Overview of Antimicrobial Therapy

Origins of Antimicrobial Drugs

The era of antimicrobials begins when Pasteur and Joubert discover that one type of bacteria could prevent the growth of another.

Learning Objectives

Recall the technical defintion of antibiotics

Key Takeaways

Key Points

  • Antibiotics are only those substances that are produced by one microorganism that kill, or prevent the growth, of another microorganism.
  • In today’s common usage, the term antibiotic is used to refer to almost any drug that attempts to rid your body of a bacterial infection.
  • The discovery of antimicrobials like penicillin and tetracycline paved the way for better health for millions around the world.

Key Terms

  • antimicrobial: An agent that destroys microbes, inhibits their growth, or prevents or counteracts their pathogenic action.
  • penicillin: Any of a group of broad-spectrum antibiotics obtained from Penicillium molds or synthesized; they have a beta-lactam structure; most are active against gram-positive bacteria and used in the treatment of various infections and diseases.

The history of antimicrobials begins with the observations of Pasteur and Koch, who discovered that one type of bacteria could prevent the growth of another. They did not know at that time that the reason one bacterium failed to grow was that the other bacterium was producing an antibiotic. Technically, antibiotics are only those substances that are produced by one microorganism that kill, or prevent the growth, of another microorganism.

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Alexander Fleming: In 1928 Alexander Fleming observed antibiosis against bacteria by a fungus of the genus Penicillium and postulated the effect was mediated by an antibacterial compound, penicillin, and that its antibacterial properties could be exploited for chemotherapy.

The discovery of antimicrobials like penicillin by Alexander Fleming and tetracycline paved the way for better health for millions around the world. Before penicillin became a viable medical treatment in the early 1940s, no true cure for gonorrhea, strep throat, or pneumonia existed. Patients with infected wounds often had to have a wounded limb removed, or face death from infection. Now, most of these infections can be cured easily with a short course of antimicrobials.

The term antibiotic was first used in 1942 by Selman Waksman and his collaborators in journal articles to describe any substance produced by a microorganism that is antagonistic to the growth of other microorganisms in high dilution. This definition excluded substances that kill bacteria, but are not produced by microorganisms (such as gastric juices and hydrogen peroxide). It also excluded synthetic antibacterial compounds such as the sulfonamides. Many antibacterial compounds are relatively small molecules with a molecular weight of less than 2000 atomic mass units. With advances in medicinal chemistry, most of today’s antibacterials chemically are semisynthetic modifications of various natural compounds.

Antibiotic Discovery

Observations of antibiosis between micro-organisms led to the discovery of natural antibacterials produced by microorganisms.

Learning Objectives

Describe the concept of ‘antibiosis’ and the contributions of the different scientists who discovered it

Key Takeaways

Key Points

  • Before the early 20th century, treatments for infections were based primarily on medicinal folklore.
  • Louis Pasteur observed, “if we could intervene in the antagonism observed between some bacteria, it would offer perhaps the greatest hopes for therapeutics”.
  • The term ‘antibiosis’, meaning “against life,” was introduced by the French bacteriologist Vuillemin as a descriptive name of the phenomenon exhibited by these early antibacterial drugs.

Key Terms

  • micro-organism: A microorganism (from the Greek: μ, mikrós, “small” and ὀ, organismós, “organism”; also spelled micro-organism, micro organism or microörganism) or microbe is a microscopic organism that comprises either a single cell (unicellular), cell clusters, or multicellular relatively complex organisms.
  • chemotherapy: Any chemical treatment intended to be therapeutic with respect to a disease state.
  • infection: An uncontrolled growth of harmful microorganisms in a host.

Before the early 20th century, treatments for infections were based primarily on medicinal folklore. Mixtures with antimicrobial properties that were used in treatments of infections were described over 2000 years ago. Many ancient cultures, including the ancient Egyptians and ancient Greeks, used specially selected mold and plant materials and extracts to treat infections. More recent observations made in the laboratory of antibiosis between micro- organisms led to the discovery of natural antibacterials produced by microorganisms.

