Bacterial resistance and public health

DEFINITION: The ability of bacteria to withstand antibiotics and other antimicrobial substances

Inappropriate use of antimicrobials such as antibiotics, antibacterial soaps, and hand sanitizers has caused some bacteria to develop resistance against the most common antibiotics, and many previously controlled infectious pathogens have become resistant to multiple drugs. Such multiresistant bacteria pose an increasing threat to public health and safety.

Bacteria are the most adaptable living organisms on earth and are found in virtually all environments—from the lowest ocean depths to the highest mountains. Bacteria resist extremes of heat, cold, acidity, alkalinity, heavy metals, and that would kill most other organisms. Deinococcus radiodurans, for example, grow within nuclear power reactors, and Thiobacillus thiooxidans can grow in toxic acid mine drainage.

The terms “super bacteria” and “superbug” are often used to refer to that have either intrinsic (naturally occurring) or acquired to multiple antibiotics. For example, two soil organisms—Pseudomonas aeruginosa and Burkholderia (Pseudomonas) cepacia—are intrinsically resistant to many antibiotics. Because many of the bacteria that acquire resistance are pathogens that were previously controlled by antibiotics, the development of resistance represents a serious public health crisis, particularly for those individuals suffering from compromised immune systems.

History of Antibiotic Use

The history of antimicrobial compounds reaches into the early twentieth century, when German chemistPaul Ehrlich received worldwide fame for discovering Salvarsan, the first relatively specific chemical prophylactic agent against the microorganisms that causes syphilis. Salvarsan had serious undesirable side effects, as arsenic was its active ingredient. In addition, despite advances in antiseptic surgery, secondary infections resulting from hospitalization were a leading cause of death in the early twentieth century. Consequently, when Scottish bacteriologist Alexander Fleming reported his discovery of a soluble antimicrobial compound called penicillin, produced by the fungus Penicillium, the news attracted worldwide attention.

Antibiotics such as penicillin are low-molecular-weight compounds excreted by bacteria and fungi. Antibiotic-producing microorganisms most often belong to a group of soil bacteria called actinomycetes. Streptomyces are good examples of antibiotic-producing actinomycetes, and most of the commercially important antibiotics are isolated from Streptomyces. It is not entirely clear what ecological role the antibiotics play in natural environments. Microorganisms produce the antibiotics in a late, stationary growth phase, rather than during an early, active growth phase, which suggests that their chief function is not to inhibit the growth of competing microorganisms. The results of some studies suggest that, in natural ecosystems, antibiotics are types of signaling molecules that play a role in intercellular communication, while antibiotic resistance genes influence metabolism.

Fleming’s discovery was not of much clinical importance until two English scientists, Howard Florey and Ernst Chain, took Fleming’s fungus and produced purified penicillin just in time for World War II. The success of penicillin as a therapeutic agent with almost miraculous effects on infection prompted other microbiologists to look for naturally occurring antimicrobial compounds. In 1943 Selman Waksman, an American biochemist born in Ukraine, discovered the antibiotic streptomycin, the first truly effective agent to control Mycobacterium tuberculosis, the bacterium that causes tuberculosis. Widespread antibiotic use began shortly after World War II and was regarded as one of the great medical advances in the fight against infectious disease. By the late 1950’s and early 1960’s, pharmaceutical companies had devoted extensive research and development programs to isolating and producing new antibiotics.

Antibiotics were so effective, and their production ultimately so efficient, that they became inexpensive enough to be routinely prescribed for all types of infections, particularly to treat upper respiratory tract infections. When it was discovered that low levels of antibiotics also promote increased growth in domesticated animals, antibiotics began to be used routinely as feed supplements. Antibiotic use became ubiquitous among humans and livestock, to the degree that downstream from intense urbanization or livestock production, water sources commonly contain detectable levels of nonmetabolized, excreted antibiotics.

Development of Antibiotic Resistance

The widespread use and, ultimately, misuse of antibiotics inevitably caused antibiotic-resistant bacteria to emerge as microorganisms adapted to this new selective pressure. The prevalence of antimicrobial consumer products such as antibacterial soaps and hand sanitizers resulted in additional selective pressure. Eventually, many strains of pathogenic organisms developed on which antibiotics have little or no effect. Relatively recently discovered pathogens, such as the Helicobacter pylori bacterium associated with peptic ulcers, have rapidly developed resistance to the antibiotics used to treat them.

