Antibiotic resistance

Antibiotic resistance (also known as bacterial resistance or drug resistance) is the phenomenon in which bacteria evolve to resist the effects of antibiotic drugs intended to kill or suppress them. It is one form of antimicrobial resistance (AMR), a term that describes the same process involving any kind of microbe (such as viruses, fungi, and protozoa, as well as bacteria) and antimicrobial agent (such as general disinfectants as well as antibiotics specifically). Scientists and health care professionals recognize antibiotic resistance as a major public health threat. Antibiotic-resistant bacteria, and especially so-called superbugs with multiple drug resistance (MDR), make treatment of many diseases more difficult. While the development of AMR is a natural evolutionary process, experts warn that it is greatly amplified by the overuse and misuse of antibiotic drugs and other antimicrobials.

Key Terms

Antibacterials: A general term for antimicrobials that target bacteria, whether as disinfectants, antiseptics, or antibiotic medications.

Antibiotics: A subset of antimicrobials that target bacteria; often used specifically to refer to substances delivered as medication.

Antimicrobial resistance (AMR): A phenomenon in which a microorganism—such as a bacterium or virus—changes to become resistant to an antimicrobial agent.

Antimicrobials: Substances that kill or inhibit the growth of microbes of any kind.

Antiseptics: A subset of antimicrobials used to reduce the chance of infection on living tissue, but not as medicine within the body.

Disinfectants: A subset of antimicrobials used for sanitizing surfaces rather than as medication; typically, they are non-selective in the types of microbes they kill.

Background

Scientific understanding of antibiotic resistance and other forms of AMR only developed after the germ theory of disease took root in the mid-nineteenth century. Once researchers understood that many diseases are caused by microbes, there was much more attention to the role of hygiene and sanitation in preventing infectious diseases, and the use of antiseptics and disinfectants became common. The development of antibiotic medications to treat bacterial diseases followed in the twentieth century.

A major turning point came when microbiologist Alexander Fleming discovered penicillin in 1928, setting up what is sometimes known as the antibiotic revolution in medicine. From the 1940s to the 1970s, scientists steadily discovered entire classes of antibiotics and developed numerous drugs to combat various diseases. However, researchers also quickly began to realize that bacteria and other microbes could relatively quickly develop resistance or even complete immunity to antimicrobial substances, especially with widespread exposure or improper treatment that allows more resistant microbes to survive and spread. Indeed, Fleming was among the earliest to warn of this threat—and penicillin-resistant strains of bacteria were identified by the mid-1940s, quickly reducing the drug's effectiveness.

Despite such warnings, excitement about the treatment potential of antibiotics contributed to their ongoing proliferation and widespread use throughout the rest of the twentieth century. In addition to medicines, researchers also carried on developing disinfectants and sanitizers, which became increasingly common in consumer products. Antibacterial agents such as triclosan were often added to soaps and other cleansers intended for everyday use. Marketing campaigns heavily promoted antibacterial hygiene products as more effective at preventing illness (even though studies sometimes cast doubt on these claims).

Meanwhile, antibiotics also came to be heavily used on livestock, as well as some crops, both to prevent infections and simply to promote growth. Studies eventually indicated that such agricultural usage could hasten the development of resistant microbes throughout the environment, leading to infections affecting not only the agricultural species but also humans. Similarly, the environmental spread of antibiotics through pollution (from sources such as cleaning products and human waste) was found to contribute to the spread of antibiotic resistance. In response, public health experts increasingly identified antibiotic overuse and misuse as a key factor in rapidly spreading antibiotic resistance.

By the early twenty-first century, numerous bacteria were known to have developed resistance to one or more drugs and represented serious threats to public health. Some of the most notable examples included carbapenem-resistant Acinetobacter, carbapenem-resistant Enterobacterales, Clostridioidesdifficile, drug-resistant Neisseriagonorrhoeae, multiple forms of Salmonella bacteria, Streptococcus pneumoniae bacteria, and methicillin-resistant Staphylococcus aureus (MRSA). Microbes with multidrug resistance (MDR), popularly known as “superbugs,” often generated particular concern from scientists and attention in the media.

Mechanisms of Resistance

Microbes have several major mechanisms of drug resistance, typically based on an attack of the drug structure, drug-bacteria interaction, or drug quantity around the bacterial cell. More than one mechanism can be used at a time to develop widespread resistance, and different mechanisms are more effective against different antibiotic classes.

Bacterial resistance develops because of changes to enzymes, target sites, or cell-wall components. Examples of enzyme-mediated resistance are the development of beta-lactamase, which targets beta-lactam antibiotics for inactivation, and the development of a new enzyme that is not affected by antibiotics. Reduced bacterial cell-wall permeability, particularly with gram-negative bacteria, is also a common resistance method; drug efflux, which occurs when bacteria pump antibiotics from the bacterial cell, is most common with tetracycline antibiotics. Changes to the target site on the bacteria, in which antibiotics cannot recognize the binding site and attack bacteria, are less common with beta-lactams and more common with quinolones and macrolides. In some cases, bacteria may otherwise block the target site to prevent antibiotic binding; this occurs against tetracycline antibiotics in particular. Bacteria may increase the amount of binding sites on the wall too, so that antibiotics cannot achieve sufficient proportional concentrations for activity, especially with sulfonamide treatment and with glycopeptides such as vancomycin.

