Chapter 9 Inhibiting Growth of Pathogens in Vivo Using Antimicrobial Agents

3/8/2023
Outline
BSci106:
MICROBIOLOGY and • Introduction • Drug Resistance
PARASITOLOGY • Characteristics of an Ideal

Antimicrobial Agent
• Some Strategies in the War
Against Drug Resistance
• How Antimicrobial Agents • Empiric Therapy
Work
• Undesirable Effects of
• Antibacterial Agents Antimicrobial Agents
Chapter 9
• Antifungal Agents • Concluding Remarks
Inhibiting the Growth of Pathogens In
Vivo Using Antimicrobial Agents • Antiprotozoal Agents
• Antiviral Agents
Copyright © 2015 Wolters Kluwer • All Rights Reserved Copyright © 2015 Wolters Kluwer • All Rights Reserved
Introduction Introduction (cont.)
• Chemotherapy is the use of any chemical (drug) to • Drugs used to treat bacterial diseases are called
treat any disease or condition. antibacterial agents; those used to treat fungal diseases,
antifungal agents; those used to treat protozoal diseases,
• A chemotherapeutic agent is any drug used to treat antiprotozoal agents; and those used to treat viral
diseases, antiviral agents.
any condition or disease.
• An antibiotic is a substance produced by a microorganism
• An antimicrobial agent is any chemical (drug) used to that kills or inhibits the growth of other microorganisms.
treat an infectious disease, either by inhibiting or by
• Antibiotics that have been chemically modified to kill a
killing pathogens in vivo. Some antimicrobial agents are
wider variety of pathogens or reduce side effects are
antibiotics. called semisynthetic antibiotics; examples include
semisynthetic penicillins, such as ampicillin and
carbenicillin.
The Discovery of Penicillin by Characteristics of an Ideal

Alexander Fleming Antimicrobial Agent
Alexander Fleming • An ideal antimicrobial agent should

– Kill or inhibit the growth of pathogens
(A) Colonies of Staphylococcus – Cause no damage to the host

aureus are growing well in this – Cause no allergic reaction in the host
area of the plate. (B) Colonies
are poorly developed in this area – Be stable when stored in solid or liquid form
of the plate because of an – Remain in specific tissues in the body long
antibiotic (penicillin) being enough to be effective
produced by a colony of
– Kill the pathogens before they mutate and
Penicillium notatum (a mould), become resistant to it
shown at C.
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How Antimicrobial Agents Work Antibacterial Agents
• The five most common mechanisms of action of • Bacteriostatic drugs inhibit growth of bacteria, whereas
antimicrobial agents are bactericidal drugs kill bacteria.
– Inhibition of cell wall synthesis • Sulfonamide drugs inhibit production of folic acid (a
vitamin) in those bacteria that require p-aminobenzoic acid
– Damage to cell membranes to synthesize folic acid; without folic acid, bacteria cannot
produce certain essential proteins and die.
– Inhibition of nucleic acid synthesis (either DNA
or RNA synthesis) – Sulfa drugs are competitive inhibitors; they are
bacteriostatic.
– Inhibition of protein synthesis
• In most Gram-positive bacteria, penicillin interferes with
– Inhibition of enzyme activity the synthesis and cross-link ing of peptidoglycan, a
component of cell walls. By inhibiting cell wall synthesis,
penicillin destroys the bacteria.
The Effect of Sulfonamide Drugs Antibacterial Agents (cont.)
• Colistin and nalidixic acid destroy only Gram-

negative bacteria; they are referred to as narrow-
spectrum antibiotics.
• Antibiotics that are destructive to both Gram-
positive and Gram-negative bacteria are called
broad-spectrum antibiotics (e.g., ampicillin,
chloramphenicol, and tetracycline).
• Multidrug therapy
– Sometimes one drug is not sufficient; two or
more drugs may be used simultaneously, as in
the treatment of tuberculosis.
Some Major Categories of

