Helicobacter pylori Infection Xử trí

Recommended Regimens for Initial Therapy

Triple therapy using a PPI with Clarithromycin and Amoxicillin or Metronidazole is the recommended regimen in areas with low Clarithromycin resistance and in patients without risk factors for macrolide resistance. The recommended duration is 14 days. Many studies have shown that regimens using Ranitidine bismuth citrate (RBC) is as effective as using a PPI; acid suppression with RBC is not as potent as with PPI but it has the advantage of added antimicrobial activity of Bismuth. Quadruple therapy with Bismuth, Metronidazole, Tetracycline and a PPI is an appropriate first-line regimen to consider in patients allergic to penicillin, with prior macrolide exposure or unknown susceptibility profile, or in areas with high Clarithromycin and Metronidazole resistance. The recommended duration is 14 days. Other agents used in combination with PPI and Bismuth include Amoxicillin, Clarithromycin, Levofloxacin, Furazolidone and Doxycycline. Concomitant therapy for 10-14 days with a PPI, Clarithromycin, Amoxicillin and a nitroimidazole (eg Tinidazole, Metronidazole) is also a first-line treatment option. High-dose dual therapy consisting of a PPI and Amoxicillin given for 14 days is an alternative first-line therapy. Sustained high intragastric pH levels increase the sensitivity of H pylori to Amoxicillin.

Sequential therapy, an alternative to Bismuth quadruple therapy, had been shown in multiple randomized trials to be effective for H pylori eradication in treatment-naive patients: PPI and Amoxicillin for 5-7 days followed by a PPI, Clarithromycin and Tinidazole or Metronidazole for another 5-7 days. Fluoroquinolone sequential therapy consisting of PPI and Amoxicillin for 5-7 days followed by fluoroquinolone, PPI and nitroimidazole for 5-7 days may be a treatment option. Hybrid therapy consists of a PPI and Amoxicillin given for 7 days followed by a PPI, Amoxicillin, Clarithromycin and a nitroimidazole for another 7 days. This is an alternative regimen to Clarithromycin-based triple therapy.

Levofloxacin-based therapy may be an option for patients with known susceptibility to Levofloxacin. Levofloxacin-based triple therapy consisting of Levofloxacin, PPI and Amoxicillin for 10-14 days may be an option. The data on Levofloxacin-based quadruple therapy, composed of Levofloxacin, Omeprazole, Nitazoxanide and Doxycycline, are limited. The pooled eradication rate of Levofloxacin-based sequential therapy, which consists of Amoxicillin and a PPI for 5-7 days, followed by Levofloxacin, Amoxicillin, a nitroimidazole and a PPI for 5-7 days, was found to be significantly higher compared to Clarithromycin-based triple or standard sequential therapies combined.

Vonoprazan-based triple therapy is an adjunct to H pylori eradication. A 2-week high-dose dual therapy with Vonoprazan and Amoxicillin is another treatment option that may be used as an alternative empiric therapy for patients without penicillin allergy. Triple therapy with Amoxicillin and Clarithromycin is suggested over PPI and Clarithromycin in patients with unknown susceptibility to Clarithromycin. Quadruple therapy with Vonoprazan, a PPI, Amoxicillin and Clarithromycin is a recommended first-line therapy in Japan. Tegoprazan-based triple therapy may be considered for H pylori eradication in patients with peptic ulcer and/or chronic atrophic gastritis. Clarithromycin resistance reduces the efficacy of triple and sequential therapy, Metronidazole resistance reduces the efficacy of sequential therapy, and dual Clarithromycin and Metronidazole resistance reduces the efficacy of sequential, concomitant and hybrid therapy.

Proton Pump Inhibitors (PPIs)

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Example drugs: Esomeprazole, Lansoprazole, Omeprazole, Pantoprazole, Rabeprazole

PPIs appear to be equally effective when used in the standard dose. Prolonging PPI therapy is recommended in gastric ulcer and complicated duodenal ulcer. PPI-Clarithromycin-based triple therapy should be up to 14 days, unless shorter therapies had been locally effective. It is postulated that the potent acid suppression with PPIs stimulates Helicobacter pylori, a neutralophile, to replicate making it susceptible to antibiotics that are bactericidal to actively dividing bacteria.

Clarithromycin

Clarithromycin binds to ribosomes, resulting in protein synthesis inhibition. Clarithromycin with Amoxicillin is considered the antibiotic combination of choice for initial therapy.

Amoxicillin

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Amoxicillin is a standard antibiotic agent used in a triple therapy regimen with PPI. This inhibits bacterial cell wall synthesis.