Cellular adaptations that help bacteria avoid any interaction with antibiotics and binding of antibiotics elsewhere on the bacteria to prevent action on the bacterial cell target also incur drug resistance. The latter method is specific to glycopeptides like vancomycin.

Once an individual bacterium has developed resistance, the trait can spread through the transfer of antimicrobial resistance genes (ARGs) between microbes. This can take place through vertical gene transfer (VGT), in which the ARGs are transferred from an organism to its offspring, as well as horizontal gene transfer (HGT), in which genetic information is transferred from one organism to another.

Prevention Efforts

Early attempts to slow the development of antibiotic resistance started in the 1980s, when hospitals began instituting guidelines to cycle, or rotate, antibiotic use for certain diseases. Cyclic administration of antibiotics consists of restricting the prescribing of the most commonly used antibiotic and favoring an alternative antibiotic treatment instead. Some research in the late twentieth and early twenty-first centuries found little evidence of success at minimizing resistance with cycling. However, other studies have supported closely monitored antibiotic prescribing to help reduce resistance buildup.

Public health officials and government regulators in many countries have pursued policies aimed at addressing the problem of antibiotic resistance and other forms of AMR. For example, in the United States, the National Antimicrobial Resistance Monitoring System (NARMS) was created in 1996 to coordinate among state and local health agencies on tracking certain antibiotic-resistant microbes found in humans, meat products, and livestock. As the federal agency responsible for drug approval in the country, the US Food and Drug Administration (FDA) became deeply involved in efforts to combat resistance, including with both research into new, more effective antibiotic drugs and educational efforts about responsible use of antimicrobials. Through the Center for Veterinary Medicine (CVM), the FDA worked to limit antimicrobial use in animals, such as withdrawing approval of fluoroquinolone antibiotics for poultry in 2005 due to evidence that widespread use had led to the development of a fluoroquinolone-resistant strain of the bacterial disease Campylobacteriosis. Beginning in 2017, the FDA required a prescription or special approval for any use of medically important antimicrobials in animals intended for human consumption. The US government released the National Strategy for Combating Antibiotic-Resistant Bacteria (CARB) in 2014, followed by the first iteration of the National Action Plan for CARB in 2015.

Similar initiatives also appeared in other countries and at the international level. For instance, the World Health Organization (WHO) introduced its Global Action Plan on Antimicrobial Resistance in 2015. The primary objectives of that plan included raising awareness of AMR, carrying out enhanced surveillance and research, and promoting preventive measures to reduce infections. The European Union and some other jurisdictions around the world banned the use of many antibiotics in livestock, especially for growth promotion rather than treatment of disease.

Bibliography

“Antimicrobial Resistance.” WorldHealthOrganization, 21 Nov. 2023, www.who.int/news-room/fact-sheets/detail/antibiotic-resistance. Accessed 12 Sept. 2024.

“Antimicrobial Resistance Facts and Stats.” Centers for Disease Control and Prevention, 16 July 2024, www.cdc.gov/antimicrobial-resistance/data-research/facts-stats/. Accessed 12 Sept. 2024.

Arias, Cesar A., and Barbara E. Murray. “Antibiotic-Resistant Bugs in the Twenty-first Century: A Clinical Super-Challenge.” New England Journal of Medicine 360.5 (2009): 439–43.

Forsbeg, Kevin J., et al. "The Shared Antibiotic Resistome of Soil Bacteria and Human Pathogens." Science 337.6098 (2012): 1107–11.

Polk, Ronald E., and Neil O. Fishman. “Antimicrobial Stewardship.” Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 7th ed. Eds. Gerald L. Mandell, John F. Bennett, and Raphael Dolin. Churchill Livingstone/Elsevier, 2010.

Rosenblatt-Farrell, Noah. “The Landscape of Antibiotic Resistance” Environmental Health Perspectives 117.6 (2009): 244–50.

Schmitz, Franz-Josef, and Ad C. Fluit. “Mechanisms of Antibacterial Resistance.” Cohen and Powderly Infectious Diseases. 3rd ed. Eds Jonathan Cohen, Steven M. Opal, and William G. Powderly. Mosby/Elsevier, 2010.

Taube, Gary. "The Bacteria Fight Back." Science 321.5887 (2008): 356–61.

“Timeline of FDA Action on Antimicrobial Resistance.” US Food & Drug Administration, 22 May 2024, www.fda.gov/animal-veterinary/antimicrobial-resistance/timeline-fda-action-antimicrobial-resistance. Accessed 12 Sept. 2024.

Walsh, Christopher. Antibiotics: Actions, Origins, Resistance. ASM, 2003.