatening complication of treatment failure. Given the availability
Tetracycline The activity of tetracycline is also independent of gastric acidity. In addition, it is inexpensive and resistance is unusual. Clinical studies have shown that doxycycline cannot substitute for tetracycline hydrochloride in combination therapies because it is much less effective against Hpylori.
TREATMENT
REGIMENS
The FDA has approved several treatment regimens for Hpylori infection (Table III). It is now recognized that therapy should always consist of at least 3 drugs. The FDA-approved dual therapies can be grouped in a new class of “approved but not recommended” treatments. One of the first 3 drug regimens involved bismuth, metronidazole, and tetracycline, known as BMT triple therapy (17) (Table II). This combination is now available as Helidac@. Therapy ideally should be chosen on the basis of local antibiotic susceptibility patterns. However, such patterns are not always available, and other clinical “rules of thumb” (see under Treatment Failures) are required. The proper therapeutic approach should be diagnosis, therapy, and confirmation of cure. Confirmation of cure should not be attempted until at least 4 weeks after the end of antibiotic therapy and at least 1 week after discontinuing PPIs. H,receptor antagonists can be continued if culture,
of noninvasive tests (eg, urea breath testing or possibly fecal H pylori antigen testing), posttherapy testing is strongly recommended for all patients. The duration of therapy should be 14 days (18). In Europe, there was a recent trend toward reducing the duration to 7 days. That practice is now in retreat, as head-to-head comparisons have shown that 14-day duration is superior to 10 days and 10 days superior to 7 (19). The combination of amoxi-
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elinicdCORNERWONE
RBc+c BMT+H,
antagonist
* UPPER GI DISORDERS
Omeprazole Clarithromycin
70-80
Ranitidine bismuth citrate Clarithromycin
70-85
14
80-95
14
80-95
lo+
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Bismuth subsalicylate* Metronidazole Tetracycline HCI
LAC
Lansoprazole Amoxicillin Clarithromycin
LA
Lansoprazole Amoxicillin
OAC
Omeprazole Amoxicillin Clarithromycin
*In mixed populations with resistant and sensitive strains. Therapy for 14 days is probably best (see Treatment Regimens).
cillin, omeprazole, and clarithromycin has recently been approved for a IO-day course (Table III).
TREATMENT
FAILURES
Patient compliance is improved by explaining the benefits of treatment, what to expect during treatment (dark stools, metallic taste, etc.), and stressing the importance of completing the course. Drug administration with meals not only decreases the chance of gastric distress but also makes the treatment more effective by prolonging drug contact time in the stomach and promoting greater dispersion. The main and more problematic cause of treatment failures is antibiotic resistance (20,21), primarily involving metronidazole or clarithromycin. Although metronidazole resistance may be overcome by increasing the dose, this is not the case with clarithromycin (22). Amoxicillin and tetracycline resistance is still relatively uncommon. It is thought that bismuth reduces or prevents development of resistance by decimating the population of Hpylori with the first dose. As such, it may become an important component of all therapies. Optimal management of the patient who fails initial treatment should begin with a culture of the
organism to determine resistance status and proceed to administration of a new combination therapy based on the results of antibiotic sensitivity testing. However, this approach is not always feasible. If metronidazole was used initially, it should be avoided in the second regimen. Similarly, clarithromycin should not be used again if treatment has failed with a clarithromycin-containing regimen. If treatment fails on a therapy combination containing both clarithromycin and metronidazole, then culture is suggested. Another approach is
25
clinical CORNERSTONE
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BMT Quudrupk Therapy Includes (all given for 2 weeks): Bismuth subsalicylate
2 tablets QID
Metronidazole
500 mg TID
Tetracycline
500 mg QID
Proton pump inhibitor
Omeprazole 20 mg BID or lansoprazole30 mg BID
Thus the patient benefits from Hpylori cure in other ways as well. Overall, the risks associated with the transmissible H pylori infection greatly outweigh any possible benefits. Accordingly, there should be a low threshold for both testing and treating. It is hoped that an effective vaccine may one day help eradicate this infection.
