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How quickly is antibiotic resistance lost?

How quickly is antibiotic resistance lost?


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I would imagine the bacterial genome is highly conserved and limited in its space, but maybe I am wrong.

If you were to take a strain of antibiotic resistant bacteria and kept them isolated, but fed well and so forth, how long would it take for them to lose their resistance? A year? A decade? 100 years? 1000 years? At some point it seems like that trait would disappear, but I have no feeling for how long. Please support your answer with a relevant citation.

EDIT:

My purpose is simple: I am thinking about a strategy for dealing with antibiotic resistance. If we were to ban them across the entire world (could be impossible) how long would we need to wait before they would be usable again. If it was a matter of years, then we could almost do a rotation of existing antibiotics (if we had enough) because I would rather not live in post-antiobitic world.


Antibiotic resistances in bacteria is commonly encoded by extrachromosomal DNA, the plasmids. These are circular pieces of DNA, which are much smaller than the hosts genome and which replicate independently from it. See the image from the Wikipedia:

These plasmids can be transfered between different bacterial cells, which then also get resistant. Plasmids are divided between daughter cells, when the parent cell divides. One of the few exceptions seems to be Mycobacterium tuberculosis, which does not seem to carry plasmids but also develops resistances. It has been hypothesized that they contain extrachromosomal single-stranded DNA ("Does Mycobacterium tuberculosis have plasmids?")

Regarding your question: Plasmids which carry antibiotic resistances will only disappear, when the antibiotic is not seen for a while, since the cells, which don't carry it, have a growth advantage over cells who are still carriers (since they save the energy of forming the plasmid). However, these resistance plasmids are nothing new, evolutionary speaking. They appeared as a countermeasure against fungal toxins.

In the lab, bacterial strains loose plasmids within a few days, when not kept under selection pressure according to my experience. There are a few paper who looked into it:


Lab strains of E. coli have been in use for many decades now. They have all retained a large number of genes encoding subunits of the flagellar apparatus and the chemotaxis system which confer absolutely no advantage under normal culture conditions. I conclude from this that the selective advantage conferred by losing "unused" genes must be very weak.

Also, most antibiotic resistance is encoded on plasmids. As @Chris points out, these can be lost easily.


If you were to take antibiotic resistant bacteria and kept them isolated, but fed well and so forth, how long would it take for them "forget" their resistance?

It's not a matter of "forgetting". Bacteria are resistant if their DNA is such that it gives them a biology that renders the antibiotic non-lethal.

You put a resistant bacteria in glycerol stocks, you can freeze them for years, maybe longer, and when you revive the population, and get it growing again, the resulting population will still be resistant.

Also, when we talk about bacteria, or any kind of evolution, single organisms don't change their DNA. Populations change their proportion of different alleles. Any allele might drift out of a population, and if the resistance-granting mutation is deleterious, natural selection might speed that along, but not all resistance-granting alleles are deleterious enough for that. If a resistance-granting allele is survival neutral in the absence of the antibiotic, or another mutation somewhere else restores the bacterias' survivability absent antibiotic to what the sensitive genotype's fitness is, the resistance-granting allele might not drift out of the population for a long time.


Superbugs: A silent health emergency

The infamous MRSA &ldquosuperbug&rdquo is shown here (stained in yellow), destroying a person&rsquos white blood cell (red).

National Institutes of Health/Wikimedia Commons

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The first of a two-part series.

Bacteria and other microbes can make us sick. But there’s a lurking danger with some germs that’s far more frightening than a bout of food poisoning or an infected wound. Today, drugs exist to fight most of these germs. They’re called antibiotics. Before these medicines came along, common infections frequently killed people. And that’s where the danger lies: What will happen if antibiotics no longer kill germs?

Already some antibiotics have lost their superpowers. Many others are beginning to lose theirs. Biologists describe this problem as resistance. Across the globe, germs are becoming resistant to antibiotic medicines. In a sense, these “superbugs” have begun to laugh at those former wonder drugs.

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But resistance is no laughing matter. As germs toughen up against drugs that are supposed to slay them, treatable conditions such as TB — tuberculosis — can spread. And surgeries that rely on antibiotics could turn from life-saving to life-threatening.

The threat is huge

“Alarming levels” of drug-resistant bacteria already exist in many parts of the world. That’s the conclusion of a 257-page report published in April. It was issued by the World Health Organization (WHO).

This United Nations agency, based in Geneva, Switzerland, recently reviewed how well these germ slayers perform in 114 countries. In some places, it found, antibiotics no longer work for half of all people being treated against common diseases. Those diseases include pneumonia and gonorrhea.

/>Across the globe, TB is the leading cause of death for young adults — often moms and dads. CDC The Centers for Disease Control and Prevention (CDC), based in Atlanta, Ga., also has been investigating the problem . It estimates that in the United States alone, antibiotic-resistant infections now sicken some two million people each year. At least 23,000 of them die.

But even antibiotic-resistant germs that don’t kill can be a problem. Their infections become harder to treat — and more expensive. Consider one estimate — $233 million — published May 20 in the journal Antimicrobial Resistance and Infection Control. That’s how much researchers calculated that it costs the United States each year to deal with just one resistant superbug. That germ causes a lung disease known as pneumonia.

Drug-immune bugs that flourish in the human gut can enter the environment with every flush of the toilet. Researchers discovered how big this problem is when they analyzed wastewater from 11 sites in one French city. Antibiotic-resistant bacteria tainted 96 percent of their samples. A May 1 paper in Clinical Infectious Diseases describes the disturbing details.

Some scientists have scouted for such germs in the environment. They collected superbugs at hospitals. Then they probed the germs, identifying parts of their genes that appear to make them resistant to antibiotics. Next, the researchers looked in the outdoor environment for that same genetic fingerprint of superbugs. And they turned up that superbug DNA in 71 places — from the soil and sea water to human wastes. The researchers reported their findings May 8 in Current Biology.

Why it’s happening

Drug designers have created antibiotics to kill bacteria, as well as some fungi and other germs. But sometimes, a few treated germs survive. They survive because they’re stronger. Or they may have certain genetic mutations that allow them to break down the drug. They might even have evolved a way to keep the drugs from harming their operational machinery. Over time, all germs susceptible to a drug will die off. That will leave behind only superbugs — those microbes that medicines can’t kill.

