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Medicine » "Trends in Helicobacter pylori Infection", book edited by Bruna Maria Roesler, ISBN 978-953-51-1239-6, Published: April 3, 2014 under CC BY 3.0 license. © The Author(s).

Chapter 9

Helicobacter pylori Infection — Challenges of Antimicrobial Chemotherapy and Emergence of Alternative Treatments

By Amidou Samie, Nicoline F. Tanih and Roland N. Ndip
DOI: 10.5772/57462

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Helicobacter pylori Infection — Challenges of Antimicrobial Chemotherapy and Emergence of Alternative Treatments

Amidou Samie1, Nicoline F. Tanih1 and Roland N. Ndip2, 3

1. Introduction

Classified as a class one carcinogen, Helicobacter pylori is a gram-negative coccobacillus (0.5 μm wide by 2 - 4 μm long), microaerophilic, flagellated organism that has chronically infected more than 50% of the world’s population [1, 2, 3, 4]. Significant evidence exist that links the bacterium to the pathogenesis and development of certain diseases such as gastric ulcers, chronic gastritis and stomach cancers, although most of the people harboring this organism are asymptomatic [5, 6]. The prevalence of infection caused by this organism increases with advancing age and is reported to be higher in developing countries and among low socio-economic populations, probably owing to conditions that favor the infection such as poor hygiene, crowded living conditions, and inadequate or no sanitation. The prevalence of this infection in human varies with geographical location and socio-demographic characteristics of the population; however does not parallel the incidence of morbidity caused by the infection [7, 8]. Studies have highlighted inconsistencies in the prevalence rates for Helicobacter and disease. In industrialized countries there is generally a low prevalence of H. pylori infection and yet a relatively high prevalence of gastric cancer. On the other hand, some countries with high Helicobacter prevalence rates have low gastric cancer prevalence [9].

Over the years, different treatment regimens have been proposed for eradication of H. pylori. Eradication of the organism has proven to be the first therapeutic approach and constitutes a reliable long-term prophylaxis of peptic ulcer relapse, accelerating ulcer healing and reducing the rate of ulcer complications [10]. Successful regimens generally require two or more antibiotics coupled with a proton pump inhibitor [11]. A proton pump inhibitor (PPI) or bismuth compounds and two antibiotics most commonly clarithromycin and metronidazole and/or amoxicillin [12]. However, problems related to poor patient compliance, undesirable side effect and resistance are presenting with numerous challenges as far as treatment failure is concern. Antibiotic resistance is a growing global concern both in the developing and in developed countries. Resistance to this organism has been delineated worldwide [13]. Many H. pylori strains have been reported to show resistance to the limited range of antibiotics used in its treatment in vitro. Of particular interest, resistance to metronidazole and clarithromycin has increased recently with more than 90% resistance reported against metronidazole and up to 36% against clarithromycin depending on regions [14, 15]. Emerging resistance of the bacterium to tetracycline, fluoroquinolones, and rifampicins, which are alternative antibiotics with known anti-H. pylori activity, have also been reported [14].

The emerging resistance to these antibiotics limits their use in the treatment of these infections [6, 16, 17]. Resistance to the antibiotics commonly used for treatment has been associated with mutations in specific genes which have been shown to be associated with these antibiotics. Clarithromycin resistance for example has been associated with point mutations in the peptidyl transferase-encoding region of 23S rRNA which affects the binding of macrolides to the bacterial ribosome, while rdxA and frxA are genes whose mutation has been associated with metronidazole resistance. Other genes such as the P-glycoprotein (P-gp) as well as mutations of GyrA, GyrB, and 16SrRNA in H. pylori have also been associated with resistance fluoroquinolone and tetracycline respectively [18, 19].

With the problem of resistance to currently recommended antibiotics; there is the need to seek alternative compounds from other sources with proven antimicrobial activity to overcome the problem. This has encourage the search of active agents from natural products, with the ultimate aim of discovering potentially useful active ingredients that can serve as template for the synthesis of new antimicrobial drugs [20]. These include medicinal plants, honey and probiotics which have been variously described to be associated with increase success rates in the eradication of H. pylori both in vitro and in vivo [21, 22, 23, 24]. Several plants have been investigated for their anti-H. pylori activity. Some of these plants with proven activity include Combretum molle, Calophyllum brasiliense, Sclerocarya birrea, Garcinia kola, Alepidea amatymbica, Bridelia. Micrantha, Peltophorum africanum, Cyrtocarpa procera Kunth and some Strychnos species [25, 26, 27]. The antimicrobial activity of honey is now well documented [28, 29]. Manyi-Loh and co-workers investigated the anti-H. pylori activity of three South African honeys; Pure honey, citrus blossom and gold crest and found that all honey varieties demonstrated varying levels of anti-H. pylori activity [24]. Evidence exists that probiotics may inhibit growth of H. pylori, stimulate an immunological response and reduce inflammatory effect of infection by bacteria increasing the rate of H. pylori eradication [21]. Some probiotics that have been tested either singly or in combination include Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus bulgaricus, Lactobacillus casei, Streptococcus thermophilus, Bifidobacterium infantis and Bifidobacterium breve [30]. In this communication, we provide information on the prevalence, epidemiology and antimicrobial chemotherapy and challenges in treatment of H. pylori in an effort to continuously highlight the clinical and epidemiological significance.

2. Helicobacter pylori infections, disease and prevalence

Helicobacter pylori (H. pylori) inhabit various areas of the human stomach [17]. The ability of this organism to convert the stomach acidic environment, a bactericidal barrier with protection against many infections, makes the environment suitable for its survival [4, 31]. Infection starts in the gastric antrum and spreads to the corpus, after extensive mucosal damage. Upon invasion, mucosa damage is caused that is eventually worsened by the acid produced in the stomach and this may lead to complications (ulcers and cancers) [16, 14]. Half of the world’s population is infected by this gastric organism [32]. Since its discovery in 1983 by Marshall and Warren, infection with H. pylori has been shown to be strongly associated with chronic gastritis, peptic ulcer and gastric cancer using technologies available at the time and others (fibre endoscopy, silver staining of histological sections and culture techniques for microaerophilic bacteria). These authors proved beyond reasonable doubts that made an indisputable link between the bacteria and the diseases mentioned [3, 33].

Confirmed is the fact that this organism causes of 90% of all duodenal ulcers, 75% of all gastric ulcers and two forms of stomach cancer; adenocarcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma [34]. The evidence of its association with gastric cancer, led to its classification as a class 1 carcinogen by the International Agency for Research on Cancer and the World Health Organization [35]. H. pylori is the first bacterium, and the second infectious organism after hepatitis B virus to be classified a carcinogen. A majority of H. pylori-infected individuals of (80–90%) have clinically asymptomatic gastritis, 10–15% develop peptic ulcer, and 1–2% gastric malignancies [36, 37]. Until the discovery of Marshall and Warren, diet, stress and life-style factors were considered major causes of gastritis and peptic ulcer, and the stomach, a sterile environment [38, 39].

Clinical outcome of long-term infection is variable and is considered to relate to bacterial virulence factors along with host genotype, physiology and environmental factors [40, 41, 42, 43]. The cytotoxin-associated gene, cagA, a marker for the cag pathogenicity island (PAI), is present in many but not all H. pylori strains. Its presence is associated with more severe clinical outcomes [44, 45]. H. pylori infection confers around a two-fold increase in the risk of developing gastric cancer particularly with strains expressing the cytotoxin-associated gene A antigen (cagA) [46]. The vacA gene is far from the cag PAI. At least some forms of vacA protein generate vacuoles in epithelial cells, disrupt tight junctions between epithelial tissues, interfere with antigen processing, etc. [47]. The vacA gene is present in all H. pylori strains and contains two importantly variable regions, s and m [40].

Geographic differences in predominant H. pylori genotypes, based either on virulence associated genes such as vacA and cagA or “housekeeping genes” have been delineated [40, 48]. Several other H. pylori genes that are related to the risk of disease have been identified some of which include, iceA and several other housekeeping genes” such as ureA, ureC, ureAB, flaA, flaB, atpA, efp, mutY, ppa, trpC, ureI, yphC etc, which may not be directly linked to disease [49, 50]. The cytotoxin-associated gene, cagA, a marker for the cag pathogenicity island (PAI), is present in many but not all H. pylori strains. Its presence is associated with more severe clinical outcomes [44, 45].

H. pylori is the principal species of the genus Helicobacter and a common human pathogen that is responsible for a variety of gastro–duodenal pathologies with high prevalence reported both in the developed and developing world since its discovery in 1983 by Marshall and Warren [51, 52]. Different studies worldwide have demonstrated the presence of this organism in their population. Substantial morbidity and mortality have been reported to be associated with H. pylori infection [15, 17, 42]. Fallen prevalence values has been observed in most developed countries; with rates from 25–50% in developed countries to 70–90% in the second and third world countries, this however varies [2, 7, 16, 53]. With improvements in treatments modalities, gastrointestinal pathology related to H. pylori is still ever present and remains a major burden on Western health systems. Populations like African American, Hispanic, Asian and Native American have experienced increased prevalence and infection rates are similar in males and females [54].

Rate of acquisition, rate of loss of infection and the length of persistence period all seem to determine the prevalence of this highly inflicting pathogen [7]. The prevalence of H. pylori infection has also been reported to vary widely by geographic area, age, socioeconomic status and even between ethnic groups of the same region [8, 15]. All these factors including environmental factors all play a role in the acquisition and transmission of H. pylori and further influence the wide variation in prevalence observed in the different population [55]. For example, variation exist the prevalence between more affluent urban populations and rural population. A lack of proper sensitization, drinking water and basic hygiene as well as poor diet and overcrowding all play a role in determining the overall prevalence of infection [2]. Although there is geographical and socio–demographic variation in the prevalence of human infection, prevalence does not parallel the incidence of morbidity caused by the infection [2, 16, 56]. Astoundingly high prevalence of H. pylori infection is observed in developing countries which does not commensurate the low prevalence of gastric cancer compared to the developed nations with a relatively low prevalence and yet a high prevalence of gastric cancer. For example, in Africa, the prevalence of infection is very high but the incidence of gastric carcinoma and other H. pylori-associated morbidities is relatively low. An anomality termed the African enigma’ [6, 42]. Apparently, coinfection with other organisms is known to modulate the H. pylori immune reaction and has been proposed to explain the “African enigma” [57]. The organism is ubiquitous with childhood acquisition seemingly being the role and may last for years or decades however, it is difficult to ascertain when infection occurs clinically hence seroprevalence data are the source of information of H. pylori rates both in geographically and demographically diverse populations [2, 52, 58, 59, 60]. Retrospective sero-epidemiological studies have shown a cohort effect consistent with the hypothesis that infection is mainly acquired in early childhood [59, 61]. Seroprevalence values of (61%–100%) have been described from various studies conducted in Africa and these values vary among countries and between different racial groups present within each country [2, 42, 53]. Seroprevalence studies in the western world have depicted rates not as high as those elaborated in Africa. Most individuals harbour specific antibodies for most of their lives especially in Africa [42].

In a rural village of Linqu Country, Shandong Province, China, a study of 98 children found that nearly 70 percent of those aged 5-6 years were infected with H. pylori, a rate equivalent to that reported for adults in that area, suggesting that most infection takes place early in childhood [61]. Generally, 50% of all children are infected by the age of 10 years, with prevalence rising to 80% in adults [7]. In their study of Kenyan school children, Nabwera and co-workers observed high prevalence among their subjects who were only aged 3–5 years, indicating that most children in the study area were infected before they reached their third birthday [62]. The highest rates of H. pylori prevalence have been reported in Eastern Europe, Asia, and many developing countries and developing populations in developed countries (for example, Native Americans) [63].

3. Repository of infection and transmission

Accurately assessing the incidence or route of transmission of H. pylori has been difficult because of the inaccuracy and cost of detecting (non-invasively) H. pylori [59]. Studies with regards to environmental factors and animal reservoirs as possible sources of infection have been examined. DNA has been extracted from food, animals and water sources suggesting they could be reservoirs of this organism [37]. However, there is no definitive evidence that they are natural or primary vehicles of transmission. Various studies have remarked a variety of factors such as bacterial host, genetic and environmental factors to determine the causative links to H. pylori infection, but knowledge of reservoirs and transmission still remains elusive [61]. Some routes of transmission have been described this include iatrogenic, oral-oral or faecal-oral routes [64, 65].

