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  • How do bacteria become resistant to antibiotics?


    Answer: Bacteria adapt, evolve and acquire antibiotic resistance.

    There are Multiple Ways a Bacteria can be Resistant to an Antibiotic (Levy, et al)

    The extensive use of a particular antibiotic and patients failing to complete treatments when they feel better do contribute to increased antibiotic resistance, but are not necessarily the primary cause of the increasing frequency of antibiotic resistance.  This post discusses the many ways that antibiotic resistance may occur, as well as the conditions and environments that promote the development of antibiotic resistant bacteria.

    What is Antibiotic Resistance?

    Antibiotics work by targeting bacteria and either killing them, or inhibiting their growth. Generally speaking, antibiotics are small molecules that disrupt essential biological processes that are unique to bacteria. There are many types of antibiotics, and there are many types of bacteria. Some bacteria are naturally resistant to certain antibiotics. Depending on the type of bacteria, different types of antibiotics are more (and less) effective. Antibiotic resistance refers to a situation where a bacteria becomes less sensitive to a particular antibiotic (or class of antibiotics). Antibiotic resistance occurs because the resistant bacteria has developed or acquired an ability to prevent the normal function of the antibiotic.

    Adaptation and Evolution of Antibiotic Resistance

    Epigenetic Adaptation (No Genetic Mutation)

    Bacteria that consistently encounter sub-inhibitory levels of an antibiotic (concentrations of the antibiotic that are too low to kill it) can develop a temporary resistance to that antibiotic. This type of resistance is called Epigenetic Adaptation, and produces no genetic changes that can be permanently inherited by subsequent generations of bacteria. This is roughly equivalent to an athlete who develops large muscles from weight lifting and physical training. Bacteria exposed to sub-inhibitory levels of an antibiotic can mobilize defenses such as pumps to expel the antibiotics, enzymes to break them down, or they can simply decrease the permeability of their cell wall to decrease their exposure to the antibiotic molecules.

    Genetic Adaptation (Genetic Mutation and Selection)

    UV Light can Cause Damage and Permanent DNA Changes (Friedberg)

    Genetic mutations are small changes in the genetic code that occur randomly during DNA replication, or as a result of exposure to mutagens like ionizing radiation (UV light) or chemicals. Many genetic mutations happen in regions of the genome that are not essential for the organism and don’t significantly change how that organism functions. When a mutation does occur in something important, it is usually disruptive and weakens the organism. Mutations that improve the fitness of an organism are rare.

    Some antibiotics are more likely than others to become less effective as the result of genetic mutations in the target bacteria. This is because resistance to some antibiotics can be acquired as a result of a single genetic mutation, while other antibiotics require a bacteria to develop multiple mutations in order to become resistant.  One example of a class of antibiotics that are susceptible to single mutation resistance are the fluoroquinolone class of antibiotics (ciprofloxacin, moxifloxacin, nadifloxacin). These antibiotics target a bacterial enzyme called DNA gyrase. The antibiotic binds this enzyme, which prevents the bacteria from properly accessing and replicating its DNA. A single mutation at a specific site in this enzyme can stop the antibiotic from binding, and allows the bacteria to become resistant to the antibiotic.  Because of this, some antibiotics (like ciprofloxacin) are not recommended for long-term use, partly because of the increased probability that an infectious bacteria will become resistant.

    Genetic Acquisition (Plasmids, Transposons, Viruses, Conjugation, Naked DNA)

    Transfer of Antibiotic Resistance Genes Between Bacteria (Furuya, et al)

    Bacteria can acquire large pieces of DNA from other bacteria, viruses and the environment. It is almost impossible for a bacteria to randomly evolve a brand new gene or enzyme that provides resistance against a particular antibiotic (at least within a time-frame of weeks, months and years). But what does happen is that bacteria acquire big chunks of foreign DNA that contain many genes. Bacteria have many ways to acquire these large pieces of DNA that often contain many complete genes.

    • Plasmids are mobile pieces of DNA (often circular) that bacteria can easily trade and acquire from the environment. Many bacteria have multiple plasmids. Plasmids can contain genes that inactivate an antibiotic (for example the a particular gene, Beta Lactamase, is commonly spread via plasmid and provides resistance to Beta-Lactam antibiotics, like Penicillin).
    • Transposons are sections of DNA that can jump from one place in the genetic code to another, or even to the genetic code of another organism.
    • Viruses (Bacteriophages) can infect bacteria and these viruses can copy and paste genetic code into the genomes of the bacteria they infect.
    • Conjugation is where two bacteria that are directly adjacent to one another create a direct connection and share DNA (think “conjugal visit”). Conjugation is probably the closest thing that bacteria have to sex.
    • Naked DNA is DNA that bacteria find in the environment and internalize. This DNA can be from bacteria that have been killed, or part of a biofilm structure (some bacteria use DNA as a scaffold structure to anchor themselves to a surface).

