We report a case of a 67-year-old female with Helicobacter pylori gastritis who experienced
continued symptoms as well as persistently positive breath tests and gastrointestinal
biopsy results despite multiple courses of evidence-based targeted antibiotic therapies.
A trial of suppressive bismuth subsalicylate monotherapy resulted in significant clinical
improvement, and repeat gastric and duodenal biopsies were negative for H. pylori
in the setting of suppressive bismuth treatment. Given the ubiquity of this infection
worldwide and its association with abdominal discomfort, indigestion, ulcerative disease,
and malignancy, this report highlights an under-reported treatment modality that can
greatly improve symptoms and suppress infection, though continued screening is needed
in such cases given the suppressive rather than eradicative mechanism of therapy.
Helicobacter pylori is a spiral-shaped, catalase-, oxidase-, and urease-positive,
gram-negative flagellated bacterium infecting ~50% of the world population [1]. Common
gastrointestinal issues associated with H. pylori include chronic gastritis, ulcerative
disease, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue (MALT)
lymphoma [2]. Given the carcinogenic effects of this common bacterium, accurate diagnosis
and treatment are crucial. Treatment is intended to be eradicative, with multiple
evidence-based targeted antibiotic regimens available. Selection of a specific treatment
regimen should consider the local antibiogram as well as susceptibility data of the
specific strain of bacteria if available to achieve high cure rates. However, in many
cases, it is difficult to eradicate the organism despite multiple courses of antibiotic
therapy. We report a case of treatment-resistant H. pylori with bismuth subsalicylate
suppressive therapy resulting in undetectable H. pylori burden in gastric specimens
and alleviated symptomatology.
CASE REPORT
A 67-year-old female developed postprandial epigastric pain and bloating in March
2015. She had no alarm symptoms such as dysphagia, weight loss, or anemia. She had
no family history of gastrointestinal cancer and never used tobacco, alcohol, or illicit
drugs. At that time, she was not taking nonsteroidal anti-inflammatory medications,
H2 blockers, or proton pump inhibitors. Laboratory workup was notable for normal complete
blood counts and complete metabolic panel, as well as a positive breath test for H.
pylori. Treatment was initiated with triple therapy (amoxicillin 1000 mg twice daily,
clarithromycin 250 mg twice daily, lansoprazole 30 mg once daily) for 7 days. She
had continued symptoms despite compliance with the antibiotic regimen, and thus an
upper endoscopy with biopsies was performed, revealing the presence of H. pylori.
Subsequently, she was treated with 10-day sequential therapy of lansoprazole 15 mg
twice daily, amoxicillin 1000 mg twice daily for the first 5 days followed by lansoprazole
15 mg twice daily, clarithromycin 500 mg twice daily, and metronidazole 500 mg twice
daily for the next 5 days. Nonetheless, repeat H. pylori breath testing was positive
a month later, leading to a course of LOAD (levofloxacin 500 mg daily, omeprazole
20 mg daily, nitazoxanide 500 mg twice daily, doxycycline 100 mg twice daily) therapy
for 10 days, which again proved unsuccessful. The patient reported compliance and
adherence to the treatment regimens, and her family members corroborated the fact
that she took all the medications each time as prescribed. Due to failure to eradicate
the bacteria despite multiple drug therapies, she underwent immunologic testing including
measurements of her immunoglobulin levels as well as CD4 and CD8 cell counts, all
of which were found to be normal. Two additional attempts with omeprazole 20 mg twice
daily, levofloxacin 250 mg twice daily, and amoxicillin 1000 mg twice daily for 10
days as well as a 10-day course of rifabutin 300 mg daily, omeprazole 20 mg twice
daily, and amoxicillin 1000 mg twice daily, were unsuccessful, with repeatedly positive
breath tests as well as persistent symptoms.
Due to concern for a multidrug-resistant strain of H. pylori, she underwent repeat
upper endoscopy in March 2017 with biopsies taken for culture and antibiotic sensitivities.
Pathology revealed H. pylori with cultures showing that the strain was indeed resistant
to clarithromycin (Table 1). Based on this new information, therapy that included
bismuth subsalicylate 300 mg 4 times a day, tetracycline 500 mg 4 times a day, metronidazole
250 mg 4 times a day, and omeprazole 20 mg twice daily was prescribed for 14 days.
A breath test done 4 weeks after completion of this regimen was again positive for
H. pylori. Subsequently, modified LOAD therapy with moxifloxacin 400 mg daily, pantoprazole
40 mg daily, nitazoxanide 500 mg twice daily, and doxycycline 100 mg twice daily for
10 days was implemented. Moxifloxacin was chosen instead of levofloxacin due to prior
exposure to levofloxacin in the recent months in attempts to treat the H. pylori with
the standard LOAD regimen. A breath test was again positive 6 weeks after completion
of the above regimen.
Table 1.
Antibiogram of the minimum inhibitory concentration (MIC) of a multidrug resistant
strain of H. pylori
Antibiotic Susceptibility
MIC, mcg/mL
Amoxicillin
0.125
Clarithromycin
>256 (R)
Metronidazole
1
Tetracycline
0.032
Abbreviations: MIC, minimum inhibitory concentration; R, resistance.
