H Pylori: antimicrobial resistance in Rhode Island

 A study from Rhode Island documented antibiotic resistance to H Pylori (thanks to Boris Skurkovich for bringing this to my attention): see h pylori resistance rhode island Gastro2021 in dropbox or doi:10.1053/j.gastro.2021.02.014. 

 

Details:

-- 189 patients from 2 hospitals in Rhode Island (total 1000 beds), who had positive gastric biopsies for H Pylori and assessed its eradication after treatment

     -- eradication determined by urea breath test in 51%, stool antigen in 40%, and biopsy in 10%

-- mean age 45, 68% male, 29% white/25% Black/ 44% Latinx

-- treatment duration 14 days (the standard now) in 91%

-- antimicrobial resistance was determined through the PyloriAR assay, which evaluates DNA mutations in the H Pylori genome associated with fluoroquinolones, metronidazole, clarithromycin, ampicillin, tetracycline and rifabutin, using “next-generation sequencing”

-- H Pylori presence was determined by quantitative real-time PCR testing

 

Results:

-- eradication rates by treatment:

    -- bismuth-based quadruple therapy: given to 54% of the patients; 88% had eradication

    -- triple therapy: 46% of patients; 61% had eradication

        -- quad therapy had statistically significant benefit over triple: OR 4.8 (2.3-10.1), p<0.001

 

-- overall, 66% of H Pylori strains were resistant to at least one antibiotic

-- 84 patients receiving clarithromycin-containing therapy had clarithromycin-resistant H Pylori: eradication failures were quite high at 56%, vs eradication success at 14%, p<0.001

-- 123 patients received metronidazole-containing therapy but had metronidazole-resistant H Pylori: no real difference in eradication failures: failures in 37% and successes in 33%, p=0.72

    -- and, those regimens in patients who had metronidazole-resistant H Pylori but had at least one other antimicrobial that the bug was sensitive to: 94% eradiation after a 14 day treatment (ie, despite metronidazole resistance)

 

Commentary

-- this study complements another broader scale one noted in a recent prior blog http://gmodestmedblogs.blogspot.com/2022/11/h-pylori-resistance-patterns-in-us.html

-- these studies are really important, given the high prevalence of H Pylori infections (>50% of the global population infected), widespread use of several of the antibiotics that are also used in combination for H Pylori (and leading to H Pylori resistance), importance of successful H Pylori treatment to decrease the myriad of H Pylori symptoms, and importance of treating even asymptomatic H Pylori infections in decreasing subsequent gastric cancer and major GI bleeds in those on NSAIDs (see http://gmodestmedblogs.blogspot.com/2022/11/h-pylori-resistance-patterns-in-us.html for more detailed information)

    -- not only do we not have much information about H Pylori antimicrobial resistance patterns in the US, but we have even more limited data on H Pylori variants. For example, the CagA H Pylori variant has a higher risk of gastric cancer (see http://gmodestmedblogs.blogspot.com/2018/01/h-pylori-ppi-use-and-gastric-cancer.html ), and the VacA variant with colorectal cancer. I suspect that these variants (and perhaps others) may be at least part of the explanation of the large variability of gastric cancer incidence around the world. But too little data or testing to know…

-- the antimicrobial resistance assay they used was successful in 95% of the cases and has a really rapid turnover, results being available in 72 hours (see http://resistancecontrol.info/wp-content/uploads/2019/05/Rupp%C3%A9.pdf for more info on this). This technique would be particularly helpful for hard-to-grow bugs (like H Pylori) that would then be subjected to an array of antibiotics to determine the extent of growth retardation by those antibiotics: all of which can take lots of time and limit scaling up the assay to lots of samples (ie not so useful clinically)

 

-- I personally have been using one of the following 2 treatment regimens:

    -- sequential therapy still involving clarithromycin: 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. So, amoxicillin effectively reverses clarithromycin resistance. A  study assessed patients with H Pylori and documented clarithromycin resistance and found the vast majority were cured with a sequential regimen, though 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 . the basic drawback of this therapy is drug-drug interactions with rifabutin

 

--the issue of metronidazole resistance is interesting: in the above study, if patients had at least one other antibiotic to which the H Pylori was sensitive, they had exceptionally high cure rates. This suggests that metronidazole may not really provide any clinical effectiveness if the other antibiotics work. This finding of little metronidazole benefit has been found in other studies using other methods of assessing metronidazole resistance: see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6905086/ and http://gmodestmedblogs.blogspot.com/2022/11/h-pylori-resistance-patterns-in-us.html .

 

Limitations:

-- we do not have much granular data on these individuals. Were they exposed to clarithromycin, for example, prior to having their H Pylori detected/treated? How long before? What was the intensity of the exposure if they had one? Were there underlying comorbidities that might have affected their clinical courses and response to treatment?

-- as with all locally-specific studies (ie Rhode Island in this case), there are questions about generalizability of the results elsewhere, and these results may change over time even in one locality. Hence, the need to perform enhanced and regular checking

-- how accurate is next-generation sequencing in determining clinical response to treatment? Are the targets of this genetic sequencing of antibiotic resistance genes complete enough? Does this approach deal with other mechanisms of antibiotic resistance, such as mediated through plasmids? This lab technique is quite impressive, but would be great to have confirmation from larger studies that the test does truly predict clinical outcomes.

 

So, I bring up this article for a few reasons:

-- a selfish one: it is very likely that antibiotic resistance patterns are similar in Providence, RI to my base in Boston, MA. So the results are likely generalizable to my area

-- the technique used next-generation sequencing (seems pretty great and would allow for location-specific resistance patterns pretty rapidly, and could then detect changes over time)

    -- the technique would also be an important public health tool to track antibiotic resistance to perhaps several different microbes as well as H Pylori

-- this is another study suggesting that metronidazole may not play a significant role in clinical outcomes. Metronidazole, however, still plays a significant role in conferring adverse effects!!! Maybe the sequential treatment above would work just fine without the second week of metronidazole?? worth studying....

-- overall, i think this study supports the above 2 treatment regimens in those areas with increased clarithromycin resistance (eg, prevalence >15% or so): the sequential and rifabutin-based ones

geoff

-----------------------------------

If you would like to be on the regular email list for upcoming blogs, please contact me at gmodest@bidmc.harvard.edu

  

to get access to all of the blogs (2 options):

1. go to https://www.bucommunitymedicine.org/ , a website from the Community Medicine section at Boston Medical Center.  This site does have a very searchable and accessible list of my blogs and is the easiest to view blogs and displays more at a time.

2. go to http://gmodestmedblogs.blogspot.com/ to see the blogs in reverse chronological order

  -- click on 3 parallel lines top left, if you want to see blogs by category, then click on "labels" and choose a category

  -- or you can just click on the magnifying glass on top right, then type in a name in the search box and get all the blogs with that name in them

please feel free to circulate this to others. also, if you send me their emails, i can add them to the list