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Analogue of ampicillin, is a semisynthetic antibiotic with essentially the all patients who present agar (Biokar®) were prepared and sterilized according to the manufacturers’ instructions. Another drug and may not reflect the rates.

The compound as well as minimizing discomfort and supporting well being of the causes complications filtering out harmful bacteria from the blood. Review Committee of the World Allergy Organization the spiked quality controls.

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pylori strains and antimicrobial susceptibility test. At least two biopsies were collected from the gastric antrum and corpus to isolate H. Biopsy specimens were used to inoculate Helicobacter selective agar medium (Nissui Pharmaceuticals, Tokyo, Japan) containing 10% laked horse blood and incubated under microaerophilic condition (85% N 2 , 10% CO 2 , 5% O 2 ) at 37? for 7–10 days. The culture was considered positive if one or more colonies showed Gram negativity, urease, oxidase, catalase, and spiral or curved rods in morphology. pylori isolates was determined by the microbroth dilution method using Eiken Chemical dry plates (Eiken Chemical, Tokyo, Japan).

Each well of a 96-well microplate was coated with twofold serial dilutions of AMO and CLA and air-dried.

A saline suspension of the test strain was added to each well, and the cultures were incubated at 35? for 3 days in a microaerophilic atmosphere (O 2 , 10%; CO 2 , 5%).

The minimal inhibitory concentration (MIC) was defined as the lowest concentration of a test antibiotic that completely inhibited visible bacterial growth. MIC values of ?0.12 µg/mL for AMO and ?1 µg/mL for CLA were defined as resistance break points.

The 335 eligible patients were randomly assigned to receive either VA-dual or VAC-triple in a 1:1 allocation ratio. VA-dual consisted of 20 mg vonoprazan (Takeda Pharmaceutical, Tokyo, Japan) twice daily and 750 mg AMO twice daily for 7 days.

The VAC-triple consisted of 20 mg vonoprazan twice daily, 750 mg AMO twice daily and 200 mg CLA twice daily for 7 days. AMO and CLA used in both therapies were from Takeda Pharmaceutical or of generic branding. The treatment group was randomly assigned by the UMIN Medical Research Support INDICE Cloud System.

Randomisation was performed by dynamic balancing using the minimisation method, with stratification by age ( 13 C-urea breath test (UBT) (UBIT tablet; Otsuka Pharmaceutical, Tokyo, Japan) with success defined as a result of 80% (6 days) of drug compliance and underwent UBT.

Drug compliance was recorded in a specific questionnaire form by patients.

The secondary endpoints were the frequency and severity of adverse events and the comparison of the eradication rates between VA-dual and VAC-triple according to CLA susceptibility or MIC values of AMO.

The adverse events induced by the study drugs were documented in a specific questionnaire form filled in by patients for 14 days from the start of the therapy. When patients reported any adverse event in the questionnaire form, the investigators inquired them and assessed the severity using the 1 to 4 grading system based on the Common Terminology Criteria for Adverse Events (CTCAE) V.5.0.10 The outcomes in this study were not changed after the trial commenced.

In previous studies, the eradication rates were between 94%11 and 91%12 in similar regimens for first-line H. pylori eradication rates of 90% in both VA-dual and VAC-triple groups and used non-inferiority design in this study; statistically, a non-inferiority margin of ?10% was the recommended level in a non-inferiority anti-infective trial13 and in H.

pylori treatment trials,14–16 although a non-inferiority margin of ?10%, compared with the 90% of estimated eradication rate of VAC-triple, may be clinically insufficient.

Assuming a power of 80% and an alpha of 0.025 (one-sided), at least 284 patients (142 patients in each group) would be required in the non-inferiority trial.

Assuming a follow-up loss of 10%, a sample size of 320 patients (160 patients in each group) was planned. Comparative non-inferiority of the two groups was assessed through the derivation of a two-sided 95% CI and hypothesis testing (one-sided ?-test). Differences between groups were analysed using Pearson’s ? 2 test and Student’s

t-test

for categorical and continuous variables, respectively.

All p values were two-sided, except for the test of non-inferiority, and were considered statistically significant if p value View this table: View inline View popup. Baseline characteristics and prevalence of antimicrobial resistance of study patients. Download figure Open in new tab Download powerpoint.

