Antimicrobial Agent

Antimicrobial Agent

What are Antibacterial Agents?

These are agents that are either produced by microbes (microbial metabolites), that can be further enhanced by Medicinal Chemistry or synthetic analogs usually inspired by traditional antimicrobial agents. They are among the most prescribed medications. Antibiotic production is measured in thousands of tons, with a market of over $40 billion worldwide, and over 20% of the most frequently prescribed medications are antimicrobial agents. There have been around 100 clinically useful agents at one time or another, over 20,000 agents mentioned in the literature and many more have been prepared and tested.

Historical Perspectives:

  • Probably no one class of agents has affected humanity more than antibiotics. It was deemed the 7th most important invention/discovery in history.
  • The impact of antibiotics on our daily life is tremendous, examples:
      1. Freed us from many devastating plagues.
      2. Perform surgery with little risk of infection.
      3. Saved many lives by controlling fever after childbirth.
      4. Combated life-threatening infections during wars.
      5. Enabled us to avoid many infectious diseases that led to many fatalities among children and young adults such as meningitis and TB.
  • This led to an increase in the overall life expectancy and tremendous success in combating infectious diseases, especially in the last fifty years.
  • The other face of the coin shows us an increase in population and life expectancy in elderly, giving rise to an increase in degenerative diseases that we are less successful fighting.
  • By the 1970s, it appeared that we had succeeded in our fight against infectious disease, only to watch new forms arising including viruses and fungi and resistant and lethal forms of others appearing. In addition developing countries are not as successful and some diseases such as malaria and TB show their ugly faces now and again. Finally recently, we have witnessed how bioterrorism can affect our everyday life.

How Did We Get Here?

  • Since the second century B.C., natural products were known and used for certain infectious diseases. For example, cinchona bark was used for malaria, and moldy bread and disease for various infections. These were used with no understanding of the diseases or their causes.
  • Sixteenth century, mercury was used for syphilis, and different oils for leprosy.
  • Around 300 years ago, the invention of the microscope lead to the discovery of bacteria, but it took more than a century to understand its role in infections.
  • In 1863, Pasteur introduced the idea of the microbial origin of putrefaction. He also introduced the idea of antibiosis (=anti-life), by using a culture of anthrax bacilli, added a common bacteria, and found that the anthrax bacteria was killed. He then injected anthrax bacilli into a subject along with the common bacteria, which led to no disease developing. This is a result of the competition for survival between microorganisms (Darwinian theory).
  • In 1881, Koch identified infectious agents, and postulated that to identify it as the causative agent for a disease, you have to isolate that infectious agent, grow that agent in cultures and then reinject into a healthy subject, who would then develop the same disease. Then you have to reisolate the same agent from the new subject
  • In the mid to late nineteenth century, the idea of sanitation gave rise to the use of mercuric chloride, chlorinated soda and other antiseptics. Washing hands, wounds and surgical rooms became common practice. Lister introduced phenol and talked about aseptic areas. Ehrlich introduced arsenicals and dyes, which were toxic and had a limited use internally, but were the basis of many agents utilized later, thus was named father of chemotherapy. His contributions are far reaching to be covered here.
  • In 1929, Fleming discovered Penicillin.
  • In 1936, Domagk was able to synthesize Sulfonamides as an extension to the ideas of Ehrlich and became the first antimicrobial agents used.
  • In 1941, Florey and Chain were able to isolate Penicillin and moved to the States and were able to convince drug authorities to mass produce this antibiotic, and thus resulting in an industry boom for these agents, and resulted in penicillin's huge role in saving many lives in WWII.
  • In 1943, Waksman discovered Streptomycin in his effort to systemically scan the soil for antibiotic-producing microorganism. This led to a flurry of other agents being produced, including Tetracyclines, Chloramphenicols. In addition, the first antifungal, Nystatin was introduced in the late forties.
  • Almost all antibiotics classes used today were discovered before 1960. Since then the newly discovered antibiotics are mostly semi-synthetic modifications of existing antibiotics.
  • Today, thousands of extracts are screened to determine their ability to kill microbes, followed by many toxicological and pharmacological tests and assays to determine their usefulness as antimicrobial agents. The more successful extracts are then modified to yield clinically useful agents.

