Susceptibility of Helicobacter pylori Isolates against Agents Commonly Administered for Eradication Therapy and the Efficacy of Chemotherapy

Although chemotherapy has been documented to be effective in the treatment of Helicobacter pylori-associated gastritis and gastroduodenal ulcers, some cases are known to have been unsuccessful in the attempt to eradicate this species. In this study, we examined the relation between the susceptibility of H. pylori isolates and the efficacy of chemotherapy. We utilized the modified agar plate dilution method to determine the minimum inhibitory concentrations (MICs) of 63 H. pylori strains isolated before treatment with several drugs routinely used during eradication chemotherapy. Among the drugs tested, amoxicillin (AMPC) and clarithromycin (CAM) demonstrated high degrees of activity with MIC₉₀, 0.39 and 0.2 μg/ml, respectively. No highly resistant strain against AMPC was detected among the strains examined, while for CAM and metronidazole (MTZ), 9.5% and 7.9% of the strains, respectively, were resistant before treatment. It should be noted that all of the MICs of the strains from patients with successful therapy were lower than those from patients with unsuccessful therapy. These findings indicate that susceptibility tests should be carried out prior to the commencement of drug administration in order to provide safer and more effective chemotherapy.     

In vitro and in vivo effects of the Mongolian drug Amu‐ru 7 on Helicobacter pylori growth and viability

Amu‐ru 7, a Mongolian folk medicine, is used to treat digestive diseases such as gastritis and gastric and duodenal ulcers. We examined the effect of Amu‐ru 7 on the growth and viability of Helicobacter pylori in vivo and in vitro. By the agar dilution method, the MIC of Amu‐ru 7 for H. pylori strains was shown to be 100–200 μg/mL with a MIC₉₀ of 200 μg/mL. Two hundred micrograms per milliliter of Amu‐ru 7 exhibited potent bactericidal activity against H. pylori in the stationary phase of growth 6 hr after treatment. Amu‐ru 7 inhibited the growth of both AMPC‐resistant and CAM‐resistant strains, and also had a combined effect with AMPC on AMPC‐resistant strain 403. The Amu‐ru 7 inhibited biofilm formation by H. pylori and induced morphological changes, such as bleb‐like formation and shortening of the cell. Although colonization of the stomach of the Mongolian gerbil by H. pylori was not cured by treatment with Amu‐ru 7, both the mean number of H. pylori colonized and the colonization rate were decreased in Amu‐ru 7 treated gerbils. These results suggest the effectiveness Amu‐ru 7 as an adjunct therapy for eradication therapies consisting of a PPI combined with antibiotics.     

Antibiotic resistance of Helicobacter pylori in Mazandaran, North of Iran

Background: The aim of this study was to investigate the prevalence of resistances in Helicobacter pylori against commonly used antibiotics including metronidazole, clarithromycin, amoxicillin, and tetracycline in Iranian patients. Methods: H. pylori isolates were collected from gastric biopsies from patients referred for upper gastrointestinal endoscopy at Tooba Medical Center, Sari, Iran, from 2007 to 2010. None of them had been using antibiotics for at least 8 months. H. pylori was identified based on morphological shape and positive biochemical tests for catalase, oxidase, and urease activity. Antibiotic resistance for metronidazole, clarithromycin, amoxicillin, and tetracycline was investigated by using epsilometer test. Resistance was defined by minimal inhibitory concentration (MIC) > 0.5 mg/L for amoxicillin (AMX), >4 mg/L for tetracycline (TET), >8 mg/L for metronidazole (MTZ), and >1 mg/L for clarithromycin (CLR). Results: Strains were collected from 132 patients, mean age 45.8 years, 52 (39%) were women. Patients had diverse diagnoses: gastritis 42 (31.8%), duodenal ulcer 45 (34%), gastric cancer 15 (11.3%), or gastric ulcer 30 (22.7%). The prevalences of resistance of H. pylori strains isolated from the patients were 73.4% for metronidazole, 30% for clarithromycin, 6.8% for amoxicillin, and 9% for tetracycline. Twenty‐eight (21.2%) were double resistant to MTZ‐CLR, 16 (12.1%) showed triple resistance to MTZ‐CLR‐AMX, and 8 (6%) were resistant to all four tested antibiotics (MTZ‐CLR‐AMX‐TET). No associations were detected between multiple resistant strains and clinical manifestations (p > .05). Conclusions: The prevalence of H. pylori antibiotic resistance to metronidazole and clarithromycin was high in Iran consistent with the reported low success rates for H. pylori treatment in this country.     

