**4. Test-and-Treat Strategy for** *H. pylori*

Proposed strategies based on the noninvasive diagnosis of H. pylori infection so-called ''testand-treat'' strategy. This strategy has been proposed for clinical practice in developed countries which has low prevalence of H. pylori infection. Test-and-treat is based on the test of the presence of H. pylori and its subsequent eradication when detected.13 The test-andscope strategy performing a test to detect H. pylori in all patients and endoscopy only in those who are shown to be infected has been considered useful in clinical practice in some developing countries which has high prevalence of H. pylori infection such as Asia.

## **5. Management of** *H. pylori* **infection in FD**

Both European (Maastricht IV/ Florence Consensus Report) and Asian consensus reports endorse *H. pylori* testing and eradication as a key management strategy for patients with dyspepsia to produce long-term relief of symptoms. [37,38]

protein synthesis and seems to act luminal or locally. [43] The site of action of tetracycline is the bacterial ribosome, resulting in the interruption of protein biosynthesis. This antibiotic should not be given to pregnant women or children because it causes permanent staining of

Functional Dyspepsia and *Helicobacter pylori* Infection

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63

Fluoroquinolones have been used more popularly for *H pylori* treatment. These drugs block DNA gyrase and DNA synthesis in the organism. Resistance to fluoroquinolones devel‐ ops rapidly, so that prior use of these medications is associated with a significant rate of

Furazolidone is a monoamine oxidase inhibitor with widely antibacterial activity based on interference with bacterial enzymes. This antibiotic has proven to be an effective part of triple therapy while the development of resistance is rare. Furazolidone is an underused

Rifabutin is a semisynthetic ansamycin antibiotic with low MIC level for *H pylori* infection. This antibiotic is becoming more common and primarily used in combination with PPI and amoxicillin. [4] Rifabutin-based triple therapy for 10 days has been tested as salvage therapy and found to have high eradication rate of over 80%. Ritabutin can have cross-resistance with

Bismuth compounds are topically active pH-independent antimicrobial drugs that disrupt the integrity of bacterial cell walls. Bismuth is directly bactericidal, even though its MIC is high for *H pylori.* Bismuth is available in two forms (bismuth subsalicylate and bismuth subcitrate), which have equivalent effect as anti–*H pylori* therapy. *H pylori* resistance has not been reported

In recent years, the efficacy of legacy triple therapy for *H. pylori* eradication has declined worldwide to an unacceptable level. The average success rate of triple therapy has also declined to about 70%. [4, 8, 41] Bismuth-based quadruple therapy containing metronidazole is more effective than triple therapy with overall eradication rate of 83% and the eradication rate is higher in metronidazole sensitive group than those of the resistant group. [45] A recent study from Thailand demonstrated that a ten-day sequential therapy is highly effective for *H. pylori* infection with eradication rate of 95% but its efficacy affected by clarithromycin resist‐ ance. [41] A study from concomitant therapy evaluated and compared the efficacy of 10-day and 5-day therapy for *H. pylori* eradication using PPI with three antibiotics and found that 10-

developing teeth. [4]

**6.5. Fluoroquinolones**

resistance. [4]

**6.6. Furazolidone**

antimicrobial. [44]

antimycobacterium. [8]

for this agent. [4]

Regimens available

**6.8. Other antimicrobial agent**

**6.7. Rifabutin**

## **6. Antibiotics use for** *H. pylori* **eradication**

#### **6.1. Amoxicillin**

Amoxicillin is a popular antibiotic for treating *H pylori* infection because it is inexpensive and well tolerated, while resistance is rare. [39, 40] Amoxicillin acts by inhibiting the synthesis of the bacterial cell wall and can act locally when delivered into the gastric lumen and systemi‐ cally once absorbed into the bloodstream. Amoxicillin is pH-dependent; its bactericidal activity increases as the pH rises. As a single agent antibiotic use is not capable of curing *H. pylori* infection, amoxicillin must be combined with other antibiotics such as clarithromycin and metronidazole. [4]

#### **6.2. Clarithromycin**

Clarithromycin, a 14-membered ring macrolide antibiotic, is a derivative of erythromycin, sharing a close spectrum and clinical application. Clarithromycin is one of the most acid-stable macrolide with a low minimum inhibitory concentration (MIC) for *H. pylori* treatment. The antimicrobial activity results from its binding to bacterial ribosomes and disrupting bacterial proteinsynthesis. [4] Currently, Clarithromycin resistance is increasing and resulting in a marked reduction in treatment success. [4, 8, 41] Increasing the clarithromycin dosage does not overcome the problem of resistance. This antibiotic frequently causes a bitter taste that causes some patients will stop treatment.

