Treating Helicobacter pylori effectively while minimizing misuse of antibiotics

Misuse of antibiotics

In triple therapy, the second antimicrobial drug (eg, amoxicillin) is given in part to prevent resistance from developing. It is not clear whether the combination is additive or synergistic, but until we can reliably maintain the intragastric pH above 6.0, which would increase the effectiveness of the amoxicillin component of the regimen, this practice cannot be considered as misuse of antibiotics.

In contrast, in the 4-drug nonbismuth combinations (concomitant, sequential, and hybrid therapies) and the new vonoprazan, clarithromycin, and metronidazole triple therapies, 1 of the antibiotics provides no benefit to some, often most, of the patients.^18–20,32 This practice should end when susceptibility data become more widely available and when vonoprazan becomes available, so that we can deliver effective vonoprazan-amoxicillin dual therapy.

First-, second-, and third-line therapies

Many recommendations give advice in terms of first-, second-, and third-line therapies. In practice, a physician should have at least 2 first-line regimens (a first and a second choice). Both should be proven highly successful as empiric therapies in one’s patient population but differ in terms of primary antibiotics. This approach allows the clinician to tailor therapy depending on whether he or she suspects antibiotic resistance (eg, if the patient has taken clarithromycin before) or the patient is allergic or cannot take 1 or more drugs.

Two treatment failures with 2 different regimens known to be effective suggest poor compliance (a difficult patient) or a multiple-drug-resistant infection (a difficult infection). That patient would require salvage therapy (Table 2), which logically should be based on antimicrobial testing or, at a minimum, consultation with someone who frequently deals with this problem.

Test of cure

Monitoring the outcome of therapy (testing for cure) is essential, as it provides a reliable measure of the local effectiveness of particular therapies and also serves as an early warning of development of resistance in one’s patient population.¹⁴

Unless there are compelling reasons, testing for cure should use noninvasive testing with the urea breath test or stool antigen test. It is recommended that this be delayed at least 4 weeks to allow the organisms if still present to repopulate the stomach sufficiently for the tests to become positive. Because antibiotics, bismuth, and proton pump inhibitors reduce the bacterial load, they should be withheld at least 2 weeks before testing. Histamine-2 receptor antagonists can be substituted for proton pump inhibitors if antisecretory therapy is needed for symptoms, and continued up to the day before testing. The urea breath test should contain citric acid to overcome any residual pH effects. Physician groups should share their experience so as to alert the community about which therapies should likely be avoided.³³

Salvage therapy

Salvage therapy is given after 2 or more treatment failures with different antibiotics. Ideally, the regimen should be based on the results of antimicrobial testing. Current regimens include rifabutin triple therapy, dual therapy (a protein pump inhibitor or vonoprazan and amoxicillin), or furazolidone quadruple therapy (Table 2).

Furazolidone is a synthetic nitrofuran derivative that is effective against many enteric organisms, including gram-negative bacteria and protozoa. It is not available in most Western countries but is available in many other parts of the world.^34,35 It is also a monoamine oxidase inhibitor and thus interacts with many drugs and foods (eg, soy sauce, aged cheeses), leading to a relatively high rate of side effects such as fever, palpitations, and skin rash.

Rifabutin-containing regimens, generally, a proton pump inhibitor, amoxicillin 1 g, and rifabutin 150 mg, all twice a day (Table 3) provide average cure rates of less than 80% (typically in the mid-70% range).³⁶ Borody et al³⁷ reported greater than 95% success with a 12-day regimen consisting of rifabutin 150 mg once daily (half-dose), amoxicillin 1.5 g 3 times a day, and pantoprazole 80 mg (approximately equivalent to omeprazole 20 mg) 3 times a day. Ciccaglione et al,³⁸ in a small study, used a 10-day quadruple regimen containing a proton pump inhibitor, amoxicillin, rifabutin, and bismuth (all twice a day), with high cure rates. The results of these studies are yet to be confirmed, and the optimal rifabutin-containing regimen remains to be determined.

PROBIOTICS

There is considerable interest in using probiotics to enhance the effectiveness of antimicrobial therapy for H pylori by increasing tolerability, reducing side effects, and therefore improving compliance.^39,40

In a meta-analysis of 14 randomized trials (N = 1,671), when probiotics were added, pooled H pylori eradication rates were only slightly improved: 83.6% (95% CI 80.5%–86.7%) with probiotics and 74.8% (95% CI 71.1%–78.5%) without probiotics by intent-to-treat analysis.⁴¹

Another meta-analysis of probiotics suggested that those containing Saccharomyces boulardii, Lactobacillus, and Bifidobacterium significantly increased the eradication rate of triple therapy in populations with high rates of antimicrobial resistance and reduced the risk of overall H pylori therapy-related adverse effects, especially diarrhea.^42,43

At present, we recommend that probiotics be considered only for patients who are likely not to comply with treatment (eg, those with irritable bowel syndrome or difficulty taking antibiotics), to try to take advantage of their ability to improve antibiotic tolerability.