Welcome back. Let's talk about Antimicrobial Resistance. What is antimicrobial resistance? It's the ability of a microbe such as a virus or a bacteria, through either inherent mutation or gene transfer, the sharing of genes, to survive an exposure to antibiotics that had previously killed it. So for example, this little disk here that's been saturated with an antibiotic, has killed off all the bacteria around it. However, in contrast, this or this disk do not kill off the bacteria, this one just a tiny bit. So you have varying amounts of susceptibility versus resistance to these disks containing antibiotics. For the purposes of our discussion in this session, I'm going to focus solely on bacteria and not on viral, or fungal, or parasitic, resistance to antimicrobial agents. Dr. Alexander Fleming in his Nobel Prize acceptance speech, warned about the rise of antimicrobial resistance. Some bacteria were inherently resistant to penicillin and Dr. Fleming warned that exposing people to small amounts of penicillin could lead to the rise of resistance, and foresaw a time of widespread resistance to penicillin. Antibiotics have been used in a number of different ways. In people, they've been used to treat disease, to prevent disease. But in livestock or food animals, they've been used for growth promotion, which is very controversial. They've also been used for disease treatment and disease prevention. So the question we must ask is can we have our pork chops in antibiotics too, because antibiotics are often used in food animals? Antibiotic resistance was first observed in post-World War II Japan. Outbreaks of resistant shigella dysentery led Japanese scientists discover that multiple antibiotic resistance genes could be transferred between bacteria. Dr. Tsutomu Watanabe, a prominent bacteriologist in Japan, concluded that any microbial resistance could become a serious problem globally, and he was correct. Dr. Watanabe noticed that the commercially raised Japanese fish would develop infections that were no longer responding to treatment with antibiotics. He attributed the rise of antimicrobial resistance to the use of low-dose growth-promoting antibiotics in livestock in the US and in Japan and in many other countries. What are the mechanisms of antimicrobial resistance? Now recall in my previous session when I talked about how antibiotics worked. They work by inhibiting cell wall synthesis, DNA synthesis, or protein synthesis. Resistance means that the bacteria have developed resistance to these mechanisms and have genes that block the drugs activities. The rise of vancomycin-resistant Enterococcus faecium, which is a mouthful, I generally call it VRE, VRE drove EU policy. In 1988 cases of VRE began appearing in chronically ill patients in London and Paris, and they developed infections with VRE. A few years later, VRE was isolated from livestock in England and Germany. At that time, avoparcin, which was a growth-promoting drug used in livestock and chemically similar to vancomycin, was attributed to the cause of the rise of VRE. Avoparcin had been used in Europe since the early 1970s. Concerns about the rise of VRE, led to the Danish banning the use of avoparcin. And the ban had dramatic effects on the farms in Denmark, you can see a nice 90% drop of VRE in farm animals. Paradoxically, however, VRE continued to increase in Danish hospitals, and that was very surprising findings. After Denmark banned avoparcin, the European Union banned avoparcin in all EU countries. Now, unfortunately paradoxically, like what we found in the VRE in the Danish hospital, we find similar findings here across the European Union hospitals. Unlike the Danish farm where you saw a 90% drop in VRE after the avoparcin ban, here you see a bit of a mess where some countries are consistently low with VRE rates. Some with rates that go down, and some countries with rates that go up. What happened with VRE in the United States? Well, VRE first emerged in US hospitals in the 1990s. In a 2019 report, the Centers for Disease Control estimated that 30% of all healthcare-associated infections that were due to Enterococcal infections were resistant to vancomycin, thus limiting treatment options. It estimated that approximately 54,500 infections and over 5,000 deaths in 2017 were due to VRE. The health care costs specifically due to VRE were estimated to be almost $540 million. Data from the National Antibiotic Resistance Monitoring System or NARMS, and the National Animal Health Monitoring System, showed zero evidence of VRE in all the specimens tested, including chickens, pigs, chicken meat, and pork chops. So to compare the experience of VRE in the European Union and in the United States, in the European Union, Europe approved avoparcin in the early 1970s. It banned the use of avoparcin after the rise of VRE on farms. Unfortunately, in the data that I showed you in the previous slide, there is no evidence that the avoparcin ban led to a reduction of VRE across the EU hospitals. In the US, the country never approved avoparcin because of concerns that it might cause cancer. Nevertheless, there are very high VRE rates in US hospitals. And there's no evidence from the monitoring systems, neither NARMS nor NAHMS, that VRE came from US farms. In January of 2017, the Food and Drug Administration issued Guidance for Industry number 213. And this guidance was to phase out all medically important antibiotics use in livestock, and all subsequent antibiotic use must be done with the oversight of a veterinarian. So there's been a mystery going on between avoparcin use, the rise of VRE. Comparing the US and the EU, there seemed to be a disconnect between what happened on the farms and what happened in the hospitals. And to understand this disconnect, we have to talk about horizontal versus vertical gene transfer. Horizontal gene transfer is the sharing of genetic material between two separate bacteria, so they can exchange genetic material back and forth. Now this bacteria might not necessarily be related to this bacteria, but nevertheless they're sharing genetic material, usually in the form of these circular areas of DNA called plasmids. In contrast to horizontal gene transfer, you have vertical gene transfer. And here you have a parent cell