#### **6.3. Metronidazole**

Metronidazole is a nitroimidazole group, which is toxic to microaerophilic organisms. Metronidazole is secreted into gastric juice and saliva, and is active after absorption with a half-life of 8 to 12 hours. [4] Metronidazoleis is a pH-independent. [42] After entry into the bacterial cell, metronidazole changes into a toxic form that alters the bacterial enzymes required for transformation. Unlike clarithromycin, metronidazole resistance can be overcome by increasing the dosage. The side effects of short-term use of metronidazole include interac‐ tions with alcohol (disulfiram like effect) and gastrointestinal symptoms such as nausea and vomiting. [4]

#### **6.4. Tetracycline**

Tetracycline, a derivative of polycyclic naphtacenecarboxamides, is a fine anti–*H. pylori* antimicrobial because it is inexpensive and pH-independent. [4] Tetracycline inhibits bacterial protein synthesis and seems to act luminal or locally. [43] The site of action of tetracycline is the bacterial ribosome, resulting in the interruption of protein biosynthesis. This antibiotic should not be given to pregnant women or children because it causes permanent staining of developing teeth. [4]

#### **6.5. Fluoroquinolones**

**5. Management of** *H. pylori* **infection in FD**

62 Dyspepsia - Advances in Understanding and Management

dyspepsia to produce long-term relief of symptoms. [37,38]

**6. Antibiotics use for** *H. pylori* **eradication**

**6.1. Amoxicillin**

metronidazole. [4]

**6.2. Clarithromycin**

**6.3. Metronidazole**

vomiting. [4]

**6.4. Tetracycline**

causes some patients will stop treatment.

Both European (Maastricht IV/ Florence Consensus Report) and Asian consensus reports endorse *H. pylori* testing and eradication as a key management strategy for patients with

Amoxicillin is a popular antibiotic for treating *H pylori* infection because it is inexpensive and well tolerated, while resistance is rare. [39, 40] Amoxicillin acts by inhibiting the synthesis of the bacterial cell wall and can act locally when delivered into the gastric lumen and systemi‐ cally once absorbed into the bloodstream. Amoxicillin is pH-dependent; its bactericidal activity increases as the pH rises. As a single agent antibiotic use is not capable of curing *H. pylori* infection, amoxicillin must be combined with other antibiotics such as clarithromycin and

Clarithromycin, a 14-membered ring macrolide antibiotic, is a derivative of erythromycin, sharing a close spectrum and clinical application. Clarithromycin is one of the most acid-stable macrolide with a low minimum inhibitory concentration (MIC) for *H. pylori* treatment. The antimicrobial activity results from its binding to bacterial ribosomes and disrupting bacterial proteinsynthesis. [4] Currently, Clarithromycin resistance is increasing and resulting in a marked reduction in treatment success. [4, 8, 41] Increasing the clarithromycin dosage does not overcome the problem of resistance. This antibiotic frequently causes a bitter taste that

Metronidazole is a nitroimidazole group, which is toxic to microaerophilic organisms. Metronidazole is secreted into gastric juice and saliva, and is active after absorption with a half-life of 8 to 12 hours. [4] Metronidazoleis is a pH-independent. [42] After entry into the bacterial cell, metronidazole changes into a toxic form that alters the bacterial enzymes required for transformation. Unlike clarithromycin, metronidazole resistance can be overcome by increasing the dosage. The side effects of short-term use of metronidazole include interac‐ tions with alcohol (disulfiram like effect) and gastrointestinal symptoms such as nausea and

Tetracycline, a derivative of polycyclic naphtacenecarboxamides, is a fine anti–*H. pylori* antimicrobial because it is inexpensive and pH-independent. [4] Tetracycline inhibits bacterial