    Bacteria can utilize one, multiple or all of these techniques to acquire DNA and that can help a bacteria become resistant to a particular type and/or class of antibiotic.

    Conditions That Cause Antibiotic Resistance

    The Necessity of “Selective Pressure”

    The average bacterial genome (all of the DNA in a cell) is approximately 1000 times smaller than the genome of an animal (including humans). This isn’t because bacteria are smaller than human cells (although they are), it is because of competition and a concept called “genomic streamlining”. A genome is not free. It takes energy and resources to maintain and replicate. The bigger the genome, the more energy it takes to keep it up and running, and to duplicate it during reproduction. At the same time, there is an incredible level of competition between bacteria for resources. Bacteria grow much faster, and in much larger numbers, than most other organisms. For example, in a single handful of dirt there are more bacteria than the entire human population of the world. The huge bacterial population and intense competition is like “survival of the fittest” on steroids; weak and inefficient bacteria are quickly squeezed out by stronger, more efficient bacteria. Excess DNA is “dead weight” in this competition and is quickly eliminated. If a section of DNA is not essential for survival or does not confer a selective advantage, it is rapidly mutated and removed from the genome by the quickly evolving bacterial population.

    How Does Selective Pressure Impact Antibiotic Resistance?

    In order for a gene to remain functional and a part of the bacteria’s genome over an extended period, it has to help improve the survival and/or competitiveness of the bacteria. If a gene stops being helpful it will eventually become non-functional and will be removed from the genome. This means that the development and maintenance of antibiotic resistance is usually dependent on the bacterial population being frequently exposed to non-lethal doses of the antibiotic (note: some bacteria are intrinsically resistant to particular antibiotics). This process eliminates those bacteria that have lost resistance, and increases the percentage of resistant bacteria. In real life, this means that antibiotic resistance is likely to emerge in environments where bacteria are frequently exposed to antibiotics. On an individual level, this means that a person is more likely to develop an antibiotic resistant infection from undergoing long-term or prophylactic antibiotic treatment, as opposed to short-term antibiotic treatments of acute infections.  This also means that bacteria may lose resistance to antibiotics that are no longer frequently used.

    Environments that Facilitate the Development of Antibiotic Resistance

    If you have read the above sections, you now know that infectious bacteria do not randomly become resistant to antibiotics. It requires an environment that provides a good source of hosts (people/animals to infect), consistent selective pressure (frequent antibiotic use) and ideally, lots of other bacteria with which to share antibiotic resistance genes (pieces of DNA that provide protection from the antibiotic). It is because of this combination of factors that antibiotic resistance is not simply about using antibiotics too much, but also about where and how antibiotics are used. That said, here are some environments which encourage the development of antibiotic resistance:

    Hospitals

    Hospitals are a Major Source of Antibiotic Resistant Bacteria

    Hospitals often are the perfect environment for developing bacterial antibiotic resistance. They have a many of the features that are necessary for antibiotic resistance to emerge. including:

    • A lot of sick people (lots of bacteria hanging around).
    • A high density of potential hosts for bacteria infection (lots of new people to infect).
    • The frequent and sustained use of antibiotics (consistent selective pressure).

    It is because of these factors that hospital acquired infections (HAIs) are often the most difficult types of infection to treat, because they are often highly resistant to standard antibiotic treatments. Hospitals are a reservoir for antibiotic resistance, and in many cases are the primary source of antibiotic resistant bacteria in the surrounding population. In the US, and other highly developed countries, hospitals are reasonably sterile and there are a number of systems in place to prevent hospital acquired infections. In many other places, the conditions are not as sanitary and this encourages the transmission of disease from patient to patient in the hospital setting.  In hospitals that have a high rate of antibiotic use but poor sterility, the development of antibiotic resistant bacteria is accelerated. It is not a coincidence that outbreaks of highly antibiotic resistant bacteria, like drug resistant Staphylococcus aureus (MRSA and VRSA) and Mycobacterium tuberculosis (XDR-TB), often originate in hospitals in countries like South Africa and Russia. In these places and others like them, high patient density, poor sterility, HIV/AIDs (see below) and high antibiotic usage combine to drive the rapid evolution of drug resistant bacteria.

    Feedlots and Industrial Animal Farms

    Industrial Animal Husbandry Uses More Antibiotics Than Human Medicine

    Many people may do not realize that industrial animal farming operations are among the largest consumers of antibiotics. Industrial operations involve large amounts of animals, packed densely into enclosed spaces. In this type of environment, disease transmission is a major problem. To prevent disease outbreaks, many operations treat their animals prophylactically with antibiotics. In fact, animal farming consumes the majority of all antibiotics used in the United States ( more antibiotics than are used in human medicine).

