SUMMARY: Antibiotic resistance is invisible to most of us until you, a family member, or an acquaintance acquires such an infection. You can check out the slides below to see state by state, US Antibiotic Resistance Risk and state Antibiotic Use. Perhaps the most reasonable mechanism to prevent antibiotic need in the first place, is explained in the post PRESERVE & RESTORE LOSS OF MICROBIOME DIVERSITY IS AGGRESSIVE PREVENTATIVE MEDICINE. These concepts are especially important given that the average American has lost 1/3 of their microbiome diversity, as estimated by Dr. Maria Gloria Dominguez-Bello as seen on this interview for the film “Microbirth.” Another study estimates 1 in 4 have 40% less bacteria (see This Danish study, or read the scientific article here).
This post teaches that the WHO, and the United States, this month took their first steps to recognize the invisible threat of antibiotic resistance, which missed the microbiome connection. You can comment to the US Request for [Microbiome] Information and help bring this to the forefront. Of course their goal of providing alternate antibiotics to wage the war on antibiotic resistance is wrought with difficulties due to the antibiotic pipeline:
- About 2000, numerous companies withdrew from antibiotic manufacturing, and the number of new antibiotics in development dropped from dozens to three.
- And the cost: The report, Review on Antimicrobial Resistance, estimates that we need 15 new antibiotics over 10 years, of which four would have to be truly new formulas (two broad-spectrum, or capable of attacking a number of bacteria, and two narrow-spectrum), while the remainder could be incremental improvements on existing formulas. It estimates the effort would require between $16 billion and $37 billion over that decade—huge amounts, but as the report points out, the global market for antibiotics now earns $40 billion every year, while resistance costs just the United States $20 billion per year in excess healthcare costs. Read more here and here, and the problem of the antibiotic pipeline, if interested.
⇒⇒Also covered last in this post, for background, is who actually lives in your gut and why it is difficult to know who truly is living in your gut. There are four dominant phyla that comprise the intestinal commensal microbiota of humans. These include Firmicutes and Bacteroidetes, which normally account for >90% of the bacterial populations in the colon, as well as Actinobacteria and Proteobacteria. The intestinal commensal populations are altered when comparing certain disease with non-disease. In addition, when some of these gut players are reduced, skewed, or absent there is health ramifications even beyond disease —for example, acetaminophen is toxic to the liver.
WHO commits unanimously to tackle antibiotic resistance
The annual World Health Assembly is the meeting of health minsters from 194 countries that serves as the decision-making body for the World Health Organization (WHO). For the first time, the global crisis of antibiotic resistance was addressed; the delegates committed unanimously to tackling the issue; WHO Director-General Dr. Margaret Chan’s welcome speech, May 2015:
“This is a unique time in history where economic progress is actually increasing threats to health instead of reducing them… As the century progressed, more and more first- and second-line antimicrobials failed. The pipeline of replacement products ran dry, raising the spectre of a post-antibiotic era in which common infections will once again kill. A draft global action plan on antimicrobial resistance is on your agenda. I urge you to adopt it.”
Five components of the WHO plan (see details here, or here for WHO pdf, or this article, World Health Organization Vows To Combat Drug Resistance):
- “Improve awareness and understanding of antimicrobial resistance,” Include instruction on resistance in school curricula and in professional training for healthcare, veterinary and agricultural personnel;
- “Strengthen surveillance and research” by rapidly gathering environmental and diagnostic data on resistant organisms and support studies of costs of resistance and alternatives to antibiotics;
- “Reduce the incidence of infection” by improving hygiene in healthcare and increase the use of vaccines to prevent infections;
- “Optimize the use of antimicrobial medicines” by reducing over-prescription and uncontrolled over-the-counter sales, and improving rapid-result diagnostic tests that make sure the correct drugs are prescribed;
- “Ensure sustainable investment in countering antimicrobial resistance, or put another way, develop the economic case for sustainable investment,” persuade pharmaceutical companies to return to making antibiotics and guaranteeing that low-income countries will have adequate access to drugs.
