H Pylori: resistance patterns in the US

 A new article explored the rates of antimicrobial resistance in H. pylori isolates from patients across the US and Europe, finding profound levels of resistance especially to metronidazole and clarithromycin (see H pylori antimicrobial resistance AmJGastro2022 in dropbox, or doi: 10.14309/ajg.0000000000002045) 

 

Details: 

-- H. pylori isolates were obtained from 907 patients in 103 centers across the US and 5 European countries 

-- mean age 51, 70% female, 90% white/8% Black 

-- BMI 29, current smoker 21%/ex-smoker 20%/never smoker 60%, alcohol use a couple of days per month 33%/couple of days per week 18%/every day 2%/never 45% 

-- dyspepsia 98%/nonbleeding peptic ulcer 2%/history of untreated peptic ulcer 2%/long term NSAIDs at a stable dose 3% 

-- H pylori infection was confirmed by ¹³C-urea breath test and gastric biopsy specimens 

 

Results: 

-- clarithromycin resistance: 201 of 907 participants (22.2%) and was above 15% in all US subregions and in all European countries except the UK (but only 8 patients from there)

    -- in the US, the greatest prevalence of clarithromycin resistance was in the Southeast (24.9%); in European countries it was in the Czech Republic (26.7%) 

-- amoxicillin resistance: 11 participants (1.2%), 8 of whom were from the US and half of those were in the West 

-- metronidazole resistance: 69.2%, with resistance in the US ranging from 54.5% in the West to 73.3% in the Southwest, and in Europe from 50% in the UK to 79.4% in Bulgaria 

 

-- somewhat more clarithromycin resistance in females (69.7% versus 60.5%), p<0.05 

-- also somewhat more common in white patients (93.0% versus 87.8%), p<0.05 (but the population was predominantly white)

 

-- Multidrug resistance: 

    -- those clarithromycin- resistant also had metronidazole resistance in 151 people (75.1%): 59.6% of these people were from Europe and 40.4% from the US 

 

-- here’s a map of the H pylori resistance patterns in the US (the “gray” states did not participate in the study):  

 

 

 

 

Commentary: 

-- H pylori is the most common bacterial infection of the world, infecting more than 50% of the world's population. It is also quite prevalent in the United States, with studies suggesting that 30 to 40% of people here are infected 

-- treatment success with eradicating H pylori has declined sharply in the last decade, attributed to clarithromycin resistance 

-- A study from Turkey found that diabetes and prior use of metronidazole and clarithromycin were associated with increased resistance to these antibiotics, and there was no association with resistance by age, sex, BMI, smoking, or alcohol use 

-- both the Maastricht V and American College of Gastroenterology clinical practice guidelines recommend that the triple regimens with the PPI and clarithromycin should not be used empirically where local resistance patterns are >15%, is unknown (as is basically the case with the United States) or if the patient has had prior exposure to a macrolide (macrolide-naivety seems to be quite unlikely in the US...) 

 

-- H. pylori is associated with lots of potential bad outcomes including gastric adenocarcinoma, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, peptic ulcer disease and gastritis, colon cancer, and increased risk of major GI bleeds in those on NSAIDs. so a couple of anecdotes and less common findings:

    -- a patient of mine with chronic urticaria/pruritus for years, who was H pylori positive (i do screen pretty much everyone, finding that even local people who never left this country are not-so-infrequently positive), treated him and he had a dramatic recovery from his pruritis. I then found a review article suggesting linkages between H pylori infection and several skin problems, including urticaria, Behcet’s disease, lichen planus, pruritus, prurigo nodularis and prurigo chronica.  (see hpylori and skin disease amjclinderm2002 in dropbox, or Wedi B. Am J Clin Dermatol. 2002; 3(4): 273).  