The host range of H. pylori is narrow and is found almost exclusively in humans and some non-human primates [66]. Humans been the only known reservoir of infection, hence the possibility of picking the infection from siblings, parents predominates via gastro-oral route [67]. Using specific culture approaches the organism has been isolated from vomitus [68, 69]. Perhaps the most important transmission route is faecal-oral transmission. Typically, isolation of this organism from faeces is not common though its isolation from faeces is established [61]. Sexual transmission of these organisms has not been observed [70].

Oral-oral transmission is regarded as a plausible route [39]. It has been shown to be potentiated by specific eating habits, such as the premastication of food by mothers before feeding children in some African countries. In Burkina Faso, premastication of food was common amongst families with high sero-positivity H. pylori status for both mother and child [71]. The importance of this cannot be over emphasized considering that childhood appears to be the critical period during which H. pylori is acquired, especially in areas of over-crowding and socio-economic deprivation [3, 24]. Possibility of dental plaque been a route of transmission has been proposed but this has failed in other studies though [72, 73]. In a recent study in South Africa, it was deduced that the oral cavity is unlikely to contribute to the spread of this organism as oral cavities were found not to favour prolonged colonization by the organism [53, 74]. Repeated use of gastric tubes from one patient to another by enodoscopists without proper sterilization may be a possible means of transmission. H. pylori infection has been shown to follow socio- other studies [73]. Gastroenterologists are occupationally at risk, however has proven the least common form of transmission [75].

4. Helicobacter pylori treatment

The need for an adequate prophylactic or therapeutic measures for H. pylori is very important being a serious, chronic, progressive and transmissible infection associated with significant morbidity and mortality especially in the developing world [76]. Over the years, several treatment regimens have been proposed for the eradication of H. pylori. However, development of a successful treatment for H. pylori infection has been fraught with difficulties; owing to its location within the stomach (that is, the mucus lining the surface epithelium, deep within the mucus secreting glands of the antrum, attached to cells and even within the cells) providing a great challenge to therapeutic measures [77]. The hostile environment in the gastric mucosa poses additional challenges reasons being the antibiotic therapy need to be active at pH values below neutral [24]. In addition, the ever existing presence of emerging resistant strains presents a formidable challenge which is at the verge of frustrating every attempt to a solution provision [78]. Infection with H. pylori will persist for life and may result in severe gastro duodenal complications without the intervention of antimicrobial therapy (treatment) [52, 79]. Complete eradication of the organism from the gut or stomach is the ultimate goal to treatment. A negative test for the bacterium four weeks or longer after treatment defines eradication [80].

There has been evolution with regards to treatment regimen for H. pylori infection since the early 1990s, when monotherapy was first recommended. However, employment of single agent is unacceptable because of extremely low eradication rates. H. pylori infections are treated with antibiotics, H2 blockers which reduces stomach acidicity and a proton pump inhibitor (PPI) that protects the stomach lining (bismuth compounds). This triple drug regimen involving; two antibiotics, bismuth salt and a proton pump inhibitor (PPI) or H2 blockers has been used as a standard treatment [13, 77, 81]. Bismuth compounds (colloidal bismuth sub citrate and bismuth subsalicylate) act by reducing intracellular ATP levels and interfere with the activity of urease enzyme, a key enzyme of H. pylori [77]. They also induce the formation of an ulcer-specific coagulum, preventing acid back diffusion and inhibit protein and cell wall synthesis as well as membrane function [82, 83]. Detachment of H. pylori from the gastric epithelium and a reduction in capsular polysaccharide production is the enabling function of bismuth compounds [77]. Typically, two types of acid reducers exist and include a proton pump inhibitor (PPI) and H2 blockers. H2 blockers include cimetidine, ranitidine, famotidine and nizatidine and this function by blocking histamine, which stimulates acid secretion. The PPI (omeprazole, lansoprazole, rabeprazole, pantoprazole and esomeprazole) on its part suppresses acid production by halting the mechanism that pumps the acid into the stomach [84]. PPI also increases antibiotic stability and efficacy [85].

The most commonly used antibiotics include metronidazole (MET), clarithromycin (CLR), amoxicillin (AMOX) and tetracycline (TET) all of which H. pylori is susceptible too except in cases of drug resistance [13, 86, 87]. Clarithromycin (500 mg twice a day [b.i.d.]) and amoxicillin (1 g b.i.d.) plus PPI for 7 days (treatment 1) are the most commonly used treatment combination the world over. Other regimens employed for 7-day include clarithromycin (500 mg b.i.d.) and metronidazole (500 mg b.i.d.) (treatment 2) and a double dose of PPI plus or amoxicillin (1 g b.i.d.) and metronidazole (500 mg b.i.d.) (treatment 3) a double dose of PPI plus [88]. Efficacy of the agents range from 85% - 95%. Susceptibility of H. pylori to these drugs has been reported to change with time, ethnicity, ulcer status, geographical location and test method [14]. Consequently, antibiotic recommended for patients may soon differ across regions of the world because different areas have begun to show resistance to particular antibiotics. These factors therefore have to be considered in making a prescription for the eradication of the infection.

5. Challenges to Helibacter pylori treatment regimens

The recommended regimens for H. pylori treatment and eradication pose a number of difficulties to patients such as poor compliance; coping with unpleasant adverse effects do little to encourage patient cooperation [15, 78]. Apart from patient non-compliance, antibiotic resistance is the major cause of treatment failure leaving clinicians with a limited list of drugs to choose from [14, 15, 89]. This can seriously affect attempts to eradicate the bacterium. Bacterial resistance to antimicrobials could be either primary (that is, present before therapy) or secondary (that is, develop as the result of failed therapy [77]. In different countries primary resistance in H. pylori has been reported in MET (6-95%), CLR (0-17%), and TET (0-6%) [90, 91]. Fairly recently, resistance to amoxicillin has been reported in many countries across the globe especially countries in Africa like Cameroon, Nigeria and South Africa where stringent control of drugs is lacking [17]. On the other hand metronidazole-containing regimens have recently been shown to have limited effectiveness owing to the alarming increase in the prevalence of resistance to this drug. Resistance to this antibiotic varies from 10% to 90% in different countries [92]. For example, Studies by Boyanova and colleagues reported a resistance rate of 28.6% for metronidazole against clinical isolates of H. pylori circulating in Sofia, Bulgaria [17, 90]. In our study in South Africa we reported a rate of 95.5% resistant. In Cameroon, studies have documented a very high resistance to metronidazole. Studies in Australia showed a resistance level of 36% of H. pylori isolates against metronidazole [93]. High resistance to metronidazole is attributed to the frequent and uncontrolled use of nitroimidazole derivatives for the treatment of protozoan infections and gynecological problems [17]. Clarithromycin resistance is referred to as the corner stone for treatment failure and is increasing worldwide [94]. A prevalence rate of 12.9% was recorded for Clarithromycin resistance in the U.S and rates as high as 24% were some European countries [91]. Resistance to clarithromycin frequently develops after treatment failure and more recently due to its increasing use in the treatment of upper respiratory tract infection [92]. Increasing prevalence of resistance to antimicrobial jeopardizes the success of therapeutic regimens aimed at the eradication of the infection making it sensitivity testing imperative prior to appropriate antibiotic selection [95]. Also, current antimicrobial susceptibility profiles of the isolates within the region should be known as this will act as a guide to clinician [96].

Resistance mechanisms to the commonly used antibiotics have been elaborated. Selection pressure may progressively increase resistance with the use of these antibiotics [88]. Plasmid associated resistance is rare. Drug efflux proteins can contribute to natural insensitivity to antibiotics and to emerging antibiotic resistance as is the case of many bacteria [97].

5.1. Metronidazole resistance mechanisms

Resistance to metronidazole (Mtz) has shown to limit the effectiveness of Mtz containing regimens [98, 99]. Mtz, a synthetic nitroimidazole is a prodrug and becomes active when reduced in the cytosol of the microorganism to a toxic metabolite. Unstable Mtz radicals react rapidly with proteins, RNA and DNA, eventually resulting in cell death [88, 99, 100]. Most Mtz sensitivity in H. pylori accounted for by NADPH nitroreductase a non-oxygen sensitive encoded by the rdxA gene reduces Mtz by a two-electron transfer step into a toxic metabolite that cannot be retransformed to its parent by molecular oxygen [99]. Resistance to Mtz is associated with mutation somewhere in the rdxA coding sequence [101]. Mutation of a second reductase NAD (P) H flavin oxidoreductase encoded by frxA could also confer low-level Mtz sensitivity in some strains [102]. Such resistance has been linked mostly to genetic mutations in the rdxA and frxA genes of the bacterium [100]. Based on gene sequencing and other reports concluded that most Mtz resistance in H. pylori depend on rdxA inactivation, of which mutations in frxA can enhance resistance, and that genes conferring Mtz resistance without rdxA inactivation are rare or nonexistent in H. pylori populations [100].

5.2. Resistance mechanisms to clarithromycin

Clarithromycin is part of the combination therapy used as the first-line therapy against H. pylori. Resistance to clarithromycin therefore is important ingredient for treatment failure. Clarithromycin acts by binding to the peptidyl transferase region of 23SrRNA and inhibits bacterial protein synthesis just like other macrolides Clarithromycin resistance has been linked to mutation in the 23S rRNA gene [103]. Several reports have demonstrated that more than 90% of macrolide resistance in H. pylori is mediated by either of two transition mutations Adenine to Guanine (A→G) at adjacent positions 2142 and 2143 in the bacterium’s 23SrRNA gene [103]. A transversion mutation (A→C) at position 2143 has been reported to be the cause of resistance in 7% of the resistant isolates. Other mutation observed in clarithromycin resistant H. pylori isolates include A2515G and T2717C, A2116G, G2141A, A2144T, T2182C, G2224A, C2245T

5.3. Amoxicillin resistance mechanisms

H. pylori resistance to amoxicillin is not common. Deloney and schiller, showed that amoxicillin resistance in H. pylori could develop because of amino acid substitutions in the penicillin binding proteins (pbp) leading to structural alterations in the protein or interference with peptidoglycan synthesis [104]. Resistance to amoxicillin and related drugs is usually as a result of decreased permeability to the drug; increased efflux of the drug from the bacterial cell, modification of the PBPs that diminish the affinity of the drug for the protein, and the presence of β-lactamases that inactivate the antibiotic by hydrolyzing its ring structure [105]. Amoxicillin-resistant H. pylori strains harbour mutations on the pbp-1a gene with amino acid substitution Ser-414→Arg appears to be involved, leading to a blockage of penicillin transport. Resistance to amoxicillin may also result from the production of β -lactamases by the bacterium [106]. Colonization of the stomach with β -lactam- resistant bacteria of other species may lead to the transfer of amoxicillin resistance to H. pylori [17]. Mutations in hopB and hopC genes of the outer membrane have also been associated with resistance in amoxicillin [107].

5.4. Tetracycline resistance mechanism

Tetracyclines are often used as a second line therapy when H. pylori infections are not cured by the first line drug regimen. Tetracycline is a protein synthesis inhibitor. This is achieved by disrupting codon-anticodon interaction on the ribosome. It binds to the 30S ribosomal subunit, preventing attachment of aminoacyl-tRNA to the acceptor site [108]. Thus bacterial peptide synthesis is stopped leading to cell death. Resistance to tetracycline has been linked to mutation in 16SrRNA-encoding genes that affect the binding site of tetracycline. The change in a nucleotide triplet (AGA-926 to 928→TTC), cognate of the positions 965 to 967 in Escherichia coli, has been associated with resistance to these compounds maybe because of the absence of the h1 loop; the binding site of tetracyclines. Strains resistant to tetracycline and no mutation in position 926 to 928 have also been described [14, 86, 109].

5.5. Resistant Mechanism to Fluoroquinolone

Fluoroquinolones have proven their worth in the treatment of most infections. In the management of H. pylori infection, they are used as salvage therapy when all other therapies cannot help (Chisholm and Owen, 2009). Their mode of action is based on inhibition of A and B subunits of the gene encoding DNA gyrase (gyrA or gyrB) in the bacterial cell [110], automatically interfering with DNA replication. Resistance to quinolones is associated mutations in gyrA at positions 87 and 91 [105, 111].