duplicating its DNA and then splitting into two daughter cells. So these two cells are the descendants of this cell. So it is very different, so this is progeny, or the parent cell splitting into two daughter cells, they are identical. Or two completely separate bacteria sharing genetic material usually in the form of a plasmid, back and forth. And that has important implications when we track antimicrobial resistance genes. When we track antimicrobial resistance genes, we track snippets of genes, like the snippet of genetic material for hair color. So if we had a large crowd of redheads, it would be virtually impossible to tell who is related to whom based just on their hair color. Yes, everybody here has red hair, but that doesn't mean that they are genetically related to each other, it just means that they all share the same gene for red hair. And that's what we've been doing with antimicrobial resistance genes. To truly understand how one organism is related to the other, you have to sequence their entire genome. Now, in the early 2000s the cost of sequencing entire genomes were prohibitively expensive. But with time, the cost of sequencing genomes has dropped precipitously until it became relatively cheap around 2015. It became so inexpensive that researchers could use it in their projects. When researchers sequenced the entire genome of VRE, very surprising findings resulted. They found that one or two clones caused the initial outbreak in people. These clones proliferated into multiple clones and became endemic in hospitals. And the clone that was the primary culprit in hospitals was VRE CC17, also known as VRE Clonal Complex 17. This hospital-associated VRE, VRE CC17, appeared to be genetically distinct from the farm associated VRE, so you had two different populations. And that would explain the disconnect that was going on between on the farms and what was going on in the hospital's. Whole genome sequencing suggested that the precursor to VRE CC17 did indeed come from an animal, but not the farm animal that everyone had assumed. Instead, the VRE CC17 ancestor appears to have come from dogs. The ancestor is known as ampicillin-resistant Enterococcus faecium CC17, or AREF CC17, appears to be the precursor to VRE CC17. And when you think about it dogs, share our homes, they share our food, we often sleep with them, and we're sharing our microbes with them all the time. We do indeed share our microbes with our pets. So for example, Dr. E.A. Scott and her colleagues swabbed a number of households in 35 randomly selected addresses. Nearly half of the homes that they swabbed, had methicillin-resistant Staph aureus on their surfaces. And they found that homes with cats or eight times more likely to have MRSA on their surfaces than homes without cats. So we need to understand our microbial world and our microbial bodies better to fully understand the rise and spread of antimicrobial resistant microbes. The challenge in understanding our microbial world better is the fact that it has been very difficult to culture soil bacteria in the laboratory. To get around that problem, scientist came up with a clever strategy called metagenomic studies, in which they extracted DNA directly from the soil. Now, they didn't know exactly from which bacteria the DNA was coming from but nevertheless, they found something very interesting. They found that antibiotic resistance genes were everywhere, they were in the Arctic, and the Antarctic, and places that had received no anthropogenic antibiotic exposure. For many years, people thought that bacteria used minute amounts of antibiotics as a form of chemical warfare against each other, but it appears to be much more subtle than that. It appears that these bacteria use small levels of of antibiotics as a form of communication with each other. And so these antibiotics that they share change their behaviors such as increasing their movement, producing biofilms, or synthesizing new chemicals. Scientists have called the finding that antimicrobial resistance genes are everywhere as the global resistome. These antimicrobial resistance genes appear to be ancient and predate the use of antibiotics by humans. They found some DNA sequences from the Alaskan permafrost dating back to the late Pleistocene era. These resistance genes were highly diverse and resistant to such antibiotics as tetracyclines, penicillins, vancomycins, and others. It's unclear however, if the microbes have been dormant or metabolically active in these areas. So how are humans impacting the global resistome? Well, through indiscriminate antibiotic use in both humans and animals, widespread human and animal waste, which leads to land and water contamination, and wildlife then spread these resistant organisms far and wide. Now unfortunately, antimicrobial resistance is becoming a worsening threat globally. In 2014, British Prime Minister David Cameron commissioned a report shared by Jim O'Neill in reviewing the problem of antimicrobial resistance. And this report highlights that around 700,000 people now are dying from resistant infections. And they estimate that if nothing is done then by 2050 around 10 million people will be dying from antimicrobial resistant infections. And that's around 2 million more than people who are dying from cancer. And these deaths from antimicrobial resistance will be global. In 2015, the World Health Assembly developed a global action plan stating that any microbial resistance was an important issue and it required a multidisciplinary One Health approach. The next year the UN General Assembly met and held a high level meeting agreeing that something had to be done about the worsening issue of antimicrobial resistance. And they sought commitments from all the member nations to develop antimicrobial national action plans. So the questions for this session then are, what is antimicrobial resistance? What our metagenomic studies and what have they found? How are humans altering the global resistome? What policies could be implemented to reduce the spread of antimicrobial resistance? Which animals are generally ignored in the ongoing debate about antimicrobial resistance bacteria, and why are they usually ignored? And with that, I'd like to thank you for your time and attention.
