Helicobacter Pylori and Other Gastrointestinal Flora

Educational Objectives

The goal of this program is to improve the management of Helicobacter pylori infection and irritable bowel syndrome. Af­ter hearing and assimilating this program, the clinician will be better able to:

1.   Review treatment strategies for patients who fail initial therapy for H pylori infection.

2.   Recognize when treatment is indicated for H pylori infection in adults and children.

3.   Utilize testing to confirm eradication of H pylori after completing treatment.

4.   Discuss the factors that protect the small intestine from bacterial overgrowth.

5.   Explain the 2 types of bacterial resistance.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Pimentel is a consultant for Salix Pharmaceuticals and Prometheus. Drs. Peek and Jones and the planning committee reported noth­ing to disclose. In his lecture, Dr. Pimentel presents information that is related to the off-label or investigational use of a therapy, product, or device.

Acknowledgments

Dr. Peek was recorded at Gastroenterology and Hepatology Update 2009, held September 11-12, 2009, in Nashville, TN, and sponsored by the Vanderbilt Digestive Disease Center. Dr. Jones was recorded at the NASPGHAN Annual Meeting, held November 12-14, 2009, in National Harbor, MD, and sponsored by the North American Society for Pediatric Gastroenterol­ogy, Hepatology, and Nutrition. Dr. Pimentel was recorded at 10th Annual Educational Meeting in Gastroenterology, held October 9-11, 2009, in Santa Monica, CA, and sponsored by the Cedars-Sinai Medical Center, Division of Gastroenterol­ogy. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this pro­gram.

Current Treatment Modalities for H pylori

Richard M. Peek Jr, MD, Mina Cobb Wallace Professor of Medicine and Cancer Biology, Director, Gastroen­terology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, TN

Helicobacter pylori infection: causes gastric inflammation; strongest risk factor for duodenal ulcer and distal gastric cancer; successful cure defined as absence of detectable organisms 4 to 6 wk after completion of therapy; gastric barriers to antimicrobial efficacy  —  acidic pH; clarithromycin and amoxicillin highly susceptible to degradation at acidic pH; active secretory mechanisms in stomach; thick gastric mucus layer within which H pylori resides; gas­tric peristalsis; many drugs used in regimens not designed to work efficiently in stomach, but depend on small bowel for absorption into bloodstream and delivery to sites where bacteria reside (deep within gastric glands and pits); factors affecting antibiotic delivery to gastric mucosa  —  properties of drug, including frequency and dose; lu­minal factors; systemic delivery; liver metabolism

Standard triple therapy: current first-line therapy and most widely used worldwide; comprised of proton pump inhibitor (PPI), amoxicillin, and clarithromycin; initial eradication rate »90%; not efficacious currently (does not reach eradication rate of 80% today); reasons for declining efficacy  —  increasing prevalence of resistant H pylori strains; study showed that throughout United States, resistance to clarithromycin 13% (in some areas, eg, Alaska £30%); metronidazole, 25%, and amoxicillin, »1%; assume strain resistant unless documented otherwise; earlier studies primarily involved H pylori–in­fected patients with duodenal ulcers (highest cure rates)

Treatment strategies after failure of initial therapy: one option to perform endoscopy, culture bacteria, and per­form antibiotic susceptibility testing; difficult to perform; takes long time to culture H pylori 

Quadruple therapy: PPI, bismuth, tetracycline, and metronidazole (eradicates bacteria in 87% to 90% of patients); ideal for clarithromycin-resistant strains; complex regimen; patient adherence problematic (requires 13-15 pills daily)

Sequential therapy: PPI plus amoxicillin bid for 5 days, then amoxicillin replaced with clarithromycin and metronida­zole (tinidazole outside United States); advantages  —  high eradication rates; effective in patients with clarithromy­cin-resistant H pylori strains (89% success rate, compared to triple therapy in one study); low side-effect profile; reduced cost (clarithromycin most expensive element of therapy); potential limitations  —  most data from one coun­try (Italy); no efficacy data from North America (limits generalizability of results); number of patients with clar­ithromycin-resistant H pylori small; adherence possibly problematic in future; uncertainty about treatment failures; pooled results of 10 trials show eradication rate of 93%

