Metronidazole-resistant Helicobacter Pylori Research Articles

Synthesis of new 2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one derivatives as anti-MRSA and anti-H. pylori agents

In this work, we have synthesized twenty five new 2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one derivatives bearing an aryl or heteroaryl methylene group on position 5 of thiazolidinone and evaluated their antimicrobial activity against Gram-positive and -negative bacteria as well as three metronidazole resistant Helicobacter pylori strains. Most of the compounds were very potent towards tested Gram-positive bacteria and showed an antibacterial efficacy substantially greater than ampicillin as the reference drug. However, no effectiveness was observed for the Gram-negative microorganisms. The compounds 9, 20 and 29 exhibited strong antimicrobial activity against Helicobacter pylori strains (inhibition zone > 30 mm) in 100 μg/disc and (inhibition zone > 20 mm) in 50 μg/disc. Taking these findings together, it seems that these potent antibacterial derivatives could be considered as promising agents for developing new anti-infectious drugs against microorganisms resistant to currently available antibiotics.Graphical

Nitro-imidazole-based ruthenium complexes with antioxidant and anti-inflammatory activities

Inflammation is a physiological process triggered in response to tissue damage, and involves events related to cell recruitment, cytokines release and reactive oxygen species (ROS) production. Failing to control the process duration lead to chronification and may be associated with the development of various pathologies, including autoimmune diseases and cancer. Considering the pharmacological potential of metal-based compounds, two new ruthenium complexes were synthesized: cis-[Ru(NO2)(bpy)2(5NIM)]PF6 (1) and cis-[RuCl(bpy)2(MTZ)]PF6 (2), where bpy = 2,2′-bipyridine, 5NIM = 5-nitroimidazole and MTZ = metronidazole. Both products were characterized by spectroscopic techniques, followed by Density Functional Theory (DFT) calculations in order to support experimental findings. Afterwards, their in vitro cytotoxic, antioxidant and anti-inflammatory activities were investigated. Compounds 1 and 2 presented expressive in vitro antioxidant activity, reducing lipid peroxidation and decreasing intracellular ROS levels with comparable effectiveness to the standard steroidal drug dexamethasone or α-tocopherol. These complexes showed no noticeable cytotoxicity on the tested cancer cell lines. Bactericidal assay against metronidazole-resistant Helicobacter pylori, a microorganism able to disrupt oxidative balance, unraveled compound 1 moderate activity over that strain. Besides this, it was able to inhibit interleukin-6 (IL-6) and tumor necrosis factor-α (TNF- α) production as well as interleukin-1β (IL-1β) and cyclooxygenase-2 (COX-2) expression in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. This latter activity is remarkable, which has not been reported for other ruthenium-based complexes. Altogether, these results suggest cis-[Ru(NO2)(bpy)2(5NIM)]PF6 complex has potential pharmacological application as an anti-inflammatory agent that deserve further biological investigation.

Synthesis of 1,2,3-Triazolo[4,5-h]quinolone Derivatives with Novel Anti-Microbial Properties against Metronidazole Resistant Helicobacter pylori.

Helicobacter pylori infection can lead to gastritis, peptic ulcer, and the development of mucosa associated lymphoid tissue (MALT) lymphoma. Treatment and eradication of H. pylori infection can prevent relapse and accelerate the healing of gastric and duodenal ulcers as well as regression of malignancy. Due to the increasing emergence of antibiotic resistance among clinical isolates of H. pylori, alternative approaches using newly discovered antimicrobial agents in combination with the standard antibiotic regimens for the treatment of H. pylori are of major importance. The purpose of the present study was to investigate the effect of newly synthesized 8-amino 7-substituted fluoroquinolone and their correspondent cyclized triazolo derivatives when either alone or combined with metronidazole against metronidazole-resistant H. pylori. Based on standard antimicrobial susceptibility testing methods and checkerboard titration assay, all of the tested compounds showed interesting antimicrobial activity against 12 clinical strains of H. pylori, with best in vitro effect for compounds 4b and 4c. Fractional inhibitory concentration (FIC) mean values showed synergistic pattern in all compounds of Group 5. In addition, additive activities of some of the tested compounds of Group 4 were observed when combined with metronidazole. In contrast, the tested compounds showed no significant urease inhibition activity. These results support the potential of new fluoroquinolone derivatives to be useful in combination with anti-H. pylori drugs in the management of H. pylori-associated diseases.

