Chapter 21 Antimicrobial Medications

1910 Paul Ehrlich became intrigued with the way cells vary in their ability to take up dyes and other substances. He began looking for a substance that would selectively harm microbial cells but not human cells. He specifically looked for a cure to syphilis due to the number of people who became mentally ill after contracting it.

He knew that arsenic had the ability to kill certain protozoa and began synthesizing arsenic compounds for a cure His 606 th attempt was successful and became the drug Salvarsan (salvation + arsenic)

21.1 History and Development of Antimicrobial Drugs 1928: Fleming discovered penicillin, produced by Penicillium. He noticed that bacteria near a mold were dissolving. Realized the mold was producing a bacteria killing substance.

1940: Howard Florey and Ernst Chain performed first clinical trials of penicillin In 1941, it was first tested on a police officer with a life threatening Staphyloccocus aureus infection. He improved within 24 hours, but there was not enough purified penicillin, so the man did eventually die of the infection.

World War II led to cooperation between the US and Britain to create enough medications to treat wounded soldiers and workers. Several different penicillins were found in cultures, which were labeled alphabetically Penicillin G seemed to work best and became most effective at treating infection

Selman Waksman discovered that a soil bacterium, Streptomyces griseus, produced the antibiotic streptomycin. This showed that molds were not the only organisms that could produce antibiotics

21.2 Features of Antimicrobial Drugs Most antibiotics come from microbes normally residing in the soil: streptomyces, bacillus, penicillum, and cephalosporium (fungi). After the antibiotics are purified, other synthetic compounds are added to increase stability.

Selective Toxicity Medically useful drugs exhibit selective toxicity – meaning they cause greater harm to the microorganisms than they do the human host. While in small doses, the medicines do carry a therapeutic index, which is the lowest dose toxic to the patient divided by the dose used for therapy.

Antimicrobial Action Antibiotics either kill microorganisms (bactericidal) or inhibit their growth (bacteriostatic). Which one is used depends on the concentration of the drug and the growth stage that the microbe is in

Spectrum of Activity Drugs vary with respect to the range of microbes they can kill or inhibit. Broad-spectrum – affect a wide range of bacteria Narrow-spectrum – affect a limited range of bacteria

Drugs differ in their action and activity but also in how they are distributed, metabolized, and excreted by the body. An important characteristic of drugs is the half-life: its rate of elimination. ◦ It is the amount of time it takes for the body to eliminate one-half of the original dosage in serum.

In some cases, antimicrobials are used in combination, but much care must be taken to prevent one counteracting the effects of another. If one drug enhances the other, they are considered synergistic. If the activity of one interferes with the other, they are considered antagonistic. If it is neither, then the combination is additive.

Adverse Effects Allergic reactions – having a hypersensitivity to a certain drug. ◦ If an allergy exists, another medicine must be prescribed. Toxic effects – Several drugs are toxic at high concentrations Suppression of Normal Flora – when the composition of normal flora is altered, then the pathogens may multiply to high numbers

Resistance to Antimicrobials Certain microbes are inherently resistant to the effects of a particular drug. This is termed innate or intrinsic resistance. If a previously sensitive organism develops resistance through spontaneous mutation, this is called acquired resistance.

21.3 Mechanisms of Action Bacterial cells have many processes that do not occur in eukaryotic cells Antimicrobial drugs target these processes

Inhibitors of Cell Wall Synthesis β-lactam drugs competitively inhibit enzymes that catalyze formation of peptide bridges between adjacent glycan strands which allow for peptidoglycan synthesis. Cell walls are only synthesized in actively growing cells, so these drugs are only effective against growing bacteria.

Penicillin binding proteins – bind penicillin, but their natural function is to synthesize peptidoglycan

Polypeptide antibiotics ◦ Bacitracin  Topical application  Inhibits cell wall biosynthesis by interfering with transport of peptidoglycan across the membrane  Against gram-positives ◦ Vancomycin  Glycopeptide  Bind the terminal amino acids that are assembled to form glycan chains  Important "last line" against antibiotic-resistant S. aureus

Inhibitors of Protein Synthesis Chloramphenicol ◦ Broad spectrum  Binds 50S subunit; inhibits peptide bond formation

Aminoglycosides ◦ Streptomycin, neomycin, gentamycin  Broad spectrum  Changes shape of protein subunit

Tetracyclines ◦ Broad spectrum  Interferes with tRNA attachment Figure 20.11

Injury to the Plasma Membrane Polymyxin B ◦ Topical ◦ Combined with bacitracin and neomycin in over-the-counter preparation

21.5 Resistance to antimicrobial drugs Drug resistance limits the usefulness of all known antimicrobials As the drugs are constantly misused, resistant strains are surviving

Microbes can acquire resistance 4 ways: Produce an enzyme that renders the drug ineffective Alteration of the target molecule – structural changes of the target change and render the drug useless Decreased uptake of the drug – altering membrane pores alters how much drug can enter the microbe Increased elimination of the drug

A variety of mutations can lead to antibiotic resistance Resistance genes are often on plasmids that can be transferred between bacteria

Misuse of antibiotics selects for resistance strains. Misuse includes: ◦ Using outdated or weakened antibiotics ◦ Using antibiotics for the common cold and other inappropriate conditions ◦ Using antibiotics in animal feed ◦ Failing to complete the prescribed regimen ◦ Using someone else's leftover prescription

Slowing the spread of resistance Physicians need to increase their efforts in identifying the specific cause of an infection and treat it with the appropriate medication Patients need to follow the specific instructions given with the medications to ensure proper dosage

A greater effort must be made to educate the public about appropriate antimicrobial usage, and about the limits of such drugs Globally, some antimicrobials are available without a prescription. In these places, it is important to cut down or eliminate this practice.

21.6 Mechanisms of antiviral drugs The most effective antiviral drugs exploit the virally encoded enzymes used to replicate viral nucleic acids. With few exceptions, these drugs are generally limited to treating infections from herpesvirus and HIV

Nucleoside and Nucleotide Analogs They can be made to form a structure similar to the structure of the DNA and RNA nucleotides. In some cases, this is incorporated in the termination of a growing nucleotide chain. In other cases, it results in a defective strand that alters the base pairs.

Protease inhibitors – inhibit the production of the enzyme protease, which is essential in the production of viral proteins ◦ Indinavir: HIV Integrase inhibitors – prevent certain viral activities ◦ HIV Inhibit attachment ◦ Zanamivir: Influenza ◦ Block CCR5: HIV Inhibit uncoating ◦ Amantadine: Influenza

21.7 Mechanisms of antifungal drugs Eukaryotic pathogens like fungi closely resemble human cells. Few drugs are available for systemic use against fungal pathogens.

Antifungal Drugs The target of most antifungals is inhibition of cell wall synthesis Echinocandins ◦ Inhibit synthesis of  -glucan, which is crucial in cell wall components ◦ Cancidas is used against Candida and Pneumocystis

Inhibition of Nucleic Acids Nucleic acid synthesis is a common feature of all eukaryotic cells and generally makes a poor target for antifungal drugs Flucytocine ◦ Can be used against yeasts ◦ Cytosine analog interferes with RNA synthesis Pentamidine isethionate ◦ Anti-Pneumocystis; may bind DNA