Race Against Time: The Development of Antibiotic Resistance

 

Race Against Time: The Development of Antibiotic Resistance

Caleb Wooley
Categories: 
Published by the PIT Journal: 

Abstract: 

Antibiotic treatments have been around since the discovery of penicillin in 1928. For the last 70 years, antibiotics have treated numerous people and prevented severe outbreaks of bacterial infections. However, some bacteria strains have become rapidly resistant, an issue that this paper explores. This resistance has led to using Vancomycin, a strong drug usually not administered unless safer treatments are ineffective. Understanding antibiotic resistance requires knowledge of the current research and what pharmaceutical companies are doing that may negatively impact the health of the population. This paper examines these issues related to growing antibotic resistance and how they could lead to a future outbreak of an uncontrollable disease. The concluding result is that researchers need to keep searching for solutions to this expanding problem.

Article: 

The discovery of penicillin in 1928 by Alexander Fleming revolutionized medical treatment for bacterial infections. When it was finally mass-produced in the 1940s, antibiotics derived from the fungus penicillium were used to treat many types of infections, such as syphilis, meningitis, and gangrene. Over the course of the last 70 years, penicillin antibiotics have saved many lives and successfully prevented the outbreak of serious bacterial infections. Unfortunately, subpopulations of bacteria develop resistance to commonly administered antibiotics. This resistance slowly spreads based on several environmental factors, and after enough time, the majority of bacteria can be resistant to first-line antibiotics like penicillin. When an infection does not respond to first-line treatment, doctors must administer second- and third-line antibiotics. Vancomycin, traditionally a drug of “last resort,” must be used when the safer treatments are not effective. The need for intravenous administration coupled with a higher nephrotoxicity, i.e. a toxic effect on the patient’s kidneys, make Vancomycin a drug of last resort. Even so, some bacteria are resistant to Vancomycin, leaving few options for safe treatment. In these cases, it is questionable whether the patient will survive. The Center for Disease Control and Prevention estimates that Vancomycin-resistant Enterococcus (VRE) causes 1,300 deaths annually out of 20,000 infections. Approximately one-third of reported Enterococcus infections are caused by drug-resistant strains. Common strains of bacteria that are resistant to antibiotics include Methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli (E. coli). Overall, the CDC estimates that about two million illnesses and 23,000 deaths can be attributed to antibiotic resistance each year in the United States. To understand antibiotic resistance, one must examine current research on the issue, pharmaceutical companies’ destructive actions, and the possibility of an epidemic.

Antibiotic resistance can be defined in several ways. The simplest definition is when a bacterium or a population of bacteria has a resistance mechanism that makes it less susceptible to treatment than other members of the same species. The mechanism can be caused by mutations in the bacteria or can be a result of horizontal gene transfer, which is the transfer of genes (resistance genes in this case) between bacteria in a manner other than reproduction. Horizontal gene transfer can occur through several different processes: transformation, transduction, and conjugation. Transformation is the genetic change that occurs when bacteria takes in naked DNA from its environment. Typically, a plasmid will contain a gene that will give antibiotic resistance to a portion of a population of bacteria. Transduction refers to the process of the transfer of genetic material from one bacterium to another by a virus (Antibiotic Resistance Q&A, CDC).  Researches use a clinical breakpoint, determined by a MIC value, to separate resistant bacteria from susceptible bacteria (Canton & Morosini, 2011). Several different strains of gram-positive bacteria, such as the strain of Staphylococcus aureus known as VRSA, are already resistant to drugs of last resort. Mechanisms of resistance to natural or semi-synthetic antibiotics include glycosylation and phosphorylation (Levy & Marshall, 2004).

As the problem continues to grow and larger populations of bacteria become resistant to current antibiotics, new antibiotics and treatments must be developed. Despite the growing fear of “superbugs,” many members of the public do not understand how antibiotic resistance can develop and what can be done in everyday life to prevent it. Making knowledge about resistance more available and understanding current research on the topic can slow the spread of resistant bacteria while new antibiotics are developed and tested. Much of current research focuses on the how antibiotic resistance develops in bacteria, such as E. coli, as well as how over-prescribing antibiotics and patient error can speed the spread (Canton & Morosini, 2011). Researchers study how populations of bacteria survive exposure to antibiotics and acquire resistance genes through horizontal gene transfer, among other processes. Many patients ignore dosage guidelines and unknowingly contribute to antibiotic resistance in their own bodies and their immediate vicinities.

The appearance of drug-resistant bacteria quickly follows the introduction of a new antibiotic, which suggests an extremely fast rate of adaptation. Not long after penicillin was introduced, penicillin-resistant Staphylococcus aureus appeared in hospitals (Levy & Marshall, 2004). Furthermore, comparison of pre-antibiotic and post-antibiotic samples indicate an increase in antibiotic resistance genes for the ß-lactamase, tetracycline, and macrolide families of antibiotics (Bhullar et al., 2012). Repeated exposure to tetracycline antibiotics (which inhibits the process of translation and therefore the creation of protein) causes the development of resistance in the form of ribosomal protection. Bacteria that can protect against the inhibition of protein synthesis will be largely resistant to this family of antibiotics.

