Helicobacteriology update

Helicobacter pylori, or formally known as Campylobacter pylori, is a Gram-negative, micro-aerophilic, spiral microorganism that can colonise the healthy stomach lining. It is associated with gastritis, peptic ulcer disease, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer^1–3. At least 50% of the world population is still infected with H. pylori and approximately 1 million new gastric cancer cases are reported annually⁴. In 1994 and 2017, the WHO classified H. pylori as a Class I carcinogen^5,6 and listed it as one of the most important (priority high) pathogens for emerging antibiotic resistance alarm^7,8, respectively.

It is interesting that 40 years after its discovery, with tens of thousands of research articles published, the route of transmission and the mechanism of how H. pylori causes cancer remains unclear. We now know that H. pylori survives poorly outside the human body. In vitro, H. pylori is known to be sensitive to heat, salt, chilli, honey, and many other common food ingredients⁹. This has made it difficult to transmit to other individuals via food sharing. However, people living under the same roof, with daily close contact, have been shown to infect each other¹⁰. On the flip side, we have also observed couples with good oral hygiene that have lived together for decades but have not infected each other. Perhaps a simple step in taking care of oral hygiene is sufficient in stopping H. pylori transmission.

The consensus is that we predominantly acquire H. pylori during childhood, perhaps via the oral-oral route, and traditionally from an infected mother to child. Whereas, in modern society, an infected father who shares the feeding duties could also be the source of infection. In situations where both parents must work, the caring duty may be given to either the grand-parents or nanny, who may be infected. Nevertheless, there is strong evidence to suggest that, as social economic status is improved, the prevalence of H. pylori declines.

Australia is one of the few countries that have a low prevalence of H. pylori (about 15%). However, the prevalence of H. pylori among the Aboriginal and the Asian communities can be as high as 50–80%^11,12. We believe that the overall low prevalence of H. pylori is the major factor for the low gastric cancer incidence in Australia (7.3 cases per 100 000 persons; 10 for males and 4.5 for females)¹³. Gastric cancer may no longer be an Australian problem, but it is still the fifth top cancer-killer in the world^4,14. Interestingly, about 50% of the newly reported gastric cancers are concentrated in the Eastern Asia countries, such as Japan, Korea, Mongolia and China⁴. Furthermore, all these Eastern Asia countries are dominated by the hpEAsia strain, and almost all of them harbour the more virulent EPIYA-D CagA toxin, noted oncoprotein^15,16. CagA is arguably the most studied virulence factor of H. pylori. It is encoded on the 40 kb cag pathogenicity island and it is the only known effector protein to be injected into host cells¹⁷. CagA can lead to inflammation¹⁸, affecting the survival of B cells¹⁹ and changes the histological characteristics of the stomach²⁰. All these effects of CagA are thought to finally lead to the formation of gastric cancer.

From our past 20 years of clinical experience in culturing antibiotic resistant clinical H. pylori isolates, we have observed a growing number of multi-drug resistant H. pylori strains in the Western Australian population. For example, in our 2015 cohort, more than 20% of H. pylori isolates were triple drug resistant. It is believed that this is primarily due to a significant increase of migrants, especially from Asia. According to the 2011 census, 32.8% of Western Australia’s population was born overseas (compared to the National average of 26.1%).

Presently, there is no standard treatment guideline for patients who carry antibiotic resistant H. pylori strains. Without the proper testing of antibiotic resistance in the laboratory, doctors are relying on experience and experimenting with different antibiotic combinations. This strategy may work for now, but we fear that it will only promote stronger antibiotic resistance in the future.

Thus, the best strategy for dealing with patients who failed multiple antibiotic treatment is to provide antibiotic susceptibility testing. Such personalised precision medicine has been proven to have high success rate. However, not every laboratory is capable of culturing such a fastidious microorganism. A robust and sensitive qPCR method to obtain quick antibiotic resistance diagnosis may be the alternative path overcoming the culturing hurdle. Besides, the only way of obtaining the H. pylori culture specimen is via endoscopy. Such a procedure can be difficult, costly, and is unavailable in the remote regions. Alternative technologies, such as the String Test that does not require medical specialists, should be investigated.

