A Review Article on Helicobacter pylori Antibiotic Resistance Profile in Iran

Now a day, antibiotic resistance is a global health threat which is considered as the major cause of treatment failures in bacterial infection. H. pylori (Helicobacter pylori) is a spiral-shaped gram negative bacterium that colonizes in gastric mucosa and is responsible for serious gastrointestinal diseases including peptic ulcers and gastric cancer. Appearance and increasing of antibiotic resistance in the recent years, mainly to metronidazole (in developing countries) and clarithromycin (in developed countries) have decreased the efficacy of H. pylori treatment regimens. The prevalence of H. pylori antibiotic resistance is not the same in all over the world and shows geographical variations. So, antibiotic treatment regimens should be administrating according to local antibiotic susceptibility pattern. Iran is a developing country in Middle East with the high prevalence of H. pylori infection about 80%. Many Iranian researchers from different provinces have Review Article Eyvazi and Hakemi-Vala; IJTDH, 10(1): 1-12, 2015; Article no.IJTDH.18719 2 investigated the susceptibility of H. pylori isolates to common antibiotics. So, the aim of this review paper was survey on the existence reports of Iranian authors to access an accurate antibiotic profile of H. pylori for efficient eradication therapy in the future.


INTRODUCTION
Helicobacter pylori (H. pylori) is an important pathogen of gastric mucosa that infects half of the world's population [1]. The prevalence of H. pylori infection is different among developing and developed countries [2]. H. pylori is a major cause of some dyspeptic disorders including chronic active gastritis, peptic ulcer diseases and gastric malignancies [1,3]. As other bacterial infections, H. pylori infection can be treated with antibiotics. Although H. pylori is susceptible to many antibiotics in vitro, its eradication is difficult in in vivo. Standard triple therapy including a proton pump inhibitor (PPI) and two antibiotics e.g. metronidazole, clarithromycin and or amoxicillin, is used to cure H. pylori infection [4]. But eradication rates are lower than 80% in several areas [5,6]due to patient's poor compliance or antibiotic resistance [7]. Prevalence of H. pylori antibiotic resistance shows geographical variation between and within countries [8]. For choosing the best treatment regimen, a local susceptibility pattern is necessary. Our aim in this review article was to survey on the resistance rate to common antibiotics against H. pylori infection based on several reports of different provinces of our country, Iran.

LITERATURE SEARCH
A comprehensive literature search was performed about prevalence of antibiotic resistance of H. pylori strains isolated from Iranian patients by using PubMed (http://www.ncbi.nlm.nih.gov) and Google Scholar (scholar.google.com). Also, molecular mechanism of resistance in H. pylori isolates that have been investigated by Iranian authors was collected and analyzed. Some data that were in abstract form or only in Persian language were excluded from this literature review.

RESISTANCE TO METRONIDAZOLE
Metronidazole (MTZ) is a 5-nitroimidazole antibiotic that is used for treatment of a variety of infections such as parasitic infections, anaerobic and microaerophilic bacterial infections (including H. pylori). Metronidazole is administered in its inactive form (2-methyl-5-nitro-1H-imidazole-1ethanol) [9]. It could be cytotoxic by transferring an electron from some metabolites such as ferredoxin (fdx A) to its nitro group in cytoplasm of anaerobic and micro-aerophilic pathogens. So, reduction of nitro group in inactive form of metronidazole, converts it to active form which has nitrose free radical. Nitrose free radical destroys all cell compounds such as DNA, RNA and proteins [9]. Metronidazole resistance in H. pylori is associated with null mutations in rdxA, the gene encoding an oxygen-insensitive NADPH nitroreductase [10]. Prevalence of metronidazole-resistance H. pylori in developing countries (such as Iran) is more than developed countries [11]. As shown in the Table 1

RESISTANCE TO AMOXICILLIN
Amoxicillin (AMX) is a broad spectrum antibiotic that belongs to the class of β-lactams. This group of antibiotics bind to penicillin-binding proteins (PBP) in bacterial cell wall and inhibit cell division [73]. Mechanism of amoxicillin resistance in H. pylori isolates is alterations in penicillin-binding proteins (PBP) [74]. Resistance to amoxicillin in most regions is low, Europe 0.5%, Asia 11.16% and USA 2.2% [11]. Also in majority of Iranian studies resistance rates were low (0,