This is not surprising. In fact, it’s quite natural. Part of evolution, it’s known as survival of the fittest.

Explainer: Where antibiotics came from

Scientists stumbled onto the first antibiotic, penicillin, around 1930. Since then, research has produced a medicine cabinet full of additional ones. It appeared that these would make many of the worst bacterial infections ever more manageable. So, during the 1970s, drug developers began focusing on noninfectious health problems, such as cancer and heart disease. As a result, in the past 30 years, no new types of antibiotics have been developed.

Right now, bacteria are outsmarting antibiotics faster than developers can make new ones. And there are no signs things will change, says Stewart Cole. He directs the Global Health Institute at the Ecole Polytechnique Fédérale de Lausanne in Switzerland.

Writing in the May 12 Philosophical Transactions of the Royal Society B, he argues that the “golden age” of antibiotic development “is a distant memory, and the likelihood of there being another seems slim.” This lack of new types of germ killers, he says, has been allowing superbugs to morph and thrive.

A pus-producing sore that is not healing quickly. It was caused by MRSA, a common bacteria that has become resistant to many of the antibiotics that used to kill Staph aureus. It’s the germ causing this infection. Gregory Moran, M.D./CDC One of the most famous of them is known as MRSA (pronounced MER-sah). The letters stand for methicillin-resistant Staphylococcus aureus . Methicillin is a widely used antibiotic. And Staph aureus is a germ that can cause boils, food poisoning, toxic-shock syndrome and more. These bacteria sicken (and sometimes kill) by releasing potent natural poisons — called toxins — into the body.

Despite its name, MRSA is resistant to far more antibiotics than just methicillin. That makes this superbug particularly nasty in hospitals and prisons. These are places where people often have open wounds or weak immune systems. Both increase a person’s chance of picking up an infection.

Too much of a good thing

Drug resistance can develop at any time. But its likelihood climbs as the use of an antibiotic increases. And this is especially true when an antibiotic is overused. That’s when a doctor prescribes it for infections it has no hope of curing.

For instance, doctors sometimes prescribe antibiotics to treat an infection before they learn if the disease is caused by bacteria. If viruses are responsible, then antibiotics will be useless. The reason: Antibiotic medicines do not kill viruses. Yet by giving an antibiotic to someone with a viral infection, that drug will reach good bacteria living in our bodies. And over time, some of these bacteria will become resistant to the drug.

Last year, the CDC reported that up to half of the antibiotics that U.S. doctors prescribed went to people who didn’t actually need them.

Take, for example, someone who visits a doctor for a lingering cough. Viral infections cause most coughs. So a viral cough won’t be helped by drugs and will tend to go away on its own. Yet 71 percent of the time, doctors will still prescribe antibiotics for patients coming in with a common cough, a May 21 study finds.

People sick with a fever, cough and sniffles — flu-like symptoms — usually have a viral infection. Studies show doctors often prescribe antibiotics for these patients even though these drugs don’t work against viruses. AnneMS / iStockphoto “I think there’s this perception among both doctors and patients that coughs don’t go away without antibiotic treatment,” Jeffrey Linder told Science News for Students . Linder, who coauthored the new report, is a doctor at Brigham & Women’s Hospital in Boston, Mass. He and Michael Barnett, also from the hospital, tracked the drugs that doctors prescribed during more than 3,000 U.S. clinic visits between 1996 and 2010. They reported their findings in the Journal of the American Medical Association .

A small number of people who visit a doctor with a cough turn out to have bacterial pneumonia. These cases do require antibiotic treatment. But Linder says doctors should easily be able to recognize these few from the hordes of people coming in with a routine, viral cough.

Perilous profit

Antibiotic overuse also has become a problem on farms. In the United States, animals — not people — receive about 80 percent of all antibiotics. Sometimes the drugs are used to save an infected animal or prevent disease from spreading through a herd. More often, though, feed suppliers put small amounts of these drugs into the food that will be given to healthy animals. These antibiotics help speed the animals’ growth. And this has boosted farmers’ profits.

But using antibiotics just to beef up livestock is “a direct threat to human health,” argues Kellogg Schwab. He’s an environmental microbiologist at Johns Hopkins University in Baltimore, Md. Earlier, he and his coworkers detected bacteria that are resistant to antibiotics in the exhaust air blowing out of farm buildings. That suggests these superbugs can spread through the air from animals to people.

Farmers often feed livestock, like these beef cattle, trace amounts of antibiotics to promote their growth. Many disease experts now think this contributes to antibiotic resistance and risks these drugs no longer working to fight human disease. SteveOehlenschlager / iStockphoto

Germs that are immune to antibiotics also can hitch a ride into your body through ground beef or the chicken breast on your cutting board. Biologists have found that much of the fresh beef, pork and poultry sold in grocery stores contains bacteria resistant to antibiotics.

Even if those germs don’t sicken us or cause other immediate harm, they can offload their resistance genes into other bacteria that normally live inside our bodies. Sometimes, like with the MRSA superbug, resistance is carried on circular pieces of DNA called plasmids. These plasmids can slip easily from one bacterial cell into another.

In this way, our gut microbes can become “a reservoir of resistance,” says Sharon Peacock. She’s a microbiologist at the University of Cambridge in England. Later, “when we actually get sick and need an antibiotic, we may already carry a resistance gene” that may keep that drug from working, she says.

In the United States, farmers have fought against banning antibiotics as growth promoters. They say it will reduce their profits because more animals will get sick, slowing their growth. But that’s not been the experience in other countries.

The U.S. Food and Drug Administration, or FDA, has proposed banning antibiotic use in healthy animals. But for more than 30 years, the livestock industry and Congress have fought such action. Recently, the FDA stepped up its efforts to end this practice.

In December 2013, FDA laid out a plan to phase out within three years the use of antibiotics on farms to boost livestock growth. Its stated reason: concern that farm use of these drugs has made more germs immune to the antibiotics needed to fight life-threatening infections in people. And that’s a worry because the same germs that sicken animals often sicken people.