Antibacterial Agents (cont.) Antibacterial Agents
• Synergism versus antagonism • Penicillins (bactericidal; interfere with cell wall

synthesis)
– Synergism is when two antimicrobial agents are
used together to produce a degree of pathogen • Cephalosporins (bactericidal; interfere with cell wall
killing that is greater than that achieved by synthesis)
either drug alone. Synergism is a good thing.
• Tetracyclines (bacteriostatic; inhibit protein synthesis)
– Antagonism is when two drugs actually work
against each other. The extent of pathogen • Aminoglycosides (bactericidal; inhibit protein
killing is less than that achieved by either drug synthesis)
alone. Antagonism is a bad thing! • Macrolides (bacteriostatic at lower doses; bactericidal
at higher doses; inhibit protein synthesis)
• Fluoroquinolones (bactericidal; inhibit DNA synthesis)
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Antifungal Agents Antiprotozoal Agents
• Most antifungal agents work in one of three ways: • Antiprotozoal agents are usually toxic to the host.
– By binding with cell membrane sterols (e.g., • Antiprotozoal agents work by
nystatin and amphotericin B)
– I nter f er ing with D NA and RNA sy nt he sis (e. g . ,
– B y in terf er ing w it h s te ro l sy nth esi s (e. g.,
clotrimazole and miconazole) chloroquine, pentamidine, and quinacrine)
– By blocking mitosis or nucleic acid synthesis – Interfering with protozoal metabolism (e.g.,
(e.g., griseofulvin and 5-flucytosine) metronidazole)
• Antifungal agents and antiprotozoal agents tend to
be more toxic to the patient because, like the
infected human, they are eukaryotic organisms.
Antiviral Agents Drug Resistance

“Superbugs”
• Antiviral agents are the newest weapons in • Superbugs are microbes (mainly bacteria) that have
antimicrobial methodology. become resistant to one or more antimicrobial
agents. Infections caused by superbugs are difficult
• Difficult to develop these agents because viruses are to treat.
produced within host cells.
• Bacterial superbugs include methicillin-resistant
• Some drugs have been developed that are effective Staphylococcus aureus (MRSA); vancomycin-
in certain viral infections, but not others; they work resistant Enterococcus spp. (VRE); multidrug-
by inhibiting viral replication within cells. resistant Mycobacterium tuberculosis (MDRTB);
multidrug-resistant strains of Acinetobacter,
• “ C o c k t a i l s ” ( s e v e r a l a nt i v i r a l d r u g s t h a t a r e Burkholderia, E. coli, Klebsiella, Pseudomonas,
administered simultaneously) are being used to Stenotrophomonas, Salmonella, Shigella, and N.
treat HIV infection. gonorrhoeae; β-lactamase-producing strains of
Streptococcus pneumoniae and Haemophilus
influenzae; carbapenemase-producing Klebsiella
pneumoniae.
Drug Resistance: How Bacteria

Superbugs Become Resistant to Drugs
• Some bacteria are naturally resistant because they lack the

Hospitals are notorious specific target site for the drug or the drug is unable to cross
havens for multidrug- the organism’s cell wall or cell membrane and, thus, cannot
reach its site of action. Resistance of this type is known as
resistant microbes. intrinsic resistance.
• If bacteria that were once susceptible to a particular drug
become resistant, this is called acquired resistance.
• 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 Drug Resistance: How Bacteria Become
(cont.) Resistant to Drugs (cont.)
• To enter a bacterial cell, a drug must be able to pass through • Bacteria can also become resistant to drugs by developing
the cell wall and cell membrane; chromosomal mutations the ability to produce multidrug-resistance (MDR) pumps
may alter the structure of the cell membrane, thus (also known as MDR transporters or efflux pumps).
preventing the drug from entering the cell; this results in – An MDR pump enables the cell to pump drugs out
drug resistance. before they can damage or kill the cell.
• Bacteria can develop the ability to produce an enzyme that • Summary: Bacteria can acquire resistance to antimicrobial
destroys or inactivates a drug. agents by chromosomal mutation or by the acquisition of
– Many bacteria have become resistant to penicillin new genes by transduction, transformation, and, most
because they have acquired the gene for penicillinase commonly, by conjugation.
production during conjugation.
• A plasmid that contains multiple genes for drug resistance is
known as a resistance factor (R-factor).
Mechanisms by Which Bacteria Become Drug Resistance

