Antibiotic Resistance

The year is 1940. You are playing with your cat, and get scratched. No big deal. Right?

Wrong. Two weeks later, you are dead.

Penicillin, the first antibiotic, was first used to treat patients in 1941 and revolutionized medicine. No longer did a scratch or an ear infection frequently result in a painful death, and battlefield injuries could be much more effectively treated. Additional antibiotics were soon developed, and it seemed as if bacterial infections were a thing of the past.

Penicillin radically altered the way that people dealt with bacterial infections

Eighty years later, the future looks much bleaker. Yes, antibiotics kill off the vast majority of bacteria. However, they also exert tremendous selective pressure on bacteria populations. The only bacteria that survive an antibiotic treatment regimen are those that are resistant. With no competition, they are able to grow exponentially and spread. Over time, the entire population of bacteria becomes resistant to the antibiotic.

In this experiment by Harvard Medical School, bacterial populations
evolved to survive in agar with a high concentration of antibiotic

One would think that the ability to resist any given antibiotic must be very rare, as it would require a very specific mutation that is exceedingly unlikely to occur by chance. However, bacteria can also exchange genetic information with each other and the environment through the processes of transduction, transformation, and conjugation. During transformation, bacteria take up circular segments of DNA from their environment, often from other dead bacteria. While this can be used experimentally to make bacteria glow green, it also has much more serious consequences. A certain strain of bacteria does not have to have an individual with just the right mutation that confers resistance. Instead, bacteria can absorb the genetic information that gives another strain resistance. This greatly increases the rate at which resistance is developed.

E. coli cells, when they have successfully absorbed the pGLO plasmid, glow green under UV light

Many antibiotics have been developed since penicillin, allowing for the treatment of infections that are resistant to a certain antibiotic. If resistance to one antibiotic is developed, another antibiotic can be used instead. The probability that a strain can develop resistance to multiple antibiotics in a short period of time is low, and many resistant infections can be treated this way. However, the more antibiotics that bacteria are exposed to, the greater the risk of infections that are resistant to multiple drugs. And herein lies the problem. Around 80% of antibiotics used in the United States are used on livestock. Kept in unhygienic and crowded conditions, infections can spread very quickly in populations of slaughterhouse destined pigs, cows, and chickens. In response, healthy animals are often treated with antibiotics as a precautionary measure. Up until 2017, antibiotics important to human medicine could be used on livestock for the purpose of promoting growth prior to slaughter, exacerbating this problem.  In addition to overuse in animals, antibiotics can also frequently be purchased without a prescription in many places outside of the United States. This excessive usage of antibiotics increases the probability that some bacteria will develop antibiotic resistance to multiple antibiotic, becoming effectively "untreatable."

Industrial farms like this one put livestock in close quarters and in unclean conditions, with antibiotics given even to healthy animals to prevent the spread of disease.

At this rate of antibiotic usage, bacterial resistance is inevitable. Short of a concerted global effort to reduce antibiotic usage in livestock and restrict access without a prescription, which is incredibly unlikely to occur (see climate change), new antibiotics must be brought to market. However, only three new classes of antibiotics have been brought to market over the last five decades, and most new antibiotics are merely variants of existing drugs. Only six new antibiotics were approved between 2010 and 2014, compared to a whopping 19 antibiotics between 1980 and 1984.

Only 3 new classes of antibiotics have been introduced in the past 50 years (malacidins, discovered in 2018, are not shown in the table)

A major reason for this is a lack of financial incentives for drug companies to invest in antibiotic research. Such research is very costly, with frequent failures, expensive clinical trials, and uncertain returns. New antibiotics typically cost around $2.6 billion to develop, and the financial payoff is slim. Unlike medications to treat chronic diseases, antibiotics are only taken for a few weeks at a time, limiting profits. Additionally, doctors are typically very hesitant to prescribe new antibiotics, fearing the development of bacteria that are resistant to those as well. Hospitals are unwilling to pay very high prices for new antibiotics either, and generic or older antibiotics are usually administered before newer ones are tried. This incentive structure has limited drug development, and only three companies are currently developing new antibiotics compared to the 18 actively doing research in 1980.

Although faced with similar financial disincentives, phage therapy development is another potential approach. First investigated at the same time as antibiotics, in phage therapy bacteriophages (a type of virus where a protein capsid protects the viral genome) specific to the bacteria causing the infection are injected. They attack only the targeted bacteria (due to strong host-specificity), and hijack the cell's replication machinery to make copies of themselves before lysing the cell and releasing the bacteriophages into the environment. Bacteriophage host specificity limits the ability of any given bacteriophage to prevent a broad range of bacterial infections, but also means that phage therapy does not have the same adverse effects on beneficial bacteria that traditional antibiotics do. Additionally, this is a self-amplifying treatment, as the bacteriophages replicate on their own.

Phage therapy exerts strong selective pressure on the targeted bacteria to develop a mutation that changes the surface proteins that the phages attach to, but this can be limited by dual-phage therapy where an additional phage is introduced that is designed to target bacteria resistant to the first phage. More research is needed in this area, but it provides a radically different approach to bacterial infections and has great promise.

The reproductive cycle of bacteriophages, shown here, allows for phage therapy to be self-amplifying

According to the United Nations, drug-resistant bacteria already kill 700,000 people annually, with projections suggesting that as many as 10 million people may die annually by 2050, an outcome so devastating that it would reduce global economic output as much as the Great Recession did. There are no simple solutions (although eating less and more humanely raised meat would be a good start), but international action (as well as the restructuring of the financial incentive system for drug development) is vital.

Organic meat products cannot legally contain antibiotics 

It is difficult to be concerned about a threat as abstract as antibiotic resistance as the global COVID-19 death toll approaches 400,000 (as of June 2). However, antibiotic resistant bacteria can exacerbate viral infections as they prey on weakened immune systems as secondary infections. Additionally, the next pandemic could be an antibiotic resistant bacteria. New antibiotics often take as long as a decade to be brought to market, and phage therapy needs to be more thoroughly researched, so action needs to be taken now to ensure that bacterial infections do not become the scourge that they were in the past.