5.6. Resistance associated to plasmid and Efflux mechanisms

Approximately half of H. pylori strains possess a plasmid with size ranging 1.8-63 kbp though the standard strain NCTC 11637 is plasmid free [112]. Plasmid size and number may vary appreciably amongst strains with a gross majority of strains possessing just one plasmid. H. pylori plasmids have also been associated with drug resistance though in their study indicated resistance was unlikely to be attributed to plasmid coded determinants [52, 113]. Drug efflux mechanism could be responsible for the observed resistance in H. pylori as well. Organisms get protected from possible toxic effects of metabolite accumulation or external compounds using the efflux mechanism. Compound efflux which is mediated through specific pumps could result in decreased susceptibility for a variety of antibiotic [114, 115]. Some families of multidrug efflux transporters have been described these include small multidrug resistance (SMR) proteins, multidrug and toxic compound extrusion (MATE) proteins, the major facilitator superfamily (MFS), the ATP-binding cassette (ABC) superfamilies, and the resistance-nodulation-cell division (RND) family (helfF, hefC, and hefI) [116]. These active multidrug efflux mechanism and therefore compound efflux needs to be taken into account when determining resistance mechanisms in this organism. The therapy used for salvage of H. pylori has as one of its medications rifampicin and rifabutin [105]. Due to their irreversible blockage of DNA-dependent RNA polymerase; they are bactericidal. The β-subunit of the polymerase encoded by rpoB gene is inhibited by these medications and annuls protein synthesis of the bacteria [35, 117]. Resistance of H. pylori to these medications has been attributed to point mutations in the rpoB gene at positions 530, 540 and 545 [118].

6. Substitutes to circumvent challenges to treatment regimens

Due to the shortcoming presented by antibiotics with regards to treatment of H. pylori; Research towards development of new antimicrobial agents/ in a bid to scavenge for possible alternatives to overcome the problem of antibiotic resistance in this bacterial pathogen has been encouraged, such as research with plant extract and other natural products that possess antimicrobial potential like honey and probiotics with or without antibiotic both in-vitro and in-vivo to test for the antimicrobial activity [22, 24, 29, 119, 120].

6.1. Plants as a potential source of H. pylori treatment

Plant and plant products have repeated shown awesome hope in the treatment of recalcitrant infection. Medicinal plants usage all over the world preface the introduction of antibiotics and other modern drugs. It is estimated that plant materials are present in or have provided the models for about 50% of Western drugs [121]. Herbal medicines remain a normal part of life for most people worldwide especially amongst Africans and Asians and remains a component of healthcare in most countries worldwide especially Africa [121, 122]. WHO (World Health Organization) estimates 3.5 million people in developing countries rely on plant-based medicine for their primary healthcare and their usage has offered great benefit [122, 123, 124]. Research on herbal product has great significance for plants components could provide lead products for the development of new drugs hence leading to improvement of therapeutic results [124].

The demand to use natural products such as plants based products for the management of intractable infections has increased over the years [22]. Great attention has been directed to the screening of medicinal plants all over the world as a means to identify cheap sources of new drugs against H. pylori, a human gastric pathogen with high morbidity rate [2]. Scientific literature is rich on plant based studies on anti-H. pylori activity. A number of plants belonging to various families as well as compounds have been screened in the search for their anti-H. pylori potential worldwide. For example, Garlic (Allium sativum L) particularly allium vegetables have been shown exhibit a broad range of antibiotic spectrum against both Gram–positive and Gram negative bacteria including susceptibility to H. pylori antibiotic resistant strains [125]. Zeyrek and Oguz demonstrated in vitro anti-H. pylori activity of capsaicin at a concentration of 50μg/ml against metronidazole resistant and metronidazole-susceptible clinical isolates [126]. This plant also known as hot pepper is consumed as a flavoring spice and is reputed for its pharmacological, physiological and antimicrobial effects [127]. There is lower ulcer prevalence in people consuming higher amount of pepper compared to controls [128]. Studies by Zhang and colleagues in the Linqu County of Shandong Province, China, suggested that dietary consumption of cranberry (Vaccitnium macrocarpon) juice may reduce H. pylori infections in adults, which remains an important public health issue worldwide [129]. More plants which have been tested and proven to exhibit anti- H. pylori activity from their different continents in the world are listed (Table 1).

Analysis of tested plant extract revealed the presence of varying numbers of components depending on different solvent combination used for extraction. For example, 52 compounds were identified from acetone extract of S. birrea (which has been reported with anti- H. pylori activity) with n-octacosane being the most abundant (41.68%). Other compounds such as pyrrolidine, terpinen-4-ol, n-eicosane, cyclopentane, n-triacontane, aromadendrene and α-gujunene were delineated in S. birrea. Terpinen-4-ol and pyrrolidine however demonstrated strong antimicrobial activity against H. pylori at all concentrations tested. The identified compounds Terpinen-4-ol could be considered for further evaluation as therapeutic or prophylactic agents in the treatment of H. pylori-related infections [130]. Other compounds including quinones, flavones, flavonoid, flavonols, tannins, coumarins, traces of alkaloid, gallotannins, steroids (including β-sitosterol), phenolics and polyphenols, Terpenoids and essential oils Alkaloids, lectins and polypeptides have been isolated from most plants and found to exhibit profound antimicrobial activities in-vitro against an array of organisms although most of these compounds have not been tested against H. pylori [131].

The stem bark of the South American trumpet tree (Tecoma ipe Mart) has been reported as an important source of active quinone compound against H. pylori furanonaphthoquinone was isolated from this plant and has proven activity against H. pylori with (MIC 0.1μg/mL). idebenone, duroquinone, menadione, juglone and coenzyme Q1 are other quinines that have been reported with anti- H. pylori at low concentration of 0.8 to 3.2 μg /mL [132]. Anti-H. pylori activity of a number of flavonoids has been reported. In Turkey for example, Cistus laurifolius flower buds which is used traditionally in folk medicine to treat gastric ailments have been shown to possess significant anti-H. pylori activity with the flavonoid; quercetin 3-methyl ether (isorhamnetin) as the active component [133]. Inhibition of urease is recorded as the mechanism of action of some flavonoids as hesperidin [134]. Antimicrobial activity of coumarins isolated from the roots of Ferulago campestris against H. pylori isolates in Italy [135]. Kawase and others, found that a number of hydroxycoumarins;7- hydroxy-4-methylcoumarin, 6, 7-dihydroxy-4-methylcoumarin, 6-hydroxy-7-methoxy-4-methylcoumarin and 5, 7- dihydroxycyclopentanocoumarin showed comparable anti-H. pylori activity with metronidazole [136]. Generally, data about specific antibiotic properties of coumarins against H. pylori are scarce.

Continent and Species Parts Used Reference
Africa Country
Combretum molle (Combretaceae)South AfricaStem bark[172]
Bridelia micrantha (Hochst, Baill., Euphorbiaceae).South AfricaStem bark[173]
Lippia javanica South AfricaLeaves[174]
Hydonora africana South Africacheck[175]
Sclerocarya birrea (Anacardiaceae)South AfricaStem bark[130]
Garcinia kola Heckel (Guttiferae) South AfricaSeeds[176]
Peltophorum africanum (Sond, Fabaceae) South AfricaStem bark[23]
Ageratum conyzoides (Linn) CameroonWhole plant [176]
Lycopodium cernuum (Linn) Pic. SermCamerooncheck[17]
Enantia chlorantha Oliver (Annonaceae)CameroonStem bark [177] [178]
Eucalyptus camaldulensis Dehnh.NigeriaLeaves[179]
Eucalyptus torelliana F. Muell. (Myrtaceae), NigeriaStem bark[179]
South America/ North America
Byrsonima intermedia A. Juss. (Malpighiaceae) BrazilLeaves [180]
Croton cajucara Benth. (Euphorbiaceae) BrazilStem bark[181]
Piper carpunya Ruiz & Pav. (syn Piper lenticellosum C.D.C.) (Piperaceae)EcuadorLeaves[182]
Calophyllum brasiliense (Camb.) BrazilStem bark[25]
Artemisia douglasiana Besser (Asteraceae)ArgentinaLeaves[183]
Alchornea triplinervia BrazilLeaves[184]
Hancornia speciosa Gomez (Apocynaceae). BrazilBark[185]
Olea europaea L. (Oleaceae)MexicoLeaves/stem[186]
Tagetes lucida Cav. (Asteraceae)MexicoLeaf/stem[186]
Amphipterygium adstringens (Schltdl.) Standl. (Anacardiaceae)MexicoBark[186]
Priva grandiflora (Ortega) Moldenke (Verbenaceae)MexicoAerial parts[186]
Eupatorium petiolare Moc. ex DC. (Asteraceae)MexicoAerial parts[186]
Monarda austromontana Epling (Lamiaceae)MexicoAerial parts[186]
Gnaphalium canescens DC. (Asteraceae)MexicoAerial parts[186]
Larrea tridentata (Sessé & Moc. ex DC.) Coville (Zygophyllaceae)MexicoAerial parts[186]
Tithonia diversifolia (Hemsl.) A.G. Asteraceae)MexicoAerial parts[186]
Grindelia inuloides Willd. (Asteraceae)MexicoAerial parts[186]
Buddleja perfoliata Kunth (Loganiaceae)MexicoAerial parts[186]
Heterotheca inuloides Cass. (Asteraceae)MexicoAerial parts[186]
Mirabilis jalapa L. (Nyctaginaceae)MexicoAerial parts[186]
Cyrtocarpa procera Kunth (Anacardiaceae)MexicoBark[186]
Teloxys graveolens (Willd.)W.A.Weber (Chenopodiaceae)MexicoAerial parts[186]
Annona cherimola Mill. (Annonaceae)MexicoLeaf/stem[186]
Mentha×piperita L. (Lamiaceae)MexicoLeaf/stem[186]
Cuphea aequipetala Cav. (Lythraceae)MexicoAerial parts[186]
Ludwigia repens J. R. Forst. (Onagraceae)MexicoAerial parts[186]
Artemisia ludoviciana Nutt. subsp. mexicana (Willd. Ex Spreng.) Fernald (Asteraceae)MexicoLeaf/stem[186]
Qualea parviflora Mart.Brazilbark [187]
Calophyllum brasiliense Brazilstem bark [25]
North America
Cyrtocarpa procera Kunth (Anacardiaceae)MexicoBark [27]
Amphipterygium adstringens (Schltdl.) Standl. (Anacardiaceae) MexicoBark [186]
Casimiroa tetrameria Leaves[188]
Wasabia japonica JapanLeaves[189]
Impatiens balsamina L AsiaRoot/stem/leaf, seed, and pod[190]
Rhizopus oligosporus Asiafenugreek extracts[191]
Plumbago zeylanica L ChinaLeaves [192]
Glycyrrhiza aspera Irann/a[193]
Juglans regia Irann/a[193]
Ligustrum vulgare Irann/a[193]
Thymus kotschyanus Irann/a[193]
Trachyspermum copticum Irann/a[193]
Xanthium brasilicum Irann/a[193]
Bacopa monniera [194]
Carthamus tinctorous L.( Asteraceae) KhorasanFlowers[195]
Satureja hortensis L.( Lamiaceae) Mashhad- KhorasanLeaves[195]
Artemisia dracunculus L. (Asteraceae)Mashhad- KhorasanLeaves[195]
Citrus sinensis L (Rutaceae) North of IranPeel of fruit[195]
Punica granatum L. (Punicaceae)Saveh- MarkaziPeel of fruit[195]
Apium petroselinum L (Apiaceae) Neishabur- KhorasanSeeds[195]
Carum bulbocastanum IranFruit[196]
Carum carvi IranFruit[196]
Mentha longifolia IranAerial[196]
Saliva limbata IranAerial[196]
Saliva sclarea IranAerial[196]
Ziziphora clinopodioides IranAerial[196]
Glycyrrhiza glabra IranRoot[196]
Thymus caramanicus IranAerial[196]
Xanthium brasilicum IranAerial [196]
Trachyspermum copticum IranFruits[196]
Acacia nilotica (L.)) (Fabaceae)PakistanLeaves, flowers[197]
Calotropis procera (Aiton)( Apocynaceae)PakistanLeaves, flowers[197]
Adhatoda vasica Nees (Zygophyllaceae)PakistanWhole plant[197]
Fagoniaar abica L(AcanthaceaePakistanWhole plant[197]
Casuarina equisetifolia L. (Casuarinaceae)Pakistanfruits[197]
Pistacia (Mastic, Kurdica, Mutica and Cabolica)Sydneygums[198]
Allium sativum L USALeaves[125]
CapsaicinPepper fruits[126]
Vaccitnium macrocarpon, C Cranberry[129]
Prunus mume JapanJuice[199]

Table 1.

