Research Progress in Detection and Drug Treatment of Helicobacter Pylori

In recent years, the topic of "Helicobacter pylori" has frequently trended on Weibo, and on the last day of February, the question "What are the symptoms after Helicobacter pylori infection?" once again trended on the platform.

Helicobacter pylori (Hp) is a Gram-negative (G-) bacillus that is acid-resistant and can survive in a strongly acidic environment. It is currently the only pathogenic microorganism known to exist on human gastric mucosa. Although most infections caused by Helicobacter pylori are asymptomatic, it is closely related to severe diseases of the upper digestive tract, such as chronic gastritis, peptic ulcer, and gastric cancer, and it is classified as a Group I carcinogen.

Detection Methods for Helicobacter pylori Infection

The detection methods for Helicobacter pylori (Hp) infection include non-invasive tests and invasive tests. Among them, non-invasive tests include the urea breath test, stool antigen test, serological antibody test, and urine Hp antibody test. The urea breath test is a commonly used method for Hp detection, which is convenient, fast, and non-invasive. However, 14C has a slight radiation risk and is not suitable for children and pregnant women. 13C is more expensive than 14C but is non-radioactive, making it suitable for pregnant women and children. Hp-specific antigens in stool samples can be detected through immunochromatography or enzyme immunoassay, which has the advantages of easy sample collection and rapid detection. However, its accuracy is relatively low. After the human body is infected with Hp, a series of inflammatory reactions will occur, leading to immune responses and the production of antibodies. The infection status of Hp can be detected by measuring the serum antibody level. However, this method cannot distinguish between current and past infections, as antibodies can still be detected in the serum after previous infections have been cured. Therefore, it is not suitable for clinical applications. Nonetheless, this method has unique value in epidemiological surveys and is generally used for screening population infections and early gastric cancer. Additionally, a positive IgG antibody for Hp in urine can also indicate Hp infection, and this method is easily accepted due to its convenience and simplicity.

Invasive tests include endoscopy, immunohistochemical staining (IHC), rapid urease test (RUT), bacterial culture, and PCR molecular detection. Endoscopy can not only determine the primary disease but also diagnose the presence of Hp infection, serving as an initial screening method. It allows for timely further examination in suspected cases of Hp infection, providing a clear direction for subsequent tests and treatments. Endoscopy is intuitive and immediate. Immunohistochemical staining (IHC) is mainly used when Hp infection is suspected in mucosal tissue but bacteria are not detected. This method detects the highest number of bacteria, and the bacteria and tissue have a significant color difference, making them easy to observe and positive results easy to detect. Therefore, it has high specificity, sensitivity, and accuracy. However, the reagents are expensive and the staining time is long. The mechanism of the rapid urease test (RUT) is that the urease produced by Hp decomposes the urea in the test reagent, generating NH3 and CO2, which turns phenolphthalein from yellow to red, thus diagnosing whether Hp is positive. The distribution of Hp in the stomach is uneven, and RUT detection is affected by the bacterial load in local tissue. Compared to the urea breath test and histological detection, RUT has the worst diagnostic sensitivity. Bacterial culture refers to the isolation and culture of bacteria in gastric mucosa tissue, which was once the gold standard for diagnosing Hp. However, due to its long duration and high operational requirements, it is not suitable for routine diagnosis. Nevertheless, if the urease test result is negative but Hp infection is still suspected, bacterial culture can be further performed for confirmation. This method is often used for antibiotic sensitivity testing, which is instructive for the treatment of resistant Hp. PCR is an important auxiliary detection method in clinical practice, mainly used for Hp detection and typing. Although its cost is relatively high, it has low requirements for Hp load in biopsy tissue specimens, fast speed, and accurate results. Additionally, PCR can provide information on the presence of relevant Hp virulence factors and information on antimicrobial drug sensitivity and resistance through DNA sequencing.

Treatment Drugs for Helicobacter pylori (Hp)

The treatment protocol for Hp is constantly being improved. Initially, the classical quadruple therapy with bismuth was the first-line treatment for Hp. Later, the standard triple therapy - a combination of proton pump inhibitor (PPI), amoxicillin, and clarithromycin - quickly became the new first-line treatment for Hp due to its high efficacy, fewer medications required, and low incidence of adverse reactions. However, as the resistance rate to clarithromycin continuously increased, the effectiveness of the standard triple therapy in eradicating Hp gradually declined. Although Hp treatment drugs are constantly being updated, the eradication rate of Hp has not significantly improved. In some regions, due to drug resistance, the eradication rate of Hp has significantly decreased, and reports of adverse reactions related to Hp treatment drugs have gradually increased.