    -- another patient about 30 years ago who had not traveled abroad developed severe, refractory, steroid-resistant ITP and was about to get a splenectomy. i had just read a report in the Lancet of an association between H pylori and ITP, tested him, found H pylori, treated it, and the ITP vanished literally within days and prior to his scheduled surgery, never to return. The newer ITP guidelines do list H pylori as having this potential association

    -- also, studies have found an increased risk of major GI bleeding with NSAIDs if there is an underlying H pylori infection (and a 2/3 reduction if H pylori is treated before starting NSAIDs!!!) see http://gmodestmedblogs.blogspot.com/2015/05/h-pylori-and-nsaids-increased-gi.html 

-- this year the NIH included H Pylori on their list of carcinogens: see http://gmodestmedblogs.blogspot.com/2022/03/carcinogen-update-now-including-h-pylori.html 

 

-- the presumed reason for H. pylori antibiotic resistance is the widespread use of these medications as single agents for other infections, and as single agents they are ineffective against H pylori, similar to the need for a cocktail of multiple meds for HIV (but single antibiotics do incubate resistance in both cases)

-- the US does not routinely perform resistance assays for H pylori (for unclear reasons to me), but a study done in 2015 in Houston reported clarithromycin resistance increased from 9.1% in 2009-10 to 24.2% in 2011-13, and 20.3% of isolates were resistant to metronidazole. This led to a small study in 2017-18 from 20 states across the US, finding resistance rates of 0% for rifabutin, 6.4% for amoxicillin, 17.4% for clarithromycin, and 43.6% for metronidazole. Of the isolates tested for levofloxacin and tetracycline resistance, 57.8% were resistant to levofloxacin and 2.8% to tetracycline. In addition, 23.9% with clarithromycin resistance had dual resistance to levofloxacin. Clarithromycin resistance ranged from 11.1% in the Western US to 23.2% and Eastern states (https://www.gastrojournal.org/article/S0016-5085(21)00572-2/pdf ) 

-- metronidazole resistance is sky-high in this study and others, but it does not seem to be associated with treatment failure to the same extent as clarithromycin resistance (pointing out how powerful a drug clarithromycin really is)

 

Prior blogs on H Pylori treatments:

-- it seems that clarithromycin resistance is related to the development of reflux channels in the cell membrane (that basically kick the clarithromycin out of the cell), and that amoxicillin pretreatment changes the structure of the organism's cell membrane and prevents this efflux. A specific study assessed patients with documented clarithromycin resistance and found the vast majority were cured with a sequential regimen though in those without amoxicillin pretreatment failed miserably (ie 89% vs 29% success rates: hpylori rx sequential annals 2007 in dropbox, or see http://gmodestmedblogs.blogspot.com/2013/11/h-pylori-therapy-sequential-vs-standard.html. the sequential regimen in basically twice-daily amoxicillin 1 gram, and a PPI for one week, then twice-daily clarithromycin 500mg, metronidazole 500mg, and PPI for the next week. 

-- a potent newer approach involves amoxicillin, omeprazole, and rifabutin, as a means to avoid clarithromycin resistance  (and also avoids using metronidazole, with the issue of resistance but also intolerance, both of which are high with both meds): http://gmodestmedblogs.blogspot.com/2022/06/h-pylori-rifabutin-based-therapy.html  

-- for direct access to the many prior H pylori blogs, go to https://www.bucommunitymedicine.org/tag/h-pylori/

 

Limitations: 

-- one issue is that immigrants may well carry the resistance patterns of the countries they came from, which may be very different from those in the US and UK (where perhaps these specific antibiotics may be used more frequently?). So the resistance patterns of the study may not apply so generally to individuals

-- it seems that all of these patients in the study were symptomatic (ie worked up by gastroenterologists for upper GI symptoms), but H. pylori is frequently asymptomatic, and a few studies have found that treating people with asymptomatic H. pylori infection decreases their risk of subsequent gastric cancer (see http://gmodestmedblogs.blogspot.com/2019/04/h-pylori-eradication-and-reduced-risk.html ). in terms of the prevalence of asymptomatic patients:

    -- 3rd NHANES survey found that of 7465 adults: overall there was a 32.5% seropositivity for H pylori, with increases by age (16.7% 20-29 yo, up to 56.9% of >70yo), and by ethnicity/race (52.7% of non-Hispanic Blacks, 61.6% of Mexican-Americans, 26.2% non-Hispanic whites), see https://academic.oup.com/jid/article/181/4/1359/856832 . they did not mention symptoms in this NHANES report, but this was random sampling of the population

    -- a VA study confirmed a large number of H Pylori cases in veterans: see http://gmodestmedblogs.blogspot.com/2019/12/h-pylori-in-us-veterans.html . 