REFERENCES to prescribe BMT quadruple therapy (Table IV), which has a good success rate even in the face of metronidazole resistance. The synthetic nitrofuran furazolidone (100 mg TlD) may be substituted for metronidazole in quadruple therapy in difficult cases.*
WHOM
TO TREAT
All patients with peptic ulcer should be tested for Hpylori and, if infected, treated. Similarly, patients on maintenance antiulcer therapy should be checked for Hpylori infection and treated if positive. The real question is whom to test, because all patients in whom H pylori is diagnosed should be treated. Recently, it has been noted that populations with a low frequency of H pylori infection have a higher prevalence of GERD than do populations with H pylori infection-associated pangastritis. As noted above, the reduction in acid secretion that accompanies pangastritis is probably responsible for this lower prevalence of GERD. One can consider that H pylori corpus gastritis is essentially equivalent to the chronic administration of an HZ-receptor antagonist. Cure of H pylori infection in patients with a weak gastroesophageal barrier may uncover the presence of GERD; cure of H pylori infection does not cause GERD. Furthermore, pangastritis is associated with an increased risk of gastric cancer. * The BMT
combination
with PPI (quadruple
therapy)
1. Graham DY, Malaty HM, Evans DG, et al. Epidemiology of Helicobacter pylori in an asympto-
matic population in the United States. Effect of age, race, and socioeconomic status. Gastroenterology. 1991;100:1495-1501. 2. Malaty HM, Engstrand L, Pedersen NL, Graham DY. Helicobacter pylori infection: genetic and environmental influences. A study of twins. Ann Intern Med. 1994;120:982-986. 3. Vincent P, Gottrand F, Pemes P, et al. High prevalence of Helicobacter pylori infection in cohabiting children. Epidemiology of a cluster, with special emphasis on molecular typing. Gut. 1994;35: 313-316. 4. Graham DY, Klein PD, Evans DC, et al. Helicobacter pylori: epidemiology, relationship to gastric cancer and the role of infants in transmission. Eur J Gastroenterol Hepatol. 1992;4:Sl-S6. 5. Dunn BE. Pathogenic mechanisms of Helicobacter pylori. Gastroenterol Clin North Am. 1993;22: 43-57. 6. Graham DY, Yamaoka Y. H pylon’ and cagA: relationships with gastric cancer, duodenal ulcer and reflux esophagi& and its complications. Helicobactel: 1998;3:145-151. 7. Graham DY. Helicobacter pylon’ infection in the pathogenesis of duodenal ulcer and gastric cancer: a model. Gastroenterology. 1997;113: 1983-1991. 8. Gutierrez 0, Melo M, Segura AM, et al. Cure of Helicobacter pylori infection improves gastric acid secretion in patients with corpus gastritis. Stand J Gastroenterol. 1997;32:664-669. 9. Crabtree JE, Farmery SM, Lindley IJD, et al. CagA cytotoxic strains of Helicobacter pylori and interleukin-8 in gastric epithelial cell lines. J Clin Pathol. 1994;47:945-950. 10. Dixon ME Helicobacter pylori and peptic ulcera-
and furazolidone
for Hpylori
26
therapy
is not FDA-approved.
clinid
tion: histopathological aspects. J Gastroenterol 1991;6:125-130. 1I. Peura DA. Helicobacter pylori and ulcerogenesis. Am J Med. 1996;100:193-258. 12. El-Zimaity HM, Ota H, Scott S, et al. A new triple stain for Helicobacter pylori suitable for the autostainer: carbol fuchsin/alcian blue/hematoxylin-eosin. Arch Path01 Lab Med. 1998;122:732-736. 13. El-Zimaity HM, Segura AM, Genta RM, et al. Histologic assessmentof Helicobacter pylori status after therapy: comparison of Giemsa, Diff-Quik, and Genta stains. Mod Pathol. 1998;11:288-291. 14. Parsonnet J, Hansen S, Rodriguez L, et al. Helicobatter pylon’ infection and gastric lymphoma. N Engl J Med. 1994;330: 1267-1271. 15. Genta RM, Robason GO, Graham DY. Simultaneous visualization of Helicobacter pylori and gastric morphology: a new stain. Hum Pathol. 1994;25: 221-226. 16. Klein PD, Malaty HM, Martin RF, et al. Noninvasive detection of Helicobacter pylori infection in clinical practice: the 13Curea breath test. Am J Gastroenterol. 1996;9 1:690-694. Hepatol.
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17. Rabeneck L, Graham DY. Helicobacter pylori: when to test, when to treat. Ann Intern Med. 1997; 126: 315-316. 18. Graham DY, Dore MP. Variability in the outcome of treatment of Helicobacter pylori infection: a critical analysis. In: Hunt RH, Tytgat GNJ, eds. Helicobatter pylori.
Basic Mechanisms
to Clinical
Cure.
Dordrecht, Netherlands: Kluwer Academic Publishers; 1998:426440. 19. Lee J, O’Morain C. Who should be treated for Helicobacter pylori infection? A review of consensusconferences and guidelines. Gastroenterology. 1997;113(suppl):S99-S 106. 20. Graham DY. Antibiotic resistance in Helicobacter pylon’: implications for therapy. Gastroenterology. 1998;115:1272-1277. 21. Van der Hulst RW, Keller JJ, Rauws EA, et al. Treatment of Helicobacter pylori: a review of the world literature. Helicobactel: 1996;1:6-19. 22. Sol1AH. Consensus conference. Medical treatment of peptic ulcer disease. Practice guidelines. Practice Parameters Committee of the American College of Gastroenterology. JAMA. 1996;275:622-629.
