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Helicobacter pylori is among the most common infections worldwide, and it can lead to burdensome sequela for the patient and the healthcare system, without appropriate treatment. Due to constantly fluctuating resistance rates, regimens must be constantly assessed to ensure effectiveness.
- treatment options
- Helicobacter pylori
1. Introduction
The gram-negative, spiral-shaped bacterium Helicobacter pylori is a widespread and prevalent opportunistic pathogen most commonly associated with gastritis, peptic ulcers, and various other gastrointestinal ailments [1]. There is robust evidence that H. pylori is acquired during childhood in most people, and is significantly determined by geography and quality of life [2]. Since the primary means of H. pylori infection are by oral–oral and fecal–oral transmission, risk factors include contaminated food or water supplies, contact with domestic animals, smoking, alcohol consumption, ill contacts, closely packed living situations, poor sanitation, poor hygiene, and most importantly, low socioeconomic status [3].
H. pylori were discovered as spiral bacteria in the stomach of dogs by Giulio Bizzozero in 1892. Since they are Campylobacter-like spiral bacteria, Barry Marshall and Robin Warren dubbed them Campylobacter pyloridis in 1983. Goodwin et al. designated them Helicobacter pylori in 1989 because of their helical form, and prevalence in the pyloric area of the stomach. H. pylori are a 0.5–1 m wide, 2–4 m long, S-shaped, short helical, Gram-negative bacteria that infect more than half of the world’s population [10].
H. pylori are a short helical, S-shaped, Gram-negative bacteria measuring 0.5–1 m in width and 2–4 m in length. They are particularly prevalent in the pyloric area of the stomach, where they cause persistent gastric infection. It is believed that more than half of the world’s population is infected with these bacteria. The specific modes of transmission and infection with H. pylori are yet unknown, but the feces-to-mouth and mouth-to-mouth pathways via water or food consumption are believed to be quite common [10].
2. Etiology, Epidemiology, Pathophysiology
H. pylori can be transmitted by the fecal–oral, gastric–oral, oral–oral, and sexual pathways. Lower socioeconomic status is a significant risk factor for a higher infection prevalence [14]. The prevalence of H. pylori varies across the globe, with a 5% prevalence in children younger than ten years old in the United States. It is more prevalent in the Hispanic and African American populations than the White population [14].
In H. pylori infection, four key factors contribute to the development of clinical illnesses such as gastritis and ulcer. First, the urease activity of H. pylori serves a crucial function in neutralizing the stomach’s acidic environment. Second, the H. pylori bacterium moves toward the host gastric epithelial cells via flagella-mediated motility. The subsequent interaction between bacterial adhesins and host cell receptors results in effective colonization and sustained infection. In addition, H. pylori produce numerous effector proteins/toxins, such as cytotoxin-associated gene A (Cag A) and vacuolating cytotoxin A (VacA), that cause host tissue damage. H. pylori gastritis is characterized by both acute and chronic inflammation due to the stimulation of eosinophils, neutrophils, mast cells, and dendritic cells. Additionally, the gastric epithelial layer secretes chemokines to trigger innate immunity and activates neutrophils, which further damage the host tissue, resulting in the establishment of gastritis and ulcer [14].
3. Antibiotics Overview
3.1. Clarithromycin
Clarithromycin is a broad-spectrum antimicrobial (macrolide class) known for covering atypical organisms. Clarithromycin is one of the five approved macrolides in the United States. It is well-known for its use against H. pylori as it remains a staple therapeutic in the triple therapy regimen. Similarly to others in the macrolide class, clarithromycin is a bacteriostatic antibiotic that reversibly binds the large 50S subunit of bacterial ribosomes at the 23S ribosomal RNA (rRNA) to inhibit protein synthesis [15,16].
Though widely considered the most effective antimicrobial agent for treating and eradicating H. pylori, the use of clarithromycin is not without significant side effects [17,18]. Adverse events associated with using clarithromycin are cited as high as 86%, most of which are gastrointestinal or taste-related [19]. The most common adverse event is taste perversion, reported with a frequency of 58% in a randomized, double-blind trial. Gastrointestinal side effects, including nausea, vomiting, diarrhea, and abdominal discomfort, are also especially common [20]. Such adverse events tend to present more commonly in children [21]. As a known cytochrome P450 (CYP) 3A4 enzyme inhibitor, clarithromycin can influence the pharmacokinetics of other drugs, and consequently induce hepatotoxicity.