Antibiotic resistance is a complex and growing problem. Many microbiologists worry that the time when antibacterial medicines no longer work could be coming. Thankfully, doctors and many patients are becoming more aware of the problem. Researchers also are hard at work creating new tools to keep superbugs from taking over.

Next: How scientists are trying to tackle the problem

Power Words

antibiotic A germ-killing substance prescribed as a medicine (or sometimes as a feed additive to promote the growth of livestock). It does not work against viruses.

bacterium (plural bacteria) A single-celled organism forming one of the three domains of life. These dwell nearly everywhere on Earth, from the bottom of the sea to inside animals.

boils (in medicine) A skin infection that starts as a hard, red, painful lump. Eventually, it gets bigger, softens and fills with pus. A common source of these is a bacterium known as Staphylococcus aureus.

bioengineer A researcher who applies technology for the beneficial manipulation of living things. Bioengineers use the principles of biology and the techniques of engineering to design organisms or products that can mimic, replace or augment the chemical or physical processes present in existing organisms. This field includes researchers who genetically modify organisms, including microbes. It also includes researchers who design medical devices such as artificial hearts and artificial limbs.

Centers for Disease Control and Prevention, or CDC An agency of the U.S. Department of Health and Human Services, CDC is charged with protecting public health and safety by working to control and prevent disease, injury and disabilities. It does this by investigating disease outbreaks, tracking exposures by Americans to infections and toxic chemicals, and regularly surveying diet and other habits among a representative cross-section of all Americans.

cholera A bacterial disease that infects the small intestine, causing sever diarrhea, vomiting and dehydration. It is spread by germs from feces that contaminate water or food.

DNA (short for deoxyribonucleic acid) A long, spiral-shaped molecule inside most living cells that carries genetic instructions. In all living things, from plants and animals to microbes, these instructions tell cells which molecules to make.

evolution A process by which species undergo changes over time, usually through genetic variation and natural selection, that leave a new type of organism better suited for its environment than the earlier type. The newer type is not necessarily more “advanced,” just better adapted to the conditions in which it developed.

fungus (plural: fungi) Any of a group of unicellular or multicellular, spore-producing organisms that feed on organic matter, both living and decaying. Molds, yeast and mushrooms are all types of fungi.

gene A segment of DNA that codes, or holds instructions, for producing a protein. Offspring inherit genes from their parents. Genes influence how an organism looks and behaves.

germ Any one-celled microorganism, such as a bacterium, fungal species or virus particle. Some germs cause disease. Others can promote the health of higher-order organisms, including birds and mammals. The health effects of most germs, however, remain unknown.

gonorrhea A serious disease that can infect the genitals, rectum and throat. This sexually transmitted disease is very common, especially among people between the ages of 15 and 24. Untreated, it can cause infertility or death. “Untreated gonorrhea may also increase your chances of getting or giving HIV – the virus that causes AIDS,” according to the U.S. Centers for Disease Control and Prevention.

growth promoter (in livestock agriculture) A medicine, usually an antibiotic, added in small doses to the feed given to animals raised for meat. Used as a preventive medicine, it can reduce the risk that animals will become sick, which would slow their growth. And that would decrease a farmer’s profits.

immune system The collection of cells and their responses that help the body fight off infection.

infection A disease that can be transmitted between organisms.

influenza (or flu) A highly contagious viral infection of the respiratory passages causing fever and severe aching. It often occurs as an epidemic.

livestock Animals raised for meat or dairy products, including cattle, sheep, goats, pigs, chickens and geese.

microbe Short formicroorganism. A living thing that is too small to see with the unaided eye, including bacteria, some fungi and many other organisms such as amoebas. Most consist of a single cell.

microbiology The study of microorganisms, principally bacteria, fungi and viruses. Scientists who study microbes and the infections they can cause or ways that they can interact with their environment are known as microbiologists.

mutation Some change that occurs to a gene in an organism’s DNA. Some mutations occur naturally. Others can be triggered by outside factors, such as pollution, radiation, medicines or something in the diet. A gene with this change is referred to as a mutant.

plasmid A small circular loop of DNA that is separate from the main chromosomal DNA of bacteria.

pneumonia A lung disease in which infection by a virus or bacterium causes inflammation and tissue damage. Sometimes the lungs fill with fluid or mucus. Symptoms include fever, chills, cough and trouble breathing.

resistance (as in drug resistance) The reduction in the effectiveness of a drug to cure a disease, usually a microbial infection. (as in disease resistance) The ability of an organism to fight off disease.

superbug A popular term for a disease-causing germ that can withstand medicines.

toxic shock syndrome A rare and potentially deadly bacterial infection caused by Staphylococcus aureus. This bacterium release toxins — natural poisons — into the body of its host. Symptoms include a sudden high fever, muscle aches, vomiting, diarrhea, a rash and sometimes seizures.

toxin A poison produced by living organisms, such as germs, bees, spiders, poison ivy and snakes.

tuberculosis A bacterial disease that causes unusual growths in the lungs or other tissues. Untreated, it can kill. The infection usually spreads when a sick individual coughs (or talks, sings or sneezes), spewing germs into the air.

virus Tiny infectious particles consisting of RNA or DNA surrounded by protein. Viruses can reproduce only by injecting their genetic material into the cells of living creatures. Although scientists frequently refer to viruses as live or dead, in fact no virus is truly alive. It doesn’t eat like animals do, or make its own food the way plants do. It must hijack the cellular machinery of a living cell in order to survive.

World Health Organization An agency of the United Nations, established in 1948, to promote health and to control communicable diseases. It is based in Geneva, Switzerland. The United Nations relies on the WHO for providing international leadership on global health matters. This organization also helps shape the research agenda for health issues and sets standards for pollutants and other things that could pose a risk to health. WHO also regularly reviews data to set policies for maintaining health and a healthy environment.

Word Find ( click here to enlarge for printing )

Citations

E. Landhuis. "The war on superbugs." Science News for Students. July 16, 2014.

A.L. Mascarelli. “Infectious animals.” Science News for Students. April 17, 2013.

Original Journal Source: M. Barnett and J. Linder. Antibiotic prescribing for adults with acute bronchitis in the United States, 1996-2010. Journal of the American Medical Association (JAMA). Published May 21, 2014. doi: 10.1001/jama.2013.286141.