Streptococcal infections are a major bacterial cause of and mortality. In the mid-1970’s Streptococcus pneumonia was uniformly susceptible to penicillin. However, penicillin-resistant streptococci strains were being isolated as early as 1967. A study in Denver, Colorado, showed that penicillin-resistant S. pneumonia strains increased from 1 percent of the isolates in 1980 to 13 percent of the isolates in 1995. One-half of the resistant strains were also resistant to another antibiotic, cephalosporin. It was apparent from the Denver study that a high correlation existed between antibiotic resistance in an individual and whether a member of the individual’s family attended day care. Children attending day care are frequently exposed to preventive antibiotics, and these may have assisted in selecting for resistant bacteria. By 1996 penicillin-resistant S. pneumoniae represented between 33 and 58 percent of the clinical isolates around the world. According to a 2023 study of children in the United States published in the journal Open Forum Infectious Diseases, 56.8 percent of S. pneumoniae isolates were found to be resistant to at least one drug class. The study also found that 30.7 percent of isolates were resistant to two or more drug classes.

The disease tuberculosis (TB) was once the leading cause of death in young adults in industrialized countries. The disease was so common and feared that it was known as the White Plague. Before 1990, multidrug-resistant M. tuberculosis was uncommon, but by the mid-1990’s increasing outbreaks were seen in hospitals and prisons, with death rates ranging from 50 to 80 percent. In a 2008 global report on anti-TB drug resistance, the World Health Organization noted that in 2006 the number of multidrug-resistant TB cases (those resistant to isoniazid and rifampicin, two of the first-line drugs used to treat the disease) had reached a record high of 489,139. Cases of the disease that were also resistant to second-line drugs were reported in 45 countries. In a 2022 study, the US Centers for Disease Control and Prevention found that 8.4 percent of tuberculosis patients had a resistance to the drug isoniazid, a common medication used to treat the illness. About 1.4 percent of patents had developed a resistance to more than one drug.

Many old pathogens have become major clinical problems because of increased antibiotic resistance. Salmonella serotypes, for example, including those causing typhoid fever, have been discovered with resistance to at least five antibiotics, including ampicillin, chloramphenicol, streptomycin, sulfanilamide, and tetracycline. Gonorrhea, caused by Neisseria gonorrhoeae, is one of the most common sexually transmitted diseases. Physicians began using a class of broad-spectrum antibiotics called fluoroquinolones when N. gonorrhoeae developed resistance to penicillin, tetracycline, and streptomycin. By the late 1990’s, however, resistance to the fluoroquinolone ciprofloxacin had developed in Hawaii and on the West Coast of the United States. The Centers for Disease Control stopped recommending fluoroquinolones for the treatment of gonorrhea in 2007 and began gonorrhea patients being treated with the cephalosporin class of drugs for signs of treatment failure due to resistance.

Some antibiotic resistance appears to be linked to antimicrobial use in farm animals. Shortly after antibiotics appeared, it was discovered that subtherapeutic levels could promote growth in animals and treat acute infections in such settings as aquaculture. One antimicrobial drug, avoparcin, is a glycopeptide (a compound containing sugars and proteins) that is used as a feed additive. Vancomycin-resistant enterococci such as Enterococcus faecium were first isolated in 1988 and appeared to be linked to drug use in animals. Antibiotic resistance in enterococci was found to be more prevalent in farm animals exposed to antimicrobial drugs, and prolonged to oral glycoproteins in tests led to vancomycin-resistant enterococci in 64 percent of the subjects. In 1997 the European Union banned the use of avoparcin, which is similar to vancomycin, as an animal feed additive. The antibiotic remained banned in Europe and Australia into the 2020s.

How Antibiotic Resistance Occurs

Antibiotic resistance occurs because the antibiotics exert a selective pressure on the bacterial pathogens. The selective pressure eliminates all but a few bacteria that can persist through evasion or mutation. One reason that the duration of antibiotic treatments is often several weeks is to ensure that bacteria that have evaded the initial exposure are killed. The rare bacteria that are resistant can persist and grow regardless of continued antibiotic exposure. Terminating antibiotic treatment early, once symptoms disappear, has the unfortunate effect of stimulating antibiotic resistance without completely eliminating the original cause of infection.