Louis Pasteur observed, “if we could intervene in the antagonism observed between some bacteria, it would offer perhaps the greatest hopes for therapeutics”. The term ‘antibiosis’, meaning “against life,” was introduced by the French bacteriologist Vuillemin as a descriptive name of the phenomenon exhibited by these early antibacterial drugs. Antibiosis was first described in 1877 in bacteria when Louis Pasteur and Robert Koch observed that an airborne bacillus could inhibit the growth of Bacillus anthracis. These drugs were later renamed antibiotics by Selman Waksman, an American microbiologist, in 1942.

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Louis Pasteur: Louis Pasteur was a French microbiologist and chemist best known for their experiments supporting the Germ theory of disease, and for his vaccinations, most notably the first vaccine against rabies.

John Tyndall first described antagonistic activities by fungi against bacteria in England in 1875. Synthetic antibiotic chemotherapy as a science and development of antibacterials began in Germany with Paul Ehrlich in the late 1880s. Ehrlich noted certain dyes would color human, animal, or bacterial cells, while others did not. He then proposed the idea that it might be possible to create chemicals that would act as a selective drug that would bind to and kill bacteria without harming the human host. After screening hundreds of dyes against various organisms, he discovered a medicinally useful drug, the synthetic antibacterial Salvarsan now called arsphenamine. In 1895, Vincenzo Tiberio, physician of the University of Naples discovered that a mold (Penicillium) in a water well has an antibacterial action. After this initial chemotherapeutic compound proved effective, others pursued similar lines of inquiry, but it was not until in 1928 that Alexander Fleming observed antibiosis against bacteria by a fungus of the genus Penicillium. Fleming postulated the effect was mediated by an antibacterial compound named penicillin, and that its antibacterial properties could be exploited for chemotherapy. He initially characterized some of its biological properties, but he did not pursue its further development.

Antibiotics and Selective Toxicity

Antibiotics are able to selectively target specific types of bacteria without harming the infected host.

Learning Objectives

Describe selective toxicity

Key Takeaways

Key Points

  • Their mechanism of action, chemical structure, or spectrum of activity are ways in which antibiotics are classified.
  • Broad spectrum antibiotics affect a wide range of bacteria, while narrow spectrum antibiotics are able to target specific types.
  • Antibiotics must go through a screening process, where they are isolated, cultured, and then tested for production of diffusible products that inhibit the growth of specific test organisms.
  • Due to potential adverse side effects, antibiotics must also be tested for their selective toxicities.

Key Terms

  • antibacterial: A drug having the effect of killing or inhibiting bacteria.
  • bactericidal: An agent that kills bacteria.
  • bacteriostatic: A drug that prevents bacterial growth and reproduction but does not necessarily kill them. When it is removed from the environment the bacteria start growing again.

Selective Toxicity in Antibiotics

Synthetic antibiotic chemotherapy as a science and development of antibacterials began in Germany with Paul Ehrlich in the late 1880s. Ehrlich noted that certain dyes would color human, animal, or bacterial cells, while others did not. He then proposed the idea that it might be possible to create chemicals that would act as a selective drug that would bind to and kill bacteria without harming the human host. After screening hundreds of dyes against various organisms, he discovered a medicinally useful drug, the synthetic antibacterial Salvarsan now called arsphenamine.

Antibiotics are commonly classified based on their mechanism of action, chemical structure, or spectrum of activity. More specifically, narrow spectrum antibiotics target specific types of bacteria, such as Gram-negative or Gram-positive bacteria, whereas broad spectrum antibiotics affect a wide range of bacteria. Following a 40-year hiatus in discovering new classes of antibacterial compounds, three new classes of antibacterial antibiotics have been brought into clinical use: cyclic lipopeptides (such as daptomycin), glycylcyclines (such as tigecycline), and oxazolidinones (such as linezolid).

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Bacterial Cultures: In antibacterial production, microorganisms must be isolated, cultured, and tested for growth inhibition of target organisms and for their selective toxicity.