Original Journal Source: J. Nesme et al. Large-scale metagenomic-based study of antibiotic resistance in the environment. Current Biology. Published May 8, 2014. doi: 10.1016/j.cub.2014.03.036.

Original Journal Source: S. Peacock. Health care: Bring microbial sequencing to hospitals. Nature. Published May 29, 2014. doi:10.1038/509557a.

Original Journal Source: B. Spellberg, J. Bartlett and D. Gilbert. The future of antibiotics and resistance. New England Journal of Medicine. Published Jan. 24, 2013. doi: 10.1056/NEJMp1215093.

Original Journal Source: S. Cole. Who will develop new antibacterial agents? Philosophical Transactions of the Royal Society B. Published May 12, 2014. doi: 10.1098/rstb.2013.0430.

Original Journal Source: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention. Antibiotic-resistant threats in the United States, 2013.

Teachers' questions: Superbugs: A silent health emergency

About Esther Landhuis

Esther Landhuis is a freelance journalist in the San Francisco Bay Area. She worked on her high school newspaper and spent a decade studying biology before discovering a career that combines writing and science.

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Fighting the next pandemic: Antibiotic resistance

Unfortunately, this child also lives in a place with limited clean water and less waste management, bringing them into frequent contact with faecal matter. This means they are regularly exposed to millions of resistant genes and bacteria, including potentially untreatable superbugs. This sad story is shockingly common, especially in places where pollution is rampant and clean water is limited.

For many years, people believed antibiotic resistance in bacteria was primarily driven by imprudent use of antibiotics in clinical and veterinary settings. But growing evidence suggests that environmental factors may be of equal or greater importance to the spread of antibiotic resistance, especially in the developing world.

Here we focus on antibiotic resistant bacteria, but drug resistance also occurs in types of other microorganisms – such as resistance in pathogenic viruses, fungi, and protozoa (called antimicrobial resistance or AMR). This means that our ability to treat all sorts of infectious disease is increasingly hampered by resistance, potentially including coronaviruses like SARS-CoV-2, which causes COVID-19.

Overall, use of antibiotics, antivirals, and antifungals clearly must be reduced, but in most of the world, improving water, sanitation, and hygiene practice – a practice known as WASH – is also critically important. If we can ensure cleaner water and safer food everywhere, the spread of antibiotic resistant bacteria will be reduced across the environment, including within and between people and animals.

As recent recommendations on AMR from the Food and Agriculture Organization of the United Nations (FAO), the World Organisation for Animal Health (OIE), and World Health Organization (WHO) suggest, to which David contributed, the “superbug problem” will not be solved by more prudent antibiotic use alone. It also requires global improvements in water quality, sanitation, and hygiene. Otherwise, the next pandemic might be worse than COVID-19.

Untreated sewage. Credit: Joa Souza/Shutterstock.com

Bacteria under stress

To understand the problem of resistance, we must go back to basics. What is antibiotic resistance, and why does it develop?

Exposure to antibiotics puts stress on bacteria and, like other living organisms, they defend themselves. Bacteria do this by sharing and acquiring defence genes, often from other bacteria in their environment. This allows them to change quickly, readily obtaining the ability to make proteins and other molecules that block the antibiotic’s effect.

This gene sharing process is natural and is a large part of what drives evolution. However, as we use ever stronger and more diverse antibiotics, new and more powerful bacterial defence options have evolved, rendering some bacteria resistant to almost everything – the ultimate outcome being untreatable superbugs.

Antibiotic resistance has existed since life began, but has recently accelerated due to human use. When you take an antibiotic, it kills a large majority of the target bacteria at the site of infection – and so you get better. But antibiotics do not kill all the bacteria – some are naturally resistant others acquire resistance genes from their microbial neighbours, especially in our digestive systems, throat, and on our skin. This means that some resistant bacteria always survive, and can pass to the environment via inadequately treated faecal matter, spreading resistant bacteria and genes wider.

The pharmaceutical industry initially responded to increasing resistance by developing new and stronger antibiotics, but bacteria evolve rapidly, making even new antibiotics lose their effectiveness quickly. As a result, new antibiotic development has almost stopped because it garners limited profit. Meanwhile, resistance to existing antibiotics continues to increase, which especially impacts places with poor water quality and sanitation.

This is because in the developed world you defecate and your poo goes down the toilet, eventually flowing down a sewer to a community wastewater treatment plant. Although treatment plants are not perfect, they typically reduce resistance levels by well over 99%, substantially reducing resistance released to the environment.

Modern sewage treatment plants remove most AMR microbes. But they are currently not affordable in much of the world. Credit: People Image Studio/Shutterstock.com

In contrast, over 70% of the world has no community wastewater treatment or even sewers and most faecal matter, containing resistant genes and bacteria, goes directly into surface and groundwater, often via open drains.

This means that people who live in places without faecal waste management are regularly exposed to antibiotic resistance in many ways. Exposure is even possible of people who may not have taken antibiotics, like our child in South Asia.

Spreading through feces

Antibiotic resistance is everywhere, but it is not surprising that resistance is greatest in places with poor sanitation because factors other than use are important. For example, a fragmented civil infrastructure, political corruption, and a lack of centralised healthcare also play key roles.

One might cynically argue that “foreign” resistance is a local issue, but antibiotic resistance spread knows no boundaries – superbugs might develop in one place due to pollution, but then become global due to international travel. Researchers from Denmark compared antibiotic resistance genes in long-haul airplane toilets and found major differences in resistance carriage among flight paths, suggesting resistance can jump-spread by travel.

The world’s current experience with the spread of SARS-CoV-2 shows just how fast infectious agents can move with human travel. The impact of increasing antibiotic resistance is no different. There are no reliable antiviral agents for SARS-CoV-2 treatment, which is the way things may become for currently treatable diseases if we allow resistance to continue unchecked.

As an example of antibiotic resistance, the “superbug” gene, blaNDM-1, was first detected in India in 2007 (although it was probably present in other regional countries). But soon thereafter, it was found in a hospital patient in Sweden and then in Germany. It was ultimately detected in 2013 in Svalbard in the High Arctic. In parallel, variants of this gene appeared locally, but have evolved as they move. Similar evolution has occurred as the COVID-19 virus has spread.