Protective effect of essential oil of Pistacia atlantica Desf. on peptic ulcer: role of α-pinene

OBJECTIVETo evaluate the efficacy of Pistacia atlantica Desf. oleoresin essential oil on peptic ulcer (PU) and its antibacterial effect on metronidazole-resistant Helicobacter pylori, as well as chemical composition of the essential oil. METHODSThe essential oil was standardized using gas chromatography mass spectrometry (GC/MS) analysis. Acute toxicity of the essential oil was assessed in animal model. In vitro anti-Helicobacter pylori activity was performed through disc diffusion and minimum inhibitory concentration method. For gastroprotective assay, rats received Pistacia atlantica Desf. essential oil (25, 50 and 100 mg/kg orally) 1 h before induction of ulcer by ethanol. Macroscopic (ulcer index and protection rate) and microscopic examination were performed. RESULTSThe GC/MS analysis of the essential oil led to the identification of twenty constituents and α-pinene is predominant constituent. The essential oil was safe up to 2000 mg/kg. All Helicobacter pylori strains were susceptible to the essential oil and the MIC ranged from 275 to 1100 µg/mL. The ulcer index for treated groups was significantly reduced compared to control (P < 0.001) with EC50 value of 12.32 mg/kg. In microscopic examination, Pistacia atlantica attenuated destruction and necrosis of gastric tissue. CONCLUSIONCurrent study exhibited protective effect of standardized Pistacia atlantica essential oil against ethanol-induced gastric ulcer and its antibacterial activity on Helicobacter pylori. α-pinene might be the responsible agent.

High rate of levofloxacin resistance in a background of clarithromycin- and metronidazole-resistant Helicobacter pylori in Vietnam

Antimicrobial resistance in Helicobacter pylori has increased worldwide and has become a major cause of treatment failure in many countries, including Vietnam. It is advisable to perform an antibiogram to provide optimal regimens for H. pylori eradication. This study evaluated the rate of antibiotic resistance to the four commonly used antibiotics against H. pylori at a tertiary care hospital in Central Vietnam and analysed point mutations in genes related to clarithromycin (CLA) and levofloxacin (LFX) resistance. A total of 92 H. pylori strains from gastric biopsy specimens were tested; 42.4% were resistant to CLA (primary, 34.2%; secondary, 73.7%), 41.3% to LFX (primary, 35.6%; secondary, 63.2%), 76.1% to metronidazole (MTZ) and 1.1% to amoxicillin. Multidrug resistance was observed in 56.5% (primary, 50.7%; secondary, 78.9%) of isolates (P<0.05). The rate of resistance to LFX was significantly higher in females than males (P<0.05). Most of the CLA- and LFX-resistant strains harboured resistance-associated mutations, with common positions at A2143G and T2182C in the 23S rRNA gene and at Asn-87 or Asp-91 in GyrA. Minimum inhibitory concentrations (MICs) increased in strains carrying quadruple mutations in their 23S rRNA gene and in strains with Asn-87 GyrA mutation (P<0.05). One high-level LFX-resistant strain (MIC=32mg/L) had new mutations with a combination of N87A, A88N and V65I. High resistance rates to CLA, MTZ and LFX discourage standard and LFX-based triple therapies as first-line treatment in Vietnam.

Nizatidine and omeprazole enhance the effect of metronidazole on Helicobacter pylori in vitro

Treatment failures are common in patients infected with metronidazole-resistant Helicobacter pylori in the gastric mucosa when triple therapy including metronidazole is used. In patients with treatment failure and metronidazole-resistant H. pylori, a higher eradication rate for H. pylori was found after secondary treatment with bismuth/ranitidine in combination with antibiotics including metronidazole, compared with the same antibiotics combined with a standard dose of omeprazole. This agrees with our previous finding that bismuth was able to reduce the susceptibility of H. pylori to metronidazole. In this study, we have found that nizatidine, an H 2-receptor antagonist, is also able to reduce the susceptibility of H. pylori to metronidazole in vitro, despite having no direct inhibitory effect on the growth of H. pylori. This agrees with earlier findings that compounds having the ability to reverse antibiotic resistance do not necessarily have an antibiotic or chemotherapeutic effect in the sense of growth inhibition. Therefore, it was decided to investigate the effect of nizatidine and omeprazole on the oxidative respiratory chain, as it is known that metronidazole is able to inhibit the activity of fumarate reductase of H. pylori. This enzyme is a key enzyme in the alternative respiratory chain under anaerobic conditions. Nizatidine was, in these preliminary experiments, found to inhibit fumarate reductase in a dose-dependent way, like metronidazole, whereas omeprazole had almost no effect on fumarate reductase. No other significant effects on the enzymes of the respiratory chain were found. The synergistic effect of nizatidine on metronidazole resistant H. pylori strains could be explained by the effect on fumarate reductase, whereas the effect of omeprazole is different and could be an inhibition of a proton pump in H. pylori. Reversal of antimicrobial resistance with the help of different non-antibiotics seems to be possible by using quite different compounds, and is therefore to be explained by different molecular mechanisms.

Co-infection with metronidazole susceptible and metronidazole resistant Helicobacter pylori: Different strains or mutation in a single strain?

Co-infection with metronidazole susceptible and metronidazole resistant Helicobacter pylori: Different strains or mutation in a single strain?

