Natural amoxicillin

pylori resistance rate to AMO is still lower than that to other antibiotics and is usually overlooked when determining the H.

However, resistance to AMO substantially differs among world regions (38% in Africa region, 14% in Eastern Mediterranean region, 12% in Southeast Asia region, 8% in Americas region, and 0%–1% in European and Western Pacific regions).30 The resistance breakpoint was set to MIC ?0.12 µg/mL, which is a stricter cut-off value than the commonly used MIC breakpoint of 0.5 ?g/mL31; because there was no AMO resistance in this study, VA-dual and VAC-triple therapies could achieve high eradication rates of H.

Thus, both VA-dual and VAC-triple therapies could be alternative regimens as first-line H.

pylori treatment in the regions with no AMO resistance. pylori eradication rate and AMO MIC values was revealed in this study, the efficacy of both VA-dual and VAC-triple therapies might be limited to the regions with moderate to high AMO resistance. A dual therapy consisting of PPI and AMO was first reported in the 1990s as a first-line treatment against H.

The efficacy of a low-dose and/or less frequent dual therapy consisting of AMO (2.0 g/day or less) and PPI (twice/day or less) resulted in unacceptable eradication rates.32–34 Recently, high-dose and high-frequency dual therapy, defined as the administration of both AMO (?2.0 g/day) and PPI (at least twice daily) for 14 days, has been reported to have greater H.

pylori eradication efficacy as first-line therapy.35–38 However, side effects and poor patient compliance due to high dose, high administration frequency and long duration of treatment are the most common setbacks. Thus, the high-dose and high-frequency AMO–PPI dual therapy has been subsequently used as a rescue/salvage treatment. As the important factor to a successful dual therapy regimen is to maintain a near-neutral pH in the stomach to make H.

pylori sensitive to AMO and vonoprazan has a stronger effect on acid secretion inhibition than other PPIs, it is expected to be more effective when used in combination with AMO for eradication of H.

We demonstrated that

VA-dual

However, the eradication effect of VA-dual did not achieve the clinically sufficient eradication rate of 90%.

Further, the 10% non-inferiority margin, compared with 90% of eradication rate for VAC-triple therapy, may be clinically inappropriate because this setting means that the lower bound of the 95% CI of the VA-dual eradication rates could be 80%, which is also insufficient for H.

Another key parameter to the success of a dual therapy regimen is to maintain steady AMO plasma concentrations above the MIC level for its bactericidal effect against H.

The results of a retrospective study in which dual therapy (vonoprazan 20 mg twice daily and AMO 500 mg three times daily for 7 days) provided an eradication rate of 93% as first-line treatment39 suggested that high administration frequency of AMO could improve the eradication rate in vonoprazan-based dual therapy to values similar to those of high-dose and high-frequency AMO–PPI dual therapy. Thus, further adjustments in the administration frequency and dose of AMO are necessary to improve the eradication effect of the VA-dual therapy.

Studies of PPI and amoxicillin dual therapies as first-line Helicobacter pylori treatment.

The results of the subgroup analysis by CLA susceptibility in this study were unexpected. The eradication rate of the CLA-resistant strain achieved with VA-dual therapy was significantly higher than that achieved with VAC-triple therapy.

As the VA-dual therapy consists of fewer antibiotic agents than the VAC-triple therapy, it is unlikely that the eradication rate of VA-dual therapy is higher than that of VAC-triple therapy, regardless of the antimicrobial resistance of H. This difference in eradication of the CLA-resistant strain between the two treatment groups can be attributed to chance as the p value was borderline and the sample size was small.

The AMO MIC cut-off amoxicillin for pimples value may also account for this difference.

Although none of the patients was infected with an AMO-resistant strain, seven patients receiving VAC-triple therapy and two patients receiving VA -dual therapy had MIC of ?0.03 µg/mL in group with patients with CLA-resistant strains.

The subgroup analysis of eradication rates according to the MIC of AMO showed that the eradication rate for the VAC-triple therapy in the 0.06 of MIC group was lower than that in the ?0.015 and 0.03 of MIC group.

This disparity in the proportion of AMO MIC between the groups potentially affected the eradication rates and resulted in a lower eradication rate in the VAC-triple group.

