When Barry Marshall, MD, and J Robin Warren, MD, first began to study certain spiral organisms as possible causative factors in gastritis, their hypothesis was largely dismissed, Dr Marshall explained during the Digestive Disease Week conference presentation of the “Barry Marshall (Nobel Laureate 2005) and Adrienne Marshall Lecture: Nobel Laureate Barry Marshall’s Legacy and the Current Challenges of H Pylori Therapy.”

Dr Marshall is professor of clinical microbiology and codirector of The Marshall Centre at the University of Western Australia in Perth, Australia. Dr Warren is now retired.

Working in the basement of Royal Perth Hospital in Australia, the young physicians labored for years to determine if Helicobacter pylori was the cause of gastric and duodenal ulcers. A small study of 100 patients showed that 100% of patients with duodenal ulcers and 77% of patients with gastric ulcers had H pylori, but these findings were “controversial for several years” and no journal would accept their papers for publication. In fact, Dr Marshall said, “One society said we couldn’t even present a poster at their meeting.”

The rejection, he explained, “just spurred us on. We overcame by doing more work, getting more data, trying to keep it blinded. We were pretty cocky about our discovery.”

To get those data, Dr Marshall finally resorted to being a human test subject himself by drinking a solution infected with H pylori, developing gastritis, and suffering through a week of vomiting before a biopsy and culture showed the presence of H pylori in his own stomach.

Finally, a double-blind placebo-controlled study in 1985 found that eradication of H pylori healed gastric and duodenal ulcers and patients did not relapse.

Those years of frustration and rejection paid off in 2005, when Drs Marshall and Warren received the Nobel Prize for Physiology. The prize committee stated, “Thanks to the pioneering discovery by Marshall and Warren, peptic ulcer disease is no longer a chronic, frequently disabling condition, but a disease that can be cured by a short regimen of antibiotics and acid secretion inhibitors.”

However, according to David Yates Graham, MD, professor of medicine at the Baylor College of Medicine in Houston, Texas, those short regimens of antibiotics are now creating a whole new challenge for treating H pylori infection. Average cure rates for H pylori are declining due to antimicrobial resistance.

“Resistance per se is not the problem,” Dr Graham stated. “The problem was, and is, the response by gastroenterology, which treats H pylori as just another gastro disease, rather than what it is, which is an infectious disease.”

Dr Graham outlined the significant differences between infectious and gastrointestinal diseases, and how their treatments are approached. For many gastrointestinal diseases, causes are largely unknown, cures are rarely possible, and there is a strong placebo effect. Relative effectiveness of treatments, rather than cure rates, are assessed.

For an infectious disease, he explained, “there is no placebo effect, the cause is known, a 100% cure is possible, and only regimens with a high cure rate are used.”

Today, Dr Graham said, patients are receiving therapies for H pylori that no longer work. “By 2000, empiric clarithromycin triple therapy was no longer effective for the treatment of H pylori. It is now 20 years later, and clarithromycin is still one of the most commonly used antibiotics used to treat H pylori.”

Resistance to metronidazole and levofloxacin are also increasing; resistance to amoxicillin remains low but is rising. Noting that the overall widespread use of antibiotics among humans and animals is contributing to increasing resistance, Dr Graham said, “this is a complex situation; antibiotics are in our drinking water, soil, and food.”

However, he stated, the fact remains that in the practice of gastroenterology, very few therapies for H pylori have been optimized, which is one of the principles of antimicrobial stewardship. When drugs for tuberculosis and pneumonia stopped performing, for example, those drugs were abandoned.

Yet in Western nations, triple therapy for H pylori has a cure rate of 72%—and thus a failure rate of 28%, meaning that more than 280,000 people are receiving almost 12,000 kilograms of unnecessary antibiotics. “Another antimicrobial stewardship principle is that no one should receive unnecessary antibiotics, but we routinely give them,” Dr Graham stated.

When judging therapies for H pylori, he said, “the only valid outcome parameter is the actual cure rate. Therapies should be optimized to reliably achieve high cure rates of more than 95%.”

Dr Graham recommended that only therapies proven to be highly effective locally should be used in treating H pylori. “All treatment decisions should be based on local results—ignore consensus recommendations unless they prove highly effective locally,” he stressed. “Continuing effectiveness should be confirmed using test-of-cure data,” and susceptibility testing using next-generation sequencing or culture is now available.

In addressing the issue of antimicrobial resistance, Dr Graham stated, “We’ve identified one of the bad guys—and it’s us. We have to start treating H pylori for what it is: an infectious disease.”

—Rebecca Mashaw

Reference

Marshall, B, Graham, DY. Barry Marshall (Nobel Laureate 2005) and Adrienne Marshall lecture: Nobel Laureate Barry Marshall’s legacy and the current challenges of H pylori therapy. Digestive Disease Week. May 22, 2021; Virtual.