antibiotic-resistant microorganisms can spread within the community

 A recent study found that antibiotic-resistant microbes can spread to the broader community not exposed to antibiotics (see microbiome population effect of antibiotics NatCommunic2023 in dropbox, or doi.org/10.1038/s41467-023-36633-7) 

 

Details: 

-- 8972 human microbiome samples were analyzed, the vast majority from the gut microbiome (7589  of them), analyzing the amino acid spans of DNA that help with predicting actual gene function (for those in the know, the open reading frames or ORFs)

    -- the study focused on 3096 gut microbiomes from healthy individuals not taking antibiotics, assessing them for many of the known antimicrobial resistance genes (ARGs) 

        --  healthy individuals were defined as those without C difficile infections, cholera, colorectal adenomas and cancer, inflammatory bowel disease, liver cirrhosis, type 2 diabetes, fatty liver, hypertension, rheumatoid arthritis, and shiga toxin-producing E coli

-- this genomic data was from 14 countries: Austria, Canada, China, Germany, Denmark, Spain, France, Israel, Italy, Kazakhstan, Madagascar, Netherlands, Sweden, and the US 

--  they optimized the 2017 Comprehensive Antibiotic Resistance Database in their search for likely clinically important antibiotic-resistant genes in the microbiome

-- national antibiotic consumption data was from the Center for Disease Dynamics, Economics and Policy (CDDEP), and the WHO

  

Results: 

-- in healthy individuals not taking antibiotics: 

    -- there was a five-fold increase in antibiotic-resistant genes (ARGs) 

    -- and a four-fold difference in richness (specifically the number of bacterial species with ARGs) across countries 

    -- these differences correlate highly with differences in per capita consumption rate of antibiotics in the countries (correlation value >0.8 for total ARG abundance) 

        -- interestingly this finding was not supported in the large-scale wastewater metagenome surveys for ARGs [i.e., wastewater analysis did not seem to predict microbe resistance] 

-- countries with the highest abundance and diversity of ARGs: Spain, France, and China 

    -- Spain and France have a very high antibiotic consumption rates, consistent with the above 

    -- China, however, has very low antibiotic consumption rates, despite 4 separate studies evaluated from China all finding increased ARGs (see below for possibly explanations).  

        -- the Netherlands, by contrast, has the lowest antibiotic consumption and the lowest abundance of ARGs: Spain had a 5-fold resistance level vs the Netherlands 

 

-- by antibiotic classes: 

    --sulfonamides and peptide antibiotics (eg colistin) have the lowest proportion of ARG genes 

    -- tetracyclines and amphenicols have the most 

  

Commentary: 

-- it is estimated that over 30,000 deaths in Europe in 2015 were attributable to antimicrobial-resistant infections

    -- in 2019, antibiotic-resistant microorganisms were the 3rd leading global cause of death, with 4.95 million deaths (see https://www.sciencealert.com/antibiotic-resistance-can-emerge-in-your-gut-even-without-antibiotics-use )

-- the WHO in 2017 published a list of 12 bacterial families that were felt to be "concerning" regarding antibiotic resistance, including 3 that were considered critical http://gmodestmedblogs.blogspot.com/2017/03/antibiotic-resistant-bacteria-of-concern.html 

    -- other relevant blogs of note:  

        -- antibiotic resistant gonorrhea in the US: http://gmodestmedblogs.blogspot.com/2023/01/antibiotic-resistant-gonorrhea-in-us.html

        -- antibiotic overprescribing: http://gmodestmedblogs.blogspot.com/2019/01/antibiotic-overprescribing-2-more.html. Of note this blog contains links to many other blogs, including ones on untreatable superbugs, benefits of not taking the full 10-day course of antibiotics, increased colorectal adenomas in women exposed to antibiotics, increased obesity and allergy in kids exposed to antibiotics, several blogs on overprescribing antibiotics, the concerning finding that drug companies have largely abandoned antibiotic development (turns out to be more profitable to have drugs that are used for the rest of one’s life for chronic conditions instead of short courses of antibiotics), and several blogs on clinically important microbiome changes related to antibiotics 

 

-- the finding of community spread of antibiotic-resistant bacteria is not so surprising:

    --There have been several articles finding that travelers to countries where there were higher levels of antibiotic-resistant bacteria have acquired multi-drug resistant colonization of their gut microbiome. For example, a recent small study of 23 people who visited Laos provided daily stool samples in 2015, finding tthat 100% had intestinal colonization rates of extended-spectrum b-lactamase-producing (ESBL) gram-negative bacteria at some time during their stay in Laos, and 70% had colonization at the end of the study. The colonization rate did change from day to day, suggesting that these colonizations were transient. 95% of individuals had 2-7 strains. See Dynamics of intestinal multidrug-resistant bacteria colonisation contracted by visitors to a high-endemic setting: a prospective, daily, real-time sampling study (thelancet.com)   

