Helicobacter pylori Infection

Initial Antimicrobial Therapy

Risk factors for macrolide (clarithromycin) resistance include:

**Prior exposure to macrolide therapy for any reason
**High local clarithromycin resistance rates ≥15 percent or eradication rates with clarithromycin triple therapy ≤85 percent

Bismuth quadruple therapy consists of bismuth subsalicylate, metronidazole, tetracycline, and a PPI given for 14 days. If tetracycline is not available, doxycycline (100 mg twice daily) may be substituted. Metronidazole resistance has a limited impact on eradication success rate in patients treated with bismuth quadruple therapy and can be overcome by increasing the dose, duration, or frequency of therapy.

Based on Malaysia National Antibiotic Guideline (NAG) 2019, triple therapy is recommended as first line, where a PPI can be given with either two of the following antibiotics: amoxicillin / clarithromycin / metronidazole.

Concomitant therapy consists of a clarithromycin, amoxicillin, metronidazole and a PPI administered together. If concomitant therapy is used to treat H. pylori, the regimen should be continued for 10 to 14 days. The efficacy of concomitant therapy was decreased in patients with clarithromycin-resistant H. pylori infection but to a smaller degree as compared with clarithromycin triple therapy (90% vs 78%). In the meta-analysis carried out by Gisbert JP & Calvet X (2012), longer durations of therapy (7 to 10 versus 3 to 5) were associated with a trend toward higher cure rates.

Hybrid therapy consists of amoxicillin and a PPI for seven days followed by amoxicillin, clarithromycin, metronidazole, and a PPI for seven days. Hybrid therapy has been suggested as an alternative to clarithromycin triple therapy. However, the complexity of the treatment regimen has limited its use as a first-line regimen in the treatment of H. pylori. In contrast to patients who received clarithromycin triple therapy, clarithromycin resistance did not significantly impact eradication rates in patients treated with reverse hybrid therapy (96% vs 89%).

The 10-day clarithromycin-containing sequential therapy regimen consists of amoxicillin and a PPI for five days, followed by clarithromycin and nitroimidazole (eg, metronidazole) plus a PPI for five days. Given the complexity of the sequential therapy regimen and the lack of superiority to 14 day clarithromycin triple therapy in North America, clarithromycin-containing sequential therapy has not been uniformly endorsed by guidelines as a first-line therapy.

Regimen	Drug			Frequency	Duration (days)
Triple therapy	PPI (standard* or double dose)			BD	14
	Either two		Clarithromycin (500 mg)	BD
			Amoxicillin (1 g)	BD
			Metronidazole (500 mg)	BD
Bismuth Quadraple	PPI (standard dose*)			BD	10-14 (recom-mend 14)
	Bismuth subcitrate (120-300 mg) OR Bismuth subsalicylate (300mg)			BD
	Doxycyline (100 mg) OR Tetracycline (500 mg)			BD QID
	Metronidazole  (400 mg)			TDS
Concomitant Therapy	PPI (standard* or double dose)			BD	10-14
	Clarithromycin (500 mg)			BD
	Amoxicillin (1 g)			BD
	Metronidazole (400 mg)			BD
Sequential Therapy (Clarithromycin-based)	PPI (standard dose*) plus amoxicillin (1 g) for 5 days followed by:			BD	10 (total)
	PPI, clarithromycin (500 mg) plus metronidazole (400 mg) for an additional 5 days			BD
Hybrid Therapy (Clarithromycin-based)	PPI (standard dose*) plus amoxicillin (1 g) for 7 days followed by:			BD	14 (total)
	PPI, amoxicillin, clarithromycin (500 mg), plus metronidazole (400 mg) for an additional 7 days			BD
Levofloxacin-based Triple Therapy	PPI (standard dose*)			BD	10-14
	Levofloxacin (500 mg)			OD
	Either one	Amoxicillin (1 g)		BD
		Metronidazole (400 mg)		BD
Levofloxacin-based Sequential Therapy	PPI (standard dose*) plus amoxicillin (1 g) for 5-7 days followed by:			BD	10-14 (total)
	PPI BD, levofloxacin (500 mg OD), amoxicillin (1 g BD) plus metronidazole (400 mg BD) for an additional 5-7 days
Ofloxacin-based Therapy (available in Helicobacter Journal, based on a comparative trial – please note that the study used Tab Rabeprazole 20 mg BD)	PPI (standard dose*)			BD	14
	Ofloxacin (400 mg)			BD
	Amoxicillin (1 g)			BD

FDA: United States Food and Drug Administration; PPI: proton pump inhibitor.