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tive VW
which, mrfortunately, is still probably
&W&y.. 3tekaWe it has a very high minimal infecthis dose, the pel.Gc ha&ix envisonment would have to be vq bad. ~,~~o~ are such that yau are wtmkd about &okra or Eschmichiu coli, then you should also worry about H pylori. Even when acid secretion is inhibited, the minimal infectious dose still remains high.
cure rate, and thus a test-of-cure follow-up is imptL&a to fietect trmt faihlres.
28
n
UPPER GI DISORDERS
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W. I NO. 5
Diagnosis and Management of Helicobacter pylori Infection Waqar
A. Qureshi,
MD
Assistant Professor and Chief of Endoscopy Baylor College of Medicine and VAMC Houston,Texas
DavidY.
Graham,
MD
Professor of Medicine and Molecular Virology Division Chief, Gastroenterology Baylor College of Medicine and VAMC Houston,Texas
Helicobacter
pylori
infects more than halfof
th e worWs population,
making
it one of the most
prevalent infections. H pylori is now accepted as the most common cause of histologic gastritis and is responsible for the majority of cases ofpeptic ulcer disease andgastric cancer. Approximately 1 in 6 (17%) persons with H pylori infection will develop peptic ulcer disease, and each year 1% to 2% of these will experience a major or lye-threatening complication, such as bleeding, pdoration, or gastric outlet obstruction. Peptic ulcer disease should no longer be regarded as a chronic, recurring, lzfeelong disease, but rather as a curable infectious disease. The diagnosis and therapy of this common infectious disorder have become increasingly straighgorward. In this articl& we discuss the possible outcomes of long-standing infection, the various diagnostic tests available, in&ding whom and when to test, and the combination drug regimens approved f or cure.
EPIDEMIOLOGY OF Helicobacter INTHE UNITED STATES Helicobacter pylori is typically acquired in child-
pylori
hood. Nevertheless, in most populations, there is an age-related increase in prevalence, which typically represents a cohort phenomenon rather than a continued acquisition pattern (1). That is to say, the high rate of infection in 60-year-old patients today reflects infection acquired in childhood when the standards of living were lower. Overall, there is a continuing decline in the prevalence of H pylori infection. In the United States, approximately 35% of adults are infected. Genetic predisposition may play a role; for example, studies have shown that monozygotic twins reared apart have a higher rate of concordance of infections
than do age-matched dizygotic twins reared apart (2). On the other hand, the frequency of H pylori infections in the black population and white Hispanic population in the United States is approximately twice that of the white population. This difference is not racial but instead is a reflection of the differences in socioeconomic status during childhood.
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clinical CORNERSTONE
Transmissionof the Disease
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UPPER GI DISORDERS
m Vol. I No. 5
environment are the critical determinants of which pattern of gastritis develops (6,7). Antrum involvement is common to all patterns. Predominantly antral gastritis is associated with normal or increased acid secretion and duodenal ulcer disease. Whether or not the corpus is inflamed appears to relate largely to dietary factors. Inflammation of the acid-secreting corpus of the stomach is associated with reduced acid secretion and gradual loss of parietal cells (8). Such pangastritis yields an increased risk of development of gastric ulcer disease and gastric cancer. Infections with H pylori that contain the proinflammatory pathogenicity island of tug genes also increase the risk of symptomatic disease (9).
The exact route of transmission remains unclear, but evidence overwhelmingly supports person-toperson transmission. This conclusion is consistent with the fact that the prevalence of Hpylori is increased in conditions characterized by overcrowding and in low socioeconomic status families (3). Many studies suggest a fecal-oral mode of transmission, although oral-oral and gastric-oral routes are also possible. H pylori infection clusters in families with young children, suggesting that
DISEASES CAUSED INFECTION
BY H pylori
H pylori infection is associated with chronic gastri-
tis, peptic ulcer disease, gastric adenocarcinoma, primary B-cell gastric lymphoma, and some cases of pernicious anemia.
Gastritis Infection with H pylori causes mucosal inflammation in virtually every patient (10). Whereas normal gastric mucosa has few or no inflammatory cells, H pylori-infected gastric mucosa shows epithelial cell damage and infiltration with polymorphonuclear and mononuclear inflammatory cells. Lymphoid follicles are another characteristic feature of H pylori infection. The lymphocytic
infants and small children, through vomiting or spitting, may spread the infection within the family (4). Although water is safe in developed countries, transmission through unclean water supplies has also been documented in Peru.