Another possible explanation for the CLA-resistant eradication difference observed between the VA-dual and VAC-triple therapies regards the pharmacokinetic interaction of vonoprazan and CLA. Because both vonoprazan and CLA are metabolised by the same hepatic enzyme (cytochrome P450 3A4), administering both drugs together increases the maximum plasma concentration and the area under the plasma concentration–time curve of vonoprazan by 1.5-fold to 1.9-fold in comparison with the administration of vonoprazan alone.40 Vonoprazan has a strong gastric acid inhibitory effect and the gastric pH level often exceeds 7 even when administered alone.9 27 Thus, when vonoprazan is administered with CLA, the maximum pH level may increase or the duration of this effect may be extended.

pylori grows at a narrow external pH range between 6 and 7 and is sensitive to growth-dependent antibiotics including AMO.

pylori growth was studied in vitro and it was reported that the growth of this bacterium was poorer at pH 7.9 than at pH 7.2.41 Thus, the vonoprazan–CLA interaction might cause suboptimal gastric acid pH levels (ie, >7), resulting in a decrease in the H. pylori sensitivity amoxicillin capsule 500 to AMO in the VAC-triple therapy. Another benefit of VA-dual therapy is related to the optimal the use of antibiotic agents, which, in the long term, will have minimal impact on the antimicrobial resistance scenario. pylori antimicrobial resistance is a global priority.

WHO published its first-ever list of antimicrobial resistant ‘priority pathogens’ in 2017, and CLA-resistant H. pylori was categorised as a high-priority bacterium in the same tier as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium .42 Macrolides, including CLA, are commonly used to

treat

The use of long-acting macrolides is significantly associated with the resistance of H. pylori to CLA43 and previous exposure of CLA has a negative impact on the success of some H. pylori treatments.44 45 The international guidelines recommend that clarithromycin be no longer used in empirical treatment for H. The resistance rates to metronidazole and levofloxacin have increased >15% in many regions of the world in recent years adding to the observed increase in CLA resistance.30 Thus, given the alarming increase of the rates of resistance to CLA and to various families of antibiotics, treatment strategies have to be re-evaluated and the best approach relies on the appropriate use of antibiotics for the treatment of H.

Therefore, antimicrobial susceptibility testing is the best way to optimise and reduce antibiotics for H. pylori eradication treatment as well as the treatment of other common infections.

However, antimicrobial susceptibility testing is not performed routinely in the clinical practice because of the invasiveness of the endoscopy procedure, the limited availability of laboratory culture facilities and cost concerns.

The VA-dual therapy offers an alternative regimen for H.

pylori eradication treatment in the era of increasing antimicrobial resistance.

We demonstrated that the VA-dual therapy provides acceptable H.

As it is a single antibiotic therapy and antibiotic consumption is low, with no use of CLA, and H. pylori is hardly resistant to AMO, we expect that VA-dual therapy will not contribute to the increase in antimicrobial resistance rates. The results of this study suggest that VA-dual therapy can amoxicillin and doxycycline together for pneumonia be used as first-line H. pylori empirical treatment, and that susceptibility-based therapies using multiple antibiotic agents should be used as rescue therapy only in cases where the VA-dual therapy fails.

This treatment strategy should limit unnecessary antibiotic usage, prevent widespread resistance development of other organisms and reduce the costs of H.

This study design has several advantages: first, the study was a randomised controlled trial corrected from multiple centres; and second, the antibacterial susceptibility of H. pylori was confirmed in all enrolled patients and was used as stratification factor in randomisation.

However, owing to the open-label nature of the study design, the lack of blinding may have influenced the reporting of side effects.

In addition, only Japanese patients enrolled in this study; as vonoprazan has been introduced recently outside of Japan, studies with a double-blind design should also be performed in other countries.

In conclusion, the 7-day vonoprazan and low-dose AMO dual therapy provided acceptable H.

pylori eradication rates and was similar to the effect of vonoprazan-based triple therapy as a first-line H. pylori eradication therapy in a country with high resistance to CLA.

The VA-dual therapy has advantages, including single antibiotic and low antibiotic consumption; however, there is also the potential to improve its eradication effect through adjustments in the administration of AMO. Thus, further studies should be demanded to develop VA-dual therapy with proper adjustments and to establish new first-line H. pylori eradication treatments in the era of growing antimicrobial resistance. We sincerely thank Mitsuru Esaki, Hitoshi Shibuya and Toshiki Horii from Nihon University School of Medicine, Toyotaka Kasai and Hiroyuki Eto from Fukaya Red Cross Hospital, and Yoshioki Yoda from Yamanashi Koseiren Health Care Center for collecting data and valuable assistance in conducting this study, and Mikitaka Iguchi from Wakayama Medical University for conducting Data and Safety Monitoring Board.