Overcoming antibiotic-resistant Helicobacter pylori infection: Current challenges and emerging approaches

Table 1 Summary of antibiotic resistance mechanisms and their global distribution

Resistance pattern	Main resistance mechanisms	Resistance prevalence by region (2013-2023)
		Africa	Americas	Asia	Europe	General
Clarithromycin	Nucleotide substitutions disrupting the antibiotic binding site in the 23S rRNA (A2142G, A2143G, A2142C, A2115G, G2212A, G2141A, A2144T, and T2289C mutations); efflux pump systems (HP0605-HP0607)	24.6% (16.4-33.9)1	16.0% (11.7-20.8)1	28.9% (26.6-31.2)1	21.3% (18.1-24.6)1	26.7% (24.7-28.8)1
Metronidazole	Partial inactivation of reductase enzymes required for metronidazole activity (mutations mainly in rdxA and possibly in frxA gene)	84.2% (78.9-88.9)1	48.1% (43.2-53.1)1	66.1% (62.1-69.9)1	29.9% (24.0-36.1)1	59.6% (55.2-63.9)1
Levofloxacin	Disrupted antibiotic binding site in the DNA gyrase (mainly gyrA but also gyrB gene mutations)	14.3% (0-49.9)1	25.0% (5.2-52.8)1	31.4% (28.3-34.6)1	13.3% (10.4-16.4)1	26.2% (23.5-28.9)1
Amoxicillin	Reduced affinity to PBPs (pbp1A gene mutations); porin protein alterations (hopB and hopC)	70.4% (64.0-76.4)1	4.8% (2.8-7.3)1	2.8% (2.0-3.7)1	0% (0-0.2)1	2.6% (1.8-3.5)1
Tetracycline	Disrupted antibiotic binding site in rRNA (mutations in 16S rRNA-encoding genes); efflux pump tetA[P] (HP1165), and other multidrug efflux systems	1% (0.1-2.5)1	1.1% (0-4.2)1	2.2% (1.3-3.2)1	0% (0-0)1	1.5% (0.9-2.3)1
Rifampicin	Amino acid exchanges disrupting antibiotic binding site in the β subunit of DNA-dependent RNA polymerase (mutations in rpoB gene)	0%3 (Algeria)[234,235]	0%-23.0%3 (Colombia)[236,237], 7.0%-19.0%3 (New York, United States)[238]	14.4%3 (Iran)[239], 5.4%-73.2%3 (China)[240]	11.4%3 (Belgium)[241], 8.3%3 (Bulgaria)[242], 1.2%3 (France)[243], 33.3%3 (Spain)[244]	Unavailable
Multi-drug resistance patterns	Accumulation of single-drug resistance genes; upregulation of multidrug efflux pump systems (hefA, gluP, HP1181 and HP1184); biofilm formation	1.6%3 (Egypt)[245], 15.7%3 (Cameroon)[246]	12.5%3 (Chile)[247]	10.0% (7-14)2 (children in East Asia)[248], 14.7%2 (India)[112], 24.9%3 (China)[249]	1.4%2 (Portugal)[116], 0.8%3 (Austria)[250], 2.4%3 (Spain)[251]	6.0%2 (children)[252]

¹Pooled primary resistance prevalence from 2013-2023 according to a meta-analysis by Yu et al[107].

²Prevalence of multiple antibiotic resistance according to meta-analyses conducted between 2013 and 2023.

³Rates derived from primary studies conducted between 2013 and 2023 (unavailable data from metanalyses). PBPs: Penicillin-binding proteins.

Table 2 Cited clinical studies conducted to analyze the effectiveness of vonoprazan