In an unrelated action, in May, 2015, the White House asked for input (by June 15) on the future of microbiome research. Read here for details of how to summit your comment(s), but the summary of the Request For Information (RFI) is:
Advanced sequencing technologies have illuminated vast networks of microorganisms that drive essential functions in all environments on Earth. The study of these communities of microorganisms, or microbiomes, is nascent, and the potential of microbiome research has only begun to be tapped. Primary to achieving this potential is a functional understanding of microbiomes, which would be greatly advanced by addressing fundamental questions common to all fields of microbiome research; developing platform technologies useful to all fields; and identifying gaps in training or fields of research that should be addressed. The Office of Science and Technology Policy (OSTP) is interested in developing an effort to unify and focus microbiome research across sectors. The views of stakeholders—academic and industry researchers, private companies, and charitable foundations—are important to inform an understanding of current and future needs in diverse fields.
The purpose of this RFI is to solicit feedback from industry, academia, research laboratories, and other stakeholder groups on both the overarching questions that unite all microbiome research and the tools, technologies, and training that are needed to answer these questions. OSTP is specifically interested in information that corresponds to the mission statements of multiple Federal agencies, private sector interests, and current White House Policy Initiatives. In particular, respondents may wish to address the following topics:
What are the most pressing, fundamental questions in microbiome research, common to most or all fields?
Over the next ten years, what are the most important research gaps that must be addressed to advance this field?
What tools, platform technologies, or technological advances would propel microbiome research from correlative to predictive?
What crucial types of scientific and technical training will be needed to take advantage of harnessing the microbiome’s potential?
What fields of microbiome research are currently underfunded or underrepresented?
What specific steps could be taken by the federal government, research institutes, universities, and philanthropies to encourage multi-disciplinary microbiome research?
Is there any additional information, not requested above, that you believe OSTP should consider in identifying crucial areas of microbiome research?
This RFI is in stark contrast to: White House outlines plan to fight antibiotic-resistant bacteria, which totally misses PRESERVE & RESTORE LOSS OF MICROBIOME DIVERSITY IS AGGRESSIVE PREVENTATIVE MEDICINE which is likely the most reasonable mechanism to prevent antibiotic resistance in the first place:
Antibiotic resistance is invisible but its microbiome decimating effect is here to stay.
Check out the slides below to see your states antibiotic use and risk of antibiotic resistance. -Center for Disease Dynamics, Economics & Policy
From the White House:
More than two million Americans develop antibiotic-resistant infections each year and about 23,000 die as a result. Ineffective antibiotics have to be replaced with new drugs and antibiotic alternatives are also needed in veterinary medicine. The five-year plan released on Friday focuses on slowing the emergence and spread of resistant infections;
- strengthening bacterial surveillance efforts;
- developing new tests to quickly identify dangerous bacteria;
- developing new drugs to fight the so-called “superbugs,” and
- working more closely with international partners to achieve these goals.
President Obama’s fiscal year 2016 budget proposal would nearly double federal funding for the fight against antibiotic resistance to $1.2 billion. ‘It’s a good plan. Now we need to carry it out,” President Obama said. “We can better protect our children and grandchildren from the reemergence of diseases and infections that the world conquered decades ago, but only if we work together, for as long as it takes.”
Academic Deficits Need Overcome to Achieve Goals
While I strive to make the complex accessible, realize the first step needed involves data information interpretation using tools few know. This comment from BENK sheds light: A number of years ago, I suggested to Rita Colwell that a summer bootcamp for incoming biology graduate students be established to teach quantitative methods and core programming/automation skills. This was modeled on the econometrics bootcamp established for incoming students at Yale. My initial conception was for a regional offering, perhaps starting in New England. Times have changed, tools have changed, but the need for graduate students who can analyze data is more pressing than ever. Now, I would probably suggest that a summer bootcamp incorporate temporal, spatial, phylogenetic analysis, design of experiment, as well as software carpentry, R, some Bayesian GLM and hierarchical modeling tools, as well as introductions to Markov chains/HMM and ODEs, with the appropriate tools for computational solution (Octave, perhaps).