THE ORGANISM AND ITS EFFECTS ON NORMAL PHYSIOLOGY H pylori is a microaerophilic
gram-negative rod. It is a spiral-shaped, highly motile organism with a unipolar flagellum that lives within and beneath the mucous layer of the stomach, often attached to gastric mucous cells. Various virulence factors enable H pylori to colonize and cause tissue injury (5). Some of these putative virulence factors are shown in Table I. Histologic examination of H pylori-infected gastric mucosa shows large numbers of acute and chronic inflammatory cells, especially phagocytes and plasma cells. H pylori infection is associated with different patterns of gastritis; the host and the
component of the inflammatory response is known as mucosa-associated lymphoid tissue, or MALT. Inflammation tends to spread upwards from the gastric antrum to involve the corpus, thereby causing a reduction in acid secretion and eventual
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I+omotes Co&?&ation Motility
Allows pathogen to escape harmful effects of acid and swim to mucosa
Urease
Production of ammonia by pathogen protects against acid
Adherence
Allows close mucosal contact and improves chances for pathogen survival and residency
Promotes lbsue Injury Cati
The pathogenicity
island of tag genes increases the mucosal inflammatory
Soluble factors
Chemotactic to leukocytes
loss of parietal cells, leading to gastric atrophy. Chronic gastritis is the precursor lesion for the development of gastric atrophy, which in turn can progress to gastric carcinoma.
response
patients with atrophic pangastritis, the risk is much higher. The mechanism for development of gastric carcinoma is most likely multifactorial. Following H pylori infection, some patients may develop autoantibodies that cross-react with gastric antigens. Patients with these autoantibodies have a higher frequency of glandular atypia and neoplastic transformation, which may explain progression of gastritis to atrophy and metaplastic changes in some patients. Once the precursor lesion has developed (atrophic pangastritis), the risk of gastric cancer appears to be relatively constant across age-groups and populations. Thus, the incidence of gastric cancer in any population reflects the proportion of the population with the precursor lesion and the average age
Peptic Ulcer Disease Hpylori infection is responsible for nearly all duodenal ulcers and approximately 70% of gastric ulcers. Most of the remaining gastric ulcers are related to nonsteroidal anti-inflammatory drug (NSAID) use. Patients who have H pylori infection and take NSAIDs have a higher risk of developing peptic ulcer disease than those with either etiologic factor alone. The evidence that H pylori causes peptic ulcer disease is now widely accepted (10). The combination of H pylori infection and a high duodenal acid load produces conditions ripe for development of duodenal ulcer disease. This lowering of the pH in the duodenum, below the pK, for glycine-conjugated bile acids, removes bile acids that normally inhibit growth of H pylori in the small intestine, allowing H pylori to colonize and inflame the duodenal mucosa and possibly reduce its ability to withstand the acid.
Gastric Cancer The risk for developing gastric cancer is most closely related to the degree of damage that the infection causes. The risk is highest in pangastritis with intestinal metaplasia and hypochlorhydria and lowest in predominantly antral gastritis. Overall, the lifetime risk of developing gastric cancer in the United States is in the range of 1% to 3%. This reflects the relatively low incidence of H pylori infection in the United States and the fact that pangastritis with intestinal metaplasia is uncommon. For those
at which it develops. For example, in Korea, both H pylori infection and its sequela, atrophic pangastritis, are common by age 30. Korea has one of the highest rates of gastric cancer in the world.
Gastric (MALT) Lymphoma The normal stomach lacks organized lymphoid tissue. Following prolonged antigen stimulation
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from chronic H pylori infection, MALT forms from lymphocytes that aggregate following H pylori infection. Over time, MALT can develop into lymphoma (10). Gastric MALT lymphomas are typically low-grade, T-cell-dependent, B-cell lymphomas whose antigenic stimulus is thought to be H pylori. Complete resolution of MALT lymphomas usually occurs following cure of the H pylori infection, provided that the lymphoma is localized to the stomach. These patients generally need careful endoscopic and clinical follow-up. We tend to follow up our patients every 3 months for the first year and then every 6 months for the second year and then yearly, possibly for life. MALT lymphomas may exist in apparently normal mucosa and therefore require histologic examination.
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special requirements for storage and processing. Ideally, the specimen should be placed in a transport medium and immediately taken to the laboratory. Saline will suffice if the sample can be processed within an hour or two. Otherwise, a glycerol-containing medium should be used. The specimen in a glycerol-containing transport medium can be stored in a standard refrigerator at 4°C until it can be taken to the laboratory. As antibiotic resistance becomes more widespread, culturing of H pylori to determine sensitivity patterns will become more common.