1. Acid Suppressants

In the treatment of Hp, the use of acid suppressants is crucial. Currently, the commonly used acid suppressants in clinical practice mainly include H2 receptor antagonists, PPIs (proton pump inhibitors), and new potassium-competitive acid blockers (P-CABs). In an acidic environment, the effectiveness of antibiotics is unstable. PPIs inhibit gastric acid secretion, increasing the pH value within the stomach, enhancing the chemical stability of antibiotics in Hp eradication regimens, and improving their bactericidal effect. The acid suppression mechanism of P-CABs acts on H+, K+-ATP enzymes, which is competitive and reversible. Compared to PPIs, P-CABs have a stronger and more prolonged acid suppression effect, requiring a shorter time to increase the pH value within the stomach. The adverse reactions of acid suppressant treatment mainly include pneumonia, spontaneous peritonitis, intestinal infections, etc. Studies have shown that long-term use of PPIs is prone to infection with Clostridium difficile, as the intestinal flora is affected, leading to a reduction in mucus bacillus and coprococcus.

The first-generation PPIs include omeprazole, lansoprazole, and pantoprazole. These drugs have a slow onset and cannot maintain continuous acid suppression for 24 hours. Omeprazole is a lipid-soluble, weakly alkaline, and highly effective acid suppressant with significant short-term effects. Lansoprazole has strong lipophilicity, which can reduce the activity of parietal cell ATP enzyme in the gastric mucosa, helping to protect the gastric mucosa. It can act on three sites of the proton pump. Compared to omeprazole, lansoprazole has more drug binding sites, higher bioavailability, and better acid suppression effects.

Pantoprazole has the advantages of high selectivity, good efficacy, and **low [insert appropriate adjective here, such as "toxicity" or "side effects"], and under neutral, weakly acidic, or acidic conditions, pantoprazole has higher chemical stability than omeprazole. Pantoprazole has a more specific selective effect on parietal cells than omeprazole and lansoprazole, with high safety. It only binds to two cysteine sequences located on the proton channels of the proton pump, and its bioavailability is up to 7 times higher than omeprazole. Pantoprazole has a weak binding affinity with cytochrome P450 enzymes and undergoes bypass metabolism through phase II metabolism via sulfate conjugation, resulting in higher safety and effectiveness when used in combination with other drugs compared to omeprazole or lansoprazole.

The second-generation PPIs include rabeprazole, esomeprazole, and ilaprazole. Among them, rabeprazole has the strongest effect in eradicating Hp. It is a partially reversible strong inhibitor of H+, K+-ATP enzyme, with four binding targets for H+, K+-ATP enzyme. Its sulfide derivative can inhibit the growth of Hp resistant to clarithromycin. Esomeprazole is currently the PPI drug with the strongest acid suppression effect. Its chemical structure lacks the left-handed optical R-isomer, which increases its blood concentration and bioavailability, and prolongs its drug half-life. As an irreversible PPI, ilaprazole is not affected by CYP2C19 gene polymorphism, showing no significant difference in treatment effect on duodenal ulcer patients with different metabolic types, making its acid suppression effect more stable and reliable.

Vonoprazan is a representative drug of the new potassium-competitive acid blockers. A phase III randomized double-blind controlled study showed that the efficacy of vonoprazan in eradicating Hp was better than that of lansoprazole.

2.Antibiotics

he 5th National Consensus Report on the Management of Helicobacter pylori Infection recommends that the eradication of Hp mainly involves six antibiotics: amoxicillin, clarithromycin, levofloxacin, tetracycline, metronidazole, and furazolidone.

Currently, the resistance to clarithromycin, metronidazole, and levofloxacin is the main reason for the failure of Hp eradication and the decline in Hp eradication rates. Clarithromycin is a 14-membered macrolide antibiotic. Its antibacterial effect is mainly achieved by blocking the connection of the 50S subunit of nuclear protein, leading to the failure of protein synthesis, inhibiting Gram-positive cocci such as Staphylococcus aureus and some Gram-negative bacteria. Metronidazole is an anaerobic antibacterial agent that mainly acts by inhibiting bacterial DNA synthesis, causing bacterial death. Levofloxacin is a broad-spectrum quinolone antibiotic that primarily accelerates bacterial death by inhibiting bacterial DNA gyrase activity.

