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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 606th 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