Rapid Urease Tests H pylori contains a large amount of urease. When
a biopsy containing this organism is placed in a urea-containing medium, the urea is split into ammonia and carbon dioxide. The ammonia causes an increase in pH, which results in color change of a pH indicator. The 3 tests most commonly used in the United States are: the CLOtest (TriMed Specialties, Lexena, Kan), hpfast (GI Supply, Camp Hill, Pa), and PyloriTek (Serim Research, Elkhart, Ind). The hpfast test has the potential advantage of superior specificity, as it starts with a lower pH and takes advantage of the fact that possible contaminants with urease activity will not react, whereas H pylori will. Nevertheless, in clinical practice, the sensitivity and specificity is in the range of 95% for all 3 tests. False-negative results may occur if the patient has recently taken antibiotics or bismuth-containing compounds or proton pump inhibitors (PPIs), as these transiently lower the bacterial density. Rapid urease testing also provides a check on the pathology laboratory. If frequent discrepancies are found, especially positive rapid urease tests and negative histology, one should question the techniques and stains used by the laboratory.
DIAGNOSTIC TESTS REQUIRING ENDOSCOPY Histology The gold standard for detection of Hpylori is histologic examination of multiple endoscopic mucosal biopsy specimens, using special stains, performed by an expert pathologist. The hematoxylin-eosin (H & E) stain used by many pathologists lacks sufficient sensitivity to detect the organism reliably; for this reason, a special stain is required. The commonly used Giemsa stain has lower specificity and sensitivity than the Diff-Quik@, Genta, or El-Zimaity stains. The Genta stain is a combination of H & E, alcian blue, and the Steiner silver stain and allows for easy recognition of H pylori and assessment of gastric morphology (11). The El-Zimaity stain is another triple stain, with the advantage of being applicable to an autostainer (12). At a minimum, we recommend utilizing a triple stain. The alternative is to ask for 2 stains, an H & E and a DiffQuik- stained slide (13). Four biopsies should be taken: one each from the greater and lesser curvatures of the antrum and corpus. Avoid handling biopsies in order to prevent loss of H pylori, which are found predominantly in the mucus.
TESTS NOT REQUIRING ENDOSCOPY Noninvasive testing includes serologic tests and urea breath tests. Laboratory-based immunoglobulin (1g)G antibody tests against H pylori are generally enzyme-linked immunosorbent assays (ELISA), which have a sensitivity and specificity
Culture It is sometimes necessary to culture the organism, especially when antibiotic susceptibility testing is needed. H pylori is a fastidious organism and has
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approaching 95%. In a previously untreated patient, a positive test generally denotes an active infection. However, these tests remain positive after treatment and cannot be used to confirm cure. Testing of IgA and IgM antibodies to Hpylori are unreliable, are not US Food and Drug Administration (FDA) approved, and should be avoided. A laboratory report that gives IgM or IgA serologic
before and 30 minutes after urea ingestion. The breath samples are collected in a special plastic bag that contains a stylet to enable transfer of the gas into a standard “red top” blood tube, which is sent to a central laboratory for processing. The 13C urea breath test is more convenient to perform because no radiation is involved and therefore special handling or clearance is not necessary (14). The sensitivity of these tests is about 95%, with specificity of 95% to 100%. A further advantage of urea breath testing is that it assessesthe H pylon’ content of the entire stomach in an overall quantitative manner and is not subject to the sampling errors that occur when biopsy specimens are taken. False-negative results may occur if patients have recently used PPIs, bismuthcontaining compounds, or antibiotics. The 14C urea breath test result may be false-positive when H,receptor antagonists are used. The urea breath test remains the test of choice to con&m eradication of infection after therapy. The 13C urea breath test is approved for initial diagnosis and for confirmation of cure. The 14C urea breath test is approved only for initial diagnosis.
results signifies that the laboratory is using nonapproved tests with unknown (and usually poor) sensitivities and specificities. IgG results that accompany IgM or IgA findings are likely also to be derived from an unproved test. Clinicians should demand that the laboratory use FDAapproved tests with known sensitivities and specificities. The main drawback of serologic testing is the inability to distinguish active infection from cured infection. Several rapid in-office tests are available that provide reliable results with only slightly lower specificity and sensitivity than the send-out ELISA tests.
Stool Tests H pylori is very difficult to culture from stool. Recently, a test for H pylori antigens in stool was introduced. Preliminary data suggest that it is approximately as accurate as serology and urea breath testing for initial diagnosis and only slightly less accurate than the urea breath test for conlirmation of cure. There are still very few data from the United States, but this test will bear watching.