Microbiome competitive crowding out concepts: We know about antibiotic resistance due to antibiotic human and livestock overuse; enter the far more ominous side effect of antibiotic use — the concomitant loss of our resident microbiota:
Ubiquitous antibiotic exposure
Antibiotic exposure affects all of us regardless if you have been prescribed such or not. “Superbugs from farms that do use antibiotics could still make their way to humans through the water supply and other means…this is how most resistance genes get to humans, rather than through the direct consumption of animals raised on antibiotics…Industrial farms feed animals low doses of the drugs in order to promote growth and ward off infections within densely packed herds. From there, natural selection does its job: The bacteria that can overpower the drugs survive and multiply, and they make their way out into the environment through water, urine, and feces. In the U.S., 80 percent of antibiotics are used in animals. It is estimated that antibiotic use globally will increase by–The Antibiotics Problem in Meat
CDiff infections moving mainstream from prior understanding of mostly hospital acquired (following routine antibiotic prep for surgery is common)
C. diff. is a spore-forming, toxin-producing bacterium that can colonize the large intestine and wreak havoc there, causing frequent watery stools and severe dehydration. The spores are resistant to heat, acid and antibiotics; they can be washed away with soap and water but are not inhibited by the alcohol-based hand sanitizers now widely used in health facilities. Thus, poor bathroom hygiene can spread this nearly ubiquitous organism to vulnerable individuals. –Wide Use of Antibiotics Allows C. Diff to Flourish.
CDiff infections are not just hospital acquired, rather medical offices including dental may be infection sites. C. diff. infections acquired outside hospitals have “increased dramatically in the past decade and may now account for up to a third of new cases. Among those infected outside hospitals, “about 80 percent had a recent health care exposure,” for example, at a clinic or a doctor’s office, where they may have been prescribed antibiotics and exposed to the spores.” –Wide Use of Antibiotics Allows C. Diff to Flourish. Also see CDC investigates deadly bacteria’s link to doctors’ offices: “a 2013 study, researchers found C. diff present in six out of seven outpatient clinics tested in Ohio, including on patients’ chairs and examining tables...patients should wash their hands after visiting the doctor’s office — with soap and water, because alcohol-based gels don’t get rid of C.diff.”
Isn’t it really ineffective hygiene that spreads CDiff, and what happens once it reaches our water supply?
Dr. Dale N. Gerding, an infectious diseases specialist at Loyola University Chicago:
- C. diff. is found in soil and water, even chlorinated water, and is a low-level contaminant in food. Most of us ingest C. diff. every day. In most people the myriad micro-organisms that normally reside in the gut protect against C. diff. infection.
- Antibiotics disrupt the healthy balance of micro-organisms. Freed of competition, C. diff spores can germinate and reproduce unchecked, and not only in people with compromised immune systems. I can’t reiterate this enough: PRESERVE & RESTORE LOSS OF MICROBIOME DIVERSITY IS AGGRESSIVE PREVENTATIVE MEDICINE
“The healthy gut microbiota has three features: a large number of micro-organisms, a large number of different species, and an increased representation of certain bacterial phyla and a decreased representation of other phyla. The disruption of any of these features can result in increased susceptibility to the growth of C. difficile… Even after infected individuals recover, about 5 percent continue to harbor the toxic strain in their stool for six months, and if they take another antibiotic during that time, the illness can recur.”
CDiff spores are resistant to heat, acid and antibiotics; they can be washed away with soap and water but are not inhibited by the alcohol-based hand sanitizers now widely used in health facilities. Just use soap and water!!!
“Following surgery to reset the broken arm bone, he was given an antibiotic to prevent postoperative infection, a common hospital practice… within a week her father developed diarrhea caused by a particularly nasty intestinal bacterium called Clostridium difficile, or C. diff. Another antibiotic seemed to eradicate the disease, but a month later the gut infection recurred. Mr. Epstein was given another antibiotic, but within days developed a fatal combination of kidney failure, dangerously low blood pressure and gastrointestinal bleeding. Although this sounds like an example of “the operation was a success but the patient died,” Mr. Epstein’s demise is really the result of inappropriate use of antibiotics, which has given rise to a virulent, antibiotic-resistant strain of C. diff., an organism that now causes close to 500,000 new cases and 30,000 deaths a year in the United States alone. –Wide Use of Antibiotics Allows C. Diff to Flourish
“Ampicillin, amoxicillin, cephalosporins, clindamycin and fluoroquinolones are the antibiotics that are most frequently associated with the disease, but almost all antibiotics have been associated with infection.” –Wide Use of Antibiotics Allows C. Diff to Flourish
In the US, only after repeated antibiotic failure (thus confirming that the CDiff strain is in fact antibiotic resistant) is FMT allowed to be administered in order to implant a new donor microbiome. Fecal microbiota transplantation has >90 percent cure for antibiotic resistant CDiff. More details on FMT can be found in PRESERVE & RESTORE LOSS OF MICROBIOME DIVERSITY IS AGGRESSIVE PREVENTATIVE MEDICINE.
