Refractory is a term used to describe something that is difficult to treat or cure. H. pylori infection can be refractory to treatment for a number of reasons. The refractoriness may not be real. Successfully cured patients are sometimes referred to specialists because of positive serology tests. A stool antigen test or a breath test rapidly resolves this issue. The patient may not adhere to the treatment regimen. In some randomized controlled trials, 30 percent of failures were attributed to poor adherence with the regimen. I spend time describing the anticipated side effects: diarrhea with amoxicillin and altered taste with clarithromycin to avoid premature discontinuation of the treatment regimen, which can lead to treatment failure and emergence of resistance. When adherence drops below 80 percent, treatment failure is likely and patients who are not adherent with one treatment regimen are often not adherent with subsequent ones. Misguided attempts to reduce the duration of treatment, reduce side effects by decreasing anti-microbial doses are physician driven causes of apparent refractoriness.
Anti-microbial resistant strains of H. pylori are increasing in prevalence in the U.S. In a small recent study of U.S. Veterans, only half of the Helicobacter pylori strains tested were susceptible to commonly used antibiotics and approximately one in three were resistant to at least one antibiotic. Half of the 65 strains studied were susceptible to all five antibiotics tested, 31 percent were resistant to levofloxacin, 20 percent were resistant to metronidazole 16 percent were resistant to clarithromycin, 0.8 percent were resistant to tetracycline, and none were resistant to amoxicillin. European studies have shown that levofloxacin resistance rises rapidly when it becomes widely used in the community and this is why I don’t use this regimen much although some guidelines recommend it as a second line treatment. In vitro testing for antimicrobial sensitivity is not widely available in the U.S. PCR based methods are promising but well-validated assays are sill not widely available in the U.S.
Standard triple therapy is becoming obsolete as clarithromycin resistance rates rise.
Standard triple therapy is becoming obsolete as clarithromycin resistance rates rise. I no longer recommend this regimen as a first line treatment. I think that every doctor who treats H. pylori (particularly those who still use triple therapy) should have some measure of the outcome of treatment in their population. Testing patients for cure a month or more after treatment ends using a urea breath test or a stool antigen test is an easy way of determining whether your first line treatment still works. I like bismuth based quadruple therapy for 14 days as a primary regimen. It is quite inexpensive if the drugs are purchased separately. A single capsule preparation is also available, combining all three anti-microbials but the cost is higher and insurance coverage varies. In patients who cannot or will not take bismuth, I use non-bismuth quadruple therapy for 14 days. Extending the duration of treatment to 14 days improves eradication rates but I fully expect that some patients will not make it beyond 10 days and I like the additional buffer. If I prescribe treatment for 10 days and the patient takes it for seven days, I know results will be unacceptable. A single open-label US trial reported an 89 percent eradication rate with the LOAD therapy (levofloxacin, omeprazole, nitazoxanide, and doxycycline ) but I think it needs additional validation before I can recommend or use it.
Patients sent to me when triple and quadruple therapy fail, are a challenge. These patients often have multi-drug resistant strains. An exception is amoxicillin because resistance to this organism is so rate. In these patients I think the option of high dose PPI with amoxicillin is a good one (rabeprazole 20 mg or esomeprazole 20 mg and amoxicillin 750 mg, four times a day for 14 days). It has been studied in Asia with excellent results in patients failing traditional treatment regimens (90-95 percent). Esomeprazole and Rabeprazole have better results in high dose dual therapy and therefore I choose one of them. If I lived in Asia, I would choose vonoprazan in Japan or Ilaprazole in Korea are both potassium-competitive inhibitory agents that profoundly suppress acid secretion and improve eradication rates. Several studies have shown good results (83 percent by intent to treat and 88 percent per protocol) in patients with multi-drug resistant strains of H. pylori and very low rates of side-effects with Rifabutin triple therapy. Some experts prefer levofloxacin triple therapy. I rarely use this regimen because resistance rates are high in the USA (15 percent and higher) and resistant strains of H. pylori emerge rapidly with widespread use. Potassium competitive acid inhibitors have shown an improvement in eradication rates in Japan with traditional antimicrobials and may be the next development in eradication for the rest of the world. We await a drug designed specifically for H. pylori eradication and tailored for conditions in the stomach where it needs to work. In conclusion, if triple and quadruple therapy fail, I turn to treatment with high dose proton pump inhibitor and amoxicillin and if that fails, rifabutin triple therapy.
Dr. Vakil serves on the scientific advisory board for the AGA Center for Diagnostics and Therapeutics.