Peptic Ulcer Disease and H. pylori: Peptic Ulcer Disease and H. pylori: Test to Cure

0:00Welcome to Board Pearls. This is episode one of two of the Peptic Ulcer Disease and H. pylori chapter, in the Stomach and Small Bowel Disorders module. This episode is H. pylori, from diagnosis through first-line treatment, test of cure, and salvage. A woman with a duodenal ulcer shows who gets tested, how the organism's biology explains every test and its false negatives, why the infection caused a duodenal rather than a gastric ulcer, why clarithromycin lost its place, how two questions about her history pick her regimen, and how cure is confirmed. A man whose infection survives treatment twice shows how a real failure is confirmed, which drugs can be used again and which can't, when to stop guessing and test for resistance, and what's left when bismuth quadruple therapy has failed.

0:45Here's the first patient. A forty-two-year-old woman has two months of gnawing epigastric pain that wakes her at night and eases when she eats. She takes no nonsteroidal anti-inflammatory drugs, NSAIDs, or aspirin. She had a sinus infection treated with azithromycin last year. She says she's allergic to penicillin, because she got a rash as a child. She's been taking over-the-counter omeprazole for a month. Endoscopy shows a clean-based eight-millimeter ulcer in the duodenal bulb.

1:14She has a duodenal ulcer, and with no NSAIDs or aspirin, the cause to look for is H. pylori. Any active or past peptic ulcer is on the testing list, which the twenty twenty-four American College of Gastroenterology, ACG, guideline broadened. It also includes mucosa-associated lymphoid tissue, MALT, lymphoma; uninvestigated dyspepsia under age sixty; functional dyspepsia; long-term NSAID or low-dose aspirin use; and unexplained iron deficiency.

1:46The rest of the list covers immune, precancerous, and family settings. It's immune thrombocytopenia, autoimmune gastritis, gastric precancerous conditions, first-degree relatives of someone with gastric cancer, and household members of someone with confirmed active infection.

2:03How she's tested follows from how H. pylori lives where it does, which also explains why tests fail. It's a spiral, gram-negative, microaerophilic bacterium that lives in the layer of mucus coating the gastric lining, a niche almost nothing else survives. It prefers a near-neutral pH, around six to eight and a half, so it protects itself by making huge amounts of urease. Urease splits urea into ammonia and carbon dioxide, and the ammonia neutralizes the acid right around the bacterium. Two of the tests detect that enzyme. Flagella let the organism swim through thick mucus, and adhesins attach it to the surface cells.

2:42Active tests detect the live bacterium or its products. The urea breath test has the patient swallow urea labeled with carbon thirteen or fourteen, and if urease is present, labeled carbon dioxide appears in the breath. The stool antigen detects bacterial protein. The rapid urease test drops a biopsy into urea with a pH indicator that changes color when ammonia forms. Histology with a special stain, Giemsa, immunohistochemistry, or Warthin-Starry, shows the organism itself. All four are accurate when done correctly.

3:18Those tests share a weakness that comes from the biology. Proton pump inhibitors, PPIs, antibiotics, and bismuth reduce the number and activity of the bacteria, and then all of these tests can be falsely negative. So the patient has to be off PPIs for one to two weeks and off antibiotics and bismuth for four weeks before testing.

3:39She's been on omeprazole for a month, so a negative rapid urease test from today's endoscopy wouldn't mean much. Histology with a special stain, on a biopsy from the body of the stomach, is the most resistant to suppression, because the pathologist sees the organism directly. It's the best single test when the PPI can't be held. The endoscopist takes biopsies for both.

4:01Serology avoids the PPI problem but answers a different question. It measures antibodies, so a PPI doesn't affect it. But antibodies persist for years after the infection is gone, so a positive result can't tell current from past infection. It's acceptable only as a first test where active testing isn't available, and it's never used to confirm cure.

4:21Her histology shows H. pylori, so she has an H. pylori duodenal ulcer. Had every test been negative, a second active test, done properly, would be needed before calling the ulcer H. pylori-negative. A negative-test ulcer is exactly where false negatives from PPI carryover or low bacterial numbers hide.

4:42Why the infection gave her a duodenal ulcer, rather than a gastric one, depends on where it settled. Infection limited mostly to the antrum destroys the D cells that make somatostatin, the brake on gastrin. Gastrin rises, the healthy body of the stomach makes more acid, and the duodenal bulb develops patches of gastric-type lining that the bacterium can colonize. That high-acid pattern causes duodenal ulcers, like hers.