3.2. Amoxicillin
Amoxicillin is an oral aminopenicillin within the beta-lactam class of antibiotics. Amoxicillin has garnered favorability because, in addition to gram-positive coverage typical of natural penicillins, it also has utility against gram-negative pathogens, including Haemophilus, Neisseria, Proteus, and E. coli [27]. Furthermore, the use of beta-lactamase inhibitors (e.g., clavulanate) can increase amoxicillin’s effectiveness against resistant gram-negative and methicillin-susceptible Staphylococcus aureus (MSSA) [28,29]. Commonly used to treat infections of the respiratory tract, urinary system, and ear, amoxicillin is also frequently used to treat H. pylori as it is one of the medications in the triple therapy regimen [30,31]. Beta-lactams bind penicillin-binding proteins, inhibiting transpeptidation, and consequently inducing autolytic destruction of the bacterial cell wall [32].
3.3. Bismuth Subsalicylate
Bismuth subsalicylate is an antacid, antidiarrheal, anti-inflammatory, and bactericidal agent which is widely known as the active ingredient in Pepto-Bismol [36,37]. Bismuth subsalicylate is fragmented in the stomach into salicylate and bismuth, which is minimally absorbed to act as a bactericidal agent. In the alimentary canal, bismuth reduces inflammation, minimizes fluid excretion, and prevents bacterial adhesion [37,38,39]. Bismuth subsalicylate is generally well tolerated, although common side effects include diarrhea, nausea, bitter taste, and dark stools [40]. Rarely, patients may present with a blackened tongue, mood changes, or neurotoxicity [41,42]. Contraindications for bismuth subsalicylate use include patients with gastrointestinal ulcers, bleeding problems, black stools before administration, or already consuming medications high in salicylate (such as anticoagulants, methotrexate, etc.)
3.4. Metronidazole
Metronidazole is a narrow-spectrum synthetic antimicrobial of the nitroimidazole class. The reduction of metronidazole, following its entry into the bacterium, is thought to produce an intermediate responsible for cytotoxic and antimicrobial effects [45,46]. Though side effects are uncommon, metronidazole may cause vomiting, nausea, diarrhea, and abdominal pain. Patients taking metronidazole in oral form also complain of a metallic taste. More serious and rarer adverse events include numbness, peripheral neuropathy, and seizures [47]. Significantly, alcohol can interact with metronidazole in a disulfiram-like reaction that typically presents with flushing, cramping, vomiting, tachycardia, and palpitations [48,49].
3.5. Tetracycline/Doxycycline
Since the 1950s, tetracycline is a broad-spectrum bacteriostatic agent that inhibits protein synthesis by binding to the 30S subunit, and effectively limiting hydrogen bond formation between amino acids [51,52]. In addition to its function as an antibacterial agent, tetracycline has antiparasitic activity, inhibiting the growth of Plasmodium falciparum, Giardia lamblia, and Trichomonas vaginalis [53]. Tetracycline has long been reported to interfere with bone mineralization and calcification; consequently, its use is contraindicated in patients under the age of 8 years [53]. Importantly, the risk of maternal hepatotoxicity renders tetracycline a potential teratogen, and its use should be avoided in pregnant and breastfeeding women [54].
3.6. Levofloxacin
Levofloxacin is a broad-spectrum antibiotic of the fluoroquinolone class. Known for its concentration-dependent bactericidal activity, high-dose, short-course levofloxacin has become an attractive therapy that maximizes the chance of regimen course completion, while minimizing the risk for resistance development [57]. Levofloxacin acts on gram-positive and gram-negative bacteria by inhibiting DNA replication, specifically DNA gyrase and topoisomerase, and is accordingly considered a bactericidal [58]. From a safety perspective, it is important to note that levofloxacin and the fluoroquinolone class possess a black box warning label for their association with tendinopathy and tendon rupture, central nervous system effects, and peripheral neuropathy [59]. Mild and common side effects of levofloxacin use include gastrointestinal symptoms, diarrhea, abdominal pain, and central nervous system-related disturbances such as dizziness, headache, and insomnia [60,61]. Other potential complications include psychiatric disturbances, such as agitation, disorientation, suicide ideation, QT prolongation, drug absorption interactions, hyper- and hypoglycemia, and photosensitivity.
