Helicobacter pylori Treatment: The 'Rules' Have Changed
David A. Johnson, MD
Hello. I am Dr David Johnson, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia.
Helicobacter pylori treatment has changed the natural history of peptic disease in this country and around the world. In addition, such treatment has affected other consequences of H pylori, in particular some of the mucosa-associated lymphoid tissue (or MALT) lymphomas and other specific disease categories that benefit from its eradication. But the treatment has changed.
Years ago, when H pylori was discovered, standard treatment involved a 7-day regimen of a proton pump inhibitor (PPI) plus amoxicillin and clarithromycin for patients who could tolerate it. Metronidazole was a substitute for amoxicillin in patients who were penicillin allergic. There has been a component alternative with bismuth-based therapies for patients who have amoxicillin allergy or clarithromycin resistance: a tetracycline/metronidazole/bismuth combination plus a PPI. This is a 10-day regimen.
We have seen, however, that the efficacy of these regimens has declined. This prompted a group of primarily Canadian experts on H pylori and evidence-based medicine to convene a 2-year analysis that culminated in a final evaluation in Toronto, Canada—hence, the Toronto Consensus Conference on Helicobacter pylori Infection in Adults.[1,2] This consensus conference resulted in several important take-home messages that should change the way we practice and treat H pylori.
High Rates of Drug Resistance
First, recognize that drug-resistance patterns have changed during the past decade and a half. Clarithromycin resistance, which was initially quite low, at 1%-8%, has risen to 16%-24%. Metronidazole resistance was relatively high to begin with and has remained relatively stable at 20%-40%. Tetracycline resistance and amoxicillin resistance are virtually unheard of at less than 1% for tetracycline and 1%-3% for amoxicillin, and thus they remain incredibly good drugs.
As we try to proactively restrict antibiotics when we do not need to use them, we need to keep in context our efforts at limiting antibiotic exposure. As we have seen these drugs used repeatedly for a variety of diseases and treatments—urinary tract infections, bronchitis, and so on—the prevalence of secondary resistance for clarithromycin and metronidazole has gone up dramatically. Resistance is up to 67%-82% for clarithromycin and 52%-77% for metronidazole. Thus, the effectiveness of these drugs has been drastically reduced. Once you have used them, you have pretty much used the last bow in the quiver and you cannot use these drugs again.
The Toronto Consensus Conference looked at evidence from 2008 forward; they avoided the earlier reports because of eradication, resistance patterns, and so on. They concluded that extending the treatment from 7 or 10 days to 14 days is and should be the new standard. The eradication rates for the 7- to 10-day regimens have fallen to approximately 50%, whereas with a 14-day regimen by either intention-to-treat or per protocol, the eradication rates were in excess of 95%. Therefore, a regimen lasting 14 days is the new rule across all treatment regimens for H pylori, regardless of which line of therapy is used.
Specifically, in areas where resistance patterns are known, therapy should be based on the resistance pattern. Now, in clinical practice we do not generally look at resistance patterns and we do not culture our H pylori. In fact, I cannot think of a single time that I have cultured for resistance patterns in 36 years of practice. Nonetheless, we certainly respect the results reported in scientific journals even though scientific journals do not always reflect our clinical practice. Clinical practice would say that we know the patients have H pylori and we treat that. So what do we do?
A New Standard?
As mentioned, empiric therapy, the standard 10-day triple therapy with clarithromycin, amoxicillin, and a PPI, should be extended to 14 days. But in areas where clarithromycin resistance is greater than 15% or eradication rates are less than 85%, that therapy should not be used. If you do not know the rate of clarithromycin resistance in your area, you may want to simply put the triple-therapy regimen aside; in that case, quadruple therapy becomes the new standard. The bismuth-based quadruple therapy would include a PPI plus bismuth subsalicylate (such as Pepto-Bismol®, Kaopectate®,Select®), amoxicillin or metronidazole, and tetracycline for 14 days. The alternative, in areas with low rates of clarithromycin resistance, would be a PPI-based triple therapy, with amoxicillin or metronidazole and clarithromycin for 14 days.
If the initial regimen for a given patient included clarithromycin or levofloxacin and had failed, these drugs should not be used at all. Thus, as a response to a failed regimen, you should stay away from those drugs, which would basically default to a bismuth-based quadruple therapy.
Similarly, levofloxacin has been used in patients whose initial triple therapy had failed; in that case, triple therapy would include levofloxacin, amoxicillin, and a PPI for 14 days. Levofloxacin does have a fairly high resistance pattern, however. A coauthor of an accompanying editorial, Dr David Graham, commented that in his area of Houston, there is a 31% resistance rate to this quinolone analog. Recognize, too, that the FDA has just put out an alert on using alternatives to quinolones when we can for sinusitis and bronchitis; the drug risks outweigh the benefits when there are alternative therapies. Because there is an alternative for H pylori, I would put levofloxacin in that category and try to stay away from it.
The consensus group also addressed the use of probiotics. They said that probiotics were not useful to attenuate side effects of the 14-day antibiotic treatment, nor were probiotics helpful proactively to improve the eradication rate. Probiotics are being proposed these days for a lot of non-evidence-based reasons, and clearly this task force said they should not be used adjunctively in H pylori eradication.
Use a 14-Day Regimen but Take Care
In conclusion, the consensus committee recommends a 14-day regimen and recognizes the high resistance patterns. But be careful when prescribing the bismuth-based therapy. The standard packaging for the tetracycline/metronidazole/bismuth combination drug is for 10 days. The recommendation now is to use this regimen for 14 days. You would have to give a pack and a half. I am not sure how you would prescribe that, but it would be a challenge for a 14-day regimen when the drug is supplied in a pre-pack of 10.
I would substitute one of the standard bismuth subsalicylate preparations, and prescribe two tablets four times a day plus the PPI, tetracycline, and metronidazole. If you do that, remind patients that their stools will be dark. Moreover, because these are salicylates, take care in patients receiving concomitant nonsteroidal anti-inflammatory drugs or those on anticoagulation. These patients may need co-therapy for protection against bleeding. Bismuth subcitrate, primarily sold in Europe, would be an alternative to bismuth subsalicylate.
Think about new treatments, new options. Think about H pylori as a 14-day-treatment disease. This is the new standard, and I believe the consensus on this is quite strong. The numbers needed to treat are in the range of 3 to 12, based on a variety of different approaches. Again, they found remarkable success when the treatment is extended to 14 days. Think about it next time you have a patient with H pylori.
I am Dr David Johnson. Thanks again for listening.