**7. Salvage therapy**

In case of first-line treatment failure or persistent symptoms, salvage therapy should be based on knowledge of previous antibiotics used and local resistance data [6]. Patients who experience treatment failure are either treated with second-line agents, prolonged treatment, or the addition of bismuth salts [6]. The most commonly used second-line regimen consists of a combination of tetracycline, amoxicillin/metronidazole, a PPI, and bismuth given daily for 10 days [6].

BQT or levofloxacin triple therapy is the preferred treatment option if the patient was previously treated with clarithromycin-containing first-line therapy. Clarithromycin or levofloxacin-containing treatment is considered if the patient received first-line BQT [15]. Clarithromycin triple therapy should not be considered in second-line treatment [14]. Combinations that can be considered for salvage treatment are BQT, levofloxacin triple therapy, concomitant therapy, rifabutin triple therapy, and high-dose dual therapy [14].

Due to the limited number of antibiotics that are effective against *H. pylori* and the interpatient and local differences in primary and secondary antibiotic resistance, there is no standard third-line regimen, and treatment should be based on endoscopy with bacterial culture and susceptibility testing [6].

## **8. Prevalence and clinical consequences of antibiotic resistance**

One of the biggest challenges in *H. pylori* treatment is the growing antibiotic resistance against agents used in first-line treatment. Therefore, it is crucial to monitor the prevalence of resistance in local settings [6]. Numerous studies have shown that antibiotic resistance reduces the success rate of different anti-*H. pylori* therapies. However, the extent to which it clinically affects the outcomes depends on the different components used, the dose of each antibiotic, and the level of resistance present in *H. pylori* strains [8]. For example, studies have shown that success rates of nitroimidazole-containing PPI-based triple therapy drop from 90% in susceptible strains to 73% in resistant strains. The addition of bismuth salt to nitroimidazole-containing triple therapy increases the success rate to 92% in nitroimidazole-susceptible strains compared to 83% in resistant strains [8].

Limited studies have shown that macrolide resistance substantially reduces the efficacy of macrolide-containing *H. pylori* therapy [8]. The efficacy/success rate of adding macrolide to triple therapy may decrease from 86% in susceptible strains to 25% in resistant strains [8].

Antibiotic resistance is a growing problem worldwide, and its prevalence varies in different countries within the Asia Pacific region [15]. Data from the first-ever comprehensive systematic review and meta-analysis of primary antibiotic resistance against *H. pylori* in the past 25 years showed that the mean overall prevalence of resistance to clarithromycin was 17%, ranging from 0% in Bhutan and Myanmar to 37% in Bangladesh [15]. Clarithromycin resistance increased from 7% before 2000 to 21% in 2011–2015, according to sub-analysis of the data [15]. In the Asia Pacific region, clarithromycin resistance was higher than 15% in countries such as Bangladesh, China, India, Iran, Japan, Nepal, New Zealand, Pakistan, Saudi Arabia, Singapore, South Korea, Turkey, and Vietnam. Clarithromycin resistance was less than 15% in countries such as Bhutan, Indonesia, Laos, Malaysia, Myanmar, Russia, Taiwan, and Thailand [15]. The southeastern Asia region has the lowest risk of clarithromycin resistance [15]. Due to the growing resistance over time in the Asia Pacific region, the efficacy of clarithromycin-based triple therapy, sequential/concomitant therapy, was lower than 80% in countries with clarithromycin resistance over 20% [15].

Metronidazole resistance is common throughout the world, reflecting the frequent use of this antibiotic in medical settings [15]. The mean overall prevalence of resistance to metronidazole was 44%, ranging from 10% in Japan to 84% in Bangladesh and 88%

in Nepal [15]. Data from 2006 to 2015 showed that metronidazole resistance was higher than 40% in most countries except Japan, Myanmar, South Korea, Taiwan, and Thailand [14]. Metronidazole resistance in the Asia Pacific region was 47%, which falls between the reported rates from Europe (35%) and Latin America (50%) [15].

The mean overall prevalence of resistance to levofloxacin was 18%, ranging from 2% in Bhutan to 66% in Bangladesh [15]. Levofloxacin resistance increased from 2% before 2000 to 27% in 2011–2015, according to sub-analysis of the data [15]. Levofloxacin resistance in the Asia Pacific region was higher (21%) compared to Europe (13%) and Latin America (19%) [15].

The mean overall prevalence of resistance to amoxicillin and tetracycline was 3% and 4%, respectively, reflecting lower use of these antibiotics in medical settings [15].

These findings collectively suggest that clarithromycin-based triple therapy can be used as first-line treatment in countries where resistance is below 15% and bismuthbased quadruple therapy and non-bismuth-based quadruple therapy should be considered where clarithromycin resistance is over 15% [15].

Due to the unavailability of molecular testing or culture and susceptibility testing in most parts of the world, empiric therapy is recommended [2]. However, empiric therapy should be based on knowledge of the patient's previous antibiotic exposure, penicillin allergy, and local resistance rates. According to the ACG guideline, BQT, concomitant/non-bismuth quadruple therapy, and clarithromycin-based triple therapy are considered first-line therapy for *H. pylori* eradication [2]. Macrolidebased triple therapy is to be used when there is no previous exposure to it and in regions where local resistance is less than 15% [2].

In summary, eradication is recommended in all patients with PUD and gastric cancer. First-line therapy should have an eradication rate of more than 80%. Since pretreatment susceptibility is rarely done in primary care settings, therapy is chosen empirically based on regional bacterial resistance patterns, local recommendations, knowledge of previous antibiotic use, drug allergy, and drug availability.

## **9. Recent developments in** *H. pylori* **treatment**

Due to the lack of culture and sensitivity testing and growing resistance against clarithromycin and metronidazole, bismuth quadruple therapy is considered a reliable empiric choice of treatment. A recent systematic review and meta-analysis showed that both BQT and high-dose dual therapy achieve similar eradication rates, with high-dose dual therapy having better adherence and fewer side effects. High-dose dual therapy involves using a high dose of a proton pump inhibitor (PPI) with 3 g of amoxicillin given daily for 14 days. This regimen achieves eradication rates of around 70–89% in patients with one or more prior treatment failures, and all major guidelines have recommended high-dose dual therapy [2].

Another development in *H. pylori* treatment is the approval of a new combination product containing omeprazole, rifabutin, and amoxicillin. In the ERADICATE Hp2 trial, this regimen successfully eradicated *H. pylori* in 84% of patients. The recommended treatment dose consists of 4 capsules to be taken 3 times daily. The daily dose of omeprazole is 120 mg, rifabutin is 150 mg, and amoxicillin is 3 g, which are given in equally divided capsules. The pack contains 12 identical capsules of the single combination product. In future research, the focus will be on developing narrowspectrum agents that have specific targets, as numerous genomes of *H. pylori* have been sequenced and various newer drug therapies are under development [2].