4. Acid Suppressants Overview
4.1. Proton Pump Inhibitors (PPIs)
Proton pump inhibitors (PPIs) are a class of medications that effectively reduce gastric acid production by irreversibly inhibiting the luminal H+/K+ ATPase of parietal cells within the stomach [64]. Accordingly, PPIs commonly treat gastroesophageal reflux disease, and peptic ulcer disease. They are also vital in H. pylori eradication as they are commonly included in triple therapy regimens [65,66]. Considering H. pylori’s preference for an acidic environment, raising gastric mucosal pH with PPIs can hinder bacterial growth, and allow gastric ulcer recovery. PPIs are also thought to allow antibiotics to concentrate in the stomach, further strengthening the efficacy of the triple therapy regime [67]. Though typically well-tolerated, PPIs can cause abdominal discomfort, dizziness, and nausea [68,69]. In addition, PPI use is commonly associated with an increased risk of enteric infections [69]. Considering drug metabolism, lower doses are generally recommended for patients with hepatic disease [70].
4.2. Vonoprazan
Vonoprazan belongs to a new class of acid-suppressant medications known as K-competitive acid blockers. K-competitive acid blockers, also called acid pump antagonists, exert their effect by minimizing potassium availability in the lumen, reducing K+/H+ ATPase cotransport, and consequently decreasing gastric acid production [71,72]. Unlike PPIs, vonoprazan binds reversibly, and has a longer half-life [73,74]. Importantly, vonoprazan was FDA-approved in 2022 to be used in triple therapy regimens to treat H. pylori [75,76].
5. First-Line Therapies
5.1. Bismuth Quadruple Therapy
The bismuth quadruple therapy (BQT) is the recommended first-line initial treatment option when areas are exhibiting high levels (>15%) of clarithromycin resistance, and low-level dual clarithromycin and metronidazole resistance (<15%) [78]. It is also the recommended first-line therapy in patients with recent macrolide exposure, or who are allergic to penicillin [5]. The BQT includes bismuth subsalicylate, metronidazole, tetracycline, and a PPI [5]. It consists of 300 to 524 mg of bismuth subsalicylate four times daily, 500 mg of metronidazole 3 to 4 times daily or 250 mg 4 times daily, and 500 mg of tetracycline hydrochloride four times daily with a standard-dose PPI [79].
5.2. Clarithromycin Triple Therapy
Clarithromycin triple therapy consists of a standard dose of PPI, clarithromycin 500 mg, and amoxicillin 1 g, all taken twice a day, or metronidazole 500 mg three times daily [5].
5.3. Concomitant Therapy
The so-called “Concomitant Therapy” consists of a standard dose of PPI, clarithromycin 500 mg, and amoxicillin 1 g with the addition of metronidazole 500 mg or tinidazole 500 mg, all taken twice a day [5]. It should be considered in patients intolerant of bismuth. Concomitant therapy over 14 days yields the highest cure rates [84].
5.4. Sequential Therapy
Clarithromycin-based sequential therapy consists of a standard dose of PPI plus amoxicillin 1 g twice daily for five days [5]. This is followed by a PPI, clarithromycin 500 mg, and either metronidazole or tinidazole at a dose of 500 mg twice daily for an additional five days. While it is comparable to clarithromycin-based triple therapy, its complexity detracts from its viability as a first-line agent. Sequential therapy has been shown to have an eradication rate of 84.3% [5]. It has not been shown to have superior outcomes to either a 14-day clarithromycin-based triple therapy or a 10–14-day bismuth quadruple therapy. Tolerability and compliance are similar to the clarithromycin-based triple therapy [80]. Due to the complexity of sequential therapy, and the lack of evidence of superiority compared to 14-day clarithromycin triple therapy, clarithromycin-containing sequential therapy has not been endorsed by guidelines in North America as a first-line treatment [87].
5.5. Hybrid Therapy
Hybrid therapy is a combined sequential and concomitant therapy. It consists of a standard dose of PPI plus Amoxicillin 1 g taken twice a day for seven days, followed by PPI, Amoxicillin, Clarithromycin 500 mg, and either metronidazole or tinidazole 500 mg taken twice a day for an additional seven days [5]. While there are a lack of data supporting hybrid therapy’s effectiveness in North America, it has been shown to have high cure rates in international studies.
6. Common Substitutions and Cautions
6.1. Penicillin Allergy
Amoxicillin is used in many first-line therapies to treat an H. pylori infection [4]. Several therapies do not contain amoxicillin, such as the bismuth quadruple therapy. The clarithromycin-based triple therapy can also be used if metronidazole is substituted for penicillin.