5:08The other pattern leads somewhere more dangerous. Infection spread across the whole stomach, including the body, often acquired early in life, damages the parietal cells instead. Acid falls, and the result is gastric ulcer, atrophy, intestinal metaplasia, and, in some, intestinal-type gastric cancer. It's the same organism with a different distribution and a different disease. It's also why eradication improves reflux in some patients and worsens it in others.

5:38Most carriers never get that far, which is why the infection's spread matters less than its effects. About half the world is infected, though far fewer people born in the United States in recent decades, with roughly ten percent prevalence by age thirty in those born after nineteen eighty. Only five to twenty percent of carriers develop an ulcer, and fewer develop cancer.

5:59Two virulence factors raise the risk. Strains carrying the cag pathogenicity island inject a protein called CagA into host cells, which disrupts them and amplifies inflammation, and those strains carry a higher cancer risk. The vacuolating cytotoxin gene is present in all strains, but only some secrete the active toxin, which damages the lining and helps the organism settle in for chronic infection. Whatever the strain, her ulcer means the infection is treated.

6:29Her treatment choice starts with why the old standard fell. Clarithromycin resistance comes from a mutation at the drug's binding site on the bacterial ribosome. It's all or nothing, so a higher dose can't overcome it, and a resistant strain simply doesn't respond. Resistance now commonly exceeds fifteen percent, the level above which clarithromycin triple therapy can't be given empirically. Levofloxacin resistance has risen the same way, through mutations in deoxyribonucleic acid, DNA, gyrase. Resistance to amoxicillin, tetracycline, and rifabutin has stayed very low, and those three drugs anchor current treatment.

7:09Optimized bismuth quadruple therapy is the only first-line regimen with a strong recommendation. It's four drugs taken together for fourteen days. They're a PPI, ideally esomeprazole or rabeprazole because they're more potent; bismuth subsalicylate; tetracycline five hundred milligrams four times a day; and metronidazole five hundred milligrams three or four times a day.

7:30Each piece has a job. The PPI raises gastric pH, which pushes the bacteria into replication, when antibiotics work best. Bismuth kills bacteria directly and works even against metronidazole-resistant strains. Two antibiotics together cover strains resistant to either one. Optimized means the full fourteen days rather than ten, tetracycline rather than doxycycline, and a potent PPI. It contains no clarithromycin, so it doesn't depend on resistance testing.

8:02It's a complicated regimen, and a patient who stops on day four isn't cured, so counseling is part of the prescription. She's warned about nausea, a black tongue and black stools from bismuth, a metallic taste from metronidazole, and a disulfiram-like reaction if she drinks alcohol on metronidazole. Bismuth subsalicylate is avoided in a patient with aspirin allergy.

8:23Two newer regimens use vonoprazan, and its pharmacology explains why they work. Vonoprazan is a potassium-competitive acid blocker. It binds the proton pump ionically rather than permanently, doesn't need acid to activate it, lasts seven to nine hours, and isn't cleared mainly by CYP2C19, so fast metabolizers don't escape it. At ten milligrams daily it suppresses acid about as much as sixty milligrams of omeprazole, and at twenty milligrams twice daily about twice that.

8:53That near-continuous acid suppression lets amoxicillin alone, without a macrolide, cure the infection. Vonoprazan dual therapy is vonoprazan twenty milligrams twice daily with amoxicillin one gram three times daily for fourteen days. Vonoprazan triple therapy is vonoprazan twenty milligrams, amoxicillin one gram, and clarithromycin five hundred milligrams, each twice daily for fourteen days. Both are approved alternatives, though neither has a strong recommendation yet, because head-to-head data against optimized bismuth quadruple therapy in American patients are still modest.

9:26Which regimen fits her is decided by questions about her history, starting with penicillin allergy. She says yes, which would rule out every amoxicillin regimen, including vonoprazan dual therapy. But most penicillin allergy labels aren't true allergies. When the regimen choice depends on the label, allergy testing to remove it is reasonable, because it reopens the amoxicillin options.

9:49Her macrolide history matters just as much, and azithromycin for a sinus infection counts. Any prior macrolide rules out the clarithromycin regimens. Prior fluoroquinolone use is asked about too, because it rules out levofloxacin. Clarithromycin triple therapy survives only where local resistance is documented under fifteen percent and the patient has never had a macrolide, conditions rarely met in the United States now.

10:14The remaining alternatives carry only conditional recommendations. They're concomitant therapy, a PPI with amoxicillin, clarithromycin, and metronidazole for fourteen days; sequential therapy in two phases of five to seven days; hybrid therapy combining the two; and a levofloxacin, omeprazole, nitazoxanide, and doxycycline regimen for seven to ten days.