Anti-H. pylori medicinal plants occurring in more than one country worldwide

6.2. Honey as a control measure of H. Pylori infections

Honey has been used in folk-medicine in many countries since antiquity [137]. It is mentioned for healing purposes in the Bible, the Koran, and the Torah. Research related to honey has revealed the promising effects of honey as an alternative source of H. pylori treatment [138]. Its beneficial qualities have been endorsed to its antimicrobial, antioxidant, anti-inflammatory properties added to its phytocomponents [139]. Documentations now exist with proven ability of Honey to inhibit microbial growth, and honey has been successfully used on infections that do not respond to standard antiseptic and antibiotic therapy [28, 137]. In addition, In New Zealand and Saudi Arabia it was observed that concentrations of honey at approximating 20% v/v can inhibit the growth of H. pylori in vitro, grounded with the fact that MedihoneyTM and manuka honeys have in vivo activity against ulcers, infected wounds and burns are significant findings which merits further and extensive investigations [138]. Honey obtained from different floral sources and different geographical region seem to vary in their antimicrobial potency due to inherent differences in their chemical composition which is greatly influenced by the prevailing climatic conditions and soil characteristics in the different geographical areas influencing the plants as well the type of honey composition produced by the foraging bees [140, 141]. Undoubtedly, several factors like floral source used to collect nectar, seasonal and environmental factors, as well as processing and storage conditions might influence the chemical composition of honey [142].

Honey is becoming acceptable as a reputable and effective therapeutic agent by practitioners of conventional medicine and by the general public [139] Honey can be used as an antiseptic for wounds, burns and ulcers, improving the assimilation of calcium and magnesium and decreasing acidity [29, 143]. Stimulation of inflammatory- cytokine production by monocytes and hydrogen peroxide produced as a result of injury or infection is likely the mechanism by which wounds are healed with the use of honey [137, 144]. Motivated by these findings, scientist sought out to investigate the activities of honeys further. Previously, the activity of honey has been reported to differ with types [145]. The presence of hydrogen peroxide, osmotic effect of honey, its naturally low pH, phenolic acids, lysosomes and flavanoids in honey are all thought to help inhibit bacterial growth when honey is applied to a wound. Its low content of water facilitates wound healing by hygroscopic absorption of water molecules on wound surfaces and by soothing of the wound [137]. Honey does not only contain sugars but also an abundance of minerals, vitamins, enzymes and amino acids [6, 137].

Anti- H. pylori activities of honey have been investigated with various honey types in different parts of the world. Honey with proven anti- H. pylori activity is listed on (Table 2). Different variety of honeys (crude) and solvent extracted honey have been shown to possess potential compounds with therapeutic activity which could be exploited further as lead molecules in the treatment of H. pylori infections [24]. Chemical analysis of the chloroform extract of the pure honey led to the identification of 24 volatile compounds belonging to known chemical families present in honey. Astoundingly, thiophene and N-methyl-D3-aziridine were identified as novel compounds [146].

Honey type Country References
Goldcrest honeySouth Africa[146]
Pure honeySouth Africa[146]
Citrus blossomSouth Africa[146]
GoldcrestSouth Africa[146]
Black forest Germany[137]
Langnese Natural Bee HoneyGermany[137]
Blossom Bee HoneySwitzerland[137]
Al-Shifa Natural HoneyIran[137]
Al-Nada Clove HoneyOman[137]
Al-Nada Chestnut HoneyOman[137]
Manuka honeyZealand, [137]

Table 2.

Honey with Anti-H. pylori activity worldwide.

6.3. Use of probiotics in the treatment and management of H. pylori infections

According to an expert consultation conducted by the Food and Agriculture Organization and the World Health Organization, probiotics are "live microorganisms which when administered in adequate amounts confer a health benefit to the host." The regular intake of probiotic microorganisms has been demonstrated to prevent several disorders including diarrhea and inflammatory bowel disease [147]. Other advantages of the use of probiotics include the inhibition of enteric pathogens such as Salmonella, Shigella and Citrobacter, the decreasing of the luminal pH through the production of lactic acid or through competition with gut pathogens for host surface receptors [148]. The usefulness of probiotics on the eradication of H. pylori remains controversial. It has been suggested that the use of probiotic might have a positive impact on Helicobacter eradication. However, some studies have demonstrated that there was no change while some have shown an increase in the eradication rate of the bacteria from about 60% to 83% [21, 149]. In vivo models demonstrated that pre-treatment with a probiotic can prevent H. pylori infection and/or that administration of probiotics markedly reduced an existing infection [150]. Probiotics are often administered as supplemental treatment for the eradication of H. pylori. In this regard, a meta-analysis of 14randomized clinical trials was conducted by [151]. This study evaluated the role of supplemental probiotics in H. pylori eradication therapy and showed that the cure rates for standard antibiotic treatment when used alone and eradication co-therapy with probiotics, were 74.8% and 83.6%, respectively. The analysis further showed that the combined treatment, had not only increased the eradication rate, but had also decreased the occurrence of adverse effects due to antibiotics, like diarrhea. Several probiotics have been shown to have a beneficial effect on H. pylori infection [150, 151]. However, the exact mechanisms of action have not been clearly elucidated yet [152].

It is believed that probiotics may play an important role in the eradication and possibly the prevention of H. pylori infection and could serve as adjunctive treatment. Several probiotics have been shown to have beneficial effects on the treatment and eradication of H. pylori the majority of these probiotics known as the lactic acid-producing bacteria. Among these Bifidobacterium is one of the favorite genera, particularly in studies focused on the prevention of gastrointestinal infection and is often used in fermented dairy products or food supplements [153]. Some studies have been done in vitro (in test tubes or petri dishes) showing bifidobacterial activity against H. pylori. Examples include Bifidobacterium lactis which has been demonstrated to have an enhancing activity on the phagocytic capacity of polymorpho-nuclear cells [154]. Bifidobacterium spp have been shown to have positive effects of H. pylori infections. These are generally administered in dairy products such as yogurt and milk. Clinical trial studies have shown that probiotics-containing yogurt can offer benefits to restore Bifidobacterium spp ⁄ E. coli ratio in children and suppress the H. pylori load with increment of serum IgA but with reduction in IL-6 in H. pylori-infected children [155]. The Lactobacillus group constitutes an important source of probiotics that have been demonstrated to have a positive effect on H. pylori treatment. Strains with this ability include Lactobacillus acidophilus, L. casei, L. johnsonii, L. salivarius some of which are used as dairy starters [156]. Most studies have shown that lactobacilli or their cell-free cultures can inhibit or even kill H. pylori by preventing its adhesion to mammalian epithelial cells and preventing interleukin-8 release [157].

Fungal organisms particularly some strains of yeast have been used as probiotic as well. The best studied example is S. boulardii which is a live yeast that has been used extensively as a probiotic and often marketed as a dietary supplement [158]. It is a non-pathogenic yeast that has been prescribed for prophylaxis and treatment of diarrheal diseases caused by bacteria (Reference). Several clinical trials and experimental studies strongly suggest that Saccharomyces boulardii has a biotherapeutic capacity for the prevention and treatment of several gastrointestinal diseases including H. pylori infections [159]. S. boulardii mediates responses resembling the protective effects of the normal healthy gut flora. In a study conducted in Turkey, S. boulardii improved anti-H. pylori antibiotherapy-associated diarrhea, epigastric discomfort, and treatment tolerability. However, S. boulardii had no significant effect on the rate of H. pylori eradication in that study [160]. Importantly, S. boulardii has demonstrated clinical and experimental effectiveness in gastrointestinal diseases with a predominant inflammatory component, indicating that this probiotic might interfere with cellular signaling pathways common in many inflammatory conditions [161]. In another study by Cremonini probiotic supplementation significantly lowered the incidence of diarrhea and taste disturbance during H. pylori eradication compared to the placebo group.

Generally, probiotics can be administered as single microbial species. However, in some cases a combination of several types of probiotic species might yield a much more satisfactory result. In a study by Dylag and colleagues, the combination of Lactobacillus, Bifidobacterium, Saccharomyces boulardi and the treatment with Escherichia coli Nissle were found to be beneficial in inducing and maintaining remission of disease activity of gut inflammation and moderately severe ulcerative colitis [162]. Preparations containing certain Lactobacillus, Bifidobacterium strains or Saccaromyces boulardii could enhance by 5-10% the rate of successful eradication of H. pylori and reduce the incidence and severity of the side effects [163]. Instead of considering the probiotics alone, they have been considered in some studies as a safe adjuvant when added to triple eradication therapy against the symptoms induced by the major gastric pathogen, Helicobacter pylori.

Several mechanisms by which probiotic bacteria inhibit H. pylori have been proposed and include immunological mechanisms, antimicrobial substances, competition for adhesion, and the production of mucosal barrier [164]. Proposed mechanisms underlying the beneficial interaction between probiotics and H. pylori, and the modulation of the colonization of the gastric mucosa by this pathogen, include the production of lactic acid with H. pylori inhibition because of decreasing gastric pH; the direct killing of H. pylori through secreted metabolites with antimicrobial properties, including bacteriocins, autolysins, and organic acids; the interference with H. pylori adhesion to epithelial cells, both through the secretion of antimicrobial molecules and through direct competition for adhesion; and the ability to reduce H. pylori-induced gastritis through the stabilization of the mucosal barrier, the secretion of mucins, and the modulation of the host immune response to the infection [149]. Infection by H. pylori, often induce and inflammatory response which in turn exacerbate the disease through the increase production of inflammatory cytokines such as IL8 and TNF alpha. The subsequent inflammatory processes as well as the bacterial infection generally persist for decades resulting in mucosal damage, gastritis, and finally gastric neoplasm further potentiated by the failure of macrophages to eliminate H. pylori [165, 166]. One of the mechanisms by which, probiotics reduce H. pylori infections is through the production of conjugated linoleic acids. Conjugated linoleic acids (CLA) produced by Lactobacillus acidophilus for example was reported to decrease the activation of nuclear factor-kappa B. In fact strains of probiotic bacteria are known to convert linoleic acid to conjugated linoleic acid which has an immunomodulatory activity [167]. A study conducted by Hwang and colleagues showed that conjugated linoleic acid decreased the expressions of IL-8mRNA/protein as well as that of TNF-a mRNA [168]. This in turn, reduces the inflammation and therefore increases the cure rate of H. pylori infection. Some probiotics such as L. acidophilus induce a Th1-polarizing response characterized by high expression of interferon beta (IFN-β) and interleukin 12 (IL-12) [169]. This anti-inflammatory effect is contrary to the inflammatory response induced by H. pylori and therefore might reduce the effect of the infection on the host and increase the eradication of the pathogen although H. pylori contain a pathogenic feature known as vac A which can block the effect of the probiotic [170]. Studies by Yang and colleagues showed that higher doses of L. acidophilus pre-treatment reduced H. pylori-induced inflammation through the inactivation of the Smad7 and NFκB pathways by reversing the effect of H. pylori infection which often induces Smad7, NFκB, IL-8, and TNF-a production [171].

Helicobacter pylori treatment has evolved tremendously over the past decade. The use of different antibiotics has resulted to antibiotic resistance which has led to the adaptation of new ways of controlling the organism. The use of medicinal plants has proven its worth. However, much still need to be done, while very few clinical trials have been conducted over the last decade. Clinical trials for the use of medicinal plants for the control of H. pylori infections are still awaited. The application of probiotics remains controversial although the tendency would be that these organisms are helpful in increasing the eradication rate as well as the reduction of the side effects of the infection.