Relative to antibiotic resistance, humans are not the only “travellers” that can carry resistance. Wildlife, such as migratory birds, can also acquire resistant bacteria and genes from contaminated water or soils and then fly great distances carrying resistance in their gut from places with poor water quality to places with good water quality. During travel, they defecate along their path, potentially planting resistance almost anywhere. The global trade of foods also facilitates spread of resistance from country to country and across the globe.

Resistant microbes don’t need planes to travel. Credit: Nick Fewings/Unsplash

What is tricky is that the spread by resistance by travel is often invisible. In fact, the dominant pathways of international resistance spread are largely unknown because many pathways overlap, and the types and drivers of resistance are diverse.

Resistant bacteria are not the only infectious agents that might be spread by environmental contamination. SARS-CoV-2 has been found in faeces and inactive virus debris found in sewage, but all evidence suggests water is not a major route of COVID-19 spread – although there are limited data from places with poor sanitation.

So, each case differs. But there are common roots to disease spread – pollution, poor water quality, and inadequate hygiene. Using fewer antibiotics is critical to reducing resistance. However, without also providing safer sanitation and improved water quality at global scales, resistance will continue to increase, potentially creating the next pandemic. Such a combined approach is central to the new WHO/FAO/OIE recommendations on AMR.

Other types of pollution and hospital waste

Industrial wastes, hospitals, farms, and agriculture are also possible sources or drivers of antibiotic resistance.

For example, about ten years ago, one of us (David) studied metal pollution in a Cuban river and found the highest levels of resistant genes were near a leaky solid waste landfill and below where pharmaceutical factory wastes entered the river. The factory releases clearly impacted resistance levels downstream, but it was metals from the landfill that most strongly correlated with resistance gene levels in the river.

There is a logic to this because toxic metals can stress bacteria, which makes the bacteria stronger, incidentally making them more resistant to anything, including antibiotics. We saw the same thing with metals in Chinese landfills where resistance gene levels in the landfill drains strongly correlated with metals, not antibiotics.

In fact, pollution of almost any sort can promote antibiotic resistance, including metals, biocides, pesticides, and other chemicals entering the environment. Many pollutants can promote resistance in bacteria, so reducing pollution in general will help reduce antibiotic resistance – an example of which is reducing metal pollution.

A man climbs a wall of garbage at a landfill in Kenya. Credit: Dai Kurokawa/EPA-EFE

Hospitals are also important, being both reservoirs and incubators for many varieties of antibiotic resistance, including well known resistant bacteria such as Vancomycin-resistant Enterococcus (VRE) and Methicillin-resistant Staphylococcus aureus (MRSA). While resistant bacteria are not necessarily acquired in hospitals (most are brought in from the community), resistant bacteria can be enriched in hospitals because they are where people are very sick, cared for in close proximity, and often provided “last resort” antibiotics. Such conditions allow the spread of resistant bacteria easier, especially superbug strains because of the types of antibiotics that are used.

Wastewater releases from hospitals also may be a concern. Recent data showed that “typical” bacteria in hospital sewage carry five to ten times more resistant genes per cell than community sources, especially genes more readily shared between bacteria. This is problematic because such bacteria are sometimes superbug strains, such as those resistant to carbapenem antibiotics. Hospital wastes are a particular concern in places without effective community wastewater treatment.

Another critical source of antibiotic resistance is agriculture and aquaculture. Drugs used in veterinary care can be very similar (sometimes identical) to the antibiotics used in human medicine. And so resistant bacteria and genes are found in animal manure, soils, and drainage water. This is potentially significant given that animals produce four times more faeces than humans at a global scale.

Watch out for the cowpats. Credit: Annie Spratt/Unsplash

Wastes from agricultural activity also can be especially problematic because waste management is usually less sophisticated. Additionally, agricultural operations are often at very large scales and less containable due to greater exposure to wildlife. Finally, antibiotic resistance can spread from farm animals to farmers to food workers, which has been seen in recent European studies, meaning this can be important at local scales.

These examples show that pollution in general increases the spread of resistance. But the examples also show that dominant drivers will differ based on where you are. In one place, resistance spread might be fuelled by human faecal contaminated water whereas, in another, it might be industrial pollution or agricultural activity. So local conditions are key to reducing the spread of antibiotic resistance, and optimal solutions will differ from place to place – single solutions do not fit all.

Locally driven national action plans are therefore essential – which the new WHO/FAO/OIE guidance strongly recommends. In some places, actions might focus on healthcare systems whereas, in many places, promoting cleaner water and safer food also is critical.

Simple steps

It is clear we must use a holistic approach (what is now called “One Health”) to reduce the spread of resistance across people, animals, and the environment. But how do we do this in a world that is so unequal? It is now accepted that clean water is a human right embedded in the UN’s 2030 Agenda for Sustainable Development. But how can we achieve affordable “clean water for all” in a world where geopolitics often outweigh local needs and realities?

Global improvements in sanitation and hygiene should bring the world closer to solving the problem of antibiotic resistance. But such improvements should only be the start. Once improved sanitation and hygiene exist at global scales, our reliance on antibiotics will decline due to more equitable access to clean water. In theory, clean water coupled with decreased use of antibiotics will drive a downward spiral in resistance.

This is not impossible. We know of a village in Kenya where they simply moved their water supply up a small hill – above rather than near their latrines. Hand washing with soap and water was also mandated. A year later, antibiotic use in the village was negligible because so few villagers were unwell. This success is partly due to the remote location of the village and very proactive villagers. But it shows that clean water and improved hygiene can directly translate into reduced antibiotic use and resistance.

Public toilets in Haryana, India. Credit: Rinku Dua/Shutterstock.com

This story from Kenya further shows how simple actions can be a critical first step in reducing global resistance. But such actions must be done everywhere and at multiple levels to solve the global problem. This is not cost-free and requires international cooperation – including focused apolitical policy, planning, and infrastructure and management practices.

