Chapter 9
Chapter 9 Outline
• Introduction
• Characteristics of an Ideal
Antimicrobial Agent
• How Antimicrobial Agents Work
• Antibacterial Agents
• Antifungal Agents
• Antiprotozoal Agents
• Antiviral Agents
• Drug Resistance
• Some Strategies in the War
Against Drug Resistance
• Empiric Therapy
• Undesirable Effects of
Antimicrobial Agents
• Concluding Remarks
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 Introduction
• Chemotherapy is the use of any chemical
(drug) to treat any disease or condition.
• A chemotherapeutic agent is any drug
used to treat any condition or disease.
Paul Ehrlich – Father of Chemotherapy
•1909, discovered an arsenic compound that
proved effective in treating syphilis called
“compound 606” or technically known as
arsphenamine (salvarsan)

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 Introduction
• An antimicrobial agent is any chemical
(drug) used to treat an infectious disease,
either by inhibiting or killing pathogens in
vivo. Some antimicrobial agents are
antibiotics.

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 Introduction
• antibacterial agents; drugs used to treat
bacterial diseases are called
• antifungal agents; those used to treat fungal
diseases
• antiprotozoal agents; those used to treat
protozoal diseases
• antiviral agents; those used to treat viral
diseases

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 Introduction
• An antibiotic is a substance produced by a
microorganism that kills or inhibits growth of other
microorganisms.
• Selman Waksman – first to used the term
“antibiotics”
• Semisynthetic antibiotics: Antibiotics that have
been chemically modified to kill a wider variety of
pathogens or reduce side effects; examples
include semisynthetic penicillins such as ampicillin
and carbenicillin

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 The discovery of penicillin by Alexander Fleming

A. Colonies of
Staphylococcus aureus are
growing well in this area of
the plate.
B. Colonies are poorly
developed in this area of
the plate because of an
antibiotic (penicillin) being
produced by a colony of
Penicillium notatum (a
mould), shown at C.

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 Characteristics of an Ideal
Antimicrobial Agent
1) Kill or inhibit the growth of pathogens
2) Cause no damage to the host
3) Cause no allergic reaction in the host
4) Be stable when stored in solid or liquid form
5) Remain in specific tissues in the body long
enough to be effective
6) Kill the pathogens before they mutate and
become resistant to it
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How Antimicrobial Agents Work
• The 5 most common mechanisms of action
of antimicrobial agents are:
1. Inhibition of cell wall synthesis
2. Damage to cell membranes
3. Inhibition of nucleic acid synthesis (either
DNA or RNA synthesis)
4. Inhibition of protein synthesis
5. Inhibition of enzyme activity

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 Antibacterial Agents
• Bacteriostatic drugs inhibit growth of
bacteria, whereas bactericidal drugs kill
bacteria.
• Sulfonamide drugs inhibit production of folic
acid (a vitamin) in those bacteria that require p-
aminobenzoic acid to synthesize folic acid;
without folic acid bacteria cannot produce certain
essential proteins and die.
– Sulfa drugs are competitive inhibitors; they are
bacteriostatic.

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The effect of sulfonamide drugs.

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 Antibacterial Agents
• In most Gram-positive bacteria,
• Penicillin interferes with the synthesis and
cross-linking of peptidoglycan, a component of
cell walls.
• By inhibiting cell wall synthesis, penicillin destroys
the bacteria.

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 Antibacterial Agents
• Vancomycin
• destroy only Gram-positive bacteria;
• Colistin and nalidixic acid
• destroy only Gram-negative bacteria;

• they are referred to as narrow-spectrum

antibiotics.

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 Antibacterial Agents
• Antibiotics that are destructive to both Gram-
positive and Gram-negative bacteria are called
broad-spectrum antibiotics (examples:
ampicillin, chloramphenicol and tetracycline).
• Multidrug therapy
– Sometimes one drug is not sufficient; 2 or more
drugs may be used simultaneously, as in the
treatment of tuberculosis.