Salvage therapy: consists of PPI with amoxicillin, then adding levofloxacin or rifabutin; levofloxacin  —  eradication rate 81% in studies; well tolerated; 10-day course superior to 7-day course; low dose as effective as high dose; resistance easily ac­quired; rifabutin  —  originally designed to treat mycobacterial infections; lower efficacy than levofloxacin; leukopenia seen in £25% of patients; resistance remains low

Concomitant therapy: consists of PPI plus amoxicillin, clarithromycin, and metronidazole; studies show good erad­ication rates; no randomized placebo-controlled double-blind trials performed

High-dose dual therapy: high-dose PPI plus amoxicillin for 14 days; relatively good eradication rates reported; speaker not in favor, unless all other therapies fail

Whom to treat: definite indications  —  peptic ulcer disease (PUD) and gastric mucosa-associated lymphoid tissue (MALT) lymphoma; questionable indications  —  family history of gastric cancer; Menetrier’s disease; before long-term nonsteroidal anti-inflammatory drug (NSAID) use; nonulcer dyspepsia (NUD); before long-term PPI use; known premalignant lesions in stomach

Dyspepsia: accounts for 2% to 3% of primary care visits and £40% of gastroenterology referrals; after investigation, majority classified as NUD; NUD  —  defined as 3-mo history of dyspepsia with no obvious structural explanation for symptoms; evidence implicating H pylori  —  gastric dysmotility (delayed gastric emptying); altered visceral sen­sation; increased sensitivity to acid; question of whether eradication of H pylori improves dyspepsia symptoms in patients with NUD; Cochrane database meta-analysis  —17 trials included in main analysis; compared antisecre­tory and antibiotic therapy with placebo and/or antisecretory therapy alone; dichotomous outcomes seen; >3500 pa­tients; no significant heterogeneity between studies; suggested benefit of treating H pylori infection in patients with NUD; 10% risk reduction in NUD symptoms in H pylori eradication group at 12 mo; number needed to treat, 14

H pylori in Children

Nicola L. Jones, MD, PhD, Associate Professor of Pediatrics and Physiology, University of Toronto, Scientist, Cell Biology Program, Research Institute, and Staff Gastroenterologist, Division of Gastroenterology, Hepatol­ogy, and Nutrition, The Hospital for Sick Children, Toronto, ON

Whom to test: based on guidelines from 3 organizations and joint European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN); indicated in patients with PUD; not indicated in patient with functional abdominal pain (no evidence that H pylori causes symptoms) or in asymptomatic children; indications  —  family history of gastric cancer (based on expert opinion, not evidence); unexplained refractory iron deficiency anemia; MALT lym­phoma; after treatment of complicated PUD

Whom to treat: children with PUD; consider if child has H pylori infection without PUD; discuss with family  —  fact that eradication of H pylori will not affect child’s symptoms; possible side effects of therapy; long-term implications of H py­lori infection; other indications  —  presence of family history of gastric cancer; unexplained refractory iron-deficiency anemia

Current recommendations for therapy: standard triple therapy  —  PPI plus amoxicillin and imidazole antibiotic or PPI plus amoxicillin and clarithromycin for 7 to 14 days; alternative  —  bismuth salts, amoxicillin, and imidazole drug or se­quential therapy; sequential therapy  —  recommended as first-line treatment; consists of amoxicillin and PPI for 5 days followed by PPI, clarithromycin, and tinidazole for 5 days; found far superior to standard triple therapy in randomized controlled trial; no North American studies; recent systematic review found benefit in adults but not in children; eradica­tion rates essentially equivalent to triple therapy; recommended as first-line therapy; adjunctive therapy with probiotics  —  some biologic studies suggest probiotics have antibacterial effect on H pylori in vitro and in animal models; may reduce side effects of, eg, prolonged antibiotic therapy; recent meta-analysis  —  (6 adult studies and 2 pediatric studies) looked at whether probiotics enhanced eradication rates; overall benefit seen in children (but not in adults); however, unknown which probiotics to use; more clinical evidence needed

Confirmation of eradication: not suggested by guidelines, unless child has complicated PUD (not true in clinical practice); urea breath test and stool antigen test effectively confirm eradication (excellent sensitivity and specific­ity); monoclonal version of stool antigen test superior to polyclonal version; serologic tests not recommended; test 4 to 8 wk after completing therapy

