Bacterial resistance and super bacteria

Categories: Bacteria; environmental issues; medicine and health; microorganisms

Bacteria are the most adaptable living organisms on earth, found in virtually all environments—from the lowest ocean depths to the highest mountains. Bacteria can resist extremes of heat, cold, acidity, alkalinity, heavy metals, and radiation that would kill most other organisms. Deinococcus radiodurans, for example, can grow within nuclear power reactors, and Thiobacillus thiooxidans can grow in toxic acid mine drainage. The term “super bacteria” generally refers to bacteria that have either intrinsic (naturally occurring) or acquired resistance to multiple antibiotics. Because many of the bacteria that acquire resistance are pathogens that previously could be controlled by antibiotics, development of antibiotic resistance is regarded as a serious public health crisis, particularly for those individuals who have compromised immune systems.

History of Antibiotic Use

In the early twentieth century German chemistPaul Ehrlich received worldwide fame for discovering Salvarsan, the first relatively specific prophylactic agent against the microorganisms that cause syphilis. Salvarsan had undesirable side effects because it contained arsenic. In addition, secondary infections resulting from hospitalization were still a leading cause of death in the early twentieth century. Scottish bacteriologist Alexander Fleming discovered a soluble antimicrobial compound produced by the fungi genus Penicillium. Two English scientists, Howard Florey and Ernst Chain, took Fleming’s fungi and produced purified penicillin just in time for use during World War II.

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.

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 1950s and early 1960s, pharmaceutical companies had extensive research and development programs devoted to isolating and producing new antibiotics.

Antibiotics were so effective, and their production ultimately so efficient, that they came 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 appear routinely as feed supplements.

Development of Antibiotic Resistance

The widespread use and, ultimately, misuse of antibiotics inevitably have caused antibiotic-resistant bacteria to appear, as microorganisms have adapted to new selective pressures. There are many strains of pathogenic organisms on which antibiotics have little or no effect.

Streptococcal infections have been a leading bacterial cause of morbidity and mortality. In the mid-1970s Streptococcus pneumonia was uniformly susceptible to penicillin. However, penicillin-resistant 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 also showed resistance to another antibiotic, cephalosporin.

Tuberculosis was once the leading cause of death in young adults in industrialized countries, so common and feared that it was known as the White Plague. Before 1990 multidrug-resistant tuberculosis was uncommon. However, by the mid-1990s there were increasing outbreaks in hospitals and prisons, in which the death rate ranged from 50 to 80 percent. Likewise, multiple drug resistance in Streptococcus pyogenes, the so-called flesh-eating streptococci, was once rare, but erythromycin- and clindimycin-resistant strains have developed.

Many old pathogens have become major clinical problems because of increased antibiotic resistance. The number of resistant isolates in England rose from 1.5 percent in 1989 to more than 34 percent in 1995. Gonorrhea, caused by Neisseria gonorrhoeae, is one of the most common sexually transmitted diseases. Physicians began using a class of broad-spectrum cephalosporin antibiotics called fluoroquinolones because N. gonorrhoeae had become resistant to penicillin, tetracycline, streptomycin. However, the exclusive use of fluoroquinolones, the only antibiotics to which N. gonorrhoeae were routinely susceptible, led to rapidly developing resistance as well. Third-generation cephalosporins such as ceftriaxone became the standard treatment against gonorrhea in 2007. However, a strain of N. gonorrhoeae resistant to ceftriaxone was discovered soon after, and gonorrhea has remained a public health threat. Even pathogens discovered in the late twentieth century such as Helicobacter pylori, associated with peptic ulcers, have rapidly developed resistance to the antibiotics used to treat them.

The development of resistance to some antibiotics 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. One such antimicrobial drug, avoparcin, is a glycopeptide (a compound containing sugars and proteins) that has been 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 has been more prevalent in farm animals exposed to antimicrobial drugs. Prolonged exposure to oral glycoproteins in tests led to vancomycin-resistant enterococci in 64 percent of the subjects.

How Antibiotic Resistance Occurs

Antibiotic resistance occurs because the antibiotics exert a selective pressure on the bacterial pathogens. This pressure eliminates all but a few bacteria that can persist through evasion or mutation. One reason antibiotic treatments may be prescribed for several weeks is to ensure that bacteria that have evaded the initial exposure are killed. 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, the spontaneous resistance of Mycobacterium tuberculosis to cycloserine and viomycin may occur in one to one thousand cells; resistance to kanamycin may occur in only one in one million cells; and resistance to rifampicin may occur in only one in one hundred million cells. Consequently, one 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 used. 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 acquiring of deoxyribonucleic acid, or DNA, directly from the environment; and the transfer of plasmids, small, circular pieces of DNA that frequently carry genes for antibiotic resistance.

Genes for antibiotic resistance take many forms. They may make the bacteria impermeable to the antibiotic, or they may subtly alter the target of the antibiotic within the cell so that it is no longer affected. The genes may also code for the production of an enzyme 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.

Strategies for Avoiding Antibiotic Resistance

The increased use of antibiotics has led to increases in morbidity, mortality caused by previously controlled infectious diseases, and health costs. Some of the recommendations to deal with this public health problem include changing antibiotic prescription patterns, changing patient attitudes about the necessity of antibiotics, increasing the worldwide surveillance of drug-resistant bacteria, improving techniques for susceptibility testing, banning the use of antibiotics as animal feed additives, and investing in research and development of new antimicrobial agents.

Gene therapy is regarded as one promising solution to antibiotic resistance. In gene therapy, the genes expressing part of the pathogen’s cell are injected into a patient and 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 pathogen are injected into a patient to cause an immediate immune response. Previous serum treatment techniques yielded mixed results. However, with the advent of monoclonal antibodies and the techniques for producing them, serum treatments can be made much more specific and the antibodies delivered in much higher concentrations.

Virus treatment for pathogenic infection is another old technique being studied. Viruses attack cells in all living organisms, including bacteria—these viruses are called bacteriophages. Viruses are also extremely specific, so that they will not infect more than one type of cell. In essence, virus treatments are a form of biocontrol. In virus treatments, the patient is injected with viruses raised against specific pathogens. Once injected, the viruses begin specifically attacking the pathogenic bacteria. Although this technology has not been widely used, it is the subject of growing research.

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The Growth of Antibiotic Resistance