1 - Aguemon BD, Struelens MJ, Masougbodji A & Ouendo EM. Prevalence and risk factors for Helicobacter pylori infection in urban and rural Beninese population. Clinical Microbiology and Infection 2005 11 611–617.
2 - Ndip RN, Malange AE, Akoachere JFT, Mackay WG, Titanji VPK and Weaver LT. Helicobacter pylori antigens in faeces of asymptomatic children in the Buea and Limbe health districts of Cameroon: a pilot study. Tropical Medicine and International Health 2004 9 1036-1040.
3 - Ahmed K, Farzana R, Walter M, Godfrey L & Martin H. Histopathological profile of gastritis in adult patients seen at a referral hospital in Kenya. World Journal of Gastroenterology 2007 14 4117–4121.
4 - Tanih NF, Clarke AM, Mkwetshana N, Green E, Ndip LM and Ndip RN (2008). Helicobacter pylori infection in Africa: Pathology and microbiological diagnosis. African Journal of Biotechnology 2008 7 4653-4662.
5 - MacKay WG, Williams CL, McMillan M, Ndip RN, ShepherdAJ & Weaver LT. Evaluation of protocol using gene capture and PCR for detection of Helicobacter pylori DNA in feces. Journal of Clinical Microbiology 2003 41 4589–4592.
6 - Tanih NF, Dube C, Green E, Mkwetshana N, Clarke AM, Ndip LM & Ndip RN. Helicobacter pylori prevalence in Africa: drug resistance and alternative approaches to treatment. Annals of Tropical Medicine and Parasitology 2009 103(3) 189-204.
7 - Segal I, Ally R & Mitchell H. Helicobacter pylori: an African perspective. Quarterly Journal of Medicine 2001 94 561–565.
8 - Malcolm et al., 2004 Malcolm CA, MacKay WG, Shepherd A & Weaver LT. Helicobacter pylori in children is strongly associated with poverty. Scottish Medical Journal 2004 49(4)136-8.
9 - Lunet N and Barros H (2003). Helicobacter pylori infection and gastric cancer: facing the enigmas. International Journal of Cancer 2003 106 953–960 (2003)
10 - Yuen B, Zbinden R, Fried M, Bauerfeind P, Bernardi M. Cultural recovery and determination of antimicrobial susceptibility in Heliocobacter pylori by using commercial transport and isolation media. Infection 2005 33 77–81.
11 - Hung IF, Chan P, Leung S, Chan FS, Hsu A, But D, Seto WK, Wong SY, Chan CK, Gu Q, Tong TS, Cheung TK, Chu KM, Wong BC. Clarithromycin-amoxycillin-containing triple therapy: a valid empirical first-line treatment for Helicobacter pylori eradication in Hong Kong? Helicobacter 2009 14(6):505-11.
12 - Malfertheiner P, Megraud F, O'Morain CA, Atherton J, Axon AT, Bazzoli F, Gensini GF, Gisbert JP, Graham DY, Rokkas T, El-Omar EM & Kuipers EJ. Management of Helicobacter pylori infection--the Maastricht IV/ Florence Consensus Report. European Helicobacter Study Group. Gut 2012 61(5) 646-64.
13 - Alarcon T, Domingo D & Lopez-Brea M (1999). Antibiotic resistance problems with Helicobacter pylori. International Journal of Antimicrobial Agents 1999 12 19–26.
14 - Megraud F. Helicobacter pylori antibiotic resistance: prevalence, importance and advances in testing. Gut 2004 53 1374–1384.
15 - Tanih NF, Okeleye BI, Naidoo N, Green E, Mkwetshana N, Clarke AM, Ndip LM, Ndip RN (2010a). Helicobacter pylori prevalence in dyspeptic patients in the Eastern Cape Province of South Africa: ethnicity and disease status. South African Medical Journal 2010a 100 734-737.
16 - Asrat D, Nilsson I, Mengistu Y, Ashenafi S, Ayenew K, Al-Soud AW, Wadström T & Kassa E (2004). Prevalence of Helicobacter pylori vacA and cagA genotypes in Ethiopian dyspeptic patients. Journal of Clinical. Microbiology 2004 42 (6) 2682–2684.
17 - Ndip RN, Malange TAE, Ojongokpoko JEA, Luma HN, Malongue A, Akoachere JFK, Ndip LM, MacMillan M & Weaver LT. Helicobacter pylori isolates recovered from gastric biopsies of patients with gastro–duodenal pathologies in Cameroon: current status of antibiogram. Tropical Medicine and International Health 2008 13 848-854.
18 - Tanih NF & Ndip RN (2013). Molecular Detection of Antibiotic Resistance in South African Isolates of Helicobacter pylori. Gastroenterology Research and Practice 2013 259457. doi: 10.1155/2013/259457.
19 - Secka O, Berg DE, Antonio M, Corrah T, Tapgun M, Walton R, Thomas V, Galano JJ, Sancho J, Adegbola RA, Thomas JE. Antimicrobial susceptibility and resistance patterns among Helicobacter pylori strains from The Gambia, West Africa. Antimicrobial Agents and Chemotherapy 2013 57(3) 1231-7.
20 - Aibinu IE, Odunayo RA, Adenipeku T, Adelowotan T & Odugbemi T. In vitro antimicrobial activity of crude extracts from plants Bryophyllum pinnatum and kalanchoe crenata. African Journal of Traditional, Complementary and Alternative Medicines 2002 4(3) 338-344.
21 - Navarro-Rodriguez T, Silva FM, Barbuti RC, Mattar R, Moraes-Filho JP, de Oliveira MN, Bogsan CS, Chinzon D & Eisig JN. Association of a probiotic to a Helicobacter pylori eradication regimen does not increase efficacy or decreases the adverse effects of the treatment: a prospective, randomized, double-blind, placebo-controlled study. BMC Gastroenterology 2013 26 13:56.
22 - Njume C, Afolayan AJ & Ndip RN. Diversity of plants used in the treatment of Helicobacter pylori associated morbidities in the Nkonkobe municipality of the Eastern Cape province of South Africa. Journal of Medicinal Plant Research 2011a 5(14) 3146 -3151.
23 - Okeleye BI, Samie A, Bessong PO, Mkwetshana NF, Green E, Clarke AM & Ndip RN. Crude ethyl acetate extract of the stem bark of Peltophorum africanum (Sond, Fabaceae) possessing in- vitro inhibitory and bactericidal activity against clinical isolates of Helicobacter pylori. Journal of Medicinal Plant Research 2010 4(14) 1432-1440.
24 - Manyi-Loh CE, Clarke AM, Mkwetshana NF & Ndip RN. Treatment of Helicobacter pylori infections: Mitigating factors and prospective natural remedies. African Journal of Biotechnology 2010a. 9:2032-2042.
25 - Souza MC, Beserra AM, Martins DC, Real VV, Santos RA, Rao VS, Silva RM & Martin DT. In vitro and in vivo anti-Helicobacter pylori activity of Calophyllum brasiliense Camb. Journal of Ethnopharmacology 2009 123(3) 452-8.
26 - Okeleye BI, Bessong PO, Ndip RN. Preliminary phytochemical screening and in vitro anti-helicobacter pylori activity of extracts of the stem bark of Bridelia micrantha (Hochst., Baill., Euphorbiaceae). Molecules 2011 16(8):6193-205.
27 - Escobedo-Hinojosa WI, Del Carpio JD, Palacios-Espinosa JF & Romero I. Contribution to the ethnopharmacological and anti-Helicobacter pylori knowledge of Cyrtocarpa procera Kunth (Anacardiaceae). Journal of Ethnopharmacology 2012 30 143(1):363-71.
28 - George NM & Cutting KF. Antibacterial honey (Medihoney™): in-vitro activity against clinical isolates of MRSA, VRE and other multiresistant Gram negative organisms, including Pseudomonas aeruginosa. Wounds 2007 19 231–236.
29 - Ndip RN, Malange- Takang AE, Echakachi CM, Malongue A, Akoachere JFK, Ndip LM, & Luma HN. In-vitro antimicrobial activity of selected honeys on clinical isolates of Helicobacter pylori. African Health Science 2007a 7 228-231.
30 - Ahmad K, Fatemeh F, Mehri N, Maryam S. Probiotics for the Treatment of Pediatric Helicobacter pylori Infection: A Randomized Double Blind Clinical Trial. Iran Journal of Pediatrics 2013 23(1) 79-84.
31 - Schreiber S, Bücker R, Groll C, Azevedo-Vethacke M, Garten D, Scheid P, Friedrich S, Gatermann S, Josenhans C & Suerbaum S. Rapid lose of motility of Helicobacter pylori in the gastric lumen in vivo. Infection and Immunity 2005 73(3) 1584-1589.
32 - Atherton JC. The pathogenesis of Helicobacter pylori-induced gastro-duodenal diseases. Annual Reviews of Pathology 2006 1 63-96.
33 - Permin H & Anderson PL. Inflammation, immunity and vaccines for Helicobacter infection. Helicobacter 2005 10 21-30.
34 - Jones KR, Cha JH & Merrell DS. Who’s winning the war? Molecular mechanisms of antibiotic resistance in Helicobacter pylori. Current Drug Therapy 2008 3 190-203.
35 - Mégraud F & Lehours P. Helicobacter pylori detection and antimicrobial susceptibility testing. Clinical Microbiology Reviews 2007 20 280-283.
36 - Wu MS, Chow LP, Lin JT & Chiou SH. Proteomic Identification of Biomarkers Related to Helicobacter pylori-associated Gastro duodenal disease: challenges and opportunities. Journal of Gastroenterology and Hepatology 2008 23(11) 1657-61. doi: 10.1111/j.1440-1746.2008.05659.x.
37 - Dube C, Tanih NF and Ndip RN. Helicobacter pylori in water sources: a global environmental health concern. Reviews on Environmental Health 2009 24(1) 1-14.
38 - Marshall MJ & Warren RJ (1983). Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet 1983. I:1273-1275.
39 - Khalifa MM, Sharaf RR & Aziz RK. Helicobacter pylori: a poor man’s gut pathogen? Gut Pathogens 2010 2 1-12.
40 - Van Doorn LJ, Figueiredo C, Mégraud F, Pena S, Midolo P, Queiroz DM, Carneiro F, Vanderborght B, Pegado MD, Sanna R, De Boer W, Schneeberger PM, Correa P, Ng EK, Atherton J, Blaser MJ, Quint WG. Geographic distribution of vacA allelic types of Helicobacter pylori. Gastroenterology 1999 116 823-830.
41 - Wang J, van Doorn LJ, Robinson PA, Ji X, Wang D, Wang Y, Ge L, Telford JL and Crabtree JE. Regional variation among vacA alleles of Helicobacter pylori in China. Journal of Clinical Microbiology 2003. 41:1942-1945.
42 - Holcombe C. Helicobacter pylori: the African enigma. Gut 1992 33 429–431.
43 - El-Omar EM, Carrington M, Cho WH, McColl KE, Bream JH, Young HA et al.. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature 2000 404 398-402.
44 - Ando T, Peek RM, Pride D, Levine SM, Takata T, Lee YC, Kusuyami K et al. (2002). Polymorphisms of Helicobacter pylori HP 0638 reflect geographic origin and correlate with cagA status. Journal of Clinical Microbiology 2002 40 239-246.
45 - Chattopadhyay S, Patra R, Ramamurthy T, Chowdhury A, Santra A, Dhali GK, Bhattacharya SK, Berg DE, Nair GB & Mukhopadhyay AK. Multiplex PCR assay for rapid detection and genotyping of Helicobacter pylori from gastric biopsy specimens. Journal of Clinical Microbiology 2004 42 2821-2824.
46 - Enroth H, Kraaz W, Engstrand L, Nyrén O & Rohan T. Helicobacter pylori Strain Types and Risk of Gastric Cancer: A Case-Control Study. Cancer Epidemiology Biomarkers and Prevention 2000 9 981-90.
47 - Cover TL & Blanke SR. Helicobacter pylori vacA, a paradigm for toxin multifunctionality. Nature Reviews Microbiology 2005 3(4) 320-32.
48 - Bravo LE, van Doorn LJ, Realpe JL & Correa P. Virulence associated genotypes of Helicobacter pylori: do they explain the African enigma. American Journal of Gastroenterology 2002 97 2839-2842.
49 - Atherton JC. The clinical relevance of strain types of Helicobacter pylori. Gut 1997 40(6) 701-3.
50 - Blaser MJ & Berg DE. Helicobacter pylori genetic diversity and risk of human disease. Journal of Clinical Investigation 2001 107 767-773.