Some are even Taking Swipes at Chlorhexidine Wipes which are increasingly being used daily in hospital settings to prevent hospital-acquired infections. This accompanying editorial raised concerns about resistance developing to chlorhexidine with its widespread use. The study, Chlorhexidine Bathing and Health Care-associated Infections: A Randomized Clinical Trial, found patients bathed with chlorhexidine-impregnated cloths and those bathed with nonantimicrobial cloths did not differ in the primary outcome, which was a composite of four hospital-associated infections: CLABSIs, catheter-associated urinary tract infections, possible or probable ventilator-associated pneumonia, and Clostridium difficile infection.
This ends this post as it’s purpose is to update you on your state’s risk of antibiotics and antibiotic resistance, as well as the lack of understanding of the microbiome and antibiotic resistance currently occurring at agency levels. You can do something about that and comment to The Office of Science and Technology Policy Request for [Microbiome] Information. Those wanting to revisit the microbiome basics can do so in the information below my signature. As an added bonus, I’ve caved and inputted some slides you requested. ♥
Last updated: February 15, 2017 at 16:01 pm to change title to “US Antibiotic Resistance and WHO”. Original title was “ANTIBIOTIC RESISTANCE AND MICROBIOME COMPETITIVE CROWDING OUT CONCEPTS”. Helps with SEO optimization.
In health through awareness,
Now for background for those new to Microbiome… First, define it to better understand competitive crowding out concepts
It was ~2001, when the initial sequence of the human genome shockingly and dramatically cut the number of human genes that was expected to be found which was then estimated to be about 100,000 human genes. Instead, we incredulously learned that humans have fewer human protein-coding genes than nematode worms or even the water flea, which has 31,000 genes. Despite this, the idea that more complex organisms require more genes was not debunked since the piggyback microbiome studies, still ongoing, is unveiling the human microbiome.
Recall the pearls of our first meeting, that the microbiota includes the organisms termed: bacteria, arachea, viruses, and eucarya. The microbiome by definition, includes the collection of ALL of the genes contained in the human microbiota; in other words, it is the cumulative genes of bacteria, arachea, viruses, and eucarya, and that is on the order of 2 to 20 million microbial genes vs only 20,000 human genes. In fact, the final number of true protein coding genes in the human genome (i.e., such genes have DNA that carries the code necessary to make a molecular chain called a polypeptide; these chains link together to form proteins and so are the bricks and mortar out of which all organism are constructed) may lie closer to 19,000 than to 20,000, see here for the study, and here for full text of the study.
It is this vast amount of microbial genes in humans (2 to 20 million) that performs functions necessary that our human genes cannot.
Big number magnitudes can be confusing; recall these slides from our early discussions:
Who actually is in our gut microbiome; why are they there?
The majority of the intestinal bacteria belong to two phyla, the Bacteroidetes and the Firmicutes (Mariat et al. 2009). -Intestinal microbiota in human health and disease: the impact of probiotics
Insights into what these phyla do was presented in the class, Gut Microbiome Gut Check: Exploring the Microbiome, 2014, instructors Professor Rob Knight, Dr. Jessica L. Metcalf, Dr. Katherine R. Amato:
- Some of the fermicutes and bacteroids role is to digest food, produce vitamins, and metabolize drugs. The composition of the microbiome determines how drugs are metabolized and if medications are toxic or not to the liver – an example is acetaminophen and liver toxicity: you need a particular group of sulfur reducing species in the gut to not have acetaminophen toxic in the liver. “The metabolism of drugs by both intestinal bacteria and further by enterocytes leading to their systemic absorption deserves further attention and may provide valuable insights into pre-systemic drug metabolism, delivery, and toxicity… sulfation of acetaminophen in the liver competes with sulfation of p-cresol, a metabolite exclusively generated by gut bacteria… A number of other drugs that are mainly metabolized through phase II sulfation pathways and could potentially be presenting with similar issues are minoxidil, tamoxifen, and apomorphine, among others.” -The Gut Microbiome and Pre-systemic Metabolism: Current State and Evolving Research.