Although it is obvious that the more dangerous, resistant strains have mutated and acquired stronger resistance genes over time, the presence of inherent resistance genes should not be overlooked. Bacteria can inherently possess the genes for antibiotic resistance and a vast amount of research explores how these genes express themselves and how bacteria populations develop resistance genes. Many organisms have an intrinsic resistome that contributes to the surprisingly quick development of resistance to a certain antibiotic. There are certain genes in bacteria, many of which are involved in “housekeeping” functions, which are widely considered pre-resistance genes (Canton & Morosini, 2011). Gene duplication contributes heavily to the evolution of housekeeping genes into antibiotic resistance genes. Furthermore, studies of the metabolic pathways of microbes shows that β -lactam antibiotics and β -lactamase enzymes were created by such microbes over two billion years ago (Spellberg et al., 2008).

While the problem is not yet out of control, it is not far from becoming a major threat to human health. The rate at which new antibiotics are being discovered has slowed dramatically in the past several decades. Researches are not keeping pace with nature and resistance is developing faster than treatment. An epidemic might sound far-fetched to some, but because of the long process of testing a drug’s viability in humans, a long response time to a deadly outbreak could result in the deaths of millions of people around the world. Pharmaceutical companies are invested in producing treatments for long-term illnesses because there is a greater financial incentive. There is significantly more profit when patients are reliant on products for long periods of time (Plumridge, 2014). The drug development pipeline has dried up in the past decade and only a few pharmaceutical companies still invest in development of antibiotics for use in short-term infections. Understanding how bacteria builds and spreads resistance is the first step in confronting the issue. Public awareness of how individuals can help slow the spread on a national scale is a vital step to solving the problem. At the same time, pharmaceutical companies and researchers need to develop new treatments and antibiotics.

Many researches in the field are conducting studies that focus on the link between the use of antibiotics and the development of resistance. They are focusing on the mechanisms that bacteria use to build resistance and the causes of resistance. When a population of bacteria is constantly challenged through the use of antibiotics, resistance can evolve quickly by several processes. A team of researchers developed a device called a “morbidostat” that monitored bacterial growth and regulated drug concentrations based on that growth so that the population was constantly challenged. The bacteria used was a wild-type strain of Escherichia coli. E. coli is the most widely studied prokaryotic model organism because it is inexpensive and easy to grow in a lab setting. After about 20 days, the strains of bacteria showed mutations for resistance to a specific drug and shared in resistance to multiple drugs (Toprak et al., 2012). This study is a good representation of the kinds of studies that are being commonly conducted in recent years. The study shows a strong link between pressure from antibiotics and the development and spread of resistance in the population of E. coli. Escherichia coli developed resistance over a span of 20 days through the accumulation of mutations. Similarly, the increasing presence of methicillin-resistant Staphylococcus aureus should raise alarm. MRSA is becoming a global pandemic due to its mutations, such as a thickening of the cell wall which resulted in low-level resistance to vancomycin (Arias & Murray, 2009).

While the mechanisms by which resistance spreads are generally understood, the link between antibiotic treatment and its development are not as clear. That is to say, we understand how it happens, but we do not have a clear grasp on how much of an effect the use of antibiotics has on quickening the time it takes for the majority of a type of bacteria to become resistant. This information is crucial because it gives researchers and drug companies a time frame to develop new antibiotic treatments for serious diseases. When put under antibiotic pressure, a very small portion of a population of bacteria is unaffected, probably due to a mutation. In determining the environmental resistome, it is important to find a community of bacteria that is untouched by antibiotics. Samples were gathered in one such place – a cave in New Mexico that has remained isolated for millions of years. The samples were placed under a high concentration of several different classes of antibiotics, designed to select for organisms with “robust resistance.” Up to 70% of the strains (none of which had come in contact with humans or antibiotics) were inherently resistant to at least three classes of antibiotics (Bhullar et al., 2012). Despite the lack of contact with humans or any kind of antibiotics, some strains of the bacteria were resistant to 14 different commercially available antibiotics. Further tests indicated that the bacteria possessed a macrolide kinase encoding gene that is related to a family of kinases found in many modern drug-resistant pathogens. A large portion of the bacteria tested (approximately 65% of the gram-negative bacteria) were resistant to antibiotics from three to four classes (Bhullar et al., 2012). Findings such as these must spur both legislative and commercial action, as they suggest that many strains of bacteria are inherently resistant to the types of antibiotics employed in modern medicine.