6.2. Alternatives to Clarithromycin
Clarithromycin-based triple therapy may be a first-line therapy to treat H. pylori with low regional levels of resistance. This therapy is not recommended when clarithromycin resistance rates are >15–20% [89]. Other therapies such as the bismuth quadruple or sequential therapies are suggested [9]. Levofloxacin-based therapies are also used as an alternative to clarithromycin. Levofloxacin has been shown to potentially have an eradication rate of >90%, especially where there is low resistance to levofloxacin [90]. The resistance to quinolones is rising; however, levofloxacin is discouraged as a first-line treatment [86].
6.3. Metronidazole and Alcohol Use
Metronidazole is contraindicated in patients who recently consumed alcohol or products that contain propylene glycol. Patients should avoid consuming alcohol until three days after metronidazole-containing therapy. There have been reports of a disulfiram reaction occurring in patients consuming alcohol while being administered metronidazole. Typically, disulfiram reactions present with flushing, nausea, vomiting, tachycardia, and palpitations [91,92].
6.4. Tetracyclines and Pregnancy
Tetracycline is contraindicated in pregnant women due to a risk of hepatotoxicity in the mother, and permanent discoloration of the teeth in the fetus [93]. There is also a risk of impaired fetal bone growth development [93]. For this reason, bismuth quadruple therapy is not advised in pregnant patients. Other first-line therapies, such as standard triple therapy, are recommended in their place.
6.5. Follow Up Eradication Confirmation
It is recommended that patients receive post-treatment eradication testing at least four weeks after the completion of antibiotic therapy [94]. PPIs should be withheld for at least one to two weeks before testing to avoid false negatives [95].
7. Second-Line Agents for Treatment Failure
7.1. Suggested Approach
With increasing H. pylori strain diversity, many first-line treatments can be ineffective at eradication. Patients require a second-line salvage therapy regimen to be administered when a refractory infection occurs or when there is a persistent positive non-serological test occurring up to four weeks after the first-line treatments are administered. When choosing a second-line therapy, patient allergies, first-line therapies previously used, local geographic resistance rates, and sensitivities should be considered. Due to low global resistance rates to amoxicillin, this antibiotic may be reused in second-line therapy regimens even if it was initially used in first-line treatment. Other previously used regimens should be avoided. Suppose there is a failure of first-line therapy in a penicillin-allergic patient. In that case, it is advised that the patient receives allergy testing to identify if they have a true penicillin allergy [5].
7.2. Bismuth Quadruple Therapy
Bismuth quadruple therapy (BQT), discussed in “initial antibiotic selection,” may be used for 14 days as a second-line regimen in treatment if previously unused as the first-line option [5]. Many alternative forms of bismuth-containing therapies are quadruple therapy variations of levofloxacin- and rifabutin-based triple therapy regimens.
7.3. Levofloxacin-Based Therapy
Levofloxacin-based triple therapy, consisting of levofloxacin, amoxicillin, and a proton pump inhibitor, is typically administered over 10 to 14 days as a second-line regimen. The dosages of each component are administered as follows: 500 mg of levofloxacin daily, 750 mg of amoxicillin three times daily, and a standard dose of a proton pump inhibitor twice daily. Levofloxacin-based therapy regimens are not indicated as second-line treatments in regions of the world with resistance rates greater than 15%, unless the strain has known sensitivity to the drug. This is due to levofloxacin experiencing increasing rates of primary and secondary resistance. Primary resistance rates ranging from 11 to 30% have been documented from data from over 50,000 patients across 45 countries, and those rates rise to 19–30% when considering secondary resistance after unsuccessful H. pylori treatment [97].
Levofloxacin-based quadruple therapies exist in addition to their triple therapy counterparts. Four popular regimens exist that all center around levofloxacin, with three of them containing bismuth as a core component.
LOAD therapy, containing levofloxacin, omeprazole, nitazoxanide, and doxycycline, is a novel treatment regimen for H. pylori eradication. Therapy lasts 7–10 days compared to the traditional 14 days of the standard triple therapy, with dosages consisting of 250 mg of levofloxacin once daily, 40 mg of omeprazole twice daily, 500 mg of nitazoxanide twice daily, and 100 mg of doxycycline once daily.