Some well intended groups have attempted to come up with novel solutions, but those solutions are often too technological. And western “off-the-shelf” water and wastewater technologies are rarely optimal for use in developing countries. They are often too complex and costly, but also require maintenance, spare parts, operating skill, and cultural buy-in to be sustainable. For example, building an advanced activated sludge wastewater treatment plant in a place where 90% of the population does not have sewer connections makes no sense.

Simple is more sustainable. As an obvious example, we need to reduce open defecation in a cheap and socially acceptable manner. This is the best immediate solution in places with limited or unused sanitation infrastructure, such as rural India. Innovation is without doubt important, but it needs to be tailored to local realities to stand a chance of being sustained into the future.

Strong leadership and governance is also critical. Antibiotic resistance is much lower in places with less corruption and strong governance. Resistance also is lower in places with greater public health expenditure, which implies social policy, community action, and local leadership can be as important as technical infrastructure.

Why aren’t we solving the problem?

While solutions to antibiotic resistance exist, integrated cooperation between science and engineering, medicine, social action, and governance is lacking. While many international organisations acknowledge the scale of the problem, unified global action is not happening fast enough.

There are various reasons for this. Researchers in healthcare, the sciences, and engineering are rarely on the same page, and experts often disagree over what should be prioritised to prevent antibiotic resistance – this muddles guidance. Unfortunately, many antibiotic resistance researchers also sometimes sensationalise their results, only reporting bad news or exaggerating results.

An Indian boy collects drinking water from a tap on the bank of Bay of Bengal. Credit: Piyal Adhirkary/EPA-EFE

Science continues to reveal probable causes of antibiotic resistance, which shows no single factor drives resistance evolution and spread. As such, a strategy incorporating medicine, environment, sanitation, and public health is needed to provide the best solutions. Governments throughout the world must act in unison to meet targets for sanitation and hygiene in accordance with the UN Sustainable Development Goals.

Richer countries must work with poorer ones. But, actions against resistance should focus on local needs and plans because each country is different. We need to remember that resistance is everyone’s problem and all countries have a role in solving the problem. This is evident from the COVID-19 pandemic, where some countries have displayed commendable cooperation. Richer countries should invest in helping to provide locally suitable waste management options for poorer ones – ones that can be maintained and sustained. This would have a more immediate impact than any “toilet of the future” technology.

And it’s key to remember that the global antibiotic resistance crisis does not exist in isolation. Other global crises overlap resistance such as climate change. If the climate becomes warmer and dryer in parts of the world with limited sanitation infrastructure, greater antibiotic resistance might ensue due to higher exposure concentrations. In contrast, if greater flooding occurs in other places, an increased risk of untreated faecal and other wastes spreading across whole landscapes will occur, increasing antibiotic resistance exposures in an unbounded manner.

Antibiotic resistance will also impact on the fight against COVID-19. As an example, secondary bacterial infections are common in seriously ill patients with COVID-19, especially when admitted to an ICU. So if such pathogens are resistant to critical antibiotic therapies, they will not work and result in higher death rates.

Regardless of context, improved water, sanitation, and hygiene must be the backbone of stemming the spread of AMR, including antibiotic resistance, to avoid the next pandemic. Some progress is being made in terms of global cooperation, but efforts are still too fragmented. Some countries are making progress, whereas others are not.

Resistance needs to be seen in a similar light to other global challenges – something that threatens human existence and the planet. As with addressing climate change, protecting biodiversity, or COVID-19, global cooperation is needed to reduce the evolution and spread of resistance. Cleaner water and improved hygiene are the key. If we do not work together now, we all will pay an even greater price in the future.

David W. Graham is a Professor of Ecosystems Engineering at Newcastle University. David’s work combines methods from engineering, theoretical ecology, mathematics, biochemistry, and molecular biology to solve problems in environmental engineering at a fundamental level.

Peter Collignon is a Professor of Infectious Diseases and Microbiology at the Australian National University. Particular interests are antibiotic resistance (especially in Staph), hospital acquired infections (especially blood stream and intravascular catheter infections) and resistance that develops through the use of antibiotics in animals. Peter can be found on Twitter @CollignonPeter

A version of this article was originally published at the Conversation and has been republished here with permission. The Conversation can be found on Twitter @ConversationUS


Heterotypic resistance in Chlamydiae

There are only a few reports describing the isolation of antibiotic-resistant C. trachomatis strains from patients [50�]. Although 11 of the 15 reportedly resistant isolates were associated with clinical treatment failure, all of the isolates screened displayed characteristics of ‘heterotypic resistance’, a form of phenotypic resistance in which a small proportion of an infecting microbial species is capable of expressing resistance at any one time. This phenomenon has also been described in Staphylococcus spp. [56,57], and parallel observations of similar phenotypic resistant states can be referred to in the literature as drug indifference, persistence, tolerance and, in some cases, as properties of biofilms [58,59]. It is possible that these descriptors of bacterial interactions with antibiotics can be associated with chlamydial aberrancy and phenotypic antibiotic resistance in Chlamydiae. For example, tolerance is often specific to antibiotics that affect cell wall synthesis, as is shown in the penicillin persistence model of Chlamydiae [58,59].

In each case of clinical resistance reported, only a small portion of the population (ρ�%) expressed resistance, and those that did also displayed altered inclusion morphology. In addition, the isolates could not survive long-term passage (in the presence or absence of antibiotics) or lost their resistance upon passage. In some cases, heterotypic resistance was observed when a large inoculum was infected on to cells, but a smaller inoculum was not resistant under the same conditions [50,60]. Many of these characteristics suggest that a form of phenotypic resistance is responsible for the sustained presence of small populations of clinical strains of C. trachomatis under antibiotic stress and may be an adaptive behavior that influences the survival of bacteria within communities rather than stable genetic resistance mechanisms employed by singular cells.