* Standard dosing of orally administered proton pump inhibitors include:
## Lansoprazole 30 mg twice daily;
## Omeprazole 20 mg twice daily;
## Pantoprazole 40 mg twice daily;
## Rabeprazole 20 mg twice daily; or;
## Esomeprazole 20 mg twice daily or 40 mg once daily (NAG 2019: 20 mg BD).

• Some North American guidelines do not support the use of sequential therapy.
• Hybrid therapy has not been universally endorsed as an option for first-line therapy.
• In patients with risk factors for macrolide resistance, clarithromycin-based therapy should be avoided.
• Generally UptoDate doses oral metronidazole as 500 mg. This is converted to 400 mg to suit availability in Malaysia, based on adaptation of dosing in Malaysia National Antibiotic Guideline (2019).
• Doses are for adults with normal renal function. Dose adjustment is warranted in patients with renal impairment for certain antibiotics (eg, levofloxacin, rifabutin, clarithromycin if end-stage disease).

Should we test for treatment success after H. pylori eradication therapy?

Whenever H. pylori infection is identified and treated, testing to prove eradication should be performed using a urea breath test, fecal antigen test or biopsy based testing at least 4 weeks after the completion of antibiotic therapy and after PPI therapy has been withheld for 1–2 weeks. (Strong recommendation; Low quality of evidence).

Salvage Therapy

(persistent H. pylori Infection)

• In patients with persistent H. pylori infection, the choice of antibiotic therapy should be guided by the patient’s initial treatment regimen, the use of other antibiotics, and the presence of relevant antibiotic allergies. Antibiotics included in the initial regimen should generally be avoided. However, amoxicillin can be reused as resistance rarely develops.
• American College of Gastroenterology (ACG) 2017: Bismuth quadruple therapy or levofloxacin salvage regimens are the preferred treatment options if a patient received a first-line treatment containing clarithromycin. [Selection of best salvage regimen should be directed by local antimicrobial resistance data and the patient’s previous exposure to antibiotics]
• Bismuth quadruple therapy should be used for 14 days when used as salvage regimen.
•  Levofloxacin-based triple therapy has demonstrated efficacy as a salvage regimen in patients who have failed initial clarithromycin triple therapy and/or bismuth quadruple therapy.
•  High dose dual therapy with amoxicillin and proton pump inhibitor (PPI) for 14 days is a salvage treatment option, particularly in patients in whom dual metronidazole/clarithromycin resistance or levofloxacin resistance is suspected.

• Culture with antibiotic sensitivity testing should be performed to guide antibiotic treatment in patients who have failed two prior treatment regimens.
• Compliance with medications should also be reinforced.
• UptoDate reserve the use of rifabutin-containing regimens for patients with ≥3 previous antibiotic failures (PPI-amoxicillin-rifabutin regime, 10 days duration).

Regimen	Drug		Frequency	Duration (days)
Bismuth Quadraple	PPI (standard dose*)		BD	10-14 (recom-mend 14)
	Bismuth subcitrate (120-300 mg) OR Bismuth subsalicylate (300mg)		BD
	Doxycyline (100 mg) OR Tetracycline (500 mg)		BD QID
	Metronidazole  (400 mg)		TDS-QID
Concomitant Therapy	PPI (standard* or double dose)		BD	10-14
	Clarithromycin (500 mg)		BD
	Amoxicillin (1 g)		BD
	Metronidazole (400 mg)		BD-TDS
Levofloxacin-based Triple Therapy	PPI (standard dose*)		BD	14
	Levofloxacin (500 mg)		OD
	Either one	Amoxicillin (1 g)	BD
		Metronidazole (400 mg)	BD
High-dose dual therapy	PPI (standard* to double dose)		TDS-QID	14
	Amoxicillin (1 g TDS or 750 mg QID)
Rifabutin-based Triple Therapy	PPI (standard dose*)		BD	10
	Rifabutin (300 mg)		OD
	Amoxicillin (1 g)		BD

References:

1. UptoDate [online]: Treatment regimens for Helicobacter pylori.
2. UptoDate algorithm [online]: Initial approach to antibiotic treatment for Helicobacter pylori infection.
3. UptoDate algorithm [online]: Approach to antibiotic treatment in patients with persistent Helicobacter pylori infection.
4. Pharmaceutical Services Dision, Malaysia. National Antibiotic Guideline (2019).
5. Chey WD et al. American College of Gastroenterology (ACG) Clinical Guideline: Treatment of Helicobacter pylori Infection. Am J Gastroenterol 2017; 112:212–238.