Urea Breath Testing
WHEN AND WHOM TO TEST FOR H pylori INFECTION
The urea breath test is the most efficient and accurate method to determine Hpylori status. Labeled urea is ingested, and if H pylori is present, its urease splits the labeled urea to release labeled CO,, which can be detected in the breath. Two forms of labeled urea are available: the radioactive isotope of carbon ( 14C) and the stable nonradioactive 13C. In the former test, i4C urea is ingested in a capsule and breath samples are collected for detection of the radioactive isotope carbon dioxide (r4C0,). A small amount of radioactivity is a drawback. The 13C nonradioactive urea is given with a test meal, and exhaled breath is sampled
Indications for testing include upper abdominal discomfort or dyspepsia, the presence or history of peptic ulcer disease, or a family history of gastric cancer. When patients present with a history typical for peptic ulcer disease or have previously been diagnosed with ulcer disease, either by endoscopy or on barium study, noninvasive testing is preferred. Patients presenting with vague upper abdominal symptoms or dyspepsia include those with ulcers, gastroesophageal reflux disease (GERD), or nonulcer dyspepsia. If the patient has “alarm
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features,” such as anemia, gastrointestinal bleeding, significant vomiting, anorexia, and weight loss, or the suspicion of a malignancy, upper endoscopy should be performed. Patients who clearly have symptoms of GERD do not usually require testing for H pylori infection. Serology or urea breath tests are appropriate to confirm H pylori infection for patients seen in the outpatient setting, in whom endoscopy does not
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terial activity against H pylori, but they may contribute to successful treatment regimens. PPIs block acid secretion at the H+,K+-ATPase pump on the gastric parietal cell. Both omeprazole (Prilosec@) and lansoprazole (Prevacid@) have antibacterial activity against H pylori.
Antimicrobials Because H pylori is a bacterial infection of a mucosal surface, both topical and systemically acting antimicrobials are helpful. Bismuth is a topical agent that is directly bactericidal to H pylori and leads to bacterial lysis within 2 hours of drug ingestion. H pylori does not seem to develop resistance to the various bismuth salts. Bismuth has an excellent safety record, although it does temporarily discolor the tongue and cause black stools. Bismuth is available as bismuth subsalicylate (Pepto-Bismol@) and as ranitidine bismuth citrate (Trite@‘). The traditional antibiotics that have proven efficacy against H pylori include clarithromycin (Biaxin@), amoxicillin, metronidazole (Flagyl@), and tetracycline hydrochloride.
appear to be necessary. Once active H pylori infection is confirmed, treatment should follow (15,16). As a general rule, one should not test for the presence of H pylori infection unless one is willing to treat the patient for the infection.
TREATMENT INFECTION
n
Claritbromycin Clarithromycin binds to bacterial ribosomes and disrupts protein synthesis, leading to cell death. It is relatively stable in the acid environment, and among the macrolides has the lowest minimum inhibitory concentration (MIC). When given in conjunction with a PPI, its concentration in the mucous layer increases markedly. Clarithromycin should be given with food and is generally well tolerated. Clarithromycin increases theophylline and carbamazepine levels.
OF H pylori
The successful elimination of H pyZori infection not only leads to the relief of symptoms and healing of ulcers but also prevents ulcer complications and possibly other sequelae of long-term H pylori infection. Treatment of H pylori infection consists of antisecretory agents and antimicrobial drugs in combination (TableII). Combination therapy is necessary because of the high rate of development of antibiotic resistance and of treatment failures when single agents are used. Some of the currently used drugs are discussed briefly here, followed by details of FDA-approved combination drug regimens.
Amoxicillin Amoxicillin is a bactericidal, acid-stable, semisynthetic penicillin. Its MIC decreases as the pH increases, which may explain its efficacy when given with a PPI. Resistance to amoxicillin is uncommon but has been reported.
Antisecretory Agents Metronidazole
Antisecretory agents help heal ulcers regardless of etiology. The Hz-receptor antagonists, cimetidine (Tagamet@), ranitidine (Zantac@), famotidine (Pepcid@), and nizatidine (Axid@), have no antibac-
The activity of metronidazole is independent of pH. Unfortunately, H pylori rapidly develops resistance to this drug; in the United States, primary resis-
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Dual Therapies (approved
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but not recommended)
A PPI or ranitidine bismuth citrate plus the following amoxicillin or clarithromycin
antibiotic:
-
Triple Therapies A PPI or a bismuth plus 2 of the following Amoxicillin Clarithromycin Metronidazole Tetracycline
antibiotics:
PPI = proton pump inhibitor.
tance ranges from 20% to 50%. Increasing the dose may sometimes overcome resistance.
histology, rapid urease testing, or the 13C urea breath test are used to confirm cure. They must be discontinued if the 14C urea breath test is used. The conditions required for positive fecal H pylori antigen testing are not known but probably are the same as those for 13C urea breath testing. Treatment success rates are high but not 100%; therefore, it is critically important to confirm cure. Both the physician and the patient who completes a course of therapy may be lulled into a false sense of security until the patient presents with recurrent disease or a life-threatening complication of treatment failure. Given the availability
Tetracycline The activity of tetracycline is also independent of gastric acidity. In addition, it is inexpensive and resistance is unusual. Clinical studies have shown that doxycycline cannot substitute for tetracycline hydrochloride in combination therapies because it is much less effective against Hpylori.