51 - Abdurasheed A, Lawal OO, Abioye-kuteyi EA & Lamikanra A. Antimicrobial susceptibility of Helicobacter pylori isolates of dyspeptic Nigerian patients. Journal of Tropical Gastroenterology 2005 26 85–88.
52 - Kusters JG, van Vliet AHM & Kuipers EJ. Pathogenesis of Helicobacter pylori infection. Clinical Microbiology Reviews 2006 19(3) 449-490.
53 - Dube C, Tanih NF, Clarke AM, Mkwetshana N, Green E, Ndip RN. H. pylori infection and transmission in Africa: household hygiene and water sources are plausible factors exacerbating spread. African Journal of Biotechnology 2009b 8(22) 6028-6035.
54 - Dehesa M, Dooley CP, Cohen H, Fitzgibbons PL, Perez-perez GI & Blaser MJ). High Prevalence of Helicobacter pylori infection and histologic gastritis in asymptomatic hispanics. Journal of Clinical Microbiology 1991 29(6) 1128-1131.
55 - Dube C, Nkosi TC, Clarke AM, Mkwetshana N, Green E, Ndip RN. Helicobacter pylori antigenemia in an asymptomatic population of the Eastern Cape Province of South Africa: Public health implications. Reviews on Environmental Health 2009b 24(3): 249 - 255
56 - Mukhopadhyay AK, Kersulyte D, Jeong JY, Datta S, Ito Y, Chowdhury A, Chowdhury S, Santra A, Bhattacharya SK, Azuma T, Nair GB, Berg DE. Distinctiveness of genotypes of Helicobacter pylori in Calcutta, India. Journal of Bacteriology 2000 182(11) 3219-27.
57 - Fritz LE, Slavik T, Delport W, Olivier B & Merwe WS. Incidence of Helicobacter felis and the effect of coinfection with Helicobacter pylori on the gastric mucosa in the African population. Journal Clinical Microbiology 2006 44(5) 1692-1696.
58 - Shi R, Xu S, Zhang H, Ding Y, Sun G, Huang X, Chen X, Li X, Yan Z & Zhang G. Prevalence and risk factors for Helicobacter pylori infection in Chinese populations. Helicobacter 2008 13(2) 157-65.
59 - Logan RPH, Walker MM. Epidemiology and diagnosis of Helicobacter pylori infection. In: ABC of Upper Gastrointestinal Tract. Logan, R.P.H., Harris, A, Misiewicz, J.J., Baron, J.H. (eds).BMJ books 2002. London pp.16-18.
60 - Kidd M, Louw JA & Marks IN. Helicobacter pylori in Africa: observations on an 'enigma within an enigma'. Journal Gastroenterology and Hepatology 1999a. 14(9) 851-8.
61 - Thomas JE, Dale A, Bunn JE, Harding M, Coward WA, Cole TJ & Weaver LT. Early Helicobacter pylori colonisation: the association with growth faltering in the Gambia. Archives of Disease of Childhood 2004 89(12) 1149-1154.
62 - Nabwera HM, Nguyen-Van –Tam JS, Logan RF & Logan RP. Prevalence of Helicobacter pylori in Kenyan school children aged 3-15 years and risk factors for infection. European Journal of Gastroenterology and Hepatology 2000 12(5) 483-487.
63 - Tkachenko MA, Zhannat NZ, Erman LV, Blashenkova EL, Isachenko SV, Isachenko OB, Graham DY & Malaty HM. Dramatic changes in the prevalence of Helicobacter pylori infection during childhood: a 10-year follow-up study in Russia. Journal of Pediatric Gastroenterology and Nutrition 200745 (4) 428-432.
64 - Janzon A, Sjöling A, Lothigius A, Ahmed D, Qadri F & Svennerholm AM. Failure to detect Helicobacter pylori in drinking and environmental water in Dhaka, Bangladesh, using highly sensitive real-time PCR assays. Applied and Environmental Microbiology 2009 75 (10) 3039-3044
65 - Tanih NF, McMillan M, Naidoo N, Ndip LM, Weaver LT &, Ndip RN. Prevalence of Helicobacter pylori vacA, cagA and iceA genotypes in South African patients with upper gastrointestinal diseases. Acta Tropica 2010c 116(1) 68-73
66 - Hannula M & Hänninen M. Phylogenetic analysis of Helicobacter species based on partial gyrB gene sequences. International Journal of Systematic and Evolutionary Biology 2007 57 (3) 444-449.
67 - Brown LM. Helicobacter pylori: Epidemiology and routes of transmission. Epidemiological Reviews 2000 22(2) 283-297.
68 - Leung WK, Siu KLK, Kwok CKL et al. Isolation of Helicobacter pylori from vomitus in children and its implication in gastro-oral transmission. American Journal Gastroenterology 1999 94 2881- 2884.
69 - Ndip RN, MacKay WG, Farthing MJG & Weaver LT. Culturing Helicobacter pylori from clinical specimens: review of microbiologic methods. Journal of Pediatric Gastroenterology and Nutrition 2003 36 616–622.
70 - Perez-Perez GL, Witskin SS, Decker MD & Blaser MJ. Seroprevalence of Helicobacter pylori infection in couples. Journal of Clinical Microbiology 1991 29 642–644.
71 - Aditya HG, Ominguez KL, Kalish M, Rivera- Hernandez D, Donohoe M, Brooks J & Mitchell D. Practice of feeding premasticated food to infants: A potential risk factor for HIV transmission. Pediatrics 2009 124 (2) 658-666.
72 - Desai HG, Gill HH, Shankaran K et al. (1991). Dental plaque: a permanent reservoir of Helicobacter pylori. Scandinavian Journal of Gastroenterology 1991. 26:1205-1208.
73 - Bernander S, Dalen J, Gastrin B et al. (2003). Absence of Helicobacter pylori in dental plaques in Helicobacter pylori positive dyspeptic patients. European Journal of Clinical Microbiology and Infectious Disease 2003 12 282-285.
74 - Olivier BJ, Bond RP, van Zyl WB, Delport M, Slavik T, Ziady C, sive Droste JT, Lastovica A & van der Merwe SW. Absence of Helicobacter pylori within the oral cavities of members of a healthy South African Community. Journal of Clinical Microbiology 2006 44(2) 635-636.
75 - Kikuchi S. & Dore MP. Epidemiology of Helicobacter pylori infection. Helicobacter 2005 10 1-10.
76 - Scarpignato C. Towards the ideal regimen for Helicobacter pylori eradication: the search continues. Digestive and Liver Disease 2004 36 243-247.
77 - Romano M & Cuomo A. Eradication of Helicobacter pylori: A clinical update. Medscape General Medicine and Gastroenterology 2004 6(1) 19.
78 - Hardin FJ & Wright RA. Helicobacter pylori: review and update. Archives of Hospital Physician 2002 38(5) 23-31.
79 - Lee YC Liou JM, Wu MS, Wu CY & Lin JT. Eradication of Helicobacter pylori to prevent gastro duodenal diseases: Hitting more than one bird with the same stone. Therapeutic Advances in Gastroenterology 2008 1(2) 111-120.
80 - Harris A & Misiewicz JJ. Management of Helicobacter pylori infection. In: ABC of Upper Gastrointestinal Tract. Logan RDH, Harris A, Misiewicz JJ, Baron JH. (eds). BMJ books London 2002 pp. 22-24.
81 - Manyi-Loh CE, Clarke AM, Munzhelele T, Green E, Mkwetshana NF & Ndip RN. Selected South African honeys and their extracts possess in vitro anti-Helicobacter pylori activity. Archive of Medical Research 2010b. 41:324-331.
82 - Meurer L & Bower D. (2002). Management of Helicobacter pylori infection. American Family Physician 2002 65 (7) 1327-36, 1339.
83 - Bland MV, Ismail S, Heinemann JA & Keenan J. The action of bismuth against Helicobacter pylori mimics but is not caused by intracellular iron deprivation. Antimicrobial Agents and Chemotherapy 2004 48 (6) 1983-1988.
84 - Gendull JH, Friedman SL & McQuaid KR. Identification of Helicobacter pylori. In: Current Diagnosis and Treatment in Gastroenterology. Gendull JH, Friedman SL, and McQuaid K R.(eds). Google books 2003 Pp. 328-335.
85 - Erah PO, Goddard AF, Barrett DA, Shaw PN & Spiller RC. The stability of amoxicillin, clarithromycin and metronidazole in gastric juice: relevance to the treatment of Helicobacter pylori infection. Journal of Antimicrobial Chemotherapy 1997 39:5-12.
86 - Cameron EAB, Powell KU, Baldwin L, Jones P, Bell GD & Williams SGJ. Helicobacter pylori: antibiotic resistance and eradication rates in Suffolk, UK, 1991-2001. Journal of Medical Microbiology 2004 53 535-538.
87 - Bonacorsi C, Raddi MSG, Iracilda ZC, Sannomiya M and Vilegas W. Anti-Helicobacter pylori activity and immunostimulatory effect of extracts from Byrsonima crassa Nied. (Malpighiaceae). Complementary and Alternative Medicine 2009 9 1472-6882.
88 - Njume C, Afolayan AJ & Ndip RN. An overview of antimicrobial resistance and the future of medicinal plants in the treatment of Helicobacter pylori infections. African Journal of Pharmacy and Pharmacology 2009 3 685-699.
89 - Glocker E, Berning M, Gerrits MM, Kusters JG & Kist M. Real-time PCR screening for 16S rRNA mutations associated with resistance to tetracycline in Helicobacter pylori. Antimicrobial Agents and Chemotherapy 2005 49 3166–3170.
90 - Boyanova L, Stancheva I, Spassova Z, Katzarov N, Mitov I & Koumanova R. Antimicrobial resistance; primary and combined resistance to four antimicrobial agents in Helicobacter pylori in Sofia, Bulgaria. Journal of Medical Microbiology 2000 49 415-418.
91 - Huynh HQ, Couper RTL, Tran CD, Moore L, Kelso R and Butler RN. Nacetylcysteine, a novel treatment for Helicobacter pylori infection. Digestive Diseases and Sciences 2004 49 (11/12) 1853-1861.
92 - Wu J & Sung J (1999). Treatment of Helicobacter pylori infection. Hong Kong Medical Journal 1999 5 (2) 145-9.
93 - Mollison LC, Stingemore N, Wake RA, Cullen DJ & McGechie DB. Antibiotic resistance in Helicobacter pylori. Medical Journal of Australia 2000 173 521-523.
94 - De Francisco V, Margiotta M, Zullo A, Hassan C, Giorgio F, Burattini O, Stoppino G, Cea U, Pace A, Zotti M, Morini S, Panella C and Ierardi E (2007). Prevalence of primary clarithromycin resistance in Helicobacter pylori strains over a 15 year period in Italy. Journal of Antimicrobial Chemotherapy 2007 59 783-785.
95 - Destura RV, Labio ED, Barrett LJ, Alcantara CS, Gloria VI, Daez MLO & Guerrant RL. Laboratory diagnosis and susceptibility profile of Helicobacter pylori infection in the Philippines. Annals of Clinical Microbiology and Antimicrobial 2004 3 25-30.
96 - Sherif M, Mohran Z, Fathy H, Rockabrand DM, Rozmajzl PJ & Frenck RW. Universal high-level primary metronidazole resistance in Helicobacter pylori isolated from children in Egypt. Journal of Clinical Microbiology 2004 42 (10) 4832-4834.
97 - Bina JE, Alm RA, Uria-Nickelsen M, Thomas SR, Trust TJ & Hancock REW. Helicobacter pylori uptake and efflux: Basis for intrinsic susceptibility to antibiotics in-vitro. Antimicrobial Agents and Chemotherapy 2000 44 248-254.
98 - Al-Qurashi AR, El-Morsy F, Al-Quorain AA. Evolution of metronidazole and tetracycline susceptibility pattern in Helicobacter pylori at a hospital in Saudi Arabia. International Journal of Antimicrobial Agents 2001 17: 233–6.
99 - Buta N, Tanih NF & Ndip RN. Increasing trend of metronidazole resistance in the treatment of Helicobacter pylori infection: A global challenge. African Journal of Biotechnology 2010 9(8) 1115-1121.
100 - Jeong JY, Mukhopadhyay AK, Akada JK, Dailidiene D, Hoffman PS & Berg DE. Roles of frxA and rdxA nitroreductases of Helicobacter pylori in susceptibility and resistance to metronidazole. Journal of Bacteriology 2001 183 5155–5162.