No association between Helicobacter pylori genotypes and antibiotic resistance phenotypes within families

Background. Triple therapy combining a proton pump inhibitor with two antibiotics, e.g. clarythromycin (CLR), metronidazole (MTZ) or amoxicillin (AMX), represents the standard in Helicobacter pylori eradication regimens. Resistance to antimicrobial agents, particularly MTZ (up to 56% in Western countries) and CLR (up to 15% in southern Europe), is frequently observed and may be associated with treatment failure [ 1 ]. Recently, several studies indicated that individual H. pylori colonies from a single anatomic site may not always yield identical genotypes, or the identical patterns of susceptibility to antibiotics [ 2 - 5 ]. Representative for every single patient we analyzed 27 H. pylori antrum isolates for susceptibility to antimicrobial agents in order to test whether identical H. pylori genotypes exhibit a similar pattern of susceptibility to antibiotics. Methods. PCR, RELP, PFGE, antibiotic susceptibility testing. Results. H. pylori genotype and antibiotic susceptibility pattern in families do not segregrate. Conclusion. Molecular typing of H. pylori from family members does not predict antibiotic susceptibility pattern.     

A Combination Effect of Epigallocatechin Gallate,a Major Compound of Green Tea Catechins,with Antibiotics on Helicobacter pylori Growth In Vitro

Since green tea catechins are known to have antimicrobial activity against a variety of microorganisms, their possible effects on Helicobacter pylori in combination with antibiotics were examined. Fifty-six clinical isolates of H. pylori, including 19 isolates highly resistant to metronidazole (MTZ) and/or clarithromycin (CLR), were used to determine in vitro sensitivity to tea catechins. The MIC₉₀ of both epigallocatechin gallate (EGCg) and epicatechin gallate (ECg) was 100 Î&frac;g/ml. However, other tea catechins tested did not show any anti-H. pylori activity. Highly antibiotic-resistant clinical isolates showed a similar sensitivity to both EGCg and ECg. The kinetic study of antibacterial activity in liquid cultures revealed a relatively slow but strong activity on the growth of H. pylori. In combination with sub-MIC of amoxicillin (AMX), the antibacterial activity of AMX was significantly enhanced by the presence of EGCg. To estimate the general combination effect between EGCg and other antibiotics, such as MTZ and CLR, on the antibacterial activity against clinical isolates, the fraction inhibitory concentration (FIC) was determined by checkerboard study. The FIC indexes showed additive effects between EGCg and antibiotics tested. These results indicate that EGCg may be a valuable therapeutic agent against H. pylori infection.Received: 2 September 2002 / Accepted: 12 November 2002     

Cross‐species discovery of syncretic drug combinations that potentiate the antifungal fluconazole

Resistance to widely used fungistatic drugs, particularly to the ergosterol biosynthesis inhibitor fluconazole, threatens millions of immunocompromised patients susceptible to invasive fungal infections. The dense network structure of synthetic lethal genetic interactions in yeast suggests that combinatorial network inhibition may afford increased drug efficacy and specificity. We carried out systematic screens with a bioactive library enriched for off‐patent drugs to identify compounds that potentiate fluconazole action in pathogenic Candida and Cryptococcus strains and the model yeast Saccharomyces. Many compounds exhibited species‐ or genus‐specific synergism, and often improved fluconazole from fungistatic to fungicidal activity. Mode of action studies revealed two classes of synergistic compound, which either perturbed membrane permeability or inhibited sphingolipid biosynthesis. Synergistic drug interactions were rationalized by global genetic interaction networks and, notably, higher order drug combinations further potentiated the activity of fluconazole. Synergistic combinations were active against fluconazole‐resistant clinical isolates and an in vivo model of Cryptococcus infection. The systematic repurposing of approved drugs against a spectrum of pathogens thus identifies network vulnerabilities that may be exploited to increase the activity and repertoire of antifungal agents.     