TREATMENT
REGIMENS
The FDA has approved several treatment regimens for Hpylori infection (Table III). It is now recognized that therapy should always consist of at least 3 drugs. The FDA-approved dual therapies can be grouped in a new class of “approved but not recommended” treatments. One of the first 3 drug regimens involved bismuth, metronidazole, and tetracycline, known as BMT triple therapy (17) (Table II). This combination is now available as Helidac@. Therapy ideally should be chosen on the basis of local antibiotic susceptibility patterns. However, such patterns are not always available, and other clinical “rules of thumb” (see under Treatment Failures) are required. The proper therapeutic approach should be diagnosis, therapy, and confirmation of cure. Confirmation of cure should not be attempted until at least 4 weeks after the end of antibiotic therapy and at least 1 week after discontinuing PPIs. H,receptor antagonists can be continued if culture,
of noninvasive tests (eg, urea breath testing or possibly fecal H pylori antigen testing), posttherapy testing is strongly recommended for all patients. The duration of therapy should be 14 days (18). In Europe, there was a recent trend toward reducing the duration to 7 days. That practice is now in retreat, as head-to-head comparisons have shown that 14-day duration is superior to 10 days and 10 days superior to 7 (19). The combination of amoxi-
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RBc+c BMT+H,
antagonist
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Omeprazole Clarithromycin
70-80
Ranitidine bismuth citrate Clarithromycin
70-85
14
80-95
14
80-95
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Bismuth subsalicylate* Metronidazole Tetracycline HCI
LAC
Lansoprazole Amoxicillin Clarithromycin
LA
Lansoprazole Amoxicillin
OAC
Omeprazole Amoxicillin Clarithromycin
*In mixed populations with resistant and sensitive strains. Therapy for 14 days is probably best (see Treatment Regimens).
cillin, omeprazole, and clarithromycin has recently been approved for a IO-day course (Table III).
TREATMENT
FAILURES
Patient compliance is improved by explaining the benefits of treatment, what to expect during treatment (dark stools, metallic taste, etc.), and stressing the importance of completing the course. Drug administration with meals not only decreases the chance of gastric distress but also makes the treatment more effective by prolonging drug contact time in the stomach and promoting greater dispersion. The main and more problematic cause of treatment failures is antibiotic resistance (20,21), primarily involving metronidazole or clarithromycin. Although metronidazole resistance may be overcome by increasing the dose, this is not the case with clarithromycin (22). Amoxicillin and tetracycline resistance is still relatively uncommon. It is thought that bismuth reduces or prevents development of resistance by decimating the population of Hpylori with the first dose. As such, it may become an important component of all therapies. Optimal management of the patient who fails initial treatment should begin with a culture of the
organism to determine resistance status and proceed to administration of a new combination therapy based on the results of antibiotic sensitivity testing. However, this approach is not always feasible. If metronidazole was used initially, it should be avoided in the second regimen. Similarly, clarithromycin should not be used again if treatment has failed with a clarithromycin-containing regimen. If treatment fails on a therapy combination containing both clarithromycin and metronidazole, then culture is suggested. Another approach is
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BMT Quudrupk Therapy Includes (all given for 2 weeks): Bismuth subsalicylate
2 tablets QID
Metronidazole
500 mg TID
Tetracycline
500 mg QID
Proton pump inhibitor
Omeprazole 20 mg BID or lansoprazole30 mg BID
Thus the patient benefits from Hpylori cure in other ways as well. Overall, the risks associated with the transmissible H pylori infection greatly outweigh any possible benefits. Accordingly, there should be a low threshold for both testing and treating. It is hoped that an effective vaccine may one day help eradicate this infection.