101 - Jenks PJ, Ferrero RL, Labigne A. The role of the rdxA gene in the evolution of metronidazole resistance in Helicobacter pylori. Journal of Antimicrobial Chemotherapy 1999 43(6):753-8.
102 - Kwon DH, Hulten K, Kato M, Kim JJ, Lee M, El-zaatari FAK, Osato MS & Graham DY. DNA sequence analysis of rdxA and frxA from 12 pairs of metronidazole-sensitive and -resistant clinical Helicobacter pylori isolates. Antimicrobial Agents and Chemotherapy 2001 45(9) 2609–2615.
103 - Ahmad N, Zakaria WR, Abdullah SA & Mohamed R. Characterisation of clarithromycin resistance in Malaysian isolates of Helicobacter pylori. World Journal of Gastroenterology 2009 15(25):3161-3165.
104 - Deloney CR & Schiller NL. Characterization of an in-vitro selected amoxicillin resistant strain of Helicobacter pylori. Antimicrobial Agents and Chemotherapy 2000 44 3363–3373.
105 - Jones KR, Cha JH, Merrell DS. Who's Winning the War? Molecular Mechanisms of Antibiotic Resistance in Helicobacter pylori. Current Drug and therapeutics 2008 3(3):190-203.
106 - Rimbara E, Noguchi N, Kawai T and Sasatsu M. Correlation between substitution in Penicillins-binding protein and amoxicillin resistance in Helicobacter pylori. Microbiology and Immunology 2007 51(10) 939-944.
107 - Matteo MJ, Granados G, Olmos M, Wonaga A. and Catalano M. Helicobacter pylori amoxicillin heteroresistance due to point mutations in pbp1A in isogenic isolates. Journal of Antimicrobial Chemotherapy 2008 61(3) 474-477.
108 - Wu JY, Kim JJ, Reddy R, Wang WM, Graham DY & Kwon DH. Tetracycline-resistant clinical Helicobacter pylori isolates with and without mutations in 16SrRNA-encoding genes. Antimicrobial Agents and Chemotherapy 2005 49(2) 578-583.
109 - Dzierzanowska FK, Rozynek R, Celinska CD, Jarosz M, Pawlowska J, Szadkowski A, Budzysnska A, Nowak J, Romanozuk W, Prosiecki R, Jozwiak P. & Dzierzanowska D. Antimicrobial resistance of Helicobacter pylori in Poland. A multicenter study. International Journal of Antimicrobial Agents 2005 26 230-234.
110 - Wang YH, Wang JP, Gorvel YT, Chu J, Wu J, and Lei HY. Helicobacter pylori impairs murine dendritic cell responses to infection. PLoS One 2010.doi:. doi: 10.1371/journal.pone.0010844.
111 - Tanih NF, Ndip RN. The acetone extract of Sclerocarya birrea (Anacardiaceae) possesses antiproliferative and apoptotic potential against human breast cancer cell lines (MCF-7). Scientific World Journal. 2013
112 - Dharmalingam S, Rao UA, Jayaraman G & Thyagarajan SP. Relationship of plasmid profile with the antibiotic sensitivity pattern of Helicobacter pylori isolates from peptic ulcer disease patients in Chennai. Indian Journal of Medical Microbiology 2003 21(4) 257-261.
113 - Owen RJ, Bell GD, Desai M, Moreno M, Gant PW, Jones PH & Linton D. Biotype and molecular fingerprints of metronidazole resistant strains of Helicobacter pylori from antral gastric mucosa. Journal of Medical Microbiology 1993 38 6-12.
114 - Borges-Walmsley MI & Walmsley AR. The structure and function of drug pumps. Trends in Microbiology 2001 9 71–79.
115 - Kutschke A & Boudewijn LM de J. Compound efflux in Helicobacter pylori. Antimicrobial Agents and Chemotherapy 2005 49(7) 3009–3010.
116 - van Amsterdam K, Bart A, & van der Ende A. Helicobacter pylori Tol C efflux pump confers resistance to metronidazole. Antimicrobial Agents and Chemotherapy 2005 49(4) 1477–1482.
117 - Chisholm SA & Owen RJ. Frameshift mutations in frxA occur frequently and do not provide a reliable marker for metronidazole resistance in UK isolates of Helicobacter pylori. Journal of Medical Microbiology 2004 53 135–140.
118 - Glocker E, Bogdan C & Kist M. Characterization of rifampicin-resistant clinical Helicobacter pylori isolates from Germany. Journal of Antimicrobial Chemotherapy 2007 59 874-879
119 - Chaudhuri S, Chowdhury A, Datta S, Mukhopadhyay AK, Chattopadhyay S, Saha DR, Dhali G, Santra A, Nair GB, Bhattacharya S & Berg DE. Anti-Helicobacter pylori therapy in India: differences in eradication efficiency associated with particular alleles of vacuolating cytotoxin (vacA) gene. Journal of Gastroenterology and Hepatology 2003 18 190-195.
120 - Tanih NF, Dube C, Green E, Mkwetshana N, Clarke AM, Ndip LM, Ndip RN. An African perspective on Helicobacter pylori prevalence, drug resistance and alternative approaches to treatment. Annals of Tropical Medicine and Parasitology 2009 103(3) 189-204.
121 - Bharati AC, Sahu AN. Ethnobotany, phytochemistry and pharmacology of Biophytum sensitivum DC. Pharmacognosy reviews 2012 6(11):68-73.
122 - Anesini C & Perez C. Screening of plants used in Argentine folk medicine for antimicrobial activity. Journal of Ethnopharmacology 1993 39 119–128.
123 - World Health Organization (1987). Report of the Second Meeting of Directors of WHO Collaborating Centres for Traditional Medicine. Document WHO/TRM/88.1. Geneva: WHO.
124 - Klos M, van de Venter M, Milne PJ, Traore HN, Meyer D, Oosthuizen V. In vitro anti-HIV activity of five selected South African medicinal plant extracts. Journal of Ethnopharmacology 2009 124(2) 182-8.
125 - Sivam GP. Protection against Helicobacter pylori and other bacterial infection by garlic. Journal of Nutrition 2001 131 (3s) 1106S-8S.
126 - Zeyrek FY & Oguz E (2005). In vitro activity of capsaicin against Helicobacter pylori. Annals of Microbiology 2005 55 (2) 125-127.
127 - Molina-Torres J, Garcia-chavez A & Ramirez-chavez E. Antimicrobial properties of alkamides present in flavouring plants traditionally used in Masoamerica: affinin and capsaicin. Journal of Ethnopharmacology 1999 64 241-248.
128 - Cichewicz RH & Thorpe PA. The antimicrobial properties of chile peppers (Capsicum species) and their uses in Mayan medicine. Journal of Ethnopharmacology 1996 52 61-70.
129 - Zhang L, Ma J, Pan K, Go VLW, Chen J & You WC. Efficacy of cranberry juice on Helicobacter pylori infection: a double-blind, randomized placebo controlled trial. Helicobacter.2005 10 (2):139-145.
130 - Njume C, Afolayan AJ, Green E & Ndip RN. Volatile compounds in the stem bark of Sclerocarya birrea (Anacardiaceae) possess potent antimicrobial activity against drug-resistant Helicobacter pylori. International Journal of Antimicrobial Agents 2011c 38 (4) 319 – 24.
131 - Ojewole JA, Mawoza T, Chiwororo WD, Owira PM. Sclerocarya birrea (A. Rich) Hochst. ['Marula'] (Anacardiaceae): a review of its phytochemistry, pharmacology and toxicology and its ethnomedicinal uses. Phytotherapy Research 2010 24(5) 633-9.
132 - Inatsu S, Ohsaki A, Nagata K. Idebenone acts against growth of Helicobacter pylori by inhibiting its respiration. Antimicrobial Agents Chemotherapy 2006 50(6):2237-9.
133 - Ustün O, Ozçelik B, Akyön Y, Abbasoglu U, Yesilada E. Flavonoids with anti-Helicobacter pylori activity from Cistus laurifolius leaves. Journal of Ethnopharmacology 2006 108(3) 457-61.
134 - Bylka W, Szaufer-Hajrych M, Matawska I and Goslinska O. Antimicrobial activity of isocytisoside and extracts of Aquilegia vulgaris L., Letters in Applied Microbiology 2004 39(1): 93-97.
135 - Basile A, Sorbo S, Spadaro V, Bruno M, Maggio A, Faraone N, Rosselli S. Antimicrobial and antioxidant activities of coumarins from the roots of Ferulago campestris (Apiaceae). Molecules 2009 14(3) 939-52.
136 - Kawase M, Tanaka T, Sohara Y, Tani S, Sakagami H, Hauer H, Chatterjee SS. Structural requirements of hydroxylated coumarins for in vitro anti-Helicobacter pylori activity. In Vivo. 2003 17(5):509-12.
137 - Nzeako BC & Al-Namaani F. The antibacterial activity of honey on Helicobacter pylori. Sultan Qaboos University Medical Journal 2006 (2) 71-76.
138 - Davis C. The use of Australian honey in moist wound management. Publication No. W05/159. Kingston, Australia: Rural Industries Research and Development Corporation 2005.
139 - Meda A, Lamien EC, Millogo J, Romito M, Nacoulma OG. Ethnopharmacological communication therapeutic uses of honey and honeybee larvae in central Burkina Faso. Journal of Ethnopharmacology 2004 95 103-107.
140 - Castro-Várquez LM, Díaz-Maroto MC, de Tores C & Pérez-Coello MS. Effects of geographical origins on the chemical and sensory characteristics of chestnut honeys. Food Research International 2010 43 2335-2340.
141 - Baltrusaitytė V, Venskutonis PR & Ceksterytė V. Radical scavenging activity of different floral origin honey and bee bread phenolic extracts. Food Chemistry 2007 101:502-514.
142 - Yao L, Datta N, Tomás-Barberán FA, Ferreres F, Martos I & Singanusong R. Flavonoids, phenolic acids and abscisic acid in Australian and New Zealand Leptospermum honeys. Food Chemistry 2003 81:159-168.
143 - Zaghloul AA, El-Shattaw HH, Kassem AA, Ibrahim EA, Reddy IK & Khan MA. Honey, a prospective antibiotic: extraction, formulation, and stability. Pharmazie 2001 56 643-647.
144 - Tonks AJ, Cooper RA, Jones KP, Blair S, Parton J & Tonks A. Honey stimulates inflammatory cytokine production from monocytes. Cytokine 2003 242-7.
145 - Basualdo C, Sgroy V, Finda MS & Marioli JM. Comparison of the antibacterial activity of honey from different provenance against bacteria usually isolated from skin wounds. Veterinary Microbiology 2007 124 375–381.
146 - Manyi –Loh CE, Clarke AM & Ndip RN. Identification of volatile compounds in solvent extracts of honeys produced in South Africa. African Journal of Agricultural Research 2011 6 (18) 4327 – 4334.
147 - Guarner F, Khan AG, Garisch J, Eliakim R, Gangl A, Thomson A, et al. World Gastroenterology Organisation Global Guidelines: probiotics and prebiotics October 2011. Journal of Clinical Gastroenterology 2012 46468–81.
148 - De Keersmaecker SC, Verhoeven TL, Desair J, Marchal K, Vanderleyden J, Nagy I. Strong antimicrobial activity of Lactobacillus rhamnosus GG against Salmonella typhimurium is due to accumulation of lactic acid. FEMS Microbiology Letters 2006 259 89-96.
149 - Dajani AI, Abu Hammour AM, Yang DH, Chung PC, Nounou MA, Yuan KY, Zakaria MA, Schi HS. Do probiotics improve eradication response to Helicobacter pylori on standard triple or sequential therapy? Saudi Journal of Gastroenterology 2013 19(3) 113-20. doi: 10.4103/1319-3767.111953.
150 - Hamilton-Miller JM. The role of probiotics in the treatment and prevention of Helicobacter pylori infection. International journal of antimicrobial agents 2003 22:360–6.
151 - Tong JL, Ran ZH, Shen J, Zhang CX, Xiao SD (2007). Meta-analysis: The effect of supplementation with probiotics on eradication rates and adverse events during Helicobacter pylori eradication therapy. Alimentary Pharmacology & Therapeutics's 2007 25 155–68.