Synergistic effects of low doses of histatin 5 and its analogues on amphotericin B anti-mycotic activity

The increase in the use of antifungal agents for prophylaxis and therapy has led to the development of antifungal drug resistance. Drug combinations may prevent or delay resistance development. The aim of the present study was to investigate whether naturally and designed cationic antifungal peptides act synergistically with commonly used antimycotics. No enhanced activity was found upon addition of dhvar4, a designed analogue of the human salivary peptide histatin 5, or PGLa to fluconazole or 5–flucytosine, respectively. In contrast, strong synergism of amphotericin B with the peptides was found against several Aspergillus, Candida, and Cryptococcus strains, and against an amphotericin B-resistant C. albicans laboratory mutant in the standardised broth microdilution assays according to the NCCLS standard method M27–T. Amphotericin B showed synergism with dhvar5, another designed analogue of histatin 5, and with magainin 2 against all seven tested strains. Combinations of amphotericin B with histatin 5, dhvar4, and PGLa showed synergism against four of the seven strains. The growth inhibitory activity of amphotericin B was enhanced by sub-MIC concentrations of peptide, but its haemolytic activity remained unaffected, suggesting that its cytotoxicity to host cells was not increased and that peptides may be suitable candidates for combination therapy.     

In Vitro Characterization of the Anti-Bacterial Activity of SQ109 against Helicobacter pylori

The most evident challenge to treatment of Helicobacter pylori, a bacterium responsible for gastritis, peptic ulcers and gastric cancer, is the increasing rate of resistance to all currently used therapeutic antibiotics. Thus, the development of novel therapies is urgently required. N-geranyl-N''-(2-adamantyl) ethane-1, 2-diamine (SQ109) is an ethylene diamine-based antitubercular drug that is currently in clinical trials for the treatment of tuberculosis (TB). Previous pharmacokinetic studies of SQ109 revealed that persistently high concentrations of SQ109 remain in the stomach 4 hours post oral administration in rats. This finding, combined with the need for new anti- Helicobacter therapies, prompted us to define the in vitro efficacy of SQ109 against H. pylori. Liquid broth micro-dilution was used for susceptibility studies to determine the antimicrobial activity of SQ109 against a total of 6 laboratory strains and 20 clinical isolates of H. pylori; the clinical isolates included a multi-drug resistant strain. All strains tested were susceptible to SQ109 with MIC and MBC ranges of 6-10 µM and 50-60 µM, respectively. SQ109 killing kinetics were concentration- and time-dependent. SQ109 killed H. pylori in 8-10 h at 140 µM (2MBCs) or 4-6 h at 200 µM (~3MBCs). Importantly, though the kinetics of killing were altered, SQ109 retained potent bactericidal activity against H. pylori at low pH. Additionally, SQ109 demonstrated robust thermal stability and was effective at killing slow growing or static bacteria. In fact, pretreatment of cultures with a bacteriostatic concentration of chloramphenicol (Cm) synergized the effects of typically bacteriostatic concentrations of SQ109 to the level of five-logs of bacterial killing. A molar-to-molar comparison of the efficacy of SQ109 as compared to metronidazole (MTZ), amoxicillin (AMX), rifampicin (RIF) and clarithromycin (CLR), revealed that SQ109 was superior to MTZ, AMX and RIF but not to CLR. Finally, the frequency of resistance to SQ109 was low and electron microscopy studies revealed that SQ109 interacted with bacterial inner membrane and cytoplasmic content(s). Collectively, our in vitro data demonstrate that SQ109 is an effective monotherapy against susceptible and multi-drug resistant strains of H. pylori and may be useful alone or in combination with other antibiotics for development as a new class of anti- Helicobacter drugs.     

Nonbismuth quadruple (concomitant) therapy: empirical and tailored efficacy versus standard triple therapy for clarithromycin-susceptible Helicobacter pylori and versus sequential therapy for clarithromycin-resistant strains

