**3. Macrolide resistance**

100 Gastrointestinal Endoscopy

were classified into four patterns and then correlated with histology results. Type 1 pattern corresponded to normal gastric mucosa, types 2 and 3 to *H. pylori* -infected mucosa and type 4 to atrophy. The sensitivity and specificity for these endoscopic findings were 92.7% and

*H. pylori*

Achlorhydia, carcinogens

imunne response, diet gastrin, host genetics

100% for type 1, and 100% and 92.7% for types 2 and 3 together, respectively (5).

Normal mucosa

Chronic active gastritis

Gastric atrophy

Intestinal metaplastia

Dysplasia

Gastric cancer

information on the susceptibility or resistance of *H. pylori* to antibiotics [2].

based on the cascade proposed by Correa et al (3, 4)

**2.** *H. pylori* **detection** 

Fig. 1. Model representing the role of *H. pylori* and other factors in gastric carcinogenesis,

Various diagnostic assays for the detection of an *H. pylori* infection are available. Histological detection and culturing of the pathogen are gold standard, which require invasive gastroduodenoscopy to obtain gastric biopsy specimens. In the last decade, noninvasive approaches, such as serological detections, the [13C] and [14C]urea breath test (UBT), and detection *H. pylori* antigen or DNA in feces, helped and improved the evaluation of *H. pylori* infection status in patients. Because of low sensitivities of most serological assays for younger than 12 years of age patients, they are not suitable for pediatric. The UBT is a well-established noninvasive diagnostic assay and gives excellent performance for both adults and children, but its specificity decreases for infants and young children and need. In addition, the performance of UBT with infants and young children requires trained staff for air sampling with a face mask, and the test also requires expensive instruments, such as an isotope ratio mass spectrometer or an infrared isotope ratio spectrometer. Enzyme immunoassays (EIAs) for the identification of *H. pylori* antigens in fecal specimens circumvent these difficulties. EIAs based on monoclonal antibodies have shown consistent excellent results, with very high sensitivities and specificities for both adults and children. A major disadvantage of all the noninvasive tests described above is their inability to provide *H. pylori* infection can be cured by antibiotics, however the ideal anti-*H. pylori* treatment has yet to be found. Many factors have been implicated in treatment failure, including ineffective penetration of antibiotics into the gastric mucosa, antibiotic inactivation by low gastric pH, lack of compliance, and emergence of acquired antibiotic resistance by *H. pylori*. Despite the success of the current anti-*Helicobacter* therapies, it is suggested that eradication rates among patients with gastritis are lower than among patients with peptic ulcer disease, with the causes of this phenomenon still being the subject of speculation [6].

The macrolide class of antimicrobial agents is over 30 years old and is still at the forefront of antimicrobial therapy as well as drug discovery and development. Clarithromycin is a recently approved 14-membered macrolide with increased stability in acid and improved pharmacokinetics, including the appearance of a microbiologically active metabolite in humans. Clarithromycin possesses broad-spectrum antimicrobial activity, inhibiting a range of gram-positive and gram-negative organisms, some anaerobes, and atypical pathogens, in many cases with greater in vitro activity than erythromycin [7].

Clarithromycin is a semi-synthetic macrolide antibiotic. Chemically, it is 6-*0*-methylerythromycin. The molecular formula is C38H69NO13, and the molecular weight is 747.96 (Figure 2). Clarithromycin is a white to off-white crystalline powder. It is soluble in acetone, slightly soluble in methanol, ethanol, and acetonitrile, and practically insoluble in water.

Currently, a seven-day, triple-drug regimen has been recommended as one of the first-line therapies for *H. pylori* management. This treatment includes omeprazole (a proton-pump inhibitor), clarithromycin, and amoxicillin or metronidazole [2, 8]. However, this therapy is being investigated because of increased eradication failures due to the prevalence of clarithromycin resistant *H. pylori* infections. Many studies have shown that between 0–50% of *H. pylori* isolates were clarithromycin resistant, which leads to a need for long term

Clarithromycin Resistance and *23S rRNA* Mutations in *Helicobacter pylori* 103

Fig. 3. Model of domain V and VI of 23S rRNA from *E. coli*, (12 , 13)

Fig. 2. The structural formula of clarithromycin

assessment of the efficacy of clarithromycin in the triple-drug regimen. It is well known that the abuse of macrolide antibiotics including clarithromycin might lead to clarithromycin resistant forms of *H. pylori* [8]. Clarithromycin is a bacteriostatic antibiotic, which belongs to a group of macrolides bound to peptidyltransferase loop of domain V and VI of the 23S rRNA molecule (Figure 3 and 4). This binding interferes with protein elongation, and thus effectively blocks bacterial protein synthesis.

The antibacterial activity of clarithromycin is similar to that of other macrolides, but clarithromycin is better absorbed in the gastric mucus layer, more acid-stable, and therefore more effective against *H. pylori*. Resistance to clarithromycin is thought to develop when substitutions in one nucleic acid at or near this binding site on the ribosome prevent the drug from binding, thereby making it ineffective [9]. Mutations A2144G, A2143G, A2142G and A2143C are the most often observed and reported by investigators, other mutations such as A2142C, A2115G, G2141A, A2142T and T2717C have been described but appear to be rare in peptidyltransferase [10, 11].