Mutations that promote resistance occur with different frequencies. For example, spontaneous resistance of M. tuberculosis to cycloserine and viomycin may occur in 1 in 1,000 cells, resistance to kanamycin may occur in only 1 in 1 million cells, and resistance to rifampicin may occur in only 1 in 100 million cells. Consequently, 1 billion bacterial cells will contain several individuals resistant to at least one antibiotic. Using multiple antibiotics further reduces the likelihood that an individual cell will be resistant to all antibiotics. However, it can cause multiple antibiotic resistance to develop in bacteria that already have resistance to some of the antibiotics.

Bacterial pathogens may not need to mutate spontaneously to acquire antibiotic resistance. There are several mechanisms by which bacteria can acquire the genes for antibiotic resistance from microorganisms that are already antibiotic-resistant. These mechanisms include conjugation (the exchange of genetic information through direct cell-to-cell contact), transduction (the exchange of genetic information from one cell to another by means of a virus), transformation (the acquisition of genetic information through the taking up of deoxyribonucleic acid, or DNA, directly from the environment), and transfer of plasmids, small circular pieces of DNA that frequently carry genes for antibiotic resistance. Exchange of genes for antibiotic resistance on plasmids is one of the most common means of developing or acquiring resistance in hospitals because of the heavy antibiotic use in these settings.

The genes for antibiotic resistance take many forms. They may make the bacteria impermeable to the antibiotic. They may subtly alter the target of the antibiotic within the cell so that it is no longer affected. The genes may code for production of an in the bacteria that specifically destroys the antibiotic. For example, fluoroquinolone antibiotics inhibit DNA replication in pathogens by binding to the enzyme required for replication. Resistant bacteria have mutations in the amino acid sequences of this enzyme that prevent the antibiotic from binding to this region. Some resistant pathogens produce an enzyme called penicillinase, which degrades the antibiotic penicillin before it can prevent cell wall formation.

New Strategies

The heavy use of antibiotics has led to increases in morbidity, mortality caused by previously controlled infectious diseases, and health costs. Some of the recommended ways of dealing with this public health problem include changing antibiotic prescription patterns, changing both doctor and patient attitudes about the necessity for antibiotics, increasing the worldwide surveillance of drug-resistant bacteria, improving techniques for susceptibility testing, and investing in the research and development of new antimicrobial agents.

Gene therapy, which remains an experimental technique, is regarded as one promising solution to antibiotic resistance. In gene therapy, the genes expressing part of a pathogen’s cell are injected into the patient to stimulate a heightened immune response. Some old technologies are also being revisited. There is increasing interest in using serum treatments, in which antibodies raised against a are injected into a patient to cause an immediate immune response. Previous serum treatment techniques have yielded mixed results, but with the advent of monoclonal antibodies and the techniques for producing them, serum treatments in future can be made much more specific and the antibodies delivered in much higher concentrations.

Another experimental treatment technique involves manipulating viruses genetically to make them target specific pathogens. Once injected into a patient, the reprogrammed viruses begin a focused attack on the pathogen. Viruses attack all living organisms, including bacteria, but are extremely specific. For this therapeutic technique, certain genes are removed to prevent the from causing disease or degrading anything other than the target pathogenic organism.

Bibliography

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Fong, Ignatius W., and Karl Drlica, eds. Antimicrobial Resistance and Implications for the Twenty-first Century. New York: Springer, 2008.

Lashley, Felissa R., and Jerry D. Durham, eds. Emerging Infectious Diseases: Trends and Issues. 2d ed. New York: Springer, 2007.

Levy, Stuart B. The Antibiotic Paradox: How the Misuse of Antibiotics Destroys Their Curative Power. 2d ed. Cambridge, Mass.: Perseus, 2002.

Mohanty, Salini, et al. "Trends in Streptococcus Pneumoniae Antimicrobial Resistance in US Children: A Multicenter Evaluation. " Open Forum Infectious Diseases, vol. 10, no. 3, 7 Mar. 2023, doi: 10.1093/ofid/ofad098. Accessed 15 July 2024.

Shnayerson, Michael, and Mark J. Plotkin. The Killers Within: The Deadly Rise of Drug-Resistant Bacteria. Boston: Little, Brown, 2002.