Background:  Using quadruple clarithromycin‐containing regimens for Helicobacter pylori eradication is controversial with high rates of macrolide resistance. Aim:  To evaluate antibiotic resistance rates and the efficacy of empirical and tailored nonbismuth quadruple (concomitant) therapy in a setting with cure rates <80% for triple and sequential therapies. Methods:  209 consecutive naive H. pylori‐positive patients without susceptibility testing were empirically treated with 10‐day concomitant therapy (proton pump inhibitors (PPI), amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg; all drugs b.i.d.). Simultaneously, 89 patients with positive H. pylori culture were randomized to receive triple versus concomitant therapy for clarithromycin‐susceptible H. pylori, and sequential versus concomitant therapy for clarithromycin‐resistant strains. Eradication was confirmed with ¹³C‐urea breath test or histology 8 weeks after completion of treatment. Results:  Per‐protocol (PP) and intention‐to‐treat eradication rates after empirical concomitant therapy without susceptibility testing were 89% (95%CI:84–93%) and 87% (83–92%). Antibiotic resistance rates were: clarithromycin, 20%; metronidazole, 34%; and both clarithromycin and metronidazole, 10%. Regarding clarithromycin‐susceptible H. pylori, concomitant therapy was significantly better than triple therapy by per protocol [92% (82–100%) vs 74% (58–91%), p = 0.05] and by intention to treat [92% (82–100%) vs 70% (57–90%), p = 0.02]. As for antibiotic‐resistant strains, eradication rates for concomitant and sequential therapies were 100% (5/5) vs 75% (3/4), for clarithromycin‐resistant/metronidazole‐susceptible strains and 75% (3/4) vs 60% (3/5) for dual‐resistant strains. Conclusions:  Empirical 10‐day concomitant therapy achieves good eradication rates, close to 90%, in settings with multiresistant H. pylori strains. Tailored concomitant therapy is significantly superior to triple therapy for clarithromycin‐susceptible H. pylori and at least as effective as sequential therapy for resistant strains.     

Mutations of Helicobacter pylori associated with fluoroquinolone resistance in Korea

Background and Aim: Fluoroquinolone resistance of Helicobacter pylori is known to be dependent on mutations in the QRDR of gyrA. This study was performed to investigate the distribution of gyrA point mutations and to evaluate the impact of the mutations on second‐line H. pylori eradication therapy. Methods: After H. pylori isolation from gastric mucosal specimens, fluoroquinolone resistance was examined using the agar dilution method. DNA sequencing of the QRDR of gyrA was performed in 89 fluoroquinolone‐resistant and 27 fluoroquinolone‐susceptible isolates. Transformation experiments were performed to confirm mutations in the resistant strains. The eradication rates of moxifloxacin‐containing triple therapy were evaluated depending on the resistance of fluoroquinolone. Results: The gyrA mutations were detected in 75.3% (55 of 73 strains) of the primary resistant strains and 100% (16 strains) of the secondary resistant strains. The most common mutations were Asp‐91 (36.0%) and Asn‐87 (33.7%). The MIC values in the transformed strains differed depending on the gyrA mutations, N87, and D91. Six patients with fluoroquinolone‐resistant strains received moxifloxacin‐containing triple therapy as the second‐line therapy, and two of three patients with Asn‐87 mutations (66.7%) failed in the eradication. By contrast, three patients with Asp‐91 mutations had successful eradication treatment. Conclusions: Fluoroquinolone resistance of H. pylori was caused by gyrA Asn‐87 and Asp‐91 point mutations. The Asn‐87 mutation seems to be an important determinant of failure of fluoroquinolone‐containing triple eradication therapy based on eradication results.     

Antibiotic synergy against biofilm-forming <Emphasis Type="Italic">Pseudomonas aeruginosa</Emphasis>

Eight antibiotics (aztreonam, ceftazidim, cefoperazon, cefepim, netilmicin, amikacin, ofloxacin and ciprofloxacin) exhibited antimicrobial activity individually and/or in combinations against 20 wild-type biofilm-forming strains of Pseudomonas aeruginosa. The strains were less susceptible in biofilm; in 10 strains antibiotic synergy was observed for the combination of aztreonam and ciprofloxacin. Synergy was also demonstrated in the case of β-lactams and aminoglycosides, β-lactams and fluoroquinolones, aminoglycosides and fluoroquinolones, and for monobactams and β-lactams although the strains were resistant to the individual antibiotics. Synergism or partial synergism was found with one or more antibiotic combinations against 32.4% of isolates.     