- The microbiome can steal genes from our food to help us digest it better. One example is the Japanese gut… it has genes that were transferred from consumption of food, namely fermented live probiotic seaweed. Incidentally, the US coverage is misleading; this is not about sushi, it’s about the seaweed called “nori” which is fermented and teeming with live bacteria. -Bacteria of the human gut microbiome catabolize red seaweed glycans with carbohydrate-active enzyme updates from extrinsic microbes.
It was Jeffery Gordon’s lab in St Louis that found no genes for degrading seaweed in the microbiome of healthy Americans:
Marine algae – seaweeds – contain special sulphur-rich carbohydrates that aren’t found on land. Fortunately, bacteria aren’t just limited to the genes that they inherit from their ancestors. They can swap genes between individuals as easily as we humans trade money or gifts. This ‘horizontal gene transfer’ means that bacteria have an entire kingdom of genes, ripe for the borrowing. All they need to do is sidle up to the right donor. And in the world’s oceans, one such donor exists – a seagoing bacterium called Zobellia galactanivorans…is a seaweed-eater.
When hungry diners wolfed down morsels of these algae, some of them also swallowed marine bacteria. Suddenly, this exotic species was thrust among our own gut residents. As the unlikely partners mingled, they traded genes, including those that allow them to break down the carbohydrates of their marine meals. The gut bacteria suddenly gained the ability to exploit an extra source of energy and those that retained their genetic loans prospered…People might only gain the genes after eating lots and lots of sushi but Hehemann has some evidence that they could be passed down from parent to child. One of the people he studied was an unweaned baby girl, who had clearly never eaten a mouthful of sushi in her life. And yet, her gut bacteria had a porphyranase gene, just as her mother’s did… This result reinforces the need to conduct a broad and culturally diverse survey of who harbours what microbes.” -Eating seaweed: Japanese gut microbiome bacteria are not like mine. I do want to note that one prominent microbiome researcher, Jonathon Eisen, UC Davis, still is not yet convinced of this whole gene stealing concept. I’ll add this reference once I find it in my resource links.
In short, we are only now discovering the breath and capability of the microbiome: “You can not disregard the microbiome; that is like throwing away the brain and saying it is useless.” –Professor Rob Knight, week 1 class, Gut Microbiome Gut Check: Exploring the Microbiome, 2014
Phylum bacteria is further broken down into classes
Intestinal microbiota in human health and disease: the impact of probiotics further explains: The phylum Bacteroidetes consists of three classes, of which the class Bacteroidetes, containing the well-known genera Bacteroides and Prevotella, is probably the most well studied.
The Firmicutes is currently the largest bacterial phylum, which contains more than 200 genera. The majority of the Firmicutes detected in the GI tract fall primarily into two main groups,
- the Clostridium coccoides group (also known as Clostridium cluster XIVa) and the
- Clostridium leptum group (also referred to as Clostridium cluster IV) ( Collins et al. 1994; Mariat et al. 2009).
- Both groups contain members of the genera Clostridium, Eubacterium and Ruminococcus that are taxonomically polyphyletic.
In addition to the two phyla Bacteroidetes and Firmicutes, other phyla such as Proteobacteria, Actinobacteria, Fusobacteria, Spirochaetes, Verrucomicrobia and Lentisphaerae, have been detected (Rajilić-Stojanović et al. 2007; Zoetendal et al. 2008).-Intestinal microbiota in human health and disease: the impact of probiotics
“It is impossible not to notice the enormous surge in human microbiome research currently underway around the world. For the past decade, new molecular methods have started to unlock the secrets of this unseen universe, and suddenly it is dawning on us that human individuals are not the dominant life-form in the symbiosis of our existence. It is often quoted that humans are 10% human and 90% microbial when a comparative count of cell numbers is taken into consideration, but perhaps more astonishingly, it is now clear that our human microbiome, the collection of genes encoded by our microbial passengers, is at least one hundred-fold greater than our own genome. The diversity of the human ‘microbiota’ is enormous, with approximately 500–1000 species existing in our gastrointestinal tracts alone. We are the vessels for this community of microbes (including bacteria, viruses, and yeasts) living on us and in us, and as we start to unravel the multitude of roles that this microbiota fulfills, it is becoming clear that our microbes play a far more relevant and important role in the maintenance of our health than we have ever stopped to consider before. Therefore, it stands to reason that we are at a pivotal point in our attitude towards microbes in a medical context.”