Fluoroquinolones have been used more popularly for *H pylori* treatment. These drugs block DNA gyrase and DNA synthesis in the organism. Resistance to fluoroquinolones devel‐ ops rapidly, so that prior use of these medications is associated with a significant rate of resistance. [4]

#### **6.6. Furazolidone**

Furazolidone is a monoamine oxidase inhibitor with widely antibacterial activity based on interference with bacterial enzymes. This antibiotic has proven to be an effective part of triple therapy while the development of resistance is rare. Furazolidone is an underused antimicrobial. [44]

#### **6.7. Rifabutin**

Rifabutin is a semisynthetic ansamycin antibiotic with low MIC level for *H pylori* infection. This antibiotic is becoming more common and primarily used in combination with PPI and amoxicillin. [4] Rifabutin-based triple therapy for 10 days has been tested as salvage therapy and found to have high eradication rate of over 80%. Ritabutin can have cross-resistance with antimycobacterium. [8]

#### **6.8. Other antimicrobial agent**

Bismuth compounds are topically active pH-independent antimicrobial drugs that disrupt the integrity of bacterial cell walls. Bismuth is directly bactericidal, even though its MIC is high for *H pylori.* Bismuth is available in two forms (bismuth subsalicylate and bismuth subcitrate), which have equivalent effect as anti–*H pylori* therapy. *H pylori* resistance has not been reported for this agent. [4]

#### Regimens available

In recent years, the efficacy of legacy triple therapy for *H. pylori* eradication has declined worldwide to an unacceptable level. The average success rate of triple therapy has also declined to about 70%. [4, 8, 41] Bismuth-based quadruple therapy containing metronidazole is more effective than triple therapy with overall eradication rate of 83% and the eradication rate is higher in metronidazole sensitive group than those of the resistant group. [45] A recent study from Thailand demonstrated that a ten-day sequential therapy is highly effective for *H. pylori* infection with eradication rate of 95% but its efficacy affected by clarithromycin resist‐ ance. [41] A study from concomitant therapy evaluated and compared the efficacy of 10-day and 5-day therapy for *H. pylori* eradication using PPI with three antibiotics and found that 10day regimen is highly effective with eradication rate of 96% and the 5-day regimen yielded eradication rate of 88%. [46] The available treatment regimens was summarized in table 1. [4]

**Author details**

**References**

40:701-3.

Ratha-korn Vilaichone and Varocha Mahachai

*North Am* 1993; 22(1):5-19.

terology 2006; 130: 1466–79.

\*Address all correspondence to: vilaichone@yahoo.com

GI Unit, Faculty of Medicine, Thammasat University Hospital, Thailand

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[1] Goodwin CS, Worsley BW. Microbiology of *Helicobacter pylori*. *Gastroenterol Clin*

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[2] Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with

[3] Atherton JC. The clinical relevance of strain type of *Helicobacter pylori*. *Gut* 1997;

[4] Vilaichone RK, Mahachai V, Graham DY. *Helicobacter pylori*: Diagnosis and manage‐

[5] Tack J, Talley NJ, Camilleri M, *et al*. Functional gastroduodenal disorders. Gastroen‐

[6] O'Connor H, Sebastian S. The burden of Helicobacter pylori infection in Europe. Ali‐

[7] Vilaichone RK, Mahachai V, Tumwasorn S, et al. Molecular epidemiology and out‐ come of infection *Helicobacter pylori* in Thailand. *Helicobacter* 2004; 9(5): 453-9.

[8] Mahachai V, Vilaichone RK. Current Status of *Helicobacter pylori* Infection in Thai‐

[9] Vilaichone RK, Mahachai V. Current management of *Helicobacter pylori* infection. *J*

[10] Ghoshal UC, Singh R, Chang F-Y, Hou X, Wong BCY, Kachintorn U. Epidemiology of uninvestigated and functional dyspepsia in Asia: facts and fiction. *J. Neurogastroen‐*

[11] Li XB, Liu WZ, Ge ZZ *et al*. Analysis of clinical characteristics of dyspeptic symptoms

[12] Kwan AC, Bao TN, Chakkaphak S *et al*. Validation of Rome IIcriteria for functional gastrointestinal disorders by factor analysis of symptoms in Asian patient sample. *J.*