New Approach for the Evaluation of Antimycobacterial Drug Combinations In Vitro (the Laboratory Model Man)

An attempt was made to study quantitatively the antimicrobial effect of combinations of commercially available antituberculosis drugs and antibiotics on the growth of multiple drug resistant strains of Mycobacteriunt intracellulare under simulated in vivo conditions. Combinations of erythromycin, isomiazid, methenamine, or exacillin eliminated populations of M. intracellulare when drug combinations in concentrations achievable in man were kept in contact with the organism for 10 hr daily. Although combinations of INH and rifampin failed to eliminate populations of M. intracellulare this pair seemed to be the most effective two-drug combination available. The requirement for successful treatment of drug-resistant mycobacterioses is the selection of an effective drug regimen and the maintenance of combined action of all drugs in the serum for approximately 10 hr daily. An in vitro model is described which enables the bacteriologist to design an effective combination of drugs and to measure its efficiency under simulated in vivo conditions.     

The bifidogenic growth stimulator inhibits the growth and respiration of Helicobacter pylori

Background: Triple therapy with amoxicillin, clarithromycin, and a proton‐pump inhibitor is a common therapeutic strategy for the eradication of Helicobacter pylori (H. pylori). However, frequent appearance of clarithromycin‐resistant strains is a therapeutic challenge. While various quinones are known to specifically inhibit the growth of H. pylori, the quinone 1,4‐dihydroxy‐2‐naphthoic acid (DHNA) produced by Propionibacterium has strong stimulating effect on Bifidobacterium. We were interested to see whether DHNA could inhibit the growth of H. pylori in in vitro or in vivo experimental setting. Materials and Methods: The minimum inhibitory concentration (MIC) of DHNA was determined by the agar dilution method. The inhibitory action of DHNA on the respiratory activity was measured by using an oxygen electrode. Germ‐free mice infected with H. pylori were given DHNA in free drinking water containing 100 μg/mL for 7 days. Results: DHNA inhibited H. pylori growth at low MIC values, 1.6–3.2 μg/mL. Likewise, DHNA inhibited clinical isolates of H. pylori, resistant to clarithromycin. However, DHNA did not inhibit other Gram negative or anaerobic bacteria in the normal flora of the human intestine. Both H. pylori cellular respiration and adenosine 5′‐triphosphate (ATP) generation were dose‐dependently inhibited by DHNA. Similarly, the culture filtrates of propionibacterial strains inhibited the growth of H. pylori, and oral administration of DHNA could eradicate H. pylori in the infected germ‐free mice. Conclusions: The bifidogenic growth stimulator DHNA specifically inhibited the growth of H. pylori including clarithromycin‐resistant strains in vitro and its colonization activity in vivo. The bactericidal activity of DHNA was via inhibition of cellular respiration. These actions of DHNA may have clinical relevance in the eradication of H. pylori.     

Primary antibiotic resistance of Helicobacter pylori isolated from Beijing children

Background: The antimicrobials resistance of Helicobacter pylori (H. pylori) was able to sharply decline the eradication rate of H. pylori both in adults and children, but there are limited studies about the primary antibiotic resistance and the related gene mutations, specifically in China. Materials and Methods: The primary resistance to 9 antibiotics of 73 H. pylori strains isolated from gastric biopsies of children recruited at Beijing Children’s Hospital was assessed, and the mutations in 23S rRNA gene of 65 macrolide‐resistant strains and in gyrA and gyrB of 12 quinolone‐resistant strains were investigated. Results: The resistance rate to clarithromycin, azithromycin, metronidazole, levofloxacin, moxifloxacin, and rifampicin was 84.9%, 87.7%, 61.6%, 13.7%, 15.1%, and 6.8%, respectively. No resistance to amoxicillin, gentamicin, and tetracycline was observed. Dual, triple, and quadruple antibacterial resistant percentage was 46.6% (34/73), 15.1% (11/73), and 2.7% (2/73), respectively. The gene mutation rate of A2142C, A2142G, and A2143G in 23S rRNA gene was 1.5% (1/65), 6.2% (4/65), and 84.6% (55/65), respectively. The detection rate of mutations of Asn87, Asp91, and Met191 in GyrA was 41.7% (5/12), 25% (3/12), and 25% (3/12), respectively. Conclusion: The high prevalence of primary antibiotic resistance was out of expectation in H. pylori strains isolated from the children in Beijing. Antibiotic susceptibility should be made clear before the antibiotic was used in the anti‐H. pylori therapy in this population. The A2143G was the most populated mutation in macrolide‐resistant strains, and Asn87 and Asp91 of GyrA were the most common mutation points in quinolone resistance strains.     