Treating antibiotic resistance: joint guidelines  —  recommend surveillance of antibiotic resistance in different geographic ar­eas; in areas where clarithromycin resistance rate >20%, susceptibility testing recommended; clarithromycin resistance rate <15% in United States; treatment failure  —  reasons include noncompliance and antibiotic resistance; strategies include mod­ifying therapy by adding or changing antibiotic, adding bismuth, or changing dose or duration; pretreatment tests  —  culture and susceptibility; molecular testing on initial biopsy to determine clarithromycin susceptibility

Summary: goal of testing to diagnose cause of symptoms, not to detect H pylori infection; antibiotic resistance rates, when available, should guide therapy; manage treatment failure by changing regimens and ensuring compliance

Manipulation of Bacterial Flora in Clinical Disease

Mark Pimentel, MD, Director, Gastrointestinal (GI) Motility Program and Director, GI Motility Labora­tory, Cedars-Sinai Medical Center, Los Angeles, CA

Introduction: more bacterial cells in intestine than human cells in body; some bacteria use substrate to produce en­ergy, eg, utilization of hydrogen gas produced by other organisms to produce methane gas; certain by-products of bacteria inhibitory to other bacteria; diet plays role in determining type of bacteria in colon; microenvironments in intestine range from oxygenated areas to anaerobic areas and from liquid to solid areas; bacteria produce sub­stances (eg, lipopolysaccharides, gases, hormones, chemicals) that interact with host, leading to neuromuscular ef­fects, mucosal toxicity, sensory effects, effects on mast cells, cytokine levels, and cellular responses

Distribution of bacteria in gut: normally, colon contains 1011 colony-forming units (CFU)/mL (half of weight of stool from bacteria); progressing proximally in intestine, number of bacteria decreases significantly; small intestine relatively clean; mechanisms that prevent small intestinal bacterial overgrowth (SIBO)  —  biliary and pancreatic se­cretions act as detergents (degrade cell walls or inhibit function of bacteria); gastric acid; ileocecal valve prevents regurgitation or reflux from bacteria in colon; mucosal immunity defends against translocation or penetration of bacteria to systemic circulation; small intestinal motility

Irritable bowel syndrome (IBS): bacteria as cause  —  respond to antibiotics; bacterial overgrowth; excessive colonic bac­teria; alteration in bacterial composition (eg, low Lactobacillus); alteration in response to bacteria; changes in flora due to acute gastroenteritis; diagnosis of SIBO  —  no gold standard; culture possible gold standard, but not practical (due to length of small intestine, number of species of bacteria, unknown number sites for sampling, inability to reach sites to collect sample, and inability to culture all organisms); standard for SIBO of 105 CFU/mL validated only in Billroth II pa­tients; glucose absorbed within 3 ft of small bowel and never reaches SIBO; therefore, glucose and sucrose breath tests tend to underdiagnose overgrowth; lactulose breath test tends to overdiagnose overgrowth by detecting colonic bacteria, especially if transit rapid; other option case-control studies; criterion for SIBO in normal intact GI tract not yet estab­lished; in literature, healthy controls had 101 to 102 CFU/mL; study by Posserud  —  showed no difference in SIBO be­tween IBS patients and controls using criterion of 105 CFU/mL; however, number of coliform bacteria in small bowel of patients with IBS increased, compared to controls; neomycin in IBS  —  if lactulose breath test normalized, patients more likely responding or responding at greater intensity; rifaximin in IBS  —  study showed that patients given rifaximin for 10 days demonstrated statistically significant improvement, with sustained benefit for 10 wk; phase IIb studies showed im­provement of bloating and global symptoms of IBS

Bacterial resistance: genomic resistance  —  cells with antibiotic resistance multiply, but proportion remains same; use of antibiotic cultivates bacteria with resistance; over time, number stabilizes or reduction in load occurs (nonstable re­sistance); plasmid resistance  —  plasmids small circular pieces of DNA that bacteria can pass to each other without multiplying; sex pili inject plasmids between bacteria after duplication within cells; more problematic; ciprofloxacin, metronidazole, penicillin, tetracyclines, and neomycin have plasmid resistance in humans, with clinical efficacy >50%; other relevant issues include nonabsorbability and localized delivery; no plasmid resistance with rifaximin (all genetic resistance dissipates); study  —  compared rifaximin to conventional antibiotics in patients with SIBO; eradica­tion rate 70% with rifaximin (40% for other antibiotics); with recurrence of bacterial overgrowth, response to rifaxi­min as effective as first time (in other group, second treatment with, eg, neomycin only 25% as effective as first time), with development of persistent resistance