#### **Legacy therapies**

Triple therapy: A PPI plus amoxicillin, 1 g , plus clarithromycin, 500 mg, or metronidazole/tinidazole, 500 mg, twice a day for 14 days

Quadruple therapy: Bismuth, metronidazole, 500 mg, tetracycline, 500 mg, three times a day plus a PPI twice a day for 14 days

#### **Concomitant triple therapies**

A PPI plus amoxicillin, 1 g, plus clarithromycin, 500 mg, and metronidazole/tinidazole, 500 mg, twice a day for 14 days

#### **Sequential therapy**

A PPI plus 1 g amoxicillin, twice a day for 5 days. On day 6 stop amoxicillin and add clarithromycin, 250 or 500 mg and metronidazole/tinidazole, 500 mg, twice a day to complete the 10-day course.

**Table 1.** Treatment regimens for *Helicobacter pylori* infections4

There are many factors that could influence the eradication rate of *H. pylori*. Compliance is a major concern and how to make the regimen conveniently used by all patients is important. Impact of drug metabolism and CYP2C19 on eradication rate is a new point of concern and needs further research to elucidate this question. The choice of a second-line therapy depends on local antibiotic resistance pattern, previous treatment, drug availability and cost. Secondline salvage therapy after primary therapy failure, levofloxacin based triple therapy resulted in eradication rate of over 80% in patients after failed triple therapy. The accumulation eradication rate after first-line and second-line therapy becomes nearly 90%. This regimen is convenient and well-tolerated but antibiotic resistance to levofloxacin needs to be monitored. Rifabutin-based triple therapy for 10 days has been tested as salvage therapy and found to have high eradication rate of over 80%. Ritabutin can have cross-resistance with antimyco‐ bacterium. Furazotidone can also be used as salvage therapy but the use is limited by its availability. The summarized efficacy of *H. pylori* treatment regimens is: [8]


### **Author details**

day regimen is highly effective with eradication rate of 96% and the 5-day regimen yielded eradication rate of 88%. [46] The available treatment regimens was summarized in table 1. [4]

Triple therapy: A PPI plus amoxicillin, 1 g , plus clarithromycin, 500 mg, or metronidazole/tinidazole, 500 mg, twice a

Quadruple therapy: Bismuth, metronidazole, 500 mg, tetracycline, 500 mg, three times a day plus a PPI twice a day for

A PPI plus amoxicillin, 1 g, plus clarithromycin, 500 mg, and metronidazole/tinidazole, 500 mg, twice a day for 14 days

A PPI plus 1 g amoxicillin, twice a day for 5 days. On day 6 stop amoxicillin and add clarithromycin, 250 or 500 mg and

There are many factors that could influence the eradication rate of *H. pylori*. Compliance is a major concern and how to make the regimen conveniently used by all patients is important. Impact of drug metabolism and CYP2C19 on eradication rate is a new point of concern and needs further research to elucidate this question. The choice of a second-line therapy depends on local antibiotic resistance pattern, previous treatment, drug availability and cost. Secondline salvage therapy after primary therapy failure, levofloxacin based triple therapy resulted in eradication rate of over 80% in patients after failed triple therapy. The accumulation eradication rate after first-line and second-line therapy becomes nearly 90%. This regimen is convenient and well-tolerated but antibiotic resistance to levofloxacin needs to be monitored. Rifabutin-based triple therapy for 10 days has been tested as salvage therapy and found to have high eradication rate of over 80%. Ritabutin can have cross-resistance with antimyco‐ bacterium. Furazotidone can also be used as salvage therapy but the use is limited by its

**•** Triple therapy containing PPI plus amoxicillin and clarithromycin or metronidazole has

**•** Sequential therapy and concomitant therapy yield high eradication rate of over 90% and

**•** Bismuth based quadruple therapy could be used as alternative first - line therapy with high

**•** Levofloxacin based- triple therapy and concomitant therapy can be used as a second line

limited efficacy for *H. pylori* eradication with expected eradication rate of 70%.

availability. The summarized efficacy of *H. pylori* treatment regimens is: [8]

metronidazole/tinidazole, 500 mg, twice a day to complete the 10-day course.

**Table 1.** Treatment regimens for *Helicobacter pylori* infections4

could be used as first - line therapy.

salvage therapy after failed first - line therapy.

eradication rate.