As observed in the “morbidostat” experiment, bacteria can constantly evolve while under pressure from antibiotic treatment. Many members of the public rely too heavily on antibiotic regimens for illnesses that may not even benefit from this type of treatment. For example, a surprisingly large portion of the population believes that when they have the flu, antibiotics will help them become healthy again. This is alarming but not uncommon. It is also important to note that patients can put pressure on doctors to prescribe antibiotics even when unnecessary. Many people who are prescribed antibiotics for treatment outside the hospital do not finish their regimen (Canton & Morosini, 2011). Patients commonly do not finish their antibiotics because they begin to feel well. In these cases, the bacteria causing the illness will survive because the patient did not finish treatment. The subpopulation of bacteria that survives is more resistant to the treatment used and will evolve to become increasingly resistant. Due to these misconceptions, the public can unknowingly aid the spread of resistant bacteria. It has been suggested that the emergence of resistance can at least be decreased with the appropriate antimicrobial treatment (Canton & Morosini, 2011). Combination therapy may sometimes be successful in avoiding development of resistance by combining early treatment and limiting the concentration of antimicrobials at the infection site within the mutant selection window.

In a meta-analysis of 24 case studies, each patient was prescribed antibiotics for either urinary infections or respiratory infections. The population of bacteria that was resistant to first-line treatment increased, and a need for second-line antibiotics was created. The resistance effect of the antibiotics was strongest in the first month after treatment and lasted up to 12 months (Costelloe et al., 2012). This research suggests that the effect of antibiotic treatment is diminished over time and does not always have a permanent impact if the conditions are right. The diseases that developed resistance were no longer more likely to survive after treatment ended.

Unfortunately, many pharmaceutical companies no longer have a strong research and development program for short-term infections. There is little money to be made in developing new treatments for short-term illnesses because the process is long and costly. After developing the drug, multiple studies must be conducted to determine if it is safe. Cancer patients pay tens of thousands of dollars for ongoing treatments, while patients who might only need a two-week antibiotic regimen will only pay hundreds. Thus, the incentive to pour money into research and development, especially for infections that are not yet widespread, is non-existent. A few companies, such as GlaxoSmithKline, still develop drugs for infectious diseases. They currently have three unnamed drugs in Phase I and Phase II trials for “bacterial infections.” And while this is good news, it is not even close to enough to combat all of the diseases that threaten us in the modern world (Plumridge, 2014).

Due to the fact that some research indicates that the use of antibiotics has little effect on development of resistance, while other studies support that conclusion, it is safe to say more research should be conducted to determine the effects of drugs on resistance development. In my research, it has become apparent that, depending on the strain of bacteria, there is an inherent ability to be resistant to certain types of antibiotics. It is also clear that resistance can develop quickly if the population of bacteria is put under pressure. More research to solidify these claims would also help shed some light on the exact relationship between pressure, medicine, and resistance. Any insight that we could gain from further research will help prevent the outbreak of a deadly disease that could have global repercussions.

 

References

Antibiotic Resistance Questions & Answers [Internet]. Atlanta (GA): Centers for Disease Control and Prevention (US); [updated 2013 Dec 18; cited 2014 Jan 15].

Arias C, Murray B. 2009. Antibiotic-resistant bugs in the 21st century - a clinical super-challenge. The New England Journal of Medicine. 1(360):439-443.

Bhullar K, Waglechner N, Pawlowski A, Koteva K, Banks E, Johnston M, Barton H, Wright G. Antibiotic Resistance Is Prevalent in an Isolated Cave Microbiome. PLoS ONE. 2012;7(4):1-13.

Canton R, and Morosini M-I. Emergence and spread of antibiotic resistance following exposure to antibiotics. FEMS Microbiology Reviews 2011;35:977–991.

Costelloe C, Metcalfe C, Lovering A, Mant D, Hay A. Effect of antibiotic prescribing in primary care on antimicrobial resistance in individual patients: systematic review and meta-analysis. BMJ 2012;340:1-16.

Levy S, Marshall B. 2004. Antibacterial resistance worldwide: causes, challenges and responses. Nature Medicine. 10(2):122-129.

Plumridge H. 2014 Jan 23. Drug makers tiptoe back into antibiotic R&D [Internet]. The Wall Street Journal; www.online.wsj.com

Spellberg B, Guidos R, Gilbert D, Bradley J, Boucher H, Schled W, Bartlett J, Edwards J. 2008. The epidemic of antibiotic-resistant infections: a call to action for the medical community from the Infectious Diseases Society of America. Oxford Journals. 46(2):155-164.

Toprak E, Veres A, Michel J, Chait R, Hartl D, Kishony R. Evolutionary paths to antibiotic resistance under dynamically sustained drug selection. Nature Genetics 2012;(44):101-105.


About the Author(s)
Caleb
Wooley
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