      -- prior studies have also had relatively small numbers of people followed for a limited amount of time and without the country diversity of this study above, noting for example that there were increases in abundance of some potentially harmful pathogens (e.g. Enterobacteriaceae) but also reductions in beneficial commensal organisms (e.g. butyrate producers); there is also concomitant decrease in overall gut microbial species diversity

    -- several other European studies have documented a correlation between outpatient antibiotic consumption and antibiotic-resistance

    -- it is well-known that several bacteria do spread within the community, such as MRSA or C. difficile bacteria, both of which have high prevalence in many communities, seemingly independent of antibiotic usage

 

-- the above study makes several important points, extending the prior studies on antibiotic-resistant bacteria spreading in the community:

    -- per capita antibiotic consumption rate in a country correlates with the abundance of antimicrobial-resistant genes in the overall population

       -- this correlation is principally driven by mobile resistance genes: ie, these genes are particularly prevalent in countries with lots of antibiotic use, seem to be transferred to those who are healthy and not on antibiotics, and are likely related to the person-to-person spread of antibiotic resistance (though the detection of the genetic material in the community is just a surrogate marker for likely clinical drug resistance)

   --  it is unclear how to explain the discrepancy between antibiotic consumption and ARGs in China. It could well be related to a reporting issue, though it could also be related to a high impact of antibiotics used in agriculture on the human gut microbiome (China does have the highest estimated use of agricultural antibiotics globally)

  

Limitations: 

-- the vast majority of antibiotic-resistant genes were associated with beta-lactams, likely reflecting the fact that this antibiotic class is the most commonly prescribed:  >50 to 60% per the WHO and other agencies, followed by macrolides in 10 to 15%, and fluoroquinolones with 10%. This distribution of antibiotics as well as the effect of newer antibiotics might change a lot in the future, potentially limiting the future generalizability of these results 

-- the ARGs found may not always be for pathogens: they could be for non-pathogenic strains of opportunistic pathogen species. This was a study of microbiome changes and did not have information on actual clinical infections that were antibiotic-resistant 

    -- though antibiotic-resistant microbial strains are profoundly important, they comprise a very small amount of the intestinal and other microbiomes. it is also conceivable that some of the detected antibiotic resistance might be associated with "unfit" microbes that would not propagate into enough antibiotic resistance to be clinically important

-- though it would seem that the gut microbiome would be the most important determinant of future antibiotic resistance, they did not have enough data to evaluate the role of the many other microbiomes: the oral cavity, skin, airways, nasal cavity, vagina, lungs)

-- their technique only provided relative changes in the gut microbiome diversity and not absolute changes, limiting our full understanding of the effects. 

-- though they excluded many people not felt to be "healthy" in their assessed population, this is from data-mining of large databases and may not truly reflect people without any health factors that might affect the microbiome (diet, exercise, stress, etc). and the health conditions cited may also not be consistent across the different countries

So, this study provides impressive data from many people in many different countries that antimicrobial resistance in the gut microbiome can be transferred from one individual to another in the community, independent of the individual's overall health. Though this has been reported in other studies, the importance of this article is that it raises front and center the broader implications of antibiotic-resistant microbes, and frames the issue as a major public health problem as opposed to focusing on the consequences of antibiotic overuse in individual patients. some implications of this broader view:

    -- it stresses the importance of decreasing antibiotic overuse within individuals, reinforcing the importance of antibiotic stewardship initiatives and suggesting these types of programs need to be widely expanded and developed in a larger, consistent way within communities. these antibiotic stewardship programs should focus on both dramatically decreasing the use of antibiotics for non-bacterial or minor bacterial infections that resolve on their own, as well as the choice of antibiotics being prescribed for important infections

    -- it reinforces the importance of decreasing the use of antibiotics in livestock, where approximately 80% of the total consumption of medically-important antibiotics are used, per the WHO (see https://www.who.int/news/item/07-11-2017-stop-using-antibiotics-in-healthy-animals-to-prevent-the-spread-of-antibiotic-resistance ), along with strong recommendations to avoid using antibiotics for non-health reasons in livestock (e.g. they are largely used to improve animals' growth and the companies' finances) and only as a targeted intervention for sick animals or those close to them. This also raises the significant issue of the huge shift to large-scale livestock farming, with tens of thousands of animals confined to small areas, where the spread of disease is facilitated

    -- it seems that we have a lot to learn from the Netherlands….

 

geoff

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