**Legacy therapies**

day for 14 days

**Concomitant triple therapies**

64 Dyspepsia - Advances in Understanding and Management

**Sequential therapy**

14 days

Ratha-korn Vilaichone and Varocha Mahachai

\*Address all correspondence to: vilaichone@yahoo.com

GI Unit, Faculty of Medicine, Thammasat University Hospital, Thailand

#### **References**


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[28] Kawamura A, Adachi K, Takashima T *et al*. Prevalence of functional dyspepsia and its relationship with *Helicobacter pylori* infection in a Japanese population. *J. Gastroen‐*

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[30] Wong WM, Xiao SD, Hu PJ *et al*. Standard treatment for *Helicobacter pylori* infection is suboptimal in non-ulcer dyspepsia compared with duodenal ulcer in Chinese. *Ali‐*

[31] Moayyedi P, Soo S, Deeks J *et al*. Eradication of *Helicobacter pylori* for non-ulcer dys‐

[32] Jin X, Li YM. Systematic review and meta-analysis from Chinese literature: the asso‐ ciation between *Helicobacter pylori* eradication and improvement of functional dys‐

[33] *Howden CW, Hunt RH.* Guidelines for the management of *Helicobacter pylori* infection. Ad Hoc Committee on Practice Parameters of the American College of Gastroenterol‐

[34] Vaira D, Malfertheiner P, Megraud F, et al. Diagnosis of *Helicobacter pylori* infection with a new non-invasive antigen-based assay. HpSA European study group. *Lancet*

[35] El-Zimaity HM, Segura AM, Genta RM, et al. Histologic assessment of Helicobacter pylori status after therapy: comparison of Giemsa, Diff-Quik, and Genta stains. *Mod*

[36] HowdenCW, Hunt RH. Guidelines for the management of Helicobacter pylori infec‐ tion. AdHoc Committee on Practice Parameters of the American College of Gastroen‐

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[38] Miwa H, Ghoshal UC, Fock KM, et al. Asian Consensus Report on Functional Dys‐

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[40] Watanabe K, Tanaka A, Imase K, et al. Amoxicillin resistance in Helicobacter pylori: studies from Tokyo, Japan from 1985 to 2003*. Helicobacter* 2005; 10(1):4–11.

**Chapter 5**

*Helicobacter pylori***—Associated Dyspepsia in Paediatrics**

*Helicobacter pylori* ubiquitously infects the human gastric mucosa since time immemorial, predictably before the man's diaspora out of East Africa around 58,000 years ago [1]. Colonization may have been somehow beneficial for human carriers, allowing the coevolution of this gram-negative bacterium and its host over the centuries. Yet, at least nowadays [2], this may not be a peaceful association, with infection almost invariably causing an acute host immune response. However, in a fully adapted manner, *H. pylori* avoids recognition and, thus, clearance, by the host immune system, with both infection and the consequent gastritis persisting throughout the patients' life. The clinical outcome of this persistence is dependent on a sophisticated crosstalk between the host and the pathogen. If often asymptomatic, the *H. pylori*-associated non-ulcer dyspepsia is clearly the strongest aetiological factor for severe gastric diseases that will develop late in adult life in a minority of infected patients, *i.e.*, peptic ulcer disease, both gastric and duodenal ulcers, and gastric cancer, namely, adenocarcinoma and mucosa associated lymphoid tissue (MALT) lymphom*a (reviewed in [3])*. Peptic ulcer disease rarely occurs soon after *H. pylori* infection [4-8] that generally starts in childhood; this presumably reflects marked differen‐

ces in the virulence [9-16] and/or in the susceptibility of young patients [17-19].

This chapter, focussing on the paediatric population, seeks to explore: the prevalence of *H. pylori* infection; the molecular mechanism used by *H. pylori* during colonization and infection; the role of this bacterium in the development of peptic ulcer-related organic dyspepsia; and the genetic/proteome profile of the *H. pylori*-strains associated with peptic ulcer disease.

> © 2013 Roxo-Rosa et al.; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Mónica Roxo-Rosa, Mónica Oleastro and

Additional information is available at the end of the chapter

Ana Isabel Lopes

**1. Introduction**

http://dx.doi.org/10.5772/56551


**Chapter 5**
