| Background&Objective: With the widespread use of antibiotics,the efficacy of standard triple therapies has decreased continuously as a result of a progressive increase in resistance to antibiotics. Bismuth-based quadruple therapy was recommended as the preferred first-line regimen for H. pylori infection instead of standard triple therapies by the Fourth Chinese National Consensus report on the management of Helicobacter pylori infection. However, a great number of high level evidence-based studies were needed to support this. Therefore, to further assess the efficacy and safety of standard triple therapy compared with other eradication treatments(other triple therapies, quadruple treatments and sequential treatments) and provide high level evidence-based medicine evidence, we conducted this systemic review and meta-analysis.Among these six commonly used antibiotics, the resistant rates of Metronidazole, clarithromycin and levofloxacin were high, while the resistant rates of tetracycline, amoxicillin and furazolidone were low. However, tetracycline and furazolidone may be inaccessible in some areas and tetracycline cannot be used in children, amoxicillin was restricted by penicillin allergy. So the kinds of antibiotics which can be choosed for H. pylori eradication were limited. Therefore, there is an essential need for investigating new regimens and compounds for H. pylori infection. CBR-2092 is a novel rifampin- quinolone hybrid antibiotic consisting of the rifamycin SV and a 4H-4-oxo- quinolizine pharmacophores. But there has been no published research investigating the antibacterial activity of CBR-2092 against Helicobacter pylori. So,we conducted this study to assess the antibacterial activity of TNP-2092 against clinical isolates of Helicobacter pylori in vitro.Methods:1. The systematic review and meta-analysis of Standard triple therapy for Helicobacter pylori infection in China.(1). Search strategyLiterature searches were conducted in the following databases(to November 2013): Pub Med, EMBASE, the Cochrane Central Register of Controlled Trials, the VIP database, the China National Knowledge Infrastructure database, and the Chinese Biomedical Database. The search terms used for all of the databases were as follows:(“Helicobacter pylori” or “triple”) and(“amoxicillin” or “clarithromycin”).(2). Outcome assessmentThe primary study outcomes for the meta-analysis included the following:(1) the efficacy of standard triple therapy compared with established and new therapies in eradicating H. pylori infection; and(2) the incidence of adverse events in standard triple therapy vs other therapies.(3). Statistical analysisA meta-analysis of all randomized controlled trials(RCTs) comparing standard triple therapy for the eradication of Helicobacter pylori with pre-existing and new therapies in China was performed using Comprehensive Meta-Analysis 2.0. The Mantel-Haenszel method was used for analyses according to age, duration of treatment and drug type. Sensitivity analyses and a cumulative metaanalysis were also performed with CMA 2.0. Publication bias was evaluated using Egger’s test, Begg’s test or a funnel plot.2. Evaluation of a novel hybrid antibiotic TNP-2092 against helicobacter pylori clinical isolates in vitro(1). Antimicrobial susceptibility of Helicobacter pylori to TNP-2092 in vitro.A total of 100 H. pylori isolates strains were selected from retained clinical isolates. The minimal inhibitory concentrations(MICs) for clarithromycin, rifampin, TNP-2092, and levofloxacin were determined using a agar dilution method.(2). Determination of killing kinetics of TNP-2092The time required for TNP-2092 to kill H. pylori cells was determined using time-kill curves by exposing ATCC43504 to a range of TNP-2092 concentrations(0-64MIC) for up to 24 h, followed by monitoring of CFUs.(3). Determination of TNP-2092 stability under different p H conditionsThe TNP-2092 stability under different p H conditions was determined using time-kill curves by exposing ATCC43504 to a range of TNP-2092 concentrations(0-4MIC) for up to 24 h under different p H conditions(7,6,5,4), followed by monitoring of CFUs.(4). Investigation of bacterial resistance mechanisms to TNP-2092DNA was extracted from the TNP-2092 resistant isolate by the method described previously. The quinolone resistance-determining region of the gyr A gene and rifamycin resistance-determining region of the rop B gene from the resistant strain were amplified by PCR and sequenced.Results:1. The systematic review and meta-analysis of Standard triple therapy for Helicobacter pylori infection in China.(1). A total of 49 RCTs including 8332 patients were assessed.(2). This meta-analysis showed that standard triple therapy with proton pump inhibitors(PPIs), amoxicillin(AMO) and clarithromycin(CLA) was inferior to sequential therapy [relative risk(RR) = 0.863; 95% confidence interval(CI): 0.824-0.904], but was not superior to quadruple therapy(RR = 1.073; 95%CI: 0.849-1.357) or other triple therapies(RR = 1.01; 95%CI: 0.936-1.089). The meta-analysis also suggested that standard triple therapy is slightly more effective than dual therapy(RR = 1.14; 95%CI: 0.99-1.31).However, the differences were not statistically significant. We removed the only trial with a regimen lasting 14 d by sensitivity analysis and found that 7-d standard triple therapy was superior to 7-d dual therapy(RR = 1.221; 95%CI: 1.084-1.374). Moreover, a sub-analysis based on the duration of quadruple therapy indicated that the 7-d and 10-d standard triple therapies were inferior to quadruple therapy(RR = 0.790; 95%CI: 0.718-0.868; RR = 0.917; 95%CI: 0.839-1.002, respectively).(3). There were no significant differences in cure rate or adverse events among standard triple therapy, quadruple therapy, and other triple therapies. Standard triple therapy had a higher occurrence of side effects than sequential therapy(RR = 1.283; 95%CI: 1.066-1.544).(4). The effectiveness of the standard triple treatment with PPI, AMO and CLA gradually reduced with time. Before 2004:88.54%;From 2005 to 2009:77.66%;From 2010 to 2013:71.13%。2. Evaluation of a novel hybrid antibiotic TNP-2092 against helicobacter pylori clinical isolates in vitro(1). Antimicrobial susceptibility of Helicobacter pylori to TNP-2092 in vitro.Overall resistance rates are as shown in Table 1. The primary resistance rates of 100 H. pylori isolates to clarithromycin, levofloxacin, rifampin and TNP-2092 were 13%(13/100), 18%(18/100), 1%(1/100) and 1%(1/100) respectively. The MIC values to TNP-2092 ranged from 0.032 to >128 ug/ml. The MIC50 of TNP-2092 is 0.125 ug/m L. However, The MIC90 of TNP-2092 is 0. 5 ug/m L.(2). Determination of killing kinetics of TNP-2092SQ109 killing kinetics were concentration- and time-dependent.(3). Determination of TNP-2092 stability under different p H conditionsThe effectiveness of the TNP-2092 on helicobacter pylori gradually reduced with the decrease of PH.(4). Investigation of bacterial resistance mechanisms to TNP-2092There is a single deletion of 295 base in gyr A gene, while the mutations in the gyr A gene were Synonymous mutations.Conclusions:1. The eradication rates with a standard triple therapy consisting of PPI, AMO, and CLA are suboptimal in China.2. TNP-2092 could be a promising candidate for rescue therapy.3. The antibacterial activity of TNP-2092 is concentration-dependent, time – dependent, and p H- dependent. The efficacy can be reduced by acid.4. The mutation in gyr A may be involved in the resistance of helicobacter pylori to TNP-2092. |
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