Relevancy of the ‘omics’ technology:
2008 marks about the time researchers began to stop examining the genome of an individual bacterial strain that had been grown in a laboratory; technological advances such as the metagenomic approach enabled examination of the collection of genomes derived from microbial communities sampled from natural environments and relevance of community function was appreciated. The term ‘functional redundancy’, takes on a new definition as omics shows the capacity for multiple microbes within the same ecosystem to carry out the same tasks:
“These microbes have recently been revealed to have functions beyond their clear role as niche dwellers that competitively exclude pathogens. These functions vary widely across body sites and between resident microbes. The microbiota is known to ‘educate’ the immune system, steering it away from needless attacks on commensal microbes such that its efforts can be concentrated on real threats. The gut microbiota also plays a role in breakdown of complex dietary compounds, provision of key molecules and micronutrients essential to health (such as B vitamins), and even makes (as yet poorly understood) contributions to mood, behaviour and sleep patterns.”-The microbiome: what it means for medicine, British Journal of Medical Practice, Dr. Emma Allen-Vercoe, et.al, Editorial.
“The microecology of the healthy human microbiota is highly diverse and carries ‘functional redundancy’, the capacity for multiple microbes within the same ecosystem to carry out the same tasks. Consequently, it has a moderate ability to withstand antibiotic-inflicted stress and to recover from it. However, because we all have a microbiota that is uniquely shaped by our environment and by other factors that are less well understood, this exclusivity means that it is not yet possible to predict individual responses to antimicrobial exposure. Furthermore, evidence indicates that disturbance of our microbial ecosystems at critical points… may result in long-lasting damage that is not easily reversible and may lead to later susceptibility to chronic diseases such as inflammatory bowel disease, asthma, atopy, diabetes, obesity, and even autism.–The microbiome: what it means for medicine, British Journal of Medical Practice, Dr. Emma Allen-Vercoe, et.al, Editorial.
There are numerous proposed mechanisms through which diet could influence the incidence of disease including direct dietary antigens, altering the gut microbiome, and affecting gastrointestinal permeability. Role of diet in the development of inflammatory bowel disease. It is very challenging to identify the components of the luminal content that drive the underlying inflammation. Luminal content is a complex mixture of bacteria, other microorganisms, digested food content, and the metabolic products of digestion of food components by the host and microbiota. Furthermore, these components are not independent of each other. –Diet and Inflammatory Bowel Disease, Review of Patient-Targeted Recommendations, Clinical Gastroenterology and Hepatology, 2014.html pdf Realize with a permeable gut, the above contents leak stimulating the immune system and this mechanism is behind many chronic diseases.
Why it is difficult to say who actually lives in the gut, with a focus on IBD. But note: while the focus is on the IBD gut, the concepts likely apply to most other chronic diseases.
A major issue with even well-funded gut microbiome projects to date is the limited population that does not well represent an “average person.” The Human Microbiome Project, NIH enlisted only 250 healthy medical students at Baylor and University of Washington to determine the microbiome at numerous body sites. What do you think about this population accurately representing all US, or world wide for that matter?
The public crowd sourcing studies such as “The American Gut Project“, “Ubiome“, and/or “23AndMe“ look to address this limitation as the microbiome data received is processed with results reported back to participants as well as the scientific community at large. As the number of participants increase the data will become more informative with better understanding of how microbiome impacts health. Thus, you can pay to have your own or your children’s microbiome DNA sequenced to learn what your microbiome looks like. Putting my lawyer hat on… think thoroughly before doing such. Just some of the issues that come to mind are: privacy and protecting your identity, sequencing accuracy, dual-use research which might have both benevolent and harmful applications, you will pay a fee for participation making withdrawal of consent somewhat more difficulty (most research participation can be easily withdrawn since it isn’t tied to your wallet), your children can be sequenced with unknowns for use of their data and identity protection, how will you react and what will you do should you receive results that correlate your DNA to others resembling disease predisposition, etc…) Just saying… do your own research and think through all ramifications if you decide to sequence.