10:37She has a penicillin label and prior azithromycin. Bismuth quadruple therapy avoids both problems, and it would be the first choice even without them. She takes it for fourteen days, and stops her over-the-counter omeprazole afterward so her test of cure is valid.

10:52Treatment isn't finished until cure is confirmed, the step most often skipped. Everyone treated is retested at least four weeks after finishing antibiotics, after holding the PPI for one to two weeks, with a urea breath test or stool antigen. Serology can't be used, because it stays positive. Her urea breath test six weeks after treatment is negative. Because household members of someone with confirmed active infection are on the testing list, they're offered testing too.

11:21The second patient's infection outlasts his first treatment. A fifty-six-year-old man with dyspepsia and a positive stool antigen was treated with vonoprazan triple therapy, vonoprazan with amoxicillin and clarithromycin, for fourteen days. A urea breath test five weeks after finishing is still positive. He has no penicillin allergy. He asks whether he should just take the same pills again, for longer.

11:45Before anything changes, two things are checked to confirm this is a true treatment failure, starting with whether the test of cure was valid. A breath test or stool antigen done too soon after antibiotics, or on a PPI, can be falsely negative, but not falsely positive for those reasons, so a positive result is usually real. His was done at five weeks, with his PPI held for two weeks. The positive result stands.

12:11The second check is whether he took the drugs. Adherence failure is common with complicated regimens, especially when side effects start. He's asked how many doses he missed and why, and his pharmacy refill records are checked. If he'd stopped on day five because of nausea, the answer would be counseling and support, not just a different set of drugs. He says he took every dose, and his refills match. He has a real treatment failure.

12:37His next regimen depends on which drugs can be reused, and that follows from how resistance works. Clarithromycin resistance from the ribosomal mutation and levofloxacin resistance from DNA gyrase mutations are all or nothing, and a failed regimen strongly suggests the strain resists whatever was in it. So clarithromycin and levofloxacin are never reused after a failure unless susceptibility testing shows the strain is still sensitive.

13:02That answers his question. Repeating the same regimen, even for longer, repeats a drug his strain has probably beaten. Amoxicillin, tetracycline, and rifabutin are different. Resistance to them remains very rare, even in exposed strains, so they can be used again, and salvage relies on them.

13:20That sets his second regimen. He failed a regimen with clarithromycin, which can't be reused, and he's never had bismuth, tetracycline, or metronidazole. So he gets optimized bismuth quadruple therapy for fourteen days. It's the recommended salvage regimen for anyone whose failed regimen didn't contain bismuth, tetracycline, and metronidazole. That covers failures of clarithromycin triple, vonoprazan triple, vonoprazan dual, and the sequential and concomitant regimens. It contains no clarithromycin, tetracycline resistance is rare, and bismuth works even against metronidazole-resistant strains.

13:58The same optimization rules apply, and the PPI deserves attention because it's an easy place to lose a regimen. He takes the full fourteen days, tetracycline rather than doxycycline, doses as written, with the same counseling. The PPI is there to raise gastric pH high enough, for long enough, that the antibiotics work, not to treat symptoms. A weak PPI at a low dose can leave the stomach acidic enough that the antibiotics underperform, and the regimen fails for a reason unrelated to resistance. So a patient who has already failed once gets esomeprazole or rabeprazole at full dose.

14:34Two other options come up at this point, and one is a trap. Vonoprazan dual therapy is a reasonable salvage option after a clarithromycin failure in a patient without penicillin allergy, because it leaves out the macrolide. But his failed regimen already contained vonoprazan and amoxicillin, so for him it's weaker than bismuth quadruple.

14:53Levofloxacin triple therapy is the trap. It's a PPI, amoxicillin, and levofloxacin five hundred milligrams, all twice daily for ten to fourteen days. Levofloxacin resistance is now common, and the drug carries a boxed warning for tendinitis and tendon rupture, so it's used only when testing shows the strain is susceptible.

15:13He takes bismuth quadruple therapy for fourteen days and takes every dose. Six weeks later, with his PPI held, the breath test is still positive.

15:23After two failures, the rule is to stop guessing. Susceptibility testing is indicated after more than one failed regimen, because each empiric failure costs weeks, side effects, and another drug that can't be used again. Culture-based testing needs a fresh gastric biopsy and is offered by only a few reference laboratories, because the organism is hard to grow.

