What can change the frequency of resistant cells in a population of bacteria?

Antibiotics and antifungals save lives, but their use can contribute to the development of resistant germs. Antimicrobial resistance is accelerated when the presence of antibiotics and antifungals pressure bacteria and fungi to adapt.

Antibiotics and antifungals kill some germs that cause infections, but they also kill helpful germs that protect our body from infection. The antimicrobial-resistant germs survive and multiply. These surviving germs have resistance traits in their DNA that can spread to other germs.

Spread of Germs & Resistance Mechanisms

To survive, germs can develop defense strategies against antibiotics and antifungals called resistance mechanisms. DNA tells the germ how to make specific proteins, which determine the germ’s resistance mechanisms. Bacteria and fungi can carry genes for many types of resistance.

When already hard-to-treat germs have the right combination of resistance mechanisms, it can make all antibiotics or antifungals ineffective, resulting in untreatable infections. Alarmingly, antimicrobial-resistant germs can share their resistance mechanisms with other germs that have not been exposed to antibiotics or antifungals.

This table gives a few examples of defense strategies used to resist the effects of antibiotics or antifungals.

Antibiotics are designed to fight bacteria by targeting specific parts of the bacteria’s structure or cellular machinery. However, over time, bacteria can defeat antibiotics in the following ways:

Survival of the Fittest (Natural Selection)

When bacteria are initially exposed to an antibiotic, those most susceptible to the antibiotic will die quickly, leaving any surviving bacteria to pass on their resistant features to succeeding generations.

Biological Mutations

Since bacteria are extremely numerous, random mutation of bacterial DNA generates a wide variety of genetic changes. Through mutation and selection, bacteria can develop defense mechanisms against antibiotics. For example, some bacteria have developed biochemical “pumps” that can remove an antibiotic before it reaches its target, while others have evolved to produce enzymes to inactivate the antibiotic.

DNA Exchange

Bacteria readily swap bits of DNA among both related and unrelated species. Thus, antibiotic-resistant genes from one type of bacteria may be incorporated into other bacteria. As a result, using any one antibiotic to treat a bacterial infection may result in other kinds of bacteria developing resistance to that specific antibiotic, as well as to other types of antibiotics.

Rapid Reproduction

Bacteria reproduce rapidly, sometimes in as little as 20 minutes. Therefore, it does not take long for the antibiotic-resistant bacteria to comprise a large proportion of a bacterial population.

Antibiotic-Resistant Bacteria and Effectiveness of Those Drugs

To date, all antibiotics have over time lost effectiveness against their targeted bacteria. The earliest antibiotics were developed in the 1940s.

These "miracle drugs" held at bay such devastating diseases as pneumonia and tuberculosis, which had previously been untreatable. But the steady evolution of resistant bacteria has resulted in a situation in which, for some illnesses, doctors now have only one or two drugs “of last resort” to use against infections by superbugs resistant to all other drugs. For example:

Staph Aureus

Nearly all strains of Staphylococcus aureus in the United States are resistant to penicillin, and many are resistant to newer methicillin-related drugs. Since 1997, strains of S. aureus have been reported to have a decreased susceptibility to vancomycin, which has been the last remaining uniformly effective treatment.

Campylobacter Infections

Today, one out of six cases of Campylobacter infections, the most common cause of food borne illness, is resistant to fluoroquinolones (the drug of choice for treating food-borne illness). As recently as ten years ago, such resistance was negligible.

Next Steps

Clearly, it is important to extend the useful lifetime of any drug that is effective against human disease. And today, this is even more important because few new antibiotics are being developed, and those that are developed tend to be extremely expensive.

In bacteria, mutations in plasmids can accumulate surprisingly fast. What does this mean for us humans, who have to fight with these new antibiotic resistant strains?

Figure 1: Staphylococcus aureus bacteria.

\"Staph\" skin infections are caused by a bacterium that can divide every half hour in optimal conditions. Theoretically, a single cell can form a colony of more than a million cells in ten hours.

Courtesy of Janice Haney Carr/CDC.