    -- another Houston study found that in their screening of 485 healthy asymptomatic volunteers, H pylori was present in 52% (see Gastroenterology 1991;100:1495–501) 

    -- this brings up the selection bias issue: is H Pylori resistance patterns the same in those who are asymptomatic as symptomatic? Are the H pylori variants (see below) associated with more aggressive infections similarly represented in asymptomatics?

-- there were only 907 patients involved in the study (though this seems to be the largest sample to date). which means about 9 people on average for each of the 108 centers used. this seems like a small number to draw sweeping conclusions about treatment (though their percentages of resistance are actually not so different from the few other articles). We certainly would not base our treatment for UTIs on the basis of antibiotic sensitivity for a few people from our area....

-- there was also a significant skew in the patients in this study: 90% white/8% Black. do their numbers truly reflect resistance patterns in the US?

    -- the epidemiology of H pylori is not so clear. it seems to have been around for at least 58,000 years, is endemic globally, is largely found initially in kids, can be cultured in vomitus and stools, but (sadly, for the most common bacterial infection in the world, and a carcinogen to boot) we do not know the route of transmission, though likely human-to-human transmission somehow

    -- it does seem in the observational studies that the infection is more common in non-white people, which is likely related to important socioeconomic differences (there are some suggestions of hereditability, but unclear). and there are some differences in the H pylori itself (the CagA variant is associated with more precancerous and gastric cancer; the VacA variant with colon cancer (and i wonder if the latter might be one reason for the decreasing age of colon cancer, leading to decreased age of screening testing now)

-- this study was exploratory, since these participants were involved in a large clinical trial not primarily designed to assess H. pylori resistance. Such a study design is open to unanticipated confounding, which would limit the accuracy of the results.

 

So, a few points: 

-- the increase in H. pylori resistance to clarithromycin and metronidazole undoubtedly relates to the high usage of these antibiotics for relatively common problems. This really reinforces the importance of limiting uses of antibiotics to very clear indications, using antibiotics topically when possible (eg, I would assume, not based on evidence i have seen, that intravaginal metronidazole gel may be superior to the relatively high dose given orally for bacterial vaginosis, and macrolide antibiotics such as clarithromycin and azithromycin are very much overprescribed for non-bacterial infections: see http://gmodestmedblogs.blogspot.com/2019/01/antibiotic-overprescribing-2-more.html) 

-- based on prior studies, I still believe that the sequential H. pylori treatment regimen is a reasonable one, and it has worked in essentially all of my patients. In that case the amoxicillin disrupts the clarithromycin resistance mechanism, as noted above 

-- another option which seems quite reasonable is rifabutin therapy, as noted above. The only real catch here is that there are many drug-drug interactions between rifabutin and a lot of other medications. So it is important to check for these interactions prior to prescribing (and routine testing of younger adults, as i think is appropriate, would lead to treatment at a younger age when they are less likely to be on a slew of meds, and there are likely to be fewer drug-drug interactions)

-- I do not understand why we do not do routine resistance testing for H. pylori, but that would be a reasonable approach to treating this infection effectively and tracking/understanding better its epidemiology and changing resistance patters (the authors of the study comment that tailoring therapy based on known resistance patterns improve eradication rates, and there is a real-time PCR kit to detect H pylori and its resistance to clarithromycin, and at a low cost).  seems that this should be pretty standardized, or at least assessing large samplings in local areas at sentinel high-volume labs, and tracking changes/publicizing them broadly in the local area....

geoff

 

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