Some antibacterials have been associated with a range of adverse effects. Side-effects range from mild to very serious depending on the antibiotics used, the microbial organisms targeted, and the individual patient. Safety profiles of newer drugs are often not as well established as for those that have a long history of use. Adverse effects range from fever and nausea to major allergic reactions, including photodermatitis and anaphylaxis. Common side-effects include diarrhea, resulting from disruption of the species composition in the intestinal flora, resulting, for example, in overgrowth of pathogenic bacteria, such as Clostridium difficile. Antibacterials can also affect the vaginal flora, and may lead to overgrowth of yeast species of the genus Candida in the vulvo-vaginal area. Additional side-effects can result from interaction with other drugs, such as elevated risk of tendon damage from administration of a quinolone antibiotic with a systemic corticosteroid.

Antibacterial Production

Despite the wide variety of known antibiotics, less than 1% of antimicrobial agents have medical or commercial value. For example, whereas penicillin has a high therapeutic index as it does not generally affect human cells, this is not so for many antibiotics. Other antibiotics simply lack advantage over those already in use, or have no other practical applications. Useful antibiotics are often discovered using a screening process. To conduct such a screen, isolates of many different microorganisms are cultured and then tested for production of diffusible products that inhibit the growth of test organisms. Most antibiotics identified in such a screen are already known and must therefore be disregarded. The remainder must be tested for their selective toxicities and therapeutic activities, and the best candidates can be examined and possibly modified. A more modern version of this approach is a rational design program. This involves screening directed towards finding new natural products that inhibit a specific target, such as an enzyme only found in the target pathogen, rather than tests to show general inhibition of a culture.

Spectrum of Antimicrobial Activity

An antibiotic’s spectrum can be broad or narrow.

Learning Objectives

Compare narrow and broad spectrum antibiotics

Key Takeaways

Key Points

  • Broad spectrum antibiotics act against a larger group of bacteria.
  • Narrow spectrum antibiotis target specific bacteria such as Gram positive or Gram negative.
  • Three new classes of antibacterial antibiotics have been brought into clinical use: cyclic lipopeptides (such as daptomycin), glycylcyclines (such as tigecycline), and oxazolidinones (such as linezolid).

Key Terms

  • Gram stain: A method of differentiating bacterial species into two large groups (Gram-positive and Gram-negative).
  • narrow spectrum antibiotic: A type of antibiotic that targets specific types of Gram positive or Gram negative bacteria.
  • broad spectrum antibiotic: A type of antibiotic that can affect a wide range of bacteria.

The range of bacteria that an antibiotic affects can be divided into narrow spectrum and broad spectrum. Narrow spectrum antibiotics act against a limited group of bacteria, either gram positive or gram negative, for example sodium fusidate only acts against staphylococcal bacteria. Broad spectrum—antibiotics act against gram positive and gram negative bacteria, for example amoxicillin.

Gram staining (or Gram’s method; is a method of differentiating bacterial species into two large groups (Gram-positive and Gram-negative ). It is based on the chemical and physical properties of their cell walls. Primarily, it detects peptidoglycan, which is present in a thick layer in Gram positive bacteria. A Gram positive results in a purple/blue color while a Gram negative results in a pink/red color. The Gram stain is almost always the first step in the identification of a bacterial organism, and is the default stain performed by laboratories over a sample when no specific culture is referred. While Gram staining is a valuable diagnostic tool in both clinical and research settings, not all bacteria can be definitively classified by this technique, thus forming Gram-variable and Gram-indeterminate groups as well.

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Gram Stain: This is a microscopic image of a Gram stain of mixed Gram-positive cocci (Staphylococcus aureus, purple) and Gram-negative bacilli (Escherichia coli, red).