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 Some Major Categories of
Antibacterial Agents
Antibacterial Agent Effect Target/Action

Penicillins bactericidal interfere with cell wall synthesis

Cephalosporins bactericidal interfere with cell wall synthesis

Tetracyclines bacteriostatic inhibit protein synthesis

Aminoglycosides bactericidal inhibit protein synthesis
Macrolides bacteriostatic at lower inhibit protein synthesis
doses; bactericidal at
higher doses
Fluoroquinolones bactericidal inhibit DNA synthesis

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 Antibacterial Agents
Synergism Antagonism
Synergism is when 2 Antagonism is when 2 drugs
antimicrobial agents actually work against each
are used together to other. The extent of
produce a degree of pathogen killing is less
pathogen killing that is than that achieved by
greater than that either drug alone.
achieved by either drug Antagonism is a bad thing!
alone. Synergism is a
good thing!

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 Antifungal Agents
• Most antifungal agents work in one of 3 ways:
– By binding with cell membrane sterols (e.g., nystatin
and amphotericin B)
– By interfering with sterol synthesis (e.g., clotrimazole
and miconazole)
– By blocking mitosis or nucleic acid synthesis (e.g.,
griseofulvin and 5-flucytosine)
• Antifungal agents and antiprotozoal agents tend to be
more toxic to the patient because (like the infected
human) they are eucaryotic organisms.
(Sterols: cholesterol, ergosterol, phytosterol)

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 Antiprotozoal Agents
• Antiprotozoal agents are usually toxic to the host.
• Antiprotozoal agents work by:
– Interfering with DNA and RNA synthesis (e.g.,
chloroquine, pentamidine, and quinacrine)
– Interfering with protozoal metabolism (e.g.,
metronidazole)

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 Antiviral Agents
• Antiviral agents are the newest weapons in antimicrobial
methodology.
• Difficult to develop these agents because viruses are
produced within host cells.
• Some drugs have been developed that are effective in
certain viral infections, but not others; they work by
inhibiting viral replication within cells.
• Antiviral agent “cocktails” (several drugs that are
administered simultaneously) are being used to treat HIV
infection.

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 Drug Resistance
“Superbugs”

• Superbugs are microbes (mainly bacteria)

that have become resistant to one or more
antimicrobial agent.
• Infections caused by superbugs are
difficult to treat!

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 Drug Resistance
“Superbugs”

• Bacterial superbugs include:

– methicillin-resistant Staphylococcus aureus (MRSA);
– vancomycin-resistant Enterococcus spp. (VRE);
– multidrug-resistant Mycobacterium tuberculosis (MDRTB);
– multidrug-resistant strains of Acinetobacter, Burkholderia,
E. coli, Klebsiella, Pseudomonas, Stenotrophomonas,
Salmonella, Shigella. and N. gonorrhoeae;
– β–lactamase-producing strains of Streptococcus
pneumoniae and Haemophilus influenzae;
– carbapenemase-producing Klebsiella pneumoniae.

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 Drug Resistance
How Bacteria Become Resistant to Drugs

• Some bacteria are naturally resistant

because
• they lack the specific target site for the drug or
the drug is unable to cross the organism’s cell
wall or cell membrane and thus, …
• cannot reach its site of action.
• Resistance of this type is known as intrinsic
resistance.

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 Drug Resistance
How Bacteria Become Resistant to Drugs

• If bacteria that were once susceptible to a

particular drug become resistant, this is
called acquired resistance.

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 Drug Resistance
How Bacteria Become Resistant to Drugs

• Before a drug enters a bacterial cell it must

first bind to proteins on the surface of the cell;
these proteins are called drug-binding
sites.
• A chromosomal mutation that affects the
structure of a drug-binding site can prevent
the drug from binding, resulting in drug
resistance

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 Drug Resistance
How Bacteria Become Resistant to Drugs

• Bacteria can develop the ability to produce an

enzyme that destroys or inactivates a drug.
– Many bacteria have become resistant to
penicillin because they have acquired the gene
for penicillinase production during conjugation.
• A plasmid that contains multiple genes for
drug resistance is known as a resistance
factor (R-factor).