While the success rate of the standard H. pylori triple therapy (PPI + amoxicillin + metronidazole/clarithromycin) is declining globally, and is even abandoned in some countries, it remains effective in Australia¹². Nevertheless, for those who failed the standard triple therapy, the alternative antibiotics used in rescue regimens include quinolones, rifampicin, tetracycline and furazolidone. While quinolones and rifampicin are effective antibiotics against H. pylori, the organism can be easily become resistant to these as well! Therefore, a better strategy in choosing antibiotic combination is required. To date, we still hear stories about patients who failed multiple times on the same treatment. It is important to remind doctors not to prescribe the same antibiotic combination to the patient who failed the H. pylori treatment, as the H. pylori must have already gained resistance to the treatment. Then again, amoxicillin resistance in H. pylori is rare. It is so rare that the mechanism of resistance is still unknown. As a result, should the patient not be allergic to penicillin, amoxicillin can be repeatedly used in subsequent H. pylori treatments. Luckily, resistance to tetracycline, furazolidone, and bismuth compound have not yet been reported. Bismuth compounds have been used in medicine for over three centuries and were first introduced to treat duodenal ulcer in 1987²¹, but have gained more attention in recent years. Not only that, there are reports about overcoming metronidazole resistance by combination with tetracycline, but simply adding bismuth to triple therapy for 14 days has been reported to have an efficacy of more than 90%²².

For many antibiotic treatments, the key factor to the success is the concurrent use of a high-dose proton-pump inhibitor (PPI). It is already known that the use of antibiotics alone is not enough to eradicate H. pylori. Acid reduction therefore plays a vital role in H. pylori treatment. To elaborate on this, the reader should note that most antibiotics were developed without the gastric mucosa in mind. Therefore, they might not act in the gastrointestinal lumen, and especially not in an acid environment. Interestingly, metronidazole and clarithromycin, which are secreted in saliva, are particularly effective against naïve H. pylori strains, perhaps for this reason. Bismuth compound acts topically on the gastric mucosa and is safe and effective (used for at least 200 years for gastrointestinal disorders). However, bismuth does not penetrate the mucus layer so always needs an extra antibiotic agent to provide a permanent cure.

Regarding acid-lowering agents, one aims to achieve around the clock pH ≥6 in the stomach. H₂ blockers (e.g. cimetidine ‘Tagamet’, ranitidine ‘Zantac’, famotidine ‘Calmicidetc’) are competitive inhibitors of acid secretion so cannot reliably do this. The PPI drugs were a breakthrough in this regard (e.g. omeprazole ‘Losec’, esomeprazole ‘Nexium’, rabeprazole ‘Aciphex’) almost completely blocking the proton pumps. However, some H. pylori could survive, perhaps reflecting an inadequate dose in some patients.

Recently, the potassium competitive acid blocker group (P-CABs) has been used (Vonoprazan), which might give a rapid and more complete acid blockade, with subsequent excellent cure rate for H. pylori. Perhaps even with just a single antibiotic such as amoxicillin. Time will tell!

But the controversy still rages, ‘should we give treatment to asymptomatic H. pylori carriers?’ Asymptomatic patients with a family history of gastric cancer, or with gastric intestinal metaplasia, or atrophic gastritis, are advised to get rid of their H. pylori. In regions with high prevalence of gastric cancer, such as Eastern Asia, where the ‘cancer strain’ of H. pylori predominates, should all be encouraged to eradicate the H. pylori infection? The risk of getting gastric cancer increases with age. Since most people acquire H. pylori during childhood, and assuming that the damage of the gastric mucosa accumulates through age, the chance of developing gastric cancer increases. Perhaps because the seeds of cancer have already been planted, getting rid of H. pylori in old age does not always eliminate the gastric cancer risk. However, it has been reported that in all age groups, patients with a history of H. pylori infection have a higher risk of gastric cancer than those that have never been infected^23–25.

Certainly, H. pylori only colonises the internal gastric luminal surfaces, albeit under the mucus layer. Therefore, it is exposed to any food or medicine ingested by the host. So, this is a perceived vulnerability for H. pylori. The ‘Holy Grail’ of H. pylori treatment is hence the discovery of orally active natural or food products which might cure the infection, or perhaps suppress it enough to allow natural immune processes to finish the task. Alas, at the present time, most natural products show zero effect on H. pylori, or at best, a weak temporary effect. Often, H. pylori tenderfoots will be excited about in vitro killings of H. pylori, but this hardly ever translates into useful clinical activity.

In summary then, susceptibility guided precision medicine is the way forward for eradication of H. pylori. New combination therapies show promise and the dream of 100% cure of the infection with minimal side effects from treatment seems achievable. The next decade will see combination therapies with newer acid blockers in widespread use at reasonable cost. Investment in new antibiotics and strategies to combat the rise of antibiotic resistant microorganisms is vital. The famous quote by Dr David Graham ‘The only good Helicobacter pylori is a dead Helicobacter pylori’²⁶ seems the way to go.

Barry Marshall is medical director of Tri-Med (http://www.trimed.com.au), a Perth company that distributes diagnostic tests for Helicobacter pylori (‘PYtest’ urea breath tests and ‘CLOtest’ biopsy rapid urease test), and marketing orphan drugs (bismuth subcitrate, tetracycline, furazolidone and rifaximin). Alfred Tay and Michael Wise declare no conflicts of interest.

This research did not receive any specific funding.