A distinct characteristic of chlamydial growth is the asynchronous differentiation of RBs to EBs that begins relatively early and continues throughout the developmental cycle. A midstage inclusion will harbor actively dividing RBs as well as nondividing EBs. It is plausible that multistage development is an evolved trait that can ensure the survival of a subset of the population regardless of the timing of antibiotic or metabolic stress. AZM, clarithromycin, levofloxacin and ofloxacin approach 100% inhibition in synchronized assays, but when used in a continuous model of C. pneumoniae infection, none of these antibiotics eliminated the organism, even in the presence of concentrations greater than four-times their minimum inhibitory concentrations (MICs) [39,40,61]. A continuous model may more accurately reflect in vivo infections because inclusions of varying developmental stages will be present at any given time. The standard MIC assay synchronizes the infection and applies antibiotics within 1𠄲 h post infection, long before EB differentiation can be observed. Perhaps chlamydia are most vulnerable in the log-phase of growth prior to EB differentiation, and are capable of expressing phenotypic resistance when both replicating and nonreplicating forms are present. This principle is corroborated by other studies, in particular one in which ciprofloxacin and ofloxacin failed to eradicate C. trachomatis in infected cells and induced persistence when antibiotics were applied to established infections (2𠄳 days post infection) [41,43]. Although it is assumed that the inclusion is a nutrient-rich environment, it is unknown whether adequate nutrient levels can support replication and sustain active metabolism, or whether toxic byproducts accumulate, particularly in the late stages of the developmental cycle when several hundred bacteria occupy a single inclusion. These factors may also contribute to the onset of phenotypic or heterotypic resistance observed both in vivo and in vitro.

It is challenging to distinguish persistence from issues of treatment compliance, re-infection of treated patients and actual antibiotic resistance in Chlamydiae. It remains even more challenging to assess the relevance of heterotypic resistance when it is observed in strains isolated from patients with clinical treatment failure. In the absence of true genetic differences, it is challenging to find a way to study antibiotic resistance that arises only under certain conditions in approximately 1% of the population and which often does not appear to manifest itself following expansion of the bacteria.


EXPERIMENTAL EVIDENCE FOR OLD RESISTANCE

In silico analyses of orthologous gene sequences have predictive value, but is there experimental evidence that resistance pre-dates the clinical use of antibiotics? Besides the studies mentioned in the introduction to this review (Mather et al. 2014 Warinner et al. 2014), few instances of resistance have been found in the limited number of sequenced of ancient microorganisms from human samples. The genome sequence of Vibrio cholera from 19th century Philadelphia did not reveal any candidate resistance genes apart from efflux (Devault et al. 2014), nor were any specific resistance genes found in several strains of the plague-causing bacillus Yersinia pestis isolated from the plague of Justinian (541–543 AD) (Wagner et al. 2014). It is not altogether surprising that resistance genes would be found sparingly in the human microbiome before the clinical use of antibiotics, because there would have been no selective pressure to maintain them. In contrast, environmental microorganisms have coevolved with antibiotics produced in Actinobacteria, and are more likely to harbor examples of resistance genes from long ago. An unparalleled source of ancient DNA is the permanently frozen soil known as “permafrost,” found under an estimated 25% of the earth’s surface (Jansson and Tas 2014). Permafrost is defined as soil that has remained frozen for at least two consecutive years, but some Arctic and Antarctic permafrost has been frozen for 1–3 million years (Wagner et al. 2014). The DNA from permafrost can be isolated and queried experimentally for antibiotic resistance genes (among other things). The seminal work of D’Costa et al. (2011) on Beringian permafrost is complemented by studies showing that functional resistance genes can be retrieved from 5000-year-old DNA (Perron et al. 2015), and that resistance had mobilized to plasmids and transposons in ancient times (Mindlin et al. 2005 Petrova et al. 2011, 2014). Modern day microorganisms found in a cave that has been isolated from the surface for four million years have also been shown to harbor functional antibiotic resistance genes (Bhullar et al. 2012). A phylogenetic tree of macrolide phosphostransferases was generated using a sequence found in the genome of a cave organism (identified as Brachybacterium paraconglomeratum), and compared with a phylogeny of macrolide phosphotransferases from a terrestrial species of Brachybacterium (B. faecium DSM 4810) and environmental Bacillus cereus (Wang et al. 2015). Analysis of 10 kb upstream of and downstream from the mph revealed that MPHs from Brachybacterium strains from both cave and terrestrial origin cluster together as a separate group among known MPHs (Bhullar et al. 2012). The results of these studies provide direct experimental evidence that antibiotic resistance is ancient, and provide a glimpse into the evolutionary history of a natural environmental phenomenon.


Dutch research has shown that the development of permanent resistance by bacteria and fungi against antibiotics cannot be prevented in the longer-term.

To help fight antibiotic resistance and protect yourself against infection:

  1. Don’t take antibiotics unless you’re certain you need them. An estimated 30% of the millions of prescriptions written each year are not needed.
  2. Finish your pills.
  3. Get vaccinated.
  4. Stay safe in the hospital.

Antimicrobial Resistance & Europe: What Happened?

Europe used to be the voice of reason in antibiotic discovery and development, but that is no longer the case. The European Medical Agency, Europe's equivalent of the FDA, is requiring so many clinical trials for antibiotics that it is no longer feasible for companies to market the drugs in the E.U. ACSH advisor Dr. David Shlaes (pictured) explains.

I recently received a notification from John Rex and Kevin Outterson regarding the fact that many recently approved antibiotics will not be marketed in Europe. At first glance, I assumed that these products were simply unable to obtain a price that would provide for a return on investment leading the companies to abandon the European marketplace. But, based on the information provided by Rex and Outterson, it's more complicated and more discouraging than that.

To go back in time, during the struggles at the FDA starting around 2000, Europe almost seemed like a haven of regulatory bliss for antibiotic developers. Many of you will remember how antibiotics almost always were approved in Europe one or more years after their approval in the US during the last part of the last century. We viewed Europe as slow, cumbersome, and driven by inconsistent and often academic concerns. But these perceived faults were clearly overcome when Europe became a regulatory haven as an alternative to an FDA that had lost its way.

During my consulting years, that covered the worst of the FDA antibiotic crisis, I often advised my clients to work through European regulators primarily and put the FDA aside or at least on a lower priority in terms of trying to negotiate clinical trial designs that could lead to approval. My clients, perhaps correctly, noted that they would have a difficult time obtaining a return on their investment without the US market and as such, the FDA became a key hurdle for them to overcome. Unfortunately, years were lost in that struggle as were several of my clients.