152 - Chen LS, Ma Y, Maubois JL, He SH, Chen LJ, Li HM. Screening for the potential probiotic yeast strains from raw milk to assimilate cholesterol. Dairy Science and Technology 2010 90 537–548.
153 - Gomi A, Harima-Mizusawa N, Shibahara-Sone H, Kano M, Miyazaki K, Ishikawa F. Effect of Bifidobacterium bifidum BF-1 on gastric protection and mucin production in an acute gastric injury rat model. Journal of Dairy Science 2013 96(2) 832-7.
154 - Arunachalam K, Gill HS, Chandra RK. Enhancement of natural immune function by dietary consumption of Bifidobacterium lactis (HN019). European Journal of Clinical Nutrition 2000 54(3) 263-7.
155 - Yang YJ, and Sheu BS. Probiotics-Containing Yogurts Suppress Helicobacter pylori Load and Modify Immune Response and Intestinal Microbiota in the Helicobacter pylori-Infected Children. Helicobacter 2012 17: 297–304
156 - Vlasova AN, Chattha KS, Kandasamy S, Liu Z, Esseili M, Shao L, Rajashekara G, Saif LJ. Lactobacilli and Bifidobacteria Promote Immune Homeostasis by Modulating Innate Immune Responses to Human Rotavirus in Neonatal Gnotobiotic Pigs. PLoS One 2013 8(10):e76962.
157 - O'Connor A, Molina-Infante J, Gisbert JP, O'Morain C. Treatment of Helicobacter pylori Infection. Helicobacter 2013 Suppl 1:58-65.
158 - McFarland LV. Review Systematic review and meta-analysis of Saccharomyces boulardii in adult patients. World Journal of Gastroenterology 2010 16(18): 2202-22.
159 - Hickson M. Probiotics in the prevention of antibiotic-associated diarrhoea and Clostridium difficile infection. Therapeutic Advances in Gastroenterology 2011 4(3) 185–197.
160 - Cindoruk M, Erkan G, Karakan T, Dursun A, Unal S. Efficacy and safety of Saccharomyces boulardii in the 14-day triple anti-Helicobacter pylori therapy: a prospective randomized placebo-controlled double-blind study. Helicobacter 2007 12 309–316.
161 - Kelesidis T and Pothoulakis C. Efficacy and safety of the probiotic Saccharomyces boulardii for the prevention and therapy of gastrointestinal disorders. Therapeutic Advances in Gastroenterology 2012 5(2) 111–125.
162 - Dylag K, Hubalewska-Mazgaj M, Surmiak M, Szmyd J, Brzozowski T. Probiotics in the mechanism of protection against gut inflammation and therapy of gastrointestinal disorders. Current Pharmaceutical Design 2013 Jun 10. [Epub ahead of print]
163 - Buzás GM. [Probiotics in gastroenterology -- from a different angle]. Orvosi hetilap 2013 154(8) 294-304.
164 - Lesbros-Pantoflickova D, Corthésy-Theulaz I, and Blum AL. Helicobacter pylori and Probiotics. Journal of Nutrition 2007 137 (3) 812S-818S.
165 - Wilson KT, Crabtree JE. Immunology of Helicobacter pylori: insights into the failure of the immune response and perspectives on vaccine studies, Gastroenterology 2007 133: 288–308.
166 - Backert S, Clyne M. Pathogenesis of Helicobacter pylori infection. Helicobacter 2011 Suppl 1:19-25.
167 - Belury MA. Dietary conjugated linoleic acid in health: physiological effects and mechanisms of action, Annual Review of Nutrition 2002 22 505–531.
168 - Hwang SW, Kim N, Kim JM, Huh CS, Ahn YT, Park SH, Shin CM, Park JH, Lee MK, Nam RH, Lee HS, Kim JS, Jung HV, Song IS (2012). Probiotic suppression of the H. pylori-induced responses by conjugated linoleic acids in a gastric epithelial cell line. Prostaglandins, Leukotrienes and Essential Fatty Acids 2012 86 225–231
169 - Weiss G, Christensen HR, Zeuthen LH, Vogensen FK, Jakobsen M, Frokiaer H. Lactobacilli and bifidobacteria induce differential interferon-beta profiles in dendritic cells. Cytokine 2011 56 520–530.
170 - Weiss G, Forster S, Irving A, Tate M, Ferrero RL, Hertzog P, Frøkiær H, Kaparakis-Liaskos M. Helicobacter pylori VacA suppresses Lactobacillus acidophilus-induced interferon beta signaling in macrophages via alterations in the endocytic pathway. mBio 2013 4(3):e00609-12. doi:10.1128/mBio.00609-12.
171 - Yang YJ, Chuang CC, Yang HB, Lu CC and Sheu BS. Lactobacillus acidophilus ameliorates H. pylori induced gastric inflammation by inactivating the Smad7 and NF_B pathways. BMC Microbiology 2012 12:38
172 - Njume C, Afolayan AJ, Samie A, Ndip RN. Inhibitory and bactericidal potential of crude acetone extracts of Combretum molle (Combretaceae) on drug-resistant strains of Helicobacter pylori. Journal of Health Population and Nutrition 2011 29(5) 438-45.
173 - Okeleye BI, Bessong PO & Ndip RN. Preliminary phytochemical screening and in- vitro anti-Helicobacter pylori activity of extracts of the stem bark of Bridelia micrantha (Hochst., Baill., Euphorbiaceae). Molecules 2011 16(8) 6193-205.
174 - Nkomo LP, Green E, Ndip RN. Preliminary phytochemical screening and in vitro anti-Helicobacter pylori activity of extracts of the leaves of Lippia javanica. Health & Environmental Research Online 2011 5 (20) 2184-2192.
175 - Nethathe BB, Ndip RN. Bioactivity of Hydonora africana on selected bacterial pathogens: Preliminary phytochemical screening. African Journal of Microbiology Research 2011 5 2820–2826.
176 - Njume C, Jide AA, Ndip RN. Aqueous and Organic Solvent-Extracts of Selected South African Medicinal Plants Possess Antimicrobial Activity against Drug-Resistant Strains of Helicobacter pylori: Inhibitory and Bactericidal Potential. International Journal of Molecular Science 2011 12(9) 5652-65.
177 - Tan PV, Boda M, Etoa FX. In vitro and in vivo anti-Helicobacter/Campylobacter activity of the aqueous extract of Enantia chlorantha. Pharmaceutical Biology 2010 48(3) 349-56. doi: 10.3109/13880200903150377.
178 - Farag TH, Stoltzfus RJ, Khalfan SS, Tielsch JM. Unexpectedly low prevalence of Helicobacter pylori infection among pregnant women on Pemba Island, Zanzibar. Transactions of the Royal Society of Tropical Medicine and Hygiene 2007 101 915–922.
179 - Adeniyi CBA, Lawal TO and Mahady GB. In vitro susceptibility of Helicobacter pylori to extracts of Eucalyptus camaldulensis and Eucalyptus torelliana. Pharmaceutical Biology 2009 47(1) 99–102.
180 - Santos RC, Kushima H, Rodrigues CM, Sannomiya M, Rocha LR, Bauab TM, Tamashiro J, Vilegas W, Hiruma-Lima CA. Byrsonima intermedia A. Juss.: gastric and duodenal anti-ulcer, antimicrobial and antidiarrheal effects in experimental rodent models. Journal of Ethnopharmacology 2012 140(2) 203-12.
181 - Rozza AL, de Mello Moraes T, Kushima H, Nunes DS, Hiruma-Lima CA, Pellizzon CH. Involvement of glutathione, sulfhydryl compounds, nitric oxide, vasoactive intestinal peptide, and heat-shock protein-70 in the gastroprotective mechanism of Croton cajucara Benth. (Euphorbiaceae) essential oil. Journal of Medicinal Food. 2011 14(9) 1011-7.
182 - Quílez A, Berenguer B, Gilardoni G, Souccar C, de Mendonça S, Oliveira LF, Martín-Calero MJ, Vidari G. Anti-secretory, anti-inflammatory and anti-Helicobacter pylori activities of several fractions isolated from Piper carpunya Ruiz & Pav. Journal of Ethnopharmacology 2010 128(3) 583-9.
183 - Vega AE, Wendel GH, Maria AO, Pelzer L. Antimicrobial activity of Artemisia douglasiana and dehydroleucodine against Helicobacter pylori. Journal of Ethnopharmacology. 2009 124(3):653-5. doi: 10.1016/j.jep.2009.04.051
184 - Lima ZP, Calvo TR, Silva EF, Pellizzon CH, Vilegas W, Brito AR, Bauab TM, Hiruma-Lima CA. Brazilian medicinal plant acts on prostaglandin level and Helicobacter pylori. Journal of Medicinal Food 2008 11(4) 701-8. doi: 10.1089/jmf.2007.0676.
185 - Moraes Tde M, Rodrigues CM, Kushima H, Bauab TM, Villegas W, Pellizzon CH, Brito AR, Hiruma-Lima CA. Hancornia speciosa: indications of gastroprotective, healing and anti-Helicobacter pylori actions. Journal of Ethnopharmacology 2008 120(2) 161-8.
186 - Castillo-Juarez I, Rivero-Cruz F, Celis H, Romero I. Anti-Helicobacter pylori activity of anacardic acids from Amphipterygium adstringens. Journal Ethnopharmacology 2007 114 72-77.
187 - Mazzolin LP, Nasser AL, Moraes TM, Santos RC, Nishijima CM, Santos FV, Varanda EA, Bauab TM, da Rocha LR, Di Stasi LC, Vilegas W, Hiruma-Lima CA. Qualea parviflora Mart.: an integrative study to validate the gastroprotective, antidiarrheal, antihemorragic and mutagenic action. Journal of Ethnopharmacology 2010 127(2) 508-14.
188 - Heinrich M, Heneka B, Ankli A, Rimpler H, Sticher O, Kostiza T. Spasmolytic and antidiarrhoeal properties of the Yucatec Mayan medicinal plant Casimiroa tetrameria. Journal of Pharmacy and Pharmacology 2005 57(9) 1081-5.
189 - Sekiguchi H, Takabayashi F, Deguchi Y, Masuda H, Toyoizumi T, Masuda S, Kinae N. Leaf extract of Wasabia japonica relieved oxidative stress induced by Helicobacter pylori infection and stress loading in Mongolian gerbils. Bioscience Biotechnology and Biochemistry 2010 74(6) 1194-9.
190 - Wang YH, Wu JJ, and Lei HY. The Autophagic induction in Helicobacter pylori-infected macrophage. Experimental Biology and Medicine 2009 34171-180.
191 - Randhir R, Shetty K. Improved alpha-amylase and Helicobacter pylori inhibition by fenugreek extracts derived via solid-state bioconversion using Rhizopus oligosporus. Asia Pacific Journal of Clinical Nutrition 2007 16(3) 382-92.
192 - Wang G, Conover RC, Olczak AA, Alamuri P, Johnson MK, Maier RJ. Oxidative stress defense mechanisms to counter iron-promoted DNA damage in Helicobacter pylori. Free Radical Research 2005 39(11):1183-91.
193 - Nariman F, Eftekhar F, Habibi Z, Falsafi T. Anti-Helicobacter pylori activities of six Iranian plants. Helicobacter 2004 9(2) 146-51.
194 - Goel RK, Sairam K, Babu MD, Tavares IA, Raman A. In vitro evaluation of Bacopa monniera on anti-Helicobacter pylori activity and accumulation of prostaglandins. Phytomedicine 200310(6-7) 523-7.
195 - Moghaddam FM, Farimiani MM, Salahvarzi S, Amin G. Chemical constituents of dichloromethane extract of cultivated Satureja khuzistanica. Evidence-Based Complementary and Alternative Medicine 2007 4 95–98.
196 - Nariman F, Eftekhar F, Habibi Z, Massarrat S, Malekzadeh R. Antibacterial Activity of Twenty Iranian Plant Extracts Against Clinical Isolates of Helicobacter pylori. Iranian Journal of Basic Medical Sciences 2009 12(2) 105-111.
197 - Amin M, Anwar F, Naz F, Mehmood T, Saari N. Anti-Helicobacter pylori and urease inhibition activities of some traditional medicinal plants. Molecules 2013 18(2) 2135-49.
198 - Sharifi MS, Ebrahimi D, Hibbert DB, Hook J, Hazell SL. Bio-activity of natural polymers from the genus Pistacia: a validated model for their antimicrobial action. Global Journal of Health Science 2011 4(1):149-61
199 - Nakajima S, Fujita K, Inoue Y, Nishio M, Seto Y. Effect of the folk remedy, Bainiku-ekisu, a concentrate of Prunus mume juice, on Helicobacter pylori infection in humans. Helicobacter 2006 11(6) 589-91.