Resistant to Antimicrobial Agents 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-
lactam ring.
• Some bacteria produce enzymes, β-lactamases, that
destroy this ring; when the β-lactam ring is
destroyed, the drug no longer works.
– There are two types of β-
lactamasespenicillinases and
cephalosporinases; some bacteria produce both
types.
• Drug companies have developed special drugs that
combine a β-lactam antibiotic with a β-lactamase
inhibitor.
Sites of β-Lactamase Attack on Penicillin Some Strategies in the War Against

and Cephalosporin Molecules Drug Resistance
• Education of healthcare • Patients should destroy any
professionals and patients excess or outdated
• Patients should stop medications
demanding antibiotics • Antibiotics should not be
every time they are, or their
child is, sick used in a prophylactic
manner
• Physicians should not be
pressured by patients and • Healthcare professionals
should prescribe drugs only should practice good
when warranted infection control
• Clinicians should prescribe • Patients should take drugs
a narrow-spectrum drug if in manner prescribed
laboratory results indicate
that it kills the pathogen
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Empiric Therapy:
Empiric Therapy Factors to Be Considered
• Empiric therapy is when drug therapy is initiated • If pathogen identity is • Is the drug the hospital
before laboratory results are available (i.e., before known, use the “pocket formulary?
the pathogen is identified and/or before chart” of antimicrobial
susceptibility test results are available). susceptibility test data from • Site of the infection?
the past year. • What other medication(s)
– Empiric therapy is sometimes necessary to save
a patient’s life. • Is the patient allergic to any is the patient taking?
antimicrobial agents? • What other medical
– Clinicians make an “educated guess” based on
past experience with the type of infectious • What is the age of the problems does the patient
disease and the most effective drugs. patient? have?
• Clinicians must take a numbe r of fac tors into • Is the patient pregnant? • Is the patient leukopenic or
consideration before prescribing antimicrobial agents. immunocompromised?
• Inpatient or outpatient?
• What is the cost of the
drug(s)?
Example of a Pocket Chart for Undesirable Effects of Antimicrobial

Aerobic Gram-Negative Bacteria Agents
• Reasons why antimicrobial agents should not be
used indiscriminately:
The chart provides a
– Organisms susceptible to the agent will die, but
quick reference resistant ones will survive; this is known as
whenever empiric selecting for resistant organisms.
therapy is necessary. – The patient may become allergic to the agent.
– Many agents are toxic to humans and some are
very toxic.
Note: this chart is different
from the one in the textbook. – With prolonged use, a broad-spectrum antibiotic
may destroy the normal flora, resulting in an
overgrowth of bacteria known as a
superinfection.
Selecting for Drug-Resistant

Organisms
A. Indigenous microbiota of
a patient before antibiotic
therapy (S, susceptible; R,
resistant).
B. After antibiotic therapy
has been initiated.
C. Resistant organisms
multiply and become the
predominant organisms.
Copyright © 2015 Wolters Kluwer • All Rights Reserved

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3/8/2023

PARASITOLOGY • Characteristics of an Ideal

Introduction Introduction (cont.)

The Discovery of Penicillin by Characteristics of an Ideal

Alexander Fleming • An ideal antimicrobial agent should

(A) Colonies of Staphylococcus – Cause no damage to the host

How Antimicrobial Agents Work Antibacterial Agents

The Effect of Sulfonamide Drugs Antibacterial Agents (cont.)

• Colistin and nalidixic acid destroy only Gram-

Some Major Categories of

• Synergism versus antagonism • Penicillins (bactericidal; interfere with cell wall

Antifungal Agents Antiprotozoal Agents

Antiviral Agents Drug Resistance

Drug Resistance: How Bacteria

• Some bacteria are naturally resistant because they lack the

Mechanisms by Which Bacteria Become Drug Resistance

Sites of β-Lactamase Attack on Penicillin Some Strategies in the War Against

Example of a Pocket Chart for Undesirable Effects of Antimicrobial

Selecting for Drug-Resistant

Copyright © 2015 Wolters Kluwer • All Rights Reserved

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