Then, in 2012, the FDA awoke from their state of hibernation realizing that the antibiotic pipeline had all but disappeared under their regulatory restrictions – especially for antibiotics targeting pneumonia and other serious infections. They quickly established new regulatory pathways that are more efficient and rapid for new antibiotics addressing resistant infections.

And here we are in 2020. Our antibiotic pipeline remains in shambles mainly due to a lack of a sufficient marketplace. But we must remember that “sufficient” depends on costs to get there and stay there. And costs, often, still depend greatly on the regulators.

Nabriva will not market Lefamulin in Europe partly because it is unable to find a commercial partner to drive sales. But more ominous in their recent SEC filing is the statement that they may not be able to continue to survive at all given marketing restrictions associated with COVID plus outstanding obligations and debt.

Plazomicin has been withdrawn from Europe apparently because the costs of the pediatric trials required in Europe “exceed all estimates of potential sales” in the region.

Eravacycline is the victim of the financial difficulties of its parent company, Tetraphase, its limited indication and its relatively poor advantages compared to competing products.

Paratek's omadacycline was withdrawn from consideration in Europe because the EMA insisted on a second trial in community-acquired pneumonia. Omadacycline was approved in the US based on two successful trials in skin infection and a single trial in pneumonia consistent with FDA guidelines for approval in both indications. FDA approved omadacycline for both indications but requested a second pneumonia study as a post-approval obligation.

In the case of both omadacycline and plazomicin, the regulators have doomed the products for the European market. Some may argue that these products do not deserve to be marketed given the availability of other agents. In fact, for omadacycline, that almost seems to be what the EMA is saying. On the other hand, the regulatory hurdles to the marketplace in Europe now become yet another nail in the coffin of new antibiotic investment in research and development. After placing so much hope in European regulators, I find I am profoundly disappointed in their actions.


Can drug-resistant bacteria lose their resistance?

In the modern world, we've come to depend upon antibiotics to rescue us from scary diseases that range from syphilis to leprosy. But one thing that really frightens doctors and public health professionals is the possibility that some of our most important antibiotics may stop working as bacteria develop resistance to them.

Unfortunately, that nightmare already is becoming a reality. A 2014 study by the World Health Organization (WHO) found high rates of antibiotic resistance among common bacteria ranging from E. coli to Staphylococcus aureus and reported that patients with drug-resistant infections in some cases are twice as likely to die. "The problem is so serious that it threatens the achievements of modern medicine," the report concluded. "A post-antibiotic era -- in which common infections and minor injuries can kill -- is a very real possibility for the 21st century" [source: WHO].

Antibiotic resistance is a result of the same basic evolutionary process that gave humans big brains and enabled us to walk upon two legs instead of dragging our knuckles on the ground. When a patient takes an antibiotic to fight a bacterial infection, the bacteria whose genetic makeup makes them susceptible to the drug are killed off or damaged. But not all of the bacteria die or become fatally weakened. That creates what geneticists call "selective pressure" for the survival of resistant strains of bacteria. Some may develop spontaneous mutations that produce enzymes that deactivate antibiotics, or else close up the entry ports that allow antibiotics into a cell. Bacteria can use viruses to transfer their drug-resistant genes from one individual to another. So once one bacterium is resistant, others quickly can join the club [source: APUA].

The good news: Bacteria can also lose their resistance to antibiotics, as well. Genetics has a sort of "use it or lose it" principle. When the selective pressure that encourages the mutations to spread is eliminated, it's possible for a bacterial population to revert to its former state of vulnerability [source: APUA].

Unfortunately, this reversal process occurs more slowly than the creation of the resistance [source: APUA]. So we probably can't depend upon it to save us from antibiotic-resistant diseases. Instead, we're better off limiting our use of antibiotics to only when it's necessary.


The Institute for Creation Research

Often the claim is made in biology classes that evolution has been observed in certain microbes&mdashgerms that over time have developed a resistance to antibiotics. For instance, penicillin is generally now less effective than before. Stronger and more focused drugs have been developed, each with initial benefits, but which must continue to be replaced with something stronger. Now, "super germs" defy treatment.

One might ask, have these single-celled germs "evolved"? And does this prove that single-celled organisms evolved into plants and people?

As is frequently the case, we must first distinguish between variation, adaptation, and recombination of existing traits (i.e., microevolution) and the appearance of new and different genes, body parts, and traits (i.e., macroevolution). Does this acquired resistance to antibiotics, this population shift, this dominant exhibition of a previously minority trait point to macroevolution? Since each species of germ remained that same species and nothing new was produced, the answer is no!

Here's how it works. In a given population of bacteria, many genes are present which express themselves in a variety of ways. In a natural environment, the genes (and traits) are freely mixed. When exposed to an antibiotic, most of the microbes die. But some, through a fortuitous genetic recombination, possess a resistance to the antibiotic. They are the only ones to reproduce, and their descendants inherit the same genetic resistance. Over time, virtually all possess this resistance. Thus the population has lost the ability to produce individuals with a sensitivity to the antibiotic. No new genetic information was produced indeed, genetic information was lost.

A new line of research has produced tantalizing results. Evidently, when stressed, some microbes go into a mutation mode, rapidly producing a variety of strains, thereby increasing the odds that some will survive the stress. This has produced some interesting areas for speculation by creationists, but it still mitigates against evolution. There is a tremendous scope of genetic potential already present in a cell, but E. coli bacteria before stress and mutation remain E. coli. Minor change has taken place, but not true evolution.

Furthermore, it has been proven that resistance to many modern antibiotics was present decades before their discovery. In 1845, sailors on an ill-fated Arctic expedition were buried in the permafrost and remained deeply frozen until their bodies were exhumed in 1986. Preservation was so complete that six strains of nineteenth-century bacteria found dormant in the contents of the sailors' intestines were able to be revived! When tested, these bacteria were found to possess resistance to several modern-day antibiotics, including penicillin. Such traits were obviously present prior to penicillin's discovery, and thus could not be an evolutionary development. 1

Here's the point. Mutations, adaptation, variation, diversity, population shifts, etc., all occur, but, these are not macroevolutionary changes.

* Dr. John Morris is President of ICR.

Cite this article: Morris, J. 1998. Do Bacteria Evolve Resistance to Antibiotics? Acts & Facts. 27 (10).