Efficacy and safety of faropenem in eradication therapy of Helicobacter pylori

Aims: While triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin is the standard therapy for Helicobacter pylori eradication, it is ineffective against clarithromycin‐resistant strains. To seek a better regimen for eradication therapy, we assessed the sensitivity of clinical strains seen in Japan to faropenem and then evaluated the efficacy and safety of eradication therapy containing this antibiotic. Methods: Minimum inhibitory concentrations (MICs) of faropenem were determined in 78 Japanese clinical H. pylori isolates using the agar dilution method. H. pylori‐positive patients were consecutively assigned to a 7‐day eradication therapy protocol with LAF (lansoprazole 60 mg/day, amoxicillin 2000 mg/day, and faropenem 600 mg/day), and then to a 14‐day protocol. The outcomes of the therapies were assessed by ¹³C‐urea breath tests. Results: All 78 strains showed MICs of faropenem that were equal to or less than 0.2 µg/mL. The eradication rates according to intention‐to‐treat analyses were 46.5% with the 7‐day therapy (n = 43) and 62.5% with the 14‐day therapy (n = 32). No special measures were required to treat the adverse events observed in approximately one‐third of the patients. Conclusions: Faropenem was found to have good antimicrobial action against H. pylori in vitro. The 14‐day LAF therapy successfully eradicated H. pylori in about two‐thirds of the patients although the incidence of adverse events was high.     

Analysis of antibiotic susceptibility patterns of Helicobacter pylori isolates from Malaysia

Background: The prevalence of antibiotic resistance varies in geographic areas. The information on the antibiotic susceptibility patterns of Helicobacter pylori (H. pylori) in our local setting is therefore relevant as a guide for the treatment options. Objective: This study was conducted to determine the primary resistance rates among H. pylori isolated from Malaysian patients. Materials and methods: Biopsy samples were obtained from the stomach antrum and corpus of 777 patients from September 2004 until 2007. H. pylori isolated from these patients were then subjected to minimum inhibitory concentration (MICs) determination using E‐test method, against metronidazole, clarithromycin, levofloxacin, ciprofloxacin, amoxicillin, and tetracycline. Results: From 777 patients, 119 were positive for H. pylori where a total of 187 strains were isolated. The resistance rates were noted to be 37.4% (metronidazole), 2.1% (clarithromycin), 1% (levofloxacin and ciprofloxacin), and 0% (amoxicillin and tetracycline). Different resistance profiles were observed among isolates from the antrum and corpus of 13 patients. Resistance to one type of antibiotic was observed in 36.4% of the strains where mono‐resistance to metronidazole was the most common. Resistance to ≥2 antibiotics was noted in 3.3% of isolates. High metronidazole MICs of ≥256 μg/mL were observed among the resistant strains. Conclusions: The resistance rates of the antibiotics used in primary treatment of H. pylori infections in Malaysia are low, and multi‐antibiotic‐resistant strains are uncommon. Infections with mixed populations of metronidazole‐sensitive and ‐resistant strains were also observed. However, the high metronidazole MIC values seen among the metronidazole‐resistant strains are a cause for concern.     

Eradication of Helicobacter pylori in children in Vietnam in relation to antibiotic resistance

Background: Low Helicobacter pylori eradication rates are common in pediatric trials especially in developing countries. The aim of the study was to investigate the role of antibiotic resistance, drug dosage, and administration frequency on treatment outcome for children in Vietnam. Materials and Methods: Antibiotics resistance of H. pylori was analyzed by the Etest in 222 pretreatment isolates from children 3–15 years of age who were originally recruited in a randomized trial with two treatment regiments: lansoprazole with amoxicillin and either clarithromycin (LAC) or metronidazole (LAM) in two weight groups with once‐ or twice‐daily administration. The study design was an observational study embedded in a randomized trial. Results: The overall resistance to clarithromycin, metronidazole, and amoxicillin was 50.9%, 65.3%, and 0.5%, respectively. In LAC, eradication was linked to the strains being susceptible to clarithromycin (78.2% vs 29.3%, p = .0001). Twice‐daily dosage of proton‐pump inhibitor (PPI) and clarithromycin was more effective for eradication than once‐daily dosage for resistant strains (50.0% vs 14.7%, p = .004) and tended to be so also for sensitive strains (87.5% vs 65.2%, p = .051). Exact antibiotic dose per body weight resulted in more eradication for resistant strains (45.3% vs 8.0%, p = .006). These differences were less pronounced for the LAM regimen, with twice‐daily PPI versus once daily for resistant strains resulting in 69.2% and 50.0% eradication (p = .096), respectively. Conclusions: Helicobacter pylori clarithromycin resistance was unexpectedly high in young children in Vietnam. Clarithromycin resistance was an important cause for eradication treatment failure. Twice‐daily administration and exact antibiotic dosing resulted in more eradicated infections when the strains were antibiotic resistant, which has implications for the study design in pediatric H. pylori eradication trials.     