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 Drug Resistance
How Bacteria Become Resistant to Drugs

• Bacteria can also become resistant to

drugs by developing the ability to produce
multidrug-resistance (MDR) pumps (also
known as MDR transporters or efflux
pumps).
– An MDR pump enables the cell to pump out
drugs before they can damage or kill the cell.

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 Drug Resistance
How Bacteria Become Resistant to Drugs

• Summary: Bacteria can acquire resistance to

antimicrobial agents
• by chromosomal mutation or
• by the acquisition of new genes by
• Transduction [ bacteriophage carry DNA from on
bacteria to another]
• Transformation [naked DNA from environment]
• most commonly, by Conjugation (plasmid containing
such gene).

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 Drug Resistance
β-Lactamases

• Every penicillin and

cephalosporin molecule contains
a double-ringed structure
(referred to as a “house and
garage”).
• The “garage” is known as the β- Penicillin core structure

lactam ring.

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 Drug Resistance
β-Lactamases

• Some bacteria produce enzymes, β-

lactamases, that destroy this ring; when
the β–lactam ring is destroyed, the drug no
longer works.
– 2 types of β-lactamases - penicillinases and
cephalosporinases; some bacteria produce
both types.

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Sites of β-lactamase Attack on Penicillin
and Cephalosporin Molecules.

Copyright © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins

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 Drug Resistance
β-Lactamases

• Drug companies have developed special

drugs that combine a β–lactam antibiotic
with a β-lactamase inhibitor.
• Augmentin (brand name): clavulanic acid combined
with amoxicillin)
• Timentin: Clavulanic acid combined with ticarcillin
• Unasyn: Sulbactam combined with ampicillin
• Zosyn: Tazobactam combined with piperacillin

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 Some Strategies in the War
Against Drug Resistance
• Education of healthcare professionals and patients
• Patients should stop demanding antibiotics every time
they are, or their child is, sick
• Physicians should not be pressured by patients and
should prescribe drugs only when warranted
• Clinicians should prescribe a narrow-spectrum drug if lab
results indicate that it kills the pathogen

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 Some Strategies in the War
Against Drug Resistance
• Patients should destroy any excess or out-dated
medications
• Antibiotics should not be used in a prophylactic manner
• Healthcare professionals should practice good infection
control
• Patients should take drugs in manner prescribed

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 Empirical Therapy
• Empirical therapy is when drug therapy is
initiated before laboratory results are
available (i.e., before the pathogen is
identified and/or before susceptibility test
results are available).
– Empiric therapy is sometimes necessary to save
a patient’s life.
– Clinicians make an “educated guess” based on
past experience with the type of infectious
disease and the most effective drugs.

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 Empiric Therapy
Clinicians must take a number of factors into consideration before prescribing
antimicrobial agents

• If pathogen identity is known, • In the hospital formulary?

use the “pocket chart” of
antimicrobial susceptibility test
data from past year.
• Is the patient allergic to any
antimicrobial agents?
• What is the age of the patient?
• Site of the infection?
• What other medication(s) is the
patient taking?
• What other medical problems
does the patient have?

• Is the patient pregnant? • Is the patient leukopenic or

immunocompromised?
• Inpatient or outpatient?
• What is the cost of the drug(s)?

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Pocket chart for aerobic
Gram-negative bacteria.
The chart is a quick
reference whenever
empiric therapy is
necessary.

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Undesirable Effects of Antimicrobial Agents
Reasons why antimicrobial agents should not be used indiscriminately

• Organisms susceptible to the agent will die, but

resistant ones will survive; this is known as selecting
for resistant organisms.
• The patient may become allergic to the agent.
• Many agents are toxic to humans and some are very
toxic.
• With prolonged use, a broad-spectrum antibiotic may
destroy the normal flora, resulting in an overgrowth
of bacteria known as a superinfection.

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Selecting for drug-resistant organisms

A. Indigenous microflora of
patient before antibiotic
therapy. (S = susceptible;
R = resistant)
B. After antibiotic therapy has
been initiated
C. Resistant organisms
multiply and become the
predominant organisms.

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