Complexities of gas production: hydrogen used by methanogens to create methane; other bacteria hydrogen sulfide (H2S) producers (affects breath test); H2S toxic gas rapidly detoxified by liver; studies showed that methane present in breath test associated with constipation-predominant IBS (C-IBS); presence of methane on breath test of humans signifies that oral-cecal transit and whole-gut transit twice as long; in animal models, 70% slowing of intestinal transit seen; study looking at neomycin found statistically significant improvement of C-IBS, compared to placebo, due to eradication of methane; amount of methane determines degree of constipation clinically; neomycin and ri­faximin symbiotically eradicate methane, but neither drug can do this by independently; study  —  found that meth­ane 92% sensitive for predicting C-IBS; methane possible diagnostic test for treatable C-IBS or as guide to therapy

Bacterial overgrowth: possible cause includes migrating motor complexes (MMCs) in small bowel due to lack of frequency; significantly reduced MMCs seen in IBS patients with positive breath test; tegaserod or erythromycin taken at bedtime after completion of course of antibiotics prolongs time to recurrence of overgrowth (from 58 days to 256 days) and IBS symptoms in subset of patients

Manipulation of flora in IBS: proposed therapies for SIBO include antibiotics, probiotics, prebiotics, diet manipula­tion, and manipulation of bowel motor function to regulate proportions of bacteria in different locations; proposed treatments of methane-positive IBS include combination antibiotics, inhibition of methanogenesis, blocking of ef­fects of methane, or adsorption of methane; possible that acute gastroenteritis reflects small bowel motor function and contributes to dysmotility and that hydrogen-related SIBO associated with IBS; methane believed to contribute to slowing of transit and C-IBS; possible that central mechanisms (eg, corticotropin-releasing factor) play role in altered motor functions or possible relationship between gut flora and gut nervous system (suggests strategy of treating with antibiotic followed by prokinetic agent)

Suggested Reading

Dehghani SM et al: Efficacy of the standard quadruple therapy versus triple therapies containing proton pump inhibitor plus amoxi­cillin and clarithromycin or amoxicillin-clavulanic acid and metronidazole for Helicobacter pylori eradication in children. Dig Dis Sci 54:1720, 2009; Francavilla R et al: Sequential treatment for Helicobacter pylori eradication in children. Gut 57:1178, 2008; Khoshini R et al: A systematic review of diagnostic tests for small intestinal bacterial overgrowth. Dig Dis Sci 53:1443, 2008; Ma­jewski M et al: Efficacy of rifaximin, a nonabsorbed oral antibiotic, in the treatment of small intestinal bacterial overgrowth. Am J Med Sci 333:266, 2007; Megraud F: Helicobacter pylori and antibiotic resistance. Gut 56:1502, 2007; Pimentel M: The prevalence of small intestinal bacterial overgrowth in irritable bowel syndrome: IBS vs healthy controls (not historical definitions). Gut 57:1334, 2008; Posserud I et al: Small intestinal bacterial overgrowth in patients with irritable bowel syndrome. Gut 56:802, 2007; Quigley EM et al: Small intestinal bacterial overgrowth: roles of antibiotics, prebiotics, and probiotics. Gastroenterology 130:S78, 2006; Ro­mano M et al: Failure of first-line eradication treatment significantly increases prevalence of antimicrobial-resistant Helicobacter py­lori clinical isolates. J Clin Patho 61:1112, 2008; Sarker SA et al: Causal relationship of Helicobacter pylori with iron-deficiency anemia or failure of iron supplementation in children. Gastroenterology 135:1534, 2008; Songür Y et al: Triple or quadruple tetracy­cline-based therapies versus standard triple treatment for Helicobacter pylori treatment. Am J Med Sc 338:50, 2009; Tummala S et al: Quantifying gastric Helicobacter pylori infection: a comparison of quantitative culture, urease breath testing, and histology. Dig Dis Sci 52:396, 2007; Zullo A et al: 13C-urea breath test values and Helicobacter pylori eradication. Dig Dis Sci 53:370, 2008.