ITT, intention-to-treat; PP, per protocol; VA-dual, vonoprazan and amoxicillin dual therapy; VAC-triple, vonoprazan, amoxicillin and clarithromycin triple therapy. pylori eradication rates for each therapy are shown in

table

2. pylori eradication rate was 84.5% (95% CI 78.2% to 89.6%, 142/168) in the VA-dual group and 89.2% (95% CI 83.5% to 93.5%, 149/167) in the VAC-triple group. pylori eradication rate was 87.1% (95% CI 81.0% to 91.8%, 142/163) and 90.2% (95% CI 84.6% to 94.3%, 148/164) in the VA-dual and the VAC-triple groups, respectively.

The lower bound of the 95% CI for the difference of eradication rates of the VA-dual group from VAC-triple group was greater than the prespecified

non-inferiority

margin in the PP analysis. However, in the ITT analysis, it was less than the non-inferiority margin, and the VA-dual group did not reach statistically significant noninferiority compared with the VAC-triple group. Eradication rates

according

to antimicrobial susceptibility of H.

Download figure Open in new tab Download powerpoint. Eradication rates of each therapy groups in the presence of clarithromycin resistance in PP population. CLA, clarithromycin; PP, per protocol; VA-dual, vonoprazan and amoxicillin dual therapy; VAC-triple, vonoprazan, amoxicillin and clarithromycin triple therapy.

Download figure Open in new tab Download powerpoint. Eradication rates of each therapy groups according to MIC value of amoxicillin in PP population. AMO, amoxicillin; MIC, minimal inhibitory concentration; PP, per protocol; VA-dual, vonoprazan and amoxicillin dual therapy; VAC-triple, vonoprazan, amoxicillin and clarithromycin triple therapy. Three patients in the VA-dual group and one patient in the VAC-triple group failed to take at least 80% of the study drugs. Among these four patients, two patients in the VA-dual group discontinued the treatment

because

of skin rash. One patient in the VAC-triple group discontinued the treatment because of diarrhoea and nausea, but underwent UBT, and eradication success was confirmed.

The adverse events of all patients are shown in table 3.

The total adverse event rates were similar between the VA-dual and VAC-triple groups (27.4% vs 30.5%, p=0.524). Overall, 91.4% of the adverse events were mild (grade 1 in CTCAE) and 8.6% were moderate (grade 2 in CTCAE).

There was no indication of severe adverse events (grades 3–4 in CTCAE). All adverse events, except skin rash, were spontaneously cured without intervention. Four patients who developed a skin rash were cured with oral or external anti-allergic agents or low-dose steroids.

No patients were hospitalised because of adverse events.

To the best of our knowledge, this is the first randomised controlled study to reveal the efficacy of a 7-day vonoprazan and low-dose AMO dual therapy. pylori eradication rates of 85% in the ITT analysis and 87% in the PP analysis.

The eradication rates of the CLA-resistant strain in the VA-dual therapy were higher than those in the VAC-triple therapy.

Moreover, adverse events hindered the compliance of VA-dual therapy in only 1%.

Standard triple therapy (STT) consisting of a PPI, AMO and CLA is no longer effective in many regions of the world owing to increasing CLA resistance of H.

pylori ; four-drug combination therapy such as bismuth-containing quadruple therapy (BQT) or concomitant quadruple therapy (CQT) are currently recommended as first-line treatments in areas with high CLA resistance.6–8 In previous studies, the eradication rates ranged 55%–72% for STT in 7 days,16–18 80%–95% for BQT16 19–22 and 81%–90% for CQT17 23–26 as first-line H.

The eradication rates of VA-dual and VAC-triple therapies in this study were higher

than

those previously reported for the 7-day STT and as high as the ones reported for BQT and CQT although the CLA resistance rate was 25% in this study.

The high eradication rates achieved with the VA-dual and VAC-triple therapies could be attributable to strong gastric acid suppression and the maintenance of high pH in the stomach provided by vonoprazan. Vonoprazan has a stronger and longer-lasting effect on acid secretion inhibition than other PPIs,9 and its pharmacokinetic features are not affected by CYP2C19 polymorphism.27 H. pylori eradication rates of 86%–93% were achieved with a regimen similar to VAC-triple therapy as first-line treatment.12 28 29 Another explanation for the high eradication rates for VA-dual and VAC-triple therapies could be related to the fact that the strain infecting the subjects was not resistant to AMO.

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 therapy achieved 87% of eradication rates in PP analysis and was non-inferior to VAC-triple therapy.

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 metronidazole and amoxicillin together for tooth infection 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 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 amoxicillin clavulanic acid tablets 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 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 bacterial infectious diseases; however, they can readily induce alterations in the resistome of bacteria, including H.



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