RESISTANCE TO FURAZOLIDONE
Furazolidone (FRZ) and nitrofurantoin belong to nitrofuran antibiotics. They are nitroheterocyclic and nitroaromatic compounds that have structure similarity with metronidazole [79]. Mechanism of resistance to this antibiotic is poorly studied. It is may be associated with mutations in the porD and oorD genes which encode δ-subunits of the pyruvate flavodoxin oxidoreductase and 2oxoglutarate reductase, respectively [80]. Prevalence of resistance to furazolidone in most of provinces of Iran is relatively low. Sirous et al.
[27] and Fallahi et al. [28] reported that all H. pylori isolates from Tehran are sensitive to this antibiotic. The same data has been achieved by Navidifar et al. from Yazd [20]. Similarly, in other studies, furazolidone resistance rates were as low as follow; 4.5%, 7.87%, 9%, and 9.4% [12,19,29,32]. But in a study from Sari (a city in the north of Iran), 61.4% of H. pylori isolates were resistance to furazolidone [24]. Resistance to nitrofurantoin has been observed in 11.6% of isolates in Tabriz [13]. Existence of low resistance rate and low cost of furazolidon made this antibiotic as a good choice for H. pylori eradication regimen. Although using of high-dose of furazolidone has shown best results for H. pylori eradication therapy, but it should be used only in low-dose, because it has severe side effects in high dose [81].

RESISTANCE TO FLUOROQUIN-OLONES
Fluoroquinolones, including ciprofloxacin (CIP), levofloxacin (LVX), sitafloxacin (STFX), garenoxacin (GRNX), moxifloxacin (MXF), and ofloxacin (OFX) are as broad spectrum antibiotics. Their mode of action is inhibition of both DNA gyrase and topoisomerase IV, a related type II topoisomerase [82,83]. These are well-tolerated antibiotics with no major side effects and show good activity against H. pylori [84,85]. Fluoroquinolones such as levofloxacin or sitafloxacin are used as a component of triple therapy when first line therapy are failed to eradicate H. pylori infection [86][87][88]. Mechanism of resistance to fluoroquinolones in H. pylori is mediated by point mutations in the Quinolones Resistance-Determining Region (QRDR) of DNA gyrase A (gyrA) gene [89]. Widely variable rates of fluoroquinolones resistance have been reported in H. pylori isolates in Iran. In most of them only resistance to ciprofloxacin has been reported. The maximum and minimum resistant rates which were reported from Tehran were 35% and 2.4%, respectively [26,33]

RESISTANCE TO RIFABUTIN
Rifabutin (RFB) is a bactericidal antibiotic that is derived from rifamycin-S and is using in the treatment of tuberculosis (TB) [90]. Rifabutin shows good activity against H. pylori isolates in vitro [91]. The mechanism of action of this antibiotic, is inhibition of the β-subunit of H. pylori RNA polymerase encoded by the rpoB gene [92]. It can be used in triple therapy (rifabutin-containing rescue therapy), if the previous H. pylori eradication regimens with key antibiotics such as metronidazole, clarithromycin, tetracycline, amoxicillin and fluoroquinolones has been failed [93]. Mechanism of resistance to rifabutin in H. pylori isolates is related to mutations in codon of 524-545 or codon 585 of the rpoB gene [92]. According to few global studies that investigated prevalence of resistance to rifabutin, the resistance rate is very low e.g. 1.4% in Germany [94] and 0.24% in Japan [95]. Rifabutin is not currently used as an anti H. pylori antibiotic in H. pylori eradication regimen in Iran. In a study of Tehran, 8 of 127 H. pylori isolates, were resistance to rifabutin (MIC 0.06 g/mL) [32].
Rifampin has a structural similarity to rifabutin. It binds to the β-subunit of bacterial RNA polymerase [92].

CONCLUSION
H. pylori, is a human gastric pathogen responsible for most gastrointestinal diseases. Antibiotic resistance is a key determinant of the outcome of eradication therapy for this infection.
In the past decades efficacy of standard triple therapies has decreased. It is because of emerging of new antibiotic resistance H. pylori strains especially in developing countries for over using antibiotics in a board range of infections. According to mentioned studies above, there are some variations in the resistant rate to different antibiotics between Iran's provinces, even in the same province or in the same time. These differences may be due to some variations including using of different susceptibility methods, turbidity of bacterial suspension, fresh or freeze biopsies and duration of incubation. However, according to mentioned studies before, the prevalence of metronidazole resistance is higher than other antibiotics varied from 30%-95%. Also resistance to clarithromycin, tetracycline and amoxicillin is remarkably high in some provinces. Similarly, resistance to fluroquinolons that have been used as an alternative therapy in H. pylori infection treatment is remarkable; they are not recommended for the first-line therapy against H. pylori infections in Iran.

CONSENT
It is not applicable.