Given failure to eradicate H. pylori with 7 different antibiotic regimens despite
adherence to treatment, suppressive therapy with bismuth subsalicylate 262 mg, 2 chewable
caplets twice a day as monotherapy, was initiated. After 2 months on bismuth subsalicylate
therapy, the patient reported marked improvement in her abdominal discomfort, bloating,
and overall quality of life. An H. pylori breath test done 4 months after starting
bismuth subsalicylate therapy was negative. An upper endoscopy in April 2018, 6 months
after starting bismuth therapy, showed chemical gastropathy on pathology but did not
grow H. pylori organisms from the gastric antrum, body, or fundus. After being on
bismuth therapy for another 6 months and feeling much better overall, the patient
discontinued therapy to assess if the H. pylori was truly eradicated or just suppressed.
An upper endoscopy with gastric mapping biopsies done 6 months after she stopped bismuth
therapy showed recurrence of H. pylori in the gastric specimens, though she remained
asymptomatic. As such, while resumption of therapy with bismuth was recommended to
prevent potential downstream effects of H. pylori infection, after a prolonged discussion
regarding the risks and benefits associated with restarting therapy, the patient decided
to continue to hold off on further treatment as her symptoms had resolved completely.
The patient has been off bismuth therapy for 2 years and has remained symptom free.
DISCUSSION
In the early 1990s, standard triple therapy with a macrolide, amoxicillin, and a proton
pump inhibitor for H. pylori infection was >90% effective in eradication [3]. However,
over the past few decades, triple therapy has declined in efficacy, mainly due to
development of macrolide resistance. To minimize development of further resistance
patterns, it is important to review a patient’s prior antibiotic use, which may predict
clarithromycin resistance. As with all bacterial infections, compliance and completion
of the prescribed duration of antibiotic therapy are important from an antibiotic
stewardship perspective.
H. pylori is reportedly most transcriptionally active at a neutral pH despite its
affinity for the acidic environment of the stomach and proximal small intestine. The
organism can generate a less acidic environment in the stomach via the effects of
its urease enzyme [4]. Because most antibiotics used to treat H. pylori depend on
active bacterial replication for their effects, proton pump inhibitors, which act
to further increase gastric pH, are prescribed concurrently in H. pylori treatment
cocktails. However, a new form of phenotypic resistance developed by H. pylori has
resulted in strains that do not only replicate at a neutral pH, and, as a result,
the strains are not sufficiently killed by routine antibiotic therapy [4]. This mechanism
of resistance is just one of many creative ways H. pylori has evaded eradication,
and it is highlighted here as an example rather than a definitive explanation for
our patient. Medication noncompliance could be another explanation for our patient’s
treatment-resistant infection, though from our perspective this is extremely unlikely,
as she was very motivated to improve her symptoms and quality of life. While the successive
therapies may not be exactly as the current guidelines advise, the patient’s initial
treatment journey began in 2014 when the treatment guidelines were different. Moreover,
she had some limiting factors preventing her from taking only guideline-based therapies
including costs. As clinicians, we also recognize that often after a patient has failed
multiple regimens, there is not clear guidance on what to do next. Ultimately, it
was the initiation of bismuth subsalicylate monotherapy that provided the most clinical
improvement for this patient. While the bismuth-based quadruple therapy failed in
this patient, likely due to the short course of bismuth in the regimen, the prolonged
course of bismuth monotherapy has successfully kept her disease suppressed. As such,
one can infer that while the bismuth was not curative as part of a short course of
therapy, it can be used to suppress H. pylori in patients who fail treatment regimens
that include this agent.
Bismuth is commonly employed in combination therapy for treatment of H. pylori, but
it is infrequently used as monotherapy. The exact mechanism of action of bismuth is
unclear, but it has been shown to inhibit adenosine triphosphate production in H.
pylori and exhibit bactericidal activity [5, 6]. As with our patient, the current
literature describes patients who were able to adequately suppress their H. pylori
levels to below detectable while on bismuth, but then commonly tested positive again
after stopping bismuth [7]. This observation provides further evidence to suggest
that bismuth, while bactericidal to some extent, is mainly providing suppressive effects.
Importantly, while H. pylori is being suppressed to low levels, patients may experience
improvement in their dyspepsia, gastritis, or ulcer-related symptomatology. There
are several advantages to bismuth therapy for treatment of H. pylori despite its suppressive
rather than curative effects; namely, it is available over the counter, is relatively
inexpensive compared with prescription antibiotics, and is overall well tolerated.
Being that bismuth is not an antibiotic and given its relatively benign side effect
profile (black colored stools, black coated tongue, constipation, mild abdominal discomfort),
it is safe to prescribe bismuth for an extended period.
Here, we report an interesting case of a treatment-resistant H. pylori infection in
a 67-year-old female that was ultimately symptomatically controlled, rather than eradicated,
with bismuth subsalicylate monotherapy. In our opinion, this is a reasonable and simple
option given the significant financial, emotional, and potentially carcinogenic burden
that persistent disease has on patients like the one presented. This case presents
learning opportunities involving important perspectives on the growing antibiotic
resistance of H. pylori, the efficacy of nonantibiotic treatment options for such
an infection, and the importance of patient–physician collaboration when faced with
difficult cases.