Effectiveness of Omeprazole-Amoxicillin-Clarithromycin (OAC) Therapy for Helicobacter pylori Infection in a Japanese Population

Background. Omeprazole or lansoprazole, amoxicillin, clarithromycin (PPI/AC) therapy has been reported to provide a high cure rate of H. pylori infection with few adverse effects. Effectiveness of H. pylori therapy may vary among different geographic regions and patient populations. However, there are few reports in Japan as to its effectiveness. We have, therefore, studied the effectiveness of H. pylori therapy in a large group of Japanese patients. Methods. For this study, 366 H. pylori-positive patients with peptic ulcer disease or non-ulcer dyspepsia (263 men and 103 women, mean age 48.5 years) were assigned to 6 groups, each receiving a different PPI/AC regimen. Group 1 received omeprazole (OPZ) 20 mg, amoxicillin (AMOX) 1500 mg, and clarithromycin (CAM) 400 mg; Group 2 OPZ 40 mg, AMOX 1500 mg, and CAM 400; and Group 3 OPZ 20 mg, AMOX 2000 mg, and CAM 600 mg daily for 14 days. The group treated with lansoprazole (LPZ) 30 mg, AMOX 1500 mg and CAM 400 mg was used for 14 days in Group 1L. OPZ 20 mg, AMOX 750 mg, and CAM 200 mg were given to Group 4 for 28 days and OPZ 20 mg, AMOX 1500 mg, CAM 400 mg was administered to Group 5 for 7 days. Cure of infection was assessed by the ¹³C urea breath test one month after completion of therapy. Results. Cure rates calculated by excluding the patients who showed borderline value of ¹³C urea breath test (Δ¹³C value between 5 and 10‰ in Groups 1, 1L, 2, 3, 4, and 5 were 82.7% (95% CI; 74–90), 88.9% (76–96), 84.9% (72–93), 81.3% (67–91), 84.6% (72–93), and 85.1% (72–94) on an intention-to-treat basis, and 88% (80–94), 95.2% (84–99), 95.6% (85– 99), 90.7% (78–97), 95.7% (85–99) and 88.9% (76–96) on a per-protocol basis, respectively. Adverse effects that affected compliance were observed in 10 of 237 patients on 14-day regiments, one of 47 on a 28-day regimen and one of 46 on a 7-day regimen. Conclusion. Two weeks PPI/AC therapy is highly effective for cure of H. pylori infection in the Japanese population. The low dose one month regimen and the one week OAC regimen were also effective in our patient population.     

Mathematical modeling of multi-drugs therapy: a challenge for determining the optimal combinations of antiviral drugs

In the current era of antiviral drug therapy, combining multiple drugs is a primary approach for improving antiviral effects, reducing the doses of individual drugs, relieving the side effects of strong antiviral drugs, and preventing the emergence of drug-resistant viruses. Although a variety of new drugs have been developed for HIV, HCV and influenza virus, the optimal combinations of multiple drugs are incompletely understood. To optimize the benefits of multi-drugs combinations, we must investigate the interactions between the combined drugs and their target viruses. Mathematical models of viral infection dynamics provide an ideal tool for this purpose. Additionally, whether drug combinations computed by these models are synergistic can be assessed by two prominent drug combination theories, Loewe additivity and Bliss independence. By combining the mathematical modeling of virus dynamics with drug combination theories, we could show the principles by which drug combinations yield a synergistic effect. Here, we describe the theoretical aspects of multi-drugs therapy and discuss their application to antiviral research.