Potentiation of the action of metronidazole on Helicobacter pylori by omeprazole and bismuth subcitrate

Treatment failures using triple therapy that include metronidazole, are common in patients infected with metronidazole-resistant Helicobacter pylori in the gastric mucosa. Higher eradication rates in such patients have been described when treatment regimens include bismuth salts compared to regimens that include proton pump inhibitors. In the present study, the synergistic effect of subinhibitory concentrations (0.25–0.5 MIC) of either bismuth subcitrate or omeprazole with metronidazole on the susceptibility of 42 H. pylori strains was investigated by agar dilution method and the Epsilometer test (Etest). With 0.5 MIC of either of the two drugs, the susceptibility of all H. pylori strains to metronidazole was reduced between two to 64 fold and six (27%) metronidazole-resistant strains (with MIC >4 mg/l) reverted to being metronidazole sensitive. These results suggested that either bismuth salts or proton pump inhibitors may be effective in the treatment of some infections with metronidazole-resistant H. pylori strains when used in sufficiently high doses.

Study of the combination of ranitidine bismuth citrate and metronidazole against metronidazole-resistant Helicobacter pylori clinical isolates.

The in-vitro activity of a combination of ranitidine bismuth citrate (RBC) and metronidazole against metronidazole-resistant Helicobacter pylori strains (MIC > or = 8 mg/L) was evaluated by agar dilution chequerboard and killing curve methods. Twenty-five metronidazole-resistant strains were used in the chequerboard method, using Mueller-Hinton agar plus 7% lysed horse blood, an inoculum of 10(6) cfu/spot and incubation in a 10% CO2 atmosphere at 37 degrees C for 3-5 days. Synergy was defined as a fractional inhibitory concentration (FIC) index of < or = 0.5, partial synergy as 0.5 < FIC < or = 1, indifference as 1 < FIC < or = 4 and antagonism as FIC > 4. For nine strains, killing curves were constructed for metronidazole and RBC individually and in combination at 1 x MIC. The number of viable colonies was counted at time 0 and after 2, 4, 6, 8 and 24 h; the combination was defined as synergic if it produced a decrease of > or = 2 log10 cfu/mL compared with the most active single agent. Metronidazole MICs ranged from 8 to 128 mg/L and RBC MICs from 0.125 to 4 mg/L. The minimum FIC ranged from 0.28 to 1 and the maximum FIC from 1 to 1.25. When RBC and metronidazole were combined, all the metronidazole-resistant H. pylori strains revealed partial (68%) or total (32%) synergy. Five out of the nine strains also exhibited synergy at 4, 6 or 8 h incubation when tested by the killing curve method although three other strains exhibited no synergy. In the last strain, a 2log10 decrease in the initial number was observed with RBC alone or combined with metronidazole.

BSS quadruple “Salvage” therapy for patients with culture proven metronidazole-resistant Helicobacter pylori

BSS quadruple “Salvage” therapy for patients with culture proven metronidazole-resistant Helicobacter pylori

Furazolidone, amoxycillin, bismuth triple therapy for Helicobacter pylori infection.

Metronidazole-resistant Helicobacter pylori are generally the rule in developing countries such as Colombia. Developing countries need an effective, simple and inexpensive non-metronidazole therapy for H. pylori infection. To evaluate the combination of bismuth, furazolidone and amoxycillin for the treatment of H. pylori infection in Colombia. Thirty patients with histologically documented H. pylori infection received the combination of bismuth subcitrate 240 mg b.d., furzolidone 100 mg q.d.s. and amoxycillin 500 mg q.d.s. for 14 days. Four or more weeks after ending therapy patients were re-endoscoped and gastric biopsies were obtained and examined using the Genta stain. Each slide was scored for presence, absence and density of H. pylori, active and chronic inflammation, intestinal metaplasia, erosions and atrophy. Cure was defined as the absence of H. pylori. All patients completed the course of therapy. Twenty-five patients were cured (86%, 95% CI: 65-94%). Mild, well-tolerated side-effects were reported by six patients (20%). This combination of bismuth, furazolidone and amoxycillin fulfills the criteria for successful H. pylori therapy and appears particularly well suited for developing countries since it is simple, inexpensive and effective. Furazolidone-containing therapies may become especially useful in the face of a world-wide increase in H. pylori resistance to metronidazole and macrolides.

In vitro susceptibility ofHelicobacter pylori to trospectomycin, pirlimycin (U-57930E), mirincamycin (U-24729A) and N-demethyl clindamycin (U-26767A)

The in vitro activity of trospectomycin, pirlimycin, mirincamycin and N-demethyl clindamycin was measured against 46 clinical isolates of Helicobacter pylori using an agar dilution technique. The MIC50 and MIC90 were 4 and 64 micrograms/ml for pirlimycin and N-demethyl clindamycin, and 32 and 128 micrograms/ml for mirincamycin, respectively. All 46 strains were sensitive to trospectomycin with an MIC50 of 8 micrograms/ml and an MIC90 of 16 micrograms/ml. Of seven strains with the highest trospectomycin MICs (8 or 16 micrograms/ml) 100% were found to be resistant to metronidazole. Among ten strains with low trospectomycin MICs (2 micrograms/ml or less) 100% were sensitive to metronidazole. Possible explantations for the apparent correlation between the MICs of the two drugs are discussed. Since all metronidazole resistant strains were sensitive to trospectomycin, this drug may be useful in treating infection with metronidazole resistant Helicobacter pylori.