7.4. High-Dose Dual Therapy
High-dose dual therapy, consisting of a proton pump inhibitor and 750 mg of amoxicillin given four times a day or 1 g three times daily over 14 days, is a superior regimen to standard rescue therapies in H. pylori infections. In one study, infections were eradicated in 95.3% of patients given the high-dose dual therapy regimen [100]. This can be particularly useful in patients with dual clarithromycin and levofloxacin-resistant strains.
7.5. Rifabutin Triple Therapy
Rifabutin triple therapy, a regimen consisting of 750 mg of amoxicillin three times daily, a proton pump inhibitor twice daily, and 300 mg of rifabutin given once daily over 14 days, has been shown to exhibit eradication rates of 83.8% versus 57.7% found in amoxicillin and proton pump inhibitor administered alone [101]. The significant difference in efficacy is most likely attributable to the increased prevalence of amoxicillin resistance in H. pylori strains, similar to the differences in the efficacy of other previously mentioned regimens.
7.6. Clarithromycin-Based therapy
In clarithromycin-based therapy containing a proton pump inhibitor, bismuth, and tetracycline, eradication rates in non-resistant strains of H. pylori have been shown to be greater than 95% successful [102]. Clarithromycin should be considered when macrolide resistance is not a concern, and the local resistance rates are less than 15%. While clarithromycin is still considered for use in rescue therapy following unsuccessful H. pylori eradication, the high prevalence of resistance in H. pylori strains to the antimicrobial often indicates the use of other drug classes in treatment [97].
7.7. Factors Associated with Treatment Failure
While many factors are associated with the failure of H. pylori eradication, the main contributors are patient noncompliance and increased antimicrobial resistance, especially to quinolones and macrolides. This resistance has also been shown to be both primary and secondary in various H. pylori strains throughout different regions of the world [97]. When considering that many antimicrobials function at a higher pH than stomach acid allows, inadequate acid suppression during treatment is also a major source of failure to eradicate infections. This possible point of failure focuses on the cytochrome P450 gene CYP2C19. This gene is responsible for the majority of the metabolism of early-generation proton pump inhibitors. It has been shown to have many polymorphisms affecting an individual’s drug clearance rate. Those with polymorphisms that increase metabolism have been associated with higher rates of eradication failure, despite exposure to susceptible antibiotics [97].
7.8. Probiotics
Probiotics, live microorganisms that can be administered as therapy, may have a future role in eradicating H. pylori by alleviating antibiotics’ side effects. The most commonly used probiotic organisms include Lactobacillus and Bifidobacterium, two Gram (+) organisms. Posed benefits to the host include promoting gut maturation/integrity, pathogen antagonism, and immune system modulation. A primary characteristic of these bacteria is their ability to anaerobically digest saccharides to produce lactic acid, a cellular product that inhibits H. pylori. Their beneficial effects come from nonimmunological mechanisms such as strengthening the mucosal barrier of the GI tract, as well as secretion of antimicrobial substances such as short-chain fatty acids. They also exhibit beneficial effects through immunological mechanisms, such as releasing anti-inflammatory cytokine secretion that reduces inflammation, and gastric acid production [102,103,104]. Several studies show the beneficial effects of probiotics when combating H. pylori. The indications for use are a supplement to first-line therapies that may help alleviate some treatment-related side effects [90].
8. Conclusions
It has been proven that receiving treatment to eradicate H. pylori infections is more beneficial than not, due to the long-term complications associated with non-treatment, such as gastritis, gastric ulcerations, and malignancies. However, choosing the appropriate treatment regimen is immensely dynamic, due to high resistant rates, prescription costs, side effects, and patient non-adherence. Due to high clarithromycin resistance rates, bismuth quadruple therapy can often be the most appropriate initial antibiotic selected for eradication. If resistance is not a local problem, clarithromycin triple therapy is still a viable first-line option due to its inexpensiveness, and well-established effectiveness. Combination capsules circumvent patient adherence concerns but should only be considered contingent upon patient affordability. If side effects create a barrier to adherence, probiotics should be considered as an addition to a regimen to ease the side effect burden. When deciding between other second-line regimens, it is important to make a patient-specific selection based on allergies, effectiveness, affordability, side effects, and ease of administration. As current regimens encounter fluctuations in resistance patterns, repurposed medications such as rifabutin may pose substantial benefits in eradicating infections in treatment-failure patients.
This entry is adapted from the peer-reviewed paper 10.3390/life12122038
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