How Do Bacteria Become Resistant to Antibiotics?

Industrial animal farming is a major source of antibiotic resistant bacteria

Answer: Bacteria adapt, evolve and acquire antibiotic resistance.

Bacteria Cell (credit - Wikipedia)The extensive use of antibiotics in human patients does contribute to increased antibiotic resistance among infection-causing bacteria. But, the short-term use of antibiotics to treat infections in an outpatient setting is not the primary cause of the increase in antibiotic-resistant bacteria. There are several factors which contribute to the growing problem of antibiotic-resistant bacteria. 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?

Bacteria Antibiotic Susceptibility Test Plate (credit - Wikipedia)Antibiotics are molecules that directly kill bacteria or inhibit their growth. Generally speaking, antibiotics are small molecules that disrupt essential biological processes that are unique to bacteria. Antibiotic resistance refers to a situation where a strain of bacteria becomes less sensitive to a particular antibiotic (or class of antibiotics). Antibiotic resistance occurs because the resistant bacteria have developed or acquired an ability to prevent the normal function of the antibiotic. There are many types of antibiotics, and there are many types of bacteria. Most antibiotics are only good at killing certain types of bacteria. Some bacteria are naturally resistant to certain antibiotics. It is important to select antibiotics which are toxic to the specific type of bacteria that is causing an infection.

Adaptation and Evolution of Antibiotic Resistance

Epigenetic Adaptation (No Genetic Mutation)

Muscles and Epigenetic AdaptationBacteria 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. This type of antibiotic resistance does not produce permanent genetic changes that can be inherited by subsequent generations of bacteria. Epigenetic Adaptation 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)

Genetic EvolutionGenetic mutations are permanent changes in an organisms genetic code. Most mutations are very small and involve the change of a single nucleotide (an individual letter in the genetic code). Some mutations involve large rearrangements of the genome. Genetic mutations occur naturally during DNA replication. Mutations can also occur 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 is the Quinolone family of antibiotics (eg. Ciprofloxacin, Nadifloxacin). Antibiotics in the Quinolone family target a bacterial enzyme called DNA gyrase. The antibiotic binds very tightly to this enzyme, which prevents the bacteria from reading and replicating its own DNA. A single mutation at a specific site in this enzyme can stop the antibiotic from binding. This specific mutation allows the bacteria to become resistant to that antibiotic. Antibiotics that can be inactivated by simple genetic mutations, such as Ciprofloxacin, are not generally recommended for long-term use because of the increased risk of generating resistant bacteria.

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

Bacterial Genetic Transfer (Wikipedia)Bacteria can acquire large pieces of DNA from other bacteria, viruses and the environment. Genetic Acquisition is the mechanism by which bacteria acquire high-level resistance to many types of antibiotics. This is especially true for antibiotics which can not be inactivated by simple genetic mutations. It is virtually 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 contain the genes that confer high-level antibiotic reistance:

  • Plasmids are mobile pieces of DNA (often circular) that bacteria can easily trade amongst themselves or simply acquire from the environment. Many bacteria have multiple plasmids. Plasmids can contain genes that inactivate a particular antibiotic. For example a gene called Beta Lactamase provides resistance to Penicillin family antibiotics and is commonly shared by bacteria via plasmid.
  • 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 of these techniques (or all of them) to acquire pieces of genetic code that provide resistance to a specific antibiotic (or a whole family of antibiotics).

Conditions That Allow Antibiotic Resistance To Develop

The Necessity of Selective Pressure

Evolution Through Selective Pressure (credit - Wikipedia)The average bacterial genome (a bacteria’s entire genetic code) is approximately 1000 times smaller than the genome of an animal (including humans). This is not because bacteria are smaller than human cells (although they are). Bacterial genomes tend to be very small because of competition and a concept called “”genomic streamlining””. A genome is not free. It takes energy and resources to maintain and replicate a genome. 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, the competition between bacteria for resources is incredibly intense. 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 it is quickly eliminated. If a section of bacterial DNA is not essential for survival or does not confer a consistent 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 a bacteria’s genome for any extended period of time, that gene must 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. From a big picture perspective, this means that antibiotic resistance is likely to develop and persist in specific 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

Examples of How Antibiotic Resistant Bacteria Spread (credit - CDC)If you have read the above sections, you now know that infectious bacteria do not randomly become resistant to antibiotics. The development of antibiotic resistance 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. 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, there are some environments which uniquely support the development of antibiotic resistance:

Hospitals

Hospital Surgery SuiteHospitals are often the perfect environment for bacteria to develop, acquire and maintain high-level antibiotic resistance. Hospitals have a many of the features that are necessary for antibiotic resistance to emerge. including:

  • A lot of infected people and contaminated surfaces (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).

Hospital Acquired Infections (HAIs) are often the most difficult types of infection to treat because they are can be 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 United States, and other highly developed countries, hospitals are reasonably sterile and there are a number of systems in place to prevent hospital acquired infections. Despite these safeguards, HAIs are one of the leading causes of morbidity among patients admitted to hospitals in the United States. In many other countries hospital conditions are less sanitary, which encourages the transmission of disease from patient to patient. 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 virulent antibiotic-resistant bacteria, such as Multi-drug Resistant Staphylococcus Aureus (MRSA) 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 farming is a major source of antibiotic resistant bacteriaMany people may do not realize that industrial animal farming operations are among the largest consumers of antibiotics in the world. 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 (continuously) with antibiotics. In fact, in the United States animal farming consumes 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 genes among different species of bacteria. Industrial animal farms 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

Assisted Care FacilityMany countries around the world place people who are elderly, infirm or disabled into various types of institutions. While the United States has started to moved away from the large-scale housing of these individuals, 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.

These environments contain dense populations of people who have weakened immune systems, which allows for more frequent and longer lasting infections. Antibiotic use can be very high in many of these environments and prophylactic antibiotic use is common. The combination of large populations of immune-compromised people and extensive antibiotic use can contribute to the emergence of antibiotic resistant bacteria.

HIV and AIDS

HIV AIDS ClinicHIV 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. Over time this process can drive Epigenetic Adaptation and select for Genetic Mutations that confer resistance.

Antibiotic Resistance and Acne Treatment

Type 2-3 Acne on Face
Type 2-3 Acne on Face
In the last ten years numerous studies have been done profiling the antibiotic susceptibility of the acne-causing bacteria, Propionibacterium acnes. The results tell a fascinating story. In countries where antibiotics are more frequently used to treat individuals with acne, antibiotic-resistant P. acnes bacteria tend to be more common. This means that in places like the United States and Europe, a significantly higher percentage of P. acnes bacteria have high-level antibiotic resistance than in places like Mexico, Chile and India. Interestingly, the frequency of P. acnes bacteria resistant to a particular antibiotic varies from country to country, and this appears to reflect the differences in prescribing frequencies of different antibiotics for acne treatment between countries. In the United States, laboratory testing indicates that P. acnes bacteria that are resistant Macrolide and Tetracycline family antibiotics (the two antibiotic families most commonly used to treat acne) are becoming more common. But this trend is not true for all countries.

Industrial animal farming is a major source of antibiotic resistant bacteria