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.

Macrolides and Moxifloxacin for Prevention of Exacerbations of Chronic Obstructive Pulmonary Disease (COPD)

Macrolides

In older studies, prophylactic, continuous use of antibiotics had no effect on the frequency of exacerbations in COPD (Francis et al 1960 & Francis et al. 1961). A study that examined the efficacy of chemoprophylaxis undertaken in winter months over a 5-year-period concluded that there was no benefit (Johnston et al. 1969).

However, more recent studies have shown that regular use of some antibiotics may reduce exacerbation rate. Therefore, there has been renewed interest in prophylactic antibiotics for patients with recurrent exacerbations (two or more per year), resulting in several placebo-controlled trials, with a macrolide being the most commonly prescribed agent. However, the benefits of antibiotic prophylaxis must be weighed against concerns about promoting antibiotic resistance and possible adverse effects. For most patients with COPD, we suggest not administering antibiotic prophylaxis.

Only carefully selected patients, such as those who continue to have frequent exacerbations in spite of optimal therapy for their COPD with bronchodilators and anti-inflammatory agents, should be considered for antibiotic prophylaxis. In such patients, we suggest prophylaxis with azithromycin. GOLD 2019 stated that azithromycin (given at 250 mg daily or at a lower dose of 250-500 mg three times per week) OR erythromycin (500 mg twice daily) for one year reduced the risk of exacerbations, compared to usual care (Seemungal et al 2008; Albert et al 2011 & Uzun et al 2014). UptoDate stated that 250 mg three times per week was oftenly used to reduce adverse effects, although this dose is less well studied.

When prophylactic antibiotics are prescribed, careful attention should be paid to contraindications, and patients should be closely monitored for adverse effects. Suspected bacterial exacerbations in patients on antibiotic prophylaxis should be treated with antibiotics that are from a different class than the prophylactic agent. Even if the regimen is successful in reducing exacerbations, interrupting treatment after 48-52 weeks should be considered. Interventions to prevent exacerbations of COPD that are unrelated to infection are discussed separately.

Azithromycin use was associated with an increased incidence of bacterial resistance, prologation of QTc intervals and impaired hearing tests (Albert et al 2011). Hearing should be assessed periodically as macrolides were associated with hearing loss in clinical trials. A post-hoc analysis suggests lesser benefit in active smokers (Han et al. 2014). There are no data showing efficacy or safety of chronic azithromycin treatment to prevent COPD exacerbations beyond one year of treatment.

Moxifloxacin

Although moxifloxacin has demonstrated efficacy for the prevention of COPD exacerbations, we generally reserve it for the treatment of serious pulmonary infections in order to reduce the risk of selecting fluoroquinolone-resistant bacteria and causing C. difficile infection.

Pulse therapy with moxifloxacin (400 mg/day for 5 days every 8 weeks) in patients with chronic bronchitis and frequent exacerbations had no beneficial effect on exacerbation rate overall. The recommendation is based on the randomised controlled trials conducted by Sethi et al. (2010), where moxifloxacin is given at 400 mg/day for 5 days every 8 weeks, for six cycles for a total duration of 48 weeks. The study revealed that:

• The patients who received moxifloxacin were less likely to have a COPD exacerbation in both the per-protocol analysis (OR 0.75, 95% CI 0.565-0.994) and in the intent-to-treat analysis (OR 0.81, 95% CI 0.645-1.008).
• A post-hoc analysis of per-protocol patients with purulent or mucopurulent sputum production at baseline showed a larger benefit with antibiotic prophylaxis (OR 0.55, 95% CI 0.36-0.84).
• Sustained emergence of moxifloxacin-resistant strains was not observed in sputum or in enteric flora.
• Gastrointestinal adverse effects were more frequent with moxifloxacin; however, C. difficile infections were not observed.

References:

1. UptoDate: Management of infection in exacerbations of chronic obstructive pulmonary disease
2.    UptoDate: Management of refractory chronic obstructive pulmonary disease
3.    Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD), 2019. Pocket Guide to COPD Diagnosis, Management, and Prevention: A Guide for Health Care Professionals.
4.    Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD), 2019. Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease.

All information accessed on 19 Sept 2019