Causative Organism

Bacterial infections can be caused by a variety of microorganisms. Some of the more important agents are shown in the image below.

Streptococcus species may cause meningitis, otitis media, community acquired pneumonia, several skin infections, sinusitis and upper respiratory infections.

Staphylococcus species may cause community acquired pneumonia, skin infections, food poisoning and urinary tract infections.

Haemophilus species may cause meningitis, sinusitis, sexually transmitted diseases and upper respiratory infections.

Chlamydia species may cause community acquired pneumonia, sexually transmitted diseases and eye infections.

Other infections may be caused by Neisseria species (meningitis and sexually transmitted diseases), Escherichia coli (food poisoning and urinary tract infections) and pseudomonas species (skin infections and urinary tract infections).

What's In a Name?
  • Antibiotics are isolated from natural products or semi-synthesized from these products e.g. various Penicillins.
  • Antimicrobials is a more general term that includes completely synthetic compounds, such as Quinolones.
  • Prefix or suffix usually indicates the class of the antibiotic, e.g.

      -cillin..................... Penicillins;
      cef- or ceph-.......... Cephalosporins;
      -floxacin................ Floroquinolones;
      -mycin................... Streptomycins;
      -micin.................... Micromonospora sp.

  • The key is selective toxicity, either accomplished by interfering with a step unique to the bacterial cell, or through dosing.
  • No agent achieves a 100% kill, but rather paves the way for the immune system to control the infection.

Classification of Antimicrobial Agents:

1. Spectrum of activity

  • Narrow spectrum against Gram positive or Gram negative or
  • Broad Spectrum against a wide variety of organisms.
  • Gram positive bacteria can be stained blue by a Gram stain developed by Hans Christian Gram, while Gram negative bacteria do not retain the Gram stain when washed with alcohol

2. According to chemical structures

For Example, ß-lactams, Polypeptides, Quinolones...etc.

3. According to mode of action

  • Bactericidal that acts by killing the bacterial cell
  • Bacteriostatic that inhibits the growth and multiplication of the bacteria
  • Minimum Inhibitory Concentration (MIC) vs. Minimum Bactericidal Concentration (MBC). Etests may be used to determine these values.

4. According to mechanism of action

For example, Inhibits cell wall synthesis, inhibits protein synthesis...etc

We will use this last classification throughout the course.

Other Issues:

  1. Prescribing antibiotics should be only for bacterial infections. Some are obvious, for example urinary infections are usually Gram negative E. Coli, while many skin infections are due to Gram positive S. aureus. If not, then perform a lab test to identify the best antibiotic to be used.
  2. Prophylactic use such as in bowel sanitization or viral sore throat may lead to emergence of resistance and development of side effects.
  3. Resistance, how it arises and how to best manage it. Probably the most significant problem that we need to deal with.
  4. Combinations, synergistic or antagonistic?
  5. Non-human use (about half of antibiotics use), mostly agricultural and animal use. Could be legitimate use for infections or for other uses such as promoting animal growth. In both cases development of resistance and contamination are obvious problems, which has only recently been addressed.
  6. Cost (expensive drugs vs. cost of sickness...etc.)
  7. Serum protein binding affects drug use. For example those with no binding are usually useful for UTI, since they are rapidly excreted, while those binding and then released slowly may have a long acting effect.
  8. The choice of route of administration is dependent on many factors. While oral use is usually preferred, physicians may prefer parenteral use to monitor side effects, or ensure compliance.
  9. When initiating therapy, it is sometimes useful to start using the antibiotics right away and to use a loading dose (usually doubling the original dose) since bacteria multiply very quickly (double every two or three hours).
  10. Patient-related factors considered when prescribing antbiotics include age, genetic variations, special cases (preganancy and lactation), history of allergy and renal/liver functions.
  11. Microorganism-related factors that are important to consider include susceptibility of the microorganism, type of infecting agent (such as aerobic vs. anaerobic) resistance to antibiotics and site of infection.
  12. Use of antibiotics may disrupt the natural flora in the body and could lead to Clostridium difficile infection, leading to Pseudomembranous colitis.