Suppose that one morning, on your way to class, you were to touch a surface, like a doorknob, that was contaminated with some lingering Staphylococcus aureus (Figure 1). The bacterium S. aureus, known by health care workers as "staph," is the most common cause of skin infections in humans. Suppose another student who had walked into the building just minutes beforehand had left the organism there, after grabbing hold of the same doorknob. Now imagine that you have an open cut on your finger, and some of the bacteria that are on that doorknob get into your wound. Although this seems like a minor event, it could actually have great repercussions for your overall health.

Mutation Rates and Bacterial Growth

Even if only a single S. aureus cell were to make its way into your wound, it would take only 10 generations for that single cell to grow into a colony of more than 1,000 (210 = 1,024), and just 10 more generations for it to erupt into a colony of more than 1 million (220 = 1,048,576). For a bacterium that divides about every half hour (which is how quickly S. aureus can grow in optimal conditions), that is a lot of bacteria in less than 12 hours. S. aureus has about 2.8 million nucleotide base pairs in its genome. At a rate of, say, 10-10 mutations per nucleotide base, that amounts to nearly 300 mutations in that population of bacteria within 10 hours!

To better understand the impact of this situation, think of it this way: With a genome size of 2.8 × 106 and a mutation rate of 1 mutation per 1010 base pairs, it would take a single bacterium 30 hours to grow into a population in which every single base pair in the genome will have mutated not once, but 30 times! Thus, any individual mutation that could theoretically occur in the bacteria will have occurred somewhere in that population—in just over a day.

Mutations, Antibiotic Resistance, and Staph Infections

Now, say that a few days after your initial infection with S. aureus, you decide to go to the local health center to have your wound examined. Maybe your finger is not healing as quickly as you had expected. Maybe its red color is a bit worrisome. Maybe the wound is starting to ooze a bit. Maybe you vaguely recall hearing or reading something about some kind of bacterial infection that is popping up on college campuses across the country and landing some students in the hospital. Concerned that your wound might be infected, the physician at the health center decides to prescribe an antibiotic.

Under a best-case scenario, the prescribed antibiotic would kill all of the replicating S. aureus cells in your body, mutant or otherwise, and your wound would quickly heal. After all, the potency of antibiotic treatment is why, when penicillin entered medical care in the 1940s, it was deemed a "miracle drug." Penicillin and other antibiotics have saved countless lives for more than half a century. Under a different scenario, however, any one of those mutations could give your S. aureus infection the ability to resist the particular drug you are being treated with. Luckily, in the real world, usually more than one mutation is required to generate drug resistance, and bacteria cannot double quite so quickly inside a person with a functioning immune system. But the problem still remains: The rapid division of bacterial cells causes them to evolve resistance to most treatments rather quickly.

Thus, although you are on antibiotics and you are otherwise healthy, a total of 600 mutations have accumulated by the time you go to bed that night. Any one of those mutations could give your staph infection the capacity to continue replicating, even in the presence of the antibiotic. All it takes is a single mutated S. aureus—one that, through one of a number of innovative biochemical means, does not die in the presence of whatever antibiotic the physician decided to prescribe—to render that antibiotic useless (at least for this particular infection). Moreover, when that mutant cell replicates, it will pass on its resistant phenotype to its daughter cells, and they to theirs. Thus, a rapidly growing proportion of the replicating bacteria still present in your body will be drug resistant. This is because the drug will kill only those cells that do not have the newly evolved drug-resistance capacity. Thus, the entire bacterial population will eventually become resistant to the prescribed antibiotic. When that happens, your infection will be said to be antibiotic resistant, and your physician will have to prescribe a different drug to combat it.

MRSA: The Spread of Drug Resistance

In fact, there is a good chance that the staph infection you picked up from that contaminated doorknob is already antibiotic resistant. Most staph infections in humans are caused by methicillin-resistant Staphylococcus aureus, or MRSA, a drug-resistant phenotype that has been circulating for more than 45 years, almost as long as methicillin has been on the market. According to the U.S. Centers for Disease Control (CDC). MRSA: Methicillin-resistant Staphylococcus aureus in health care settings. (2007)

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