    Like highly unsanitary and overcrowded hospitals, the high level of antibiotic use in industrial animal farming drives the evolution of antibiotic resistance in bacteria.  In addition, the sewage produced by these operations can contain significant levels of un-metabolized antibiotics. These residual antibiotics combined with the huge and diverse population of bacteria living in the untreated sewage encourages the transfer of antibiotic resistance among different species of bacteria.  This can also cause the spread of antibiotic resistant bacteria to neighboring wildlife.  It also partly explains why detectable levels of antibiotics are found in many rivers, lakes and other waterways.

    Nursing Homes, Sanitoriums and Other Residential Institutions

    Nursing Homes Have High Rates of Antibiotic Usage and Immuno-Compromised People

    Many countries around the world place people who are infirm or disabled into various institutions.  While the United States has largely moved away from large scale housing of disabled, diseased or infirm patients, the practice is still common in many places around the world.  In wealthier countries, these people are often placed into assisted living facilities, retirement homes and hospices.

    In these environments there are dense populations of people who often have weakened immune systems.  The combination of these people with high levels of antibiotic use can contribute to the emergence of antibiotic resistant bacteria.  Elderly and disabled people often have compromised immune systems and this encourages more frequent and longer lasting infections. Prophylactic antibiotic use is common in these environments.

    HIV and AIDS

    HIV Patients in South Africa

    HIV and AIDS lead to higher rates of antibiotic resistance for two closely related reasons. First, because people who suffer from HIV and AIDS have an impaired immune system they are often highly susceptible to bacterial infection. As a result, many physicians place these patients on a permanent course of antibiotics to prevent infection. (Note: This is becoming less of a factor in places where effective anti-retrovirals are available, because they mitigate the need for prophylactic antibiotic treatment.)

    The second reason HIV and AIDS foster antibiotic resistant bacteria is that they cause more infections to happen and they make antibiotics less effective (indirectly). Even in a person with a healthy immune system, a bacterial infection may not be completely eliminated by a course of antibiotics. However, in most cases the antibiotic weakens and kills most of the bacteria and the immune system is able to target and eliminate the surviving bacteria.   But in a person with HIV, this small population of bacteria that remain after antibiotic treatment are not cleared by the immune system. This process selects for those bacteria that are slightly more resistant to the antibiotic treatment than the majority.

    Regions with High Levels of Antibiotic Use

    Correlation Between Penicillin Use and Penicillin Resistant Bacteria in Different Countries (Furuya, et al)

    In the last ten years numerous studies have been done profiling the antibiotic susceptibility of the acne causing bacteria, P. acnes. The results tell a fascinating story. In countries that prescribe patients antibiotics to treat acne at higher rates, there are higher rates of antibiotic resistant P. acnes. This means that in places like the United States and Europe, a significantly higher percentage of P. acnes bacteria are resistant than in places like Mexico, Chile and India. Additionally, the frequency of P. acnes bacteria resistant to a particular antibiotic varies from country to country, and reflects the differences in prescribing frequencies of different drugs between countries.

    Related Posts from The Science of Acne

    In Depth: What is Propionibacterium acnes?
    In Depth: Antibiotic Susceptibility of Propionibacterium acnes
    Overview: Oral antibiotics for Acne
    Overview: Topical antibiotics for Acne

    References and Sources

    Books

    Dyer. 2003. A Field Guide to Bacteria (Comstock Book)
    Medigan, et al. 2008. Brock Biology of Microorganisms (12th Edition)
    Willey. 2010. Prescott’s Microbiology
    Aarestrup. 2005. Antimicrobial Resistance in Bacteria of Animal Origin
    Dunn. 2011. The Wild Life of Our Bodies: Predators, Parasites, and Partners That Shape Who We Are Today
    Coyne. 2009 Why Evolution Is True

    Online Resources

    Antibiotic Resistance of Propionibacterium acnes in Acne Vulgaris @ eMedicine
    How Bacteria Become Resistant to Antibiotics @ Discovery Health

    Research Articles

    Levy, et al. 2004. Antibacterial resistance worldwide: causes, challenges and responses.
    Furuya, et al. 2005. Antimicrobial-resistant bacteria in the community setting.
    Friedberg. 2003. DNA damage and repair.
    Oprica, et al. 2005. European surveillance study on the antibiotic susceptibility of Propionibacterium acnes.
    Gould. 2006. Genetic basis of resistance in Propionibacterium acnes strains isolated from diverse types of infection in different European countries.
    Silbergeld, et al. 2008. Industrial Food Animal Production, Antimicrobial Resistance, and Human Health.
    Walsh. 2000. Molecular mechanisms that confer antibacterial drug resistance.
    Rooney, et al. 2009. Nursing homes as a reservoir of extended-spectrum b-lactamase (ESBL)-producing ciprofloxacin-resistant Escherichia coli.
    Gould. 2006. Costs of hospital-acquired methicillin-resistant Staphylococcus aureus (MRSA) and its control.
    Davies, et al. 2010. Origins and Evolution of Antibiotic Resistance.
    Grau, et al. 2009. Trends in mortality and antibiotic resistance among HIV infected patients with invasive pneumococcal disease.

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