Treating Helicobacter pylori effectively while minimizing misuse of antibiotics
ABSTRACT
Experts now recommend that all Helicobacter pylori infections be eradicated unless there are compelling reasons not to. As with other infectious diseases, effective therapy should be based on susceptibility.
KEY POINTS
- We recommend clinicians have 2 first-line options to accommodate prior antibiotic use or drug allergy.
- We recommend 4-drug combinations as first-line treatments, ie, either concomitant therapy or bismuth-containing quadruple therapy, to be taken for 14 days.
- Concomitant therapy consists of the combination of amoxicillin, metronidazole, clarithromycin, and a proton pump inhibitor.
- Bismuth quadruple therapy consists of the combination of bismuth, tetracycline, metronidazole, and a proton pump inhibitor.
- After 2 treatments have failed, therapy with different regimens should be based on susceptibility testing.
Bismuth quadruple therapy is an alternative
Bismuth quadruple therapy (Table 1) consists of:
- Bismuth
- Tetracycline
- Metronidazole
- A proton pump inhibitor.
This was the first truly effective regimen for H pylori. Its advantage is that it can partially or completely overcome metronidazole resistance.21,22 As such, it is potentially ideal, as it should be effective despite resistance to clarithromycin, metronidazole, or levofloxacin, and it can be used in patients allergic to penicillin.
The major downside is a high frequency of side effects, particularly abdominal pain, nausea, and vomiting, often resulting in poor adherence. Most regimens that contain antibiotics have side effects, but adherence seems to be more of a problem with bismuth quadruple therapy, probably because of the combination of the high doses of metronidazole and tetracycline.22 In our experience, this regimen can be effective if the physician takes the time to explain to the patient that side effects are common but treatment success depends on completing the full course of 14 days.
Another problem is that tetracycline has become difficult to obtain in many areas, and doxycycline cannot be substituted in those with metronidazole resistance. To date, it has been difficult or impossible to obtain the same excellent results with doxycycline as can be obtained with tetracycline. It is not clear why.21
To use bismuth quadruple therapy one must often use a name-brand product, Pylera. Pylera is packaged as a 10-day course, which is effective against metronidazole-susceptible infections. However, 14 days are generally required to achieve a high cure rate with metronidazole-resistant infections, which are the main indication for use of this product. Moreover, Pylera does not include a proton pump inhibitor, which must be prescribed separately.
In the United States, Pylera is expensive, costing $740 to $790 with a coupon for a 10-day supply and proportionally more for the required 14-day supply (www.goodrx.com/pylera?drug-name=pylera), whereas in Europe it costs less than 70 Euros ($73).21 If generic tetracycline is available, the US cost for 14 days of generic bismuth quadruple therapy is less than $50.
An alternate and simpler approach is to substitute amoxicillin for tetracycline.23 This regimen has been used successfully in China and was shown to be noninferior to the tetracycline-containing regimen in a head-to-head comparison.24
Recent studies have confirmed earlier Italian studies suggesting that twice-a-day bismuth and tetracycline is effective, which would further simplify therapy and possibly reduce side effects.21,23,24 These variations on bismuth quadruple therapy have not yet been optimized to where one can reliably achieve 95% or greater cure rates, and further studies are needed.
Why include more than 1 antibiotic?
The H pylori load in the stomach is typically large, which increases the odds that a subpopulation of resistant organisms is present. Resistance may be due to a relatively high rate of mutation in certain bacterial genes.25 This is particularly a problem with clarithromycin, metronidazole, and fluoroquinolones and is reflected in a high rate of resistance among patients for whom single-drug regimens have failed. These drugs are always given with a second antimicrobial to which H pylori rarely becomes resistant, such as amoxicillin or tetracycline.
Why include a proton pump inhibitor?
An antisecretory drug is needed to increase the gastric pH, which makes antimicrobial therapy more effective. It also decreases antibiotic washout from the stomach and likely protects and increases the gastric concentration of some antibiotics.
The activities of amoxicillin, fluoroquinolones, and to a lesser degree clarithromycin are pH-dependent. For example, keeping the gastric pH above 6.0 promotes H pylori replication,26,27 making it is more susceptible to amoxicillin (reviewed in detail by Dore et al21). A gastric pH of 6.0 or more is very difficult to achieve with proton pump inhibitors, and has been accomplished regularly only in people who metabolize these drugs slowly (“slow metabolizers”) who received both the proton pump inhibitor and amoxicillin every 6 hours for 14 days.21
With standard clarithromycin, metronidazole, or fluoroquinolone triple therapy, proton pump inhibitors appear to provide satisfactory cure rates when given for 14 days in standard doses. However, double doses (eg, 40 mg of omeprazole or an equivalent) may be slightly better, especially in the presence of resistance.
The cure rate reflects the sum of the 2 populations of organisms: the susceptible and the resistant. In triple therapy, increasing the gastric pH with a proton pump inhibitor makes the amoxicillin component of the regimen more effective against resistant organisms and thus increases the cure rate. For example, in Western countries, esomeprazole 40 mg (approximately equivalent to rabeprazole 40 mg, omeprazole or lansoprazole 60 mg, or pantoprazole 240 mg)28 given twice a day in a 14-day triple therapy regimen cures about 40% to 50% of resistant infections. This benefit will be evident in an improvement in cure rates in populations in which resistance has reduced the average cure rate. This is also why meta-analyses have shown better results with second-generation proton pump inhibitors and with longer duration of therapy.29,30
Generally, we recommend omeprazole 40 mg twice a day or an equivalent (Tables 1–3).
Would a potassium-competitive acid blocker be better than a proton pump inhibitor?
Vonoprazan is a potassium-competitive acid blocker. It does not require intermediate complex formation and is stable at low pH. It has a longer half-life than proton pump inhibitors, and its bioavailability is unaffected by food.31 It was recently approved in Japan for H pylori eradication in combination with clarithromycin or metronidazole plus amoxicillin.18
Vonoprazan is more effective than current proton pump inhibitors for keeping the gastric pH high. There are no published studies of vonoprazan dual therapy in Western countries, but given twice a day for 7 days along with twice-daily amoxicillin it cured only approximately 80% of clarithromycin-resistant strains. Further studies are needed to identify the optimum proton pump inhibitor or potassium-competitive acid blocker, dose, and duration.