15:47Molecular testing has become the practical choice. Done on stool or a biopsy, it's now widely available. It looks directly for the resistance mutations, in the 23S ribosomal ribonucleic acid, RNA, gene for clarithromycin and the gyrA gene for levofloxacin, without growing the organism. The next regimen is one the strain is susceptible to, for the full fourteen days at optimized doses. A levofloxacin-susceptible strain, for example, would make levofloxacin triple therapy reasonable.

16:18His stool molecular test shows resistance to both clarithromycin and levofloxacin.

16:24With bismuth quadruple failed and both resistance-prone drugs out, what's left is rifabutin triple therapy. It's a PPI, amoxicillin one gram, and rifabutin fifty milligrams, each three times daily, for ten to fourteen days. A single combination capsule of omeprazole ten milligrams, amoxicillin two hundred fifty milligrams, and rifabutin twelve and a half milligrams, four capsules three times a day for fourteen days, makes adherence simpler. Resistance to rifabutin is exceptionally rare, so it keeps working in heavily treated patients. And amoxicillin can be reused, so the whole regimen is built from drugs his strain is unlikely to resist.

17:04Rifabutin isn't used first for three reasons. It's expensive. It carries a rare risk of bone marrow suppression. And it belongs to the same family as drugs used against mycobacteria, so wide use could breed resistance where it matters for tuberculosis. So it's held for patients who've failed other regimens, including bismuth quadruple, or who have confirmed multidrug-resistant strains. The best rifabutin dose in treatment-experienced patients isn't well defined, and guidelines acknowledge that gap.

17:33He takes rifabutin triple therapy for fourteen days. His breath test six weeks later, with the PPI held, is negative. He's cured.

17:42A penicillin allergy label matters most at this stage. With one, every amoxicillin regimen, including rifabutin triple and vonoprazan dual, would seem closed, and his options after bismuth quadruple would be very limited. Allergy testing can remove an inaccurate label and reopen the regimens salvage depends on.

18:02Every course in both patients ended with a test of cure, and that's the rule, not a courtesy. Patients are retested after every course, because a patient who feels better can still be infected, and a missed failure leaves the ulcer and cancer risk in place.

18:19Here are the traps the boards set in these patients. A breath test, stool antigen, or rapid urease test isn't done on a PPI, or soon after antibiotics or bismuth. Serology doesn't diagnose active infection or confirm cure. Clarithromycin triple therapy isn't given to someone who's had azithromycin. A penicillin allergy label isn't accepted without question when it decides the regimen. Bismuth quadruple therapy isn't shortened to ten days, and doxycycline isn't swapped in. And bismuth subsalicylate isn't given to a patient with aspirin allergy.

18:52The salvage traps close the list. A failure isn't called without checking test timing and adherence. The failed regimen isn't repeated or extended. Clarithromycin isn't reused after a clarithromycin-containing regimen failed. Empiric levofloxacin isn't the answer. Bismuth quadruple isn't given again after it has failed. Guessing doesn't continue after two failures, because resistance testing comes next. Rifabutin isn't used first-line. And the test of cure isn't skipped after any course.

19:22So, start to finish. Antral infection raises acid and causes duodenal ulcers, while infection of the whole stomach lowers acid and leads to gastric ulcer, atrophy, and cancer. Test the broadened list of patients with an active test, after holding PPIs for one to two weeks and antibiotics or bismuth for four. Histology on a body biopsy is most resilient, and serology never confirms cure.

19:48Clarithromycin resistance has ended empiric clarithromycin triple therapy. First-line is optimized bismuth quadruple therapy for fourteen days, with vonoprazan regimens as alternatives. Ask about penicillin allergy and any prior macrolide, and retest everyone at least four weeks after treatment.

20:06After a confirmed failure, never reuse clarithromycin or levofloxacin unless susceptibility is proven, while amoxicillin, tetracycline, and rifabutin can be reused. After a failure without bismuth, give optimized bismuth quadruple therapy, or vonoprazan dual therapy after a clarithromycin failure in a patient without penicillin allergy.

20:28After two failures, test for resistance, usually by molecular testing of stool or biopsy, and treat to the result. After bismuth quadruple fails, use rifabutin triple therapy. Levofloxacin is only for documented susceptibility. And retest after every course.

20:46Episode two is the ulcer itself: NSAID and aspirin injury and who needs protection, the ulcer that won't heal, and the ulcer that perforates or penetrates.

20:58For the full chapter, the practice vignettes, and the topic-tagged question bank, head to board pearls dot com. You'll find the rest of the series on Apple Podcasts, Spotify, or wherever you listen to podcasts. That brings us to the end of episode one of two of chapter six, and I'll see you in the next one.