DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

General Principles of
Antimicrobial Therapy
Tawanda Gumbo
SCIENTIFIC BASIS OF ANTIMICROBIAL
CHEMOTHERAPY
An important revolution in human understanding of
nature was the germ theory of disease based on the
work of Louis Pasteur and Robert Koch, which linked
specific microorganisms to specific diseases (Koch,
1876; Pasteur, 1861). Modern chemotherapy is predicated
on this idea, radical in its time. The germ theory
developed considerably in the 20th century, with identification
and characterization of many microbial
pathogens and their pathogenic mechanisms and the
introduction of antimicrobial drugs. With the use of
these drugs came issues of appropriate regimens, drug
resistance, drug interactions, and toxicity.
Although the antimicrobials are a large group of
diverse structures with myriad mechanisms of actions
against bacteria, viruses, fungi, and parasites, we can,
nonetheless, develop generalizations about important
issues surrounding the use of antimicrobial agents. This
chapter reviews the general classes of antimicrobial
drugs, their mechanisms of action, mechanisms of
resistance, and patterns of kill by different classes of
the drugs. It also discusses principles for the selection
of an appropriate antibiotic, dose, dose schedule, and
type of antibiotic therapy. The pharmacological properties
and uses of individual classes of antimicrobials are
discussed in Chapters 49 through 59.
Classes and Actions of Antimicrobial Agents.
Microorganisms of medical importance fall into four
categories: bacteria, viruses, fungi, and parasites. The
first broad classification of antibiotics follows this classification
closely, so that we have (1) antibacterial, (2)
antiviral, (3) antifungal, and (4) antiparasitic agents.
Within each of these major categories, drugs are further
categorized by their biochemical properties.
Antimicrobial molecules should be viewed as ligands
whose receptors are microbial proteins. The term pharmacophore,
first introduced by Ehrlich, defines that
active chemical moiety of the drug that binds to the
microbial receptor. The microbial proteins targeted by
the antibiotic are essential components of biochemical
reactions in the microbes, and interference with these
physiological pathways kills the microorganisms. To
the extent that an antimicrobial agent targets a protein
that is not widely expressed in other bacteria, the drug
will be relatively selective in its antimicrobial effect.
The biochemical processes commonly inhibited include
cell wall synthesis in bacteria and fungi, cell membrane
synthesis, synthesis of 30s and 50s ribosomal subunits,
nucleic acid metabolism, function of topoisomerases,
viral proteases, viral integrases, viral envelope fusion
proteins, folate synthesis in parasites, and parasitic
chemical detoxification processes. Classification of an
antibiotic is based on:
• the class and spectrum of microorganisms it kills
• the biochemical pathway it interferes with
• the chemical structure of its pharmacophore
Because antimicrobial agents are ligands that
bind to their targets to produce effects, the relationship
between drug concentration and effect on a population
of organisms is still modeled using the standard Hilltype
curve for receptor and agonist (Chapters 2 and 3),
characterized by three parameters: the inhibitory
concentration 50, or IC 50
(also termed EC 50
), a measure
of the antimicrobial agent’s potency; the maximal
effect, E max
; and H, the slope of the curve, or Hill
factor. In antimicrobial therapy, the relationship is often
expressed as an inhibitory sigmoid E max
model, to take
into account the control bacterial population without
treatment (E con
) as a fourth parameter (Equation 48–1 and