A broad spectrum antibiotic acts against both Gram-positive and Gram-negative bacteria, in contrast to a narrow spectrum antibiotic, which is effective against specific families of bacteria. An example of a commonly used broad-spectrum antibiotic is ampicillin. Broad spectrum antibiotics are properly used in the following medical situations: empirically (i.e., based on the experience of the practitioner), prior to the formal identification of the causative bacteria and when there is a wide range of possible illnesses and a potentially serious illness would result if treatment is delayed. This occurs, for example, in meningitis, where the patient can become fatally ill within hours if broad-spectrum antibiotics are not initiated. Broad spectrum antibiotics are also used for drug resistant bacteria that do not respond to other, more narrow spectrum antibiotics and in the case of superinfections, where there are multiple types of bacteria causing illness, thus warranting either a broad-spectrum antibiotic or combination antibiotic therapy.

Following a 40-year hiatus in discovering new classes of antibacterial compounds, three new classes of antibacterial antibiotics have been brought into clinical use: cyclic lipopeptides (such as daptomycin), glycylcyclines (such as tigecycline), and oxazolidinones (such as linezolid).

Antibiotic Classifications

Bactericidal antibiotics kill bacteria; bacteriostatic antibiotics slow their growth or reproduction.

Learning Objectives

Compare the two classes of antibiotics: bactericidal and bacteriostatic antibiotics

Key Takeaways

Key Points

  • Bactericidal antibodies inhibit cell wall synthesis.
  • Bacteriostatic antibiotics limit the growth of bacteria by interfering with bacterial protein production, DNA replication, or other aspects of bacterial cellular metabolism.
  • Bacteriostatic antibiotics must work together with the immune system to remove the microorganisms from the body.

Key Terms

  • bactericidal: An agent that kills bacteria.
  • bacteriostatic: A drug that prevents bacterial growth and reproduction but does not necessarily kill them. When it is removed from the environment the bacteria start growing again.

Antibiotics can be divided into two classes based on their mechanism of action. Bactericidal antibiotics kill bacteria; bacteriostatic antibiotics inhibit their growth or reproduction.

One way that bactericidal antibodies kill bacteria is by inhibiting cell wall synthesis. Examples include the Beta-lactam antibiotics (penicillin derivatives (penams) ), cephalosporins (cephems), monobactams, and carbapenems) and vancomycin. Other ways that bactericidal antibiotics kill bacteria include inhibiting bacterial enzymes or protein translation. Other batericidal agents include daptomycin, fluoroquinolones, metronidazole, nitrofurantoin, co-trimoxazole and telithromycin. Aminoglycosidic antibiotics are usually considered bactericidal, although they may be bacteriostatic with some organisms. The MBC (minimum bactericidal concentration) is the minimum concentration of drug which can kill 99.99% of the population.

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Mechanism of penicillin inhibition: Penicillin and most other β-lactam antibiotics act by inhibiting penicillin-binding proteins, which normally catalyze cross-linking of bacterial cell walls.

Bacteriostatic antibiotics limit the growth of bacteria by interfering with bacterial protein production, DNA replication, or other aspects of bacterial cellular metabolism. This group includes: tetracyclines, sulfonamides, spectinomycin, trimethoprim, chloramphenicol, macrolides and lincosamides. They must work together with the immune system to remove the microorganisms from the body. However, there is not always a precise distinction between them and bactericidal antibiotics. High concentrations of some bacteriostatic agents are also bactericidal. The MIC (minimum inhibitory concentration) is the minimum concentration of drug which can inhibit the growth of the microorganism.

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Structure of tetracycline: Tetracycline antibiotics are protein synthesis inhibitors, inhibiting the binding of aminoacyl-tRNA to the mRNA-ribosome complex. They do so mainly by binding to the 30S ribosomal subunit in the mRNA translation complex.

Further categorization is based on their target specificity. “Narrow-spectrum” antibacterial antibiotics target specific types of bacteria, such as Gram-negative or Gram-positive bacteria, whereas broad-spectrum antibiotics affect a wide range of bacteria, usually both gram positive and gram negative cells. Following a 40-year hiatus in discovering new classes of antibacterial compounds, three new classes of antibacterial antibiotics have been brought into clinical use: cyclic lipopeptides (such as daptomycin), glycylcyclines (such as tigecycline), and oxazolidinones (such as linezolid).