Metronidazole

Metronidazole causes cell death by inducing breakage of DNA double strands. It is thought that avoiding Metronidazole in initial therapy will give better results with the drug when it is used in quadruple therapy after initial treatment failure. Metronidazole may be substituted for Amoxicillin in penicillin-allergic patients. If resistance to Metronidazole is a problem (which it may be in developing countries), Furazolidone can be used as an alternative.

Bismuth

Bismuth has a cytoprotective effect on GI mucosa. There is stimulation of prostaglandin production and modulation of immune response. Bismuth salt deposits adhere to the H pylori cell wall, inducing vacuolization and distortion of bacterial cell and loss of adherence from gastric epithelium. If Bismuth is unavailable, consider Levofloxacin, Rifabutin and high-dose dual (PPI with Amoxicillin) therapies.

Tetracycline

Tetracycline prevents protein synthesis. Doxycycline or Bismuth-containing quadruple therapy combining Amoxicillin-Metronidazole or Furazolidone- Metronidazole may be used if Tetracycline is not available.

Potassium-Competitive Acid Blockers (PCABs)

Example drugs: Tegoprazan, Vonoprazan

Potassium-competitive acid blockers reversibly block gastric acid secretion by competitively binding with potassium to the proton pumps (H+/K+-ATPase) present in gastric wall cells; do not require activation by acid. This may be given combined with antibacterials in triple therapy to increase H pylori eradication rates.

Treatment Options for Patients with Penicillin Allergy and/or Previous Macrolide Exposure 

• With penicillin allergy and macrolide exposure: Bismuth quadruple therapy
• With penicillin allergy but without macrolide exposure: Clarithromycin triple therapy with Metronidazole; Bismuth quadruple therapy
• Without penicillin allergy but with macrolide exposure: Bismuth quadruple therapy; Levofloxacin triple or sequential therapy
• Without penicillin allergy or macrolide exposure: Bismuth quadruple therapy; concomitant therapy; Clarithromycin triple therapy with Amoxicillin

Adjuvant Therapy

Probiotics

Probiotics are live bacteria that help restore microbial balance in the intestine. Studies showed that Bifidobacterium and Lactobacillus sp may have inhibitory properties against Helicobacter pylori infection. This reduces the risk of adverse effects from H pylori eradication treatment, though additional studies still need to be done.

Statins 

Studies showed that statins used as an adjuvant to triple therapy may help reduce the inflammation caused by Helicobacter pylori infection and may increase H pylori eradication rates. Further trials are needed to confirm the inhibitory effect of statins to Helicobacter pylori infection.

ALTERNATIVE REGIMENS FOR INITIAL TREATMENT FAILURE

Treatment failure occurs when symptoms persist or recur within 14 days after completion of therapy. This may be due to non-compliance, intake of NSAIDs, antimicrobial resistance, low intragastric pH, high bacterial load, penicillin allergy, or cigarette smoking. Selection of treatment options should be guided by local antimicrobial resistance data and the patient’s prior antibiotic exposure. When first-line therapy is unsuccessful, second-line therapy should avoid antibiotics that had been previously used.

Quadruple therapy with PPI, Bismuth, Metronidazole and Tetracycline taken for 7-14 days is typically the preferred regimen after initial treatment failure and for high Clarithromycin resistance. If Bismuth is not available, concomitant therapy with PPI, Clarithromycin, Amoxicillin, and a nitroimidazole for 14 days may be used.

Triple therapy with Levofloxacin for 14 days may also be given after initial treatment failure and for high Clarithromycin resistance. Levofloxacin-containing or Clarithromycin-containing salvage regimens are preferred treatment options after initial quadruple therapy with Bismuth. Triple therapy with a PPI, Amoxicillin and Metronidazole is the recommended second-line regimen in Japan. Triple therapy with a PPI, Amoxicillin or Metronidazole, and Sitafloxacin is recommended as third-line therapy in Japan.

High-dose dual therapy with Amoxicillin and a PPI for 14 days may be considered in patients without penicillin allergy who had previously received either a Clarithromycin-based triple therapy or a Bismuth quadruple therapy, or in whom dual Clarithromycin and Metronidazole resistance or Levofloxacin resistance is suspected. Triple therapy with Vonoprazan, Amoxicillin and Metronidazole for 7 days may be considered as an alternative regimen after initial treatment failure. If the alternative regimens fail, the patient should be referred to an expert and antibiotic susceptibility testing should be considered to guide retreatment. If testing is not available, patient may be given Rifabutin triple therapy (Rifabutin, Amoxicillin and a PPI) for 12 days. Regimens containing Rifabutin should be given to patients with ≥3 eradication treatment failures.