REFERENCES to prescribe BMT quadruple therapy (Table IV), which has a good success rate even in the face of metronidazole resistance. The synthetic nitrofuran furazolidone (100 mg TlD) may be substituted for metronidazole in quadruple therapy in difficult cases.*
WHOM
TO TREAT
All patients with peptic ulcer should be tested for Hpylori and, if infected, treated. Similarly, patients on maintenance antiulcer therapy should be checked for Hpylori infection and treated if positive. The real question is whom to test, because all patients in whom H pylori is diagnosed should be treated. Recently, it has been noted that populations with a low frequency of H pylori infection have a higher prevalence of GERD than do populations with H pylori infection-associated pangastritis. As noted above, the reduction in acid secretion that accompanies pangastritis is probably responsible for this lower prevalence of GERD. One can consider that H pylori corpus gastritis is essentially equivalent to the chronic administration of an HZ-receptor antagonist. Cure of H pylori infection in patients with a weak gastroesophageal barrier may uncover the presence of GERD; cure of H pylori infection does not cause GERD. Furthermore, pangastritis is associated with an increased risk of gastric cancer. * The BMT
combination
with PPI (quadruple
therapy)
1. Graham DY, Malaty HM, Evans DG, et al. Epidemiology of Helicobacter pylori in an asympto-
matic population in the United States. Effect of age, race, and socioeconomic status. Gastroenterology. 1991;100:1495-1501. 2. Malaty HM, Engstrand L, Pedersen NL, Graham DY. Helicobacter pylori infection: genetic and environmental influences. A study of twins. Ann Intern Med. 1994;120:982-986. 3. Vincent P, Gottrand F, Pemes P, et al. High prevalence of Helicobacter pylori infection in cohabiting children. Epidemiology of a cluster, with special emphasis on molecular typing. Gut. 1994;35: 313-316. 4. Graham DY, Klein PD, Evans DC, et al. Helicobacter pylori: epidemiology, relationship to gastric cancer and the role of infants in transmission. Eur J Gastroenterol Hepatol. 1992;4:Sl-S6. 5. Dunn BE. Pathogenic mechanisms of Helicobacter pylori. Gastroenterol Clin North Am. 1993;22: 43-57. 6. Graham DY, Yamaoka Y. H pylon’ and cagA: relationships with gastric cancer, duodenal ulcer and reflux esophagi& and its complications. Helicobactel: 1998;3:145-151. 7. Graham DY. Helicobacter pylon’ infection in the pathogenesis of duodenal ulcer and gastric cancer: a model. Gastroenterology. 1997;113: 1983-1991. 8. Gutierrez 0, Melo M, Segura AM, et al. Cure of Helicobacter pylori infection improves gastric acid secretion in patients with corpus gastritis. Stand J Gastroenterol. 1997;32:664-669. 9. Crabtree JE, Farmery SM, Lindley IJD, et al. CagA cytotoxic strains of Helicobacter pylori and interleukin-8 in gastric epithelial cell lines. J Clin Pathol. 1994;47:945-950. 10. Dixon ME Helicobacter pylori and peptic ulcera-
and furazolidone
for Hpylori
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therapy
is not FDA-approved.
clinid
tion: histopathological aspects. J Gastroenterol 1991;6:125-130. 1I. Peura DA. Helicobacter pylori and ulcerogenesis. Am J Med. 1996;100:193-258. 12. El-Zimaity HM, Ota H, Scott S, et al. A new triple stain for Helicobacter pylori suitable for the autostainer: carbol fuchsin/alcian blue/hematoxylin-eosin. Arch Path01 Lab Med. 1998;122:732-736. 13. El-Zimaity HM, Segura AM, Genta RM, et al. Histologic assessmentof Helicobacter pylori status after therapy: comparison of Giemsa, Diff-Quik, and Genta stains. Mod Pathol. 1998;11:288-291. 14. Parsonnet J, Hansen S, Rodriguez L, et al. Helicobatter pylon’ infection and gastric lymphoma. N Engl J Med. 1994;330: 1267-1271. 15. Genta RM, Robason GO, Graham DY. Simultaneous visualization of Helicobacter pylori and gastric morphology: a new stain. Hum Pathol. 1994;25: 221-226. 16. Klein PD, Malaty HM, Martin RF, et al. Noninvasive detection of Helicobacter pylori infection in clinical practice: the 13Curea breath test. Am J Gastroenterol. 1996;9 1:690-694. Hepatol.
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17. Rabeneck L, Graham DY. Helicobacter pylori: when to test, when to treat. Ann Intern Med. 1997; 126: 315-316. 18. Graham DY, Dore MP. Variability in the outcome of treatment of Helicobacter pylori infection: a critical analysis. In: Hunt RH, Tytgat GNJ, eds. Helicobatter pylori.
Basic Mechanisms
to Clinical
Cure.
Dordrecht, Netherlands: Kluwer Academic Publishers; 1998:426440. 19. Lee J, O’Morain C. Who should be treated for Helicobacter pylori infection? A review of consensusconferences and guidelines. Gastroenterology. 1997;113(suppl):S99-S 106. 20. Graham DY. Antibiotic resistance in Helicobacter pylon’: implications for therapy. Gastroenterology. 1998;115:1272-1277. 21. Van der Hulst RW, Keller JJ, Rauws EA, et al. Treatment of Helicobacter pylori: a review of the world literature. Helicobactel: 1996;1:6-19. 22. Sol1AH. Consensus conference. Medical treatment of peptic ulcer disease. Practice guidelines. Practice Parameters Committee of the American College of Gastroenterology. JAMA. 1996;275:622-629.
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tive VW
which, mrfortunately, is still probably
&W&y.. 3tekaWe it has a very high minimal infecthis dose, the pel.Gc ha&ix envisonment would have to be vq bad. ~,~~o~ are such that yau are wtmkd about &okra or Eschmichiu coli, then you should also worry about H pylori. Even when acid secretion is inhibited, the minimal infectious dose still remains high.
cure rate, and thus a test-of-cure follow-up is imptL&a to fietect trmt faihlres.
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