No. of patients	Group with vonoprazan (days)	Eradication	Control group (days)	Eradication	Identification	Ref.
1046	Vonoprazan 20 mg + amoxicillin 1 g + clarithromycin 500 mg (14 days)	80.8%1	Lansoprazole 30 mg + amoxicillin 1 g + clarithromycin 500 mg (14 days)	68.5%1	NCT04167670	[135]
118	Vonoprazan 20 mg + amoxicillin 1 g + clarithromycin 500 mg (7 days)	96.7%1	Omeprazole 20 mg + amoxicillin 1 g + clarithromycin 500 mg (14 days)	88.5%1	TCTR20210219007	[134]
600	Vonoprazan 20 mg + amoxicillin 1 g (14 days)	92.5%2	Rabeprazole 20 mg + bismuth potassium citrate/tinidazole/clarithromycin, combined packet 4.2 g (14 days)	81.5%2	NCT05469685	[32]
234	Vonoprazan 20 mg + amoxicillin 1 g + furazolidone 100 mg + bismuth 200 mg (10 days)	96.2%1	Esomeprazole 20 mg + amoxicillin 1000 mg + furazolidone 100 mg + bismuth 200 mg (14 days)	93.6%1	NCT04907747	[136]

¹Eradication rate by intention-to-treat.

²Eradication rate per-protocol.

Table 3 Overview of current treatments, potential approaches, and future directions in overcoming antibiotic resistance in Helicobacter pylori

	AST-guided therapy		Empirical therapy						Antibiofilm agents	Probiotics
	By phenotypic determination	By molecular determination	BQT	Non-BQT	CLA-TT	LEV-TT or LEV-QT	AMX-DT	RIF-TT
Advantages	Antimicrobial stewardship; AST can be done for all recommended antibiotics (vs molecular-AST)	Antimicrobial stewardship; reliable to detect CLA resistance; does not require the isolation of viable species; non-inferior efficacy vs BQT; less cost vs non-BQT in some RCTs	Optimal reliability (> 90% cure rate) regardless of resistance profile in Europe and some Latin American countries	Possible option when bismuth is not available	Reduced costs; fewer antibiotics	In second-line therapy, LEV-QT is comparable to BQT in areas with increased trends in resistance	Good reliability in general	Good reliability in general	May improve eradication rates in biofilm-forming multidrug-resistant strains	May improve eradication rates and lower the risk of side effects
Limitations	Highly time-consuming; affected by collection, transport, and techniques; availability	Limited number of antimicrobial agents; limited correlation with MET resistance; availability	Complex dosing in conventional regimens; availability	Not indicated in regions with dual resistance > 15%	Indicated only if CLA resistance < 15% in updated data	High trends in resistance compromise LEV-TT efficacy	High resistance rates in Africa and some areas in Asia	Potential adverse events; costs	Currently, only NAC has been shown effective in clinical trials	Methodological aspects regarding low-quality studies; heterogeneity of strains
Emerging approaches	Vonoprazan-containing AST-guided therapies; non-invasive AST, including CLA resistance in stool samples		Sc-BQT; 10-day BQT (non-inferior efficacy and lower adverse events vs 14-day BQT); vonoprazan-containing BQT and TT; vonoprazan-amoxicillin; BQT with amoxicillin-tetracycline						NAC; rhamnolipids; SUNCs; Pistacia vera L. oleoresin; Casearia sylvestris leaf derivative; ARM1	Lactobacillus reuteri; Saccharomyces spp.
Future steps	Update regional and local resistance surveillance, especially in developing countries; validation of PCR-AST in diverse populations by correlating detected mutations with actual resistance profiles; identification of novel mutations and determinants of resistance through WGS; development and validation of non-invasive molecular-AST		Cost-effectiveness evaluation between empirical and AST-guided therapies in both RCTs and real-world data; evaluation of vonoprazan-containing therapies through multicenter RCTs in different regions and populations; evaluation of the impact of different antimicrobial therapies on the gut microbiota resistome through multicenter RCTs						Further evaluation of potential agents in high-quality clinical trials	Determination of specific strains and formulations through high-quality and multicenter RCTs

AMX: Amoxicillin; ARM1: Armeniaspirol A; AST: Antimicrobial susceptibility testing; BQT: Bismuth-containing quadruple therapy; CLA: Clarithromycin; DT: Dual therapy; LEV: Levofloxacin; MET: Metronidazole; NAC: N-acetylcysteine; Non-BQT: Non-bismuth-containing quadruple therapy; QT: Quadruple therapy; RCT: Randomized controlled trial; RIF: Rifabutin; Sc-BQT: Single-capsule bismuth-containing quadruple therapy; SUNCs: Silver Ultra-NanoClusters; TT: Triple therapy; WGS: Whole-genome sequencing.