The resistance rate of Hp to amoxicillin, tetracycline, and furazolidone is relatively low. Amoxicillin is a semi-synthetic penicillin-like β-lactam antibiotic that binds to bacterial transpeptidase to prevent the synthesis of cell walls, resulting in the entry of a large amount of water and ultimately leading to cell expansion and death. Amoxicillin has strong inhibitory and bactericidal effects on both Gram-positive and Gram-negative bacteria, but long-term use can cause neurological damage. Tetracycline is a time-dependent broad-spectrum antibiotic with a half-life of 8 to 10 hours. Its bactericidal effect does not increase with the increase of blood drug concentration, but its antibiotic effect lasts for a long time, inhibiting bacterial growth for a prolonged period. Gastrointestinal reactions are the most common adverse reactions of tetracycline, such as nausea and vomiting. Furazolidone is a nitrofuran antibiotic that acts on bacterial oxidoreductase, inhibiting acetyl-CoA and affecting normal bacterial metabolism, thus exerting an antibacterial effect. Furazolidone has low resistance and **low toxicity at common doses, with few adverse reactions. However, there have also been reports of adverse reactions such as skin rash and jaundice associated with furazolidone.

3.Bismuth Compounds

Bismuth compounds are mucosal protectants that inhibit Hp primarily by inhibiting the production of proteases, urease, and phospholipases produced by Hp. The 5th National Consensus Report on the Management of Helicobacter pylori Infection recommends bismuth potassium citrate and bismuth pectinate. There is no need to consider the issue of drug resistance when using bismuth compounds. They have a high success rate in initial treatment, especially in areas where the eradication rate of Hp is low due to antibiotic resistance. Bismuth compounds are easily accessible, and therefore, the current recommendation in China is to use a quadruple therapy containing bismuth compounds to eradicate Hp. The short-term use of bismuth compounds has obvious effects and is relatively safe, with minor adverse reactions such as dizziness, nausea, and black stool. However, long-term use may affect health, with the potential for acute renal failure, bismuth encephalopathy, and other diseases. Bismuth compounds should not be used by patients with severe renal insufficiency, persistent diarrhea, or lactating women. The daily dose of bismuth compounds should not exceed 600 mg within 24 hours, and continuous oral administration should not exceed 6 weeks. Currently, bismuth compounds are available as over-the-counter drugs, posing potential risks of misuse. It is important to select non-bismuth-containing eradication regimens for patients with contraindications to bismuth compounds, and to closely monitor adverse reactions among patients using bismuth-containing eradication regimens, avoiding overdose and extending the treatment duration.

4.Probiotics

Research has found that microecological agents developed based on the adverse reactions of bismuth compounds can effectively reduce their treatment-related adverse reactions. Probiotics include anaerobic bacteria such as Bifidobacterium, aerobic or facultative anaerobic bacteria such as Enterococcus, and aerobic bacteria such as Bacillus subtilis. Probiotics can reduce the occurrence of adverse reactions by regulating the intestinal flora, form a mechanical barrier to prevent Hp invasion, and produce lactic acid, bacteriocins, and hydrogen peroxide to form a chemical barrier in the intestine, directly inhibiting or killing Hp, and thus improving the eradication rate of Hp.

5.Traditional Chinese Medicine

In addition, research has found that 38 types of traditional Chinese medicines, including Scutellaria baicalensis, Coptis chinensis, Rheum palmatum, and Phellodendron amurense, have varying degrees of antibacterial effects against Hp. Currently, research on the inhibitory effects of traditional Chinese medicine against Hp is still ongoing. Some literature reports have indicated that curcumin, an active ingredient in Curcuma longa, has an inhibitory effect on Hp. Furthermore, research on the eradication of Hp using compound traditional Chinese medicine preparations and Chinese patent medicines is also being conducted.

References

[1] Zhang Junxuan, Fang Chaoran, Shi Xinxin, Tan Haoyu, Hao Xin, Li Jianhui. Research Progress on Therapeutic Drugs for the Eradication of Helicobacter pylori [J]. Medical Recapitulation, 2020, 26(02): 316-321.

[2] Tan Yuwei, Zhu Yanli, Xue Yu, Gao Jiafu. Latest Research Progress on the Treatment of Helicobacter pylori Infection with New Drugs [J]. Guangdong Chemical Industry, 2021, 48(10): 117+94.

[3] Wang Wanwan, Yan Yu. Research Progress on Helicobacter pylori Infection, Testing, and Drug Development [J]. Guangdong Chemical Industry, 2022, 49(04): 102-104.

About the Author:

Xiaomichong, a researcher in pharmaceutical quality, has been dedicated to pharmaceutical quality research and verification of drug analysis methods for a long time. Currently, she works in a large domestic pharmaceutical research and development company, engaged in drug inspection analysis and verification of analytical methods.