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

1378 or by subsequent transfers to other susceptible recipient
strains. Horizontal transfer of resistance offers several
advantages over mutation selection. Lethal mutation of
an essential gene is avoided; the level of resistance often
is higher than that produced by mutation, which tends to
yield incremental changes; the gene, which still can be
transmitted vertically, can be mobilized and rapidly
amplified within a population by transfer to susceptible
cells; and the resistance gene can be eliminated when it
no longer offers a selective advantage.
Horizontal Gene Transfer. Horizontal transfer of resistance
genes is greatly facilitated by and is largely
dependent on mobile genetic elements. Mobile genetic
elements include plasmids and transducing phages.
Other mobile elements—transposable elements, integrons,
and gene cassettes—also participate in the
process. Transposable elements are of three general
types: insertion sequences, transposons, and transposable
phages. Only insertion sequences and transposons
are important for resistance.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Insertion sequences (Mahillon and Chandler, 1998) are short
segments of DNA encoding enzymatic functions (e.g., transposase and
resolvase) for site-specific recombination with inverted repeat
sequences at either end. They can copy themselves and insert themselves
into a chromosome or a plasmid. Insertion sequences do not
encode resistance, but they function as sites for integration of other
resistance-encoding elements (e.g., plasmids or transposons).
Transposons are insertion sequences that also code for other functions,
one of which can be drug resistance. Because transposons move
between chromosome and plasmid, the resistance gene can “hitchhike”
with a transferable element out of the host and into a recipient.
Transposons are mobile elements that excise and integrate in the bacterial
genomic or plasmid DNA (i.e., from plasmid to plasmid, from
plasmid to chromosome, or from chromosome to plasmid). Integrons
(Fluit and Schmitz, 2004) are not formally mobile and do not copy
themselves, but they encode an integrase and provide a specific site
into which mobile gene cassettes integrate. Gene cassettes encode
resistance determinants, usually lacking a promoter, with a downstream
repeat sequence. The integrase recognizes this repeat sequence
and directs insertion of the cassette into position behind a strong promoter
that is present on the integron. Integrons may be located within
transposons or in plasmids, and therefore may be mobilizable, or
located on the chromosome.
Transduction is acquisition of bacterial DNA from a phage (a
virus that propagates in bacteria) that has incorporated DNA from a
previous host bacterium within its outer protein coat. If the DNA
includes a gene for drug resistance, the newly infected bacterial cell
may acquire resistance. Transduction is particularly important in the
transfer of antibiotic resistance among strains of S. aureus.
Transformation is the uptake and incorporation into the host genome
by homologous recombination of free DNA released into the environment
by other bacterial cells. Transformation is the molecular
basis of penicillin resistance in pneumococci and Neisseria (Spratt,
1994). Conjugation, as the name implies, is gene transfer by direct
cell-to-cell contact through a sex pilus or bridge. This complex and
fascinating mechanism for the spread of antibiotic resistance is
extremely important because multiple resistance genes can be transferred
in a single event. The transferable genetic material consists of
two different sets of plasmid-encoded genes that may be on the same
or different plasmids. One set encodes the actual resistance; the second
encodes genes necessary for the bacterial conjugation process.
Conjugation with genetic exchange between nonpathogenic and pathogenic
microorganisms probably occurs in the GI tracts of humans
and animals. The efficiency of transfer is low; however, antibiotics
can exert a powerful selective pressure to allow emergence of the
resistant strain. Genetic transfer by conjugation is common among
gram-negative bacilli, and resistance is conferred on a susceptible cell
as a single event. Enterococci also contain a broad range of host-range
conjugative plasmids that are involved in the transfer and spread of
resistance genes among gram-positive organisms.
CLINICAL SUMMARY
Antimicrobial agents work by targeting specific biochemical
properties of pathogens, and therefore have a
narrow spectrum of organisms that they can kill.
Infection is usually in a particular anatomical compartment.
Important determinants of success of antimicrobial
therapy include proper selection of antimicrobial
therapy based on microbiology results and susceptibility
testing, knowledge of drug penetration into the
infected compartment, and knowledge of compartmental
pharmacokinetics. The proper dose and dosing
schedule are chosen by integrating microbial pharmacokinetic-pharmacodynamic
information, expected pharmacokinetic
variability, and the minimum inhibitory
concentration of the pathogen. The goals of therapy
should be clear. Prophylaxis, pre-emptive therapy,
empirical therapy, and definitive therapy should have
treatment goals and duration of therapy clearly spelled
out in the beginning, based on proper evidence. The general
rule is monotherapy, except in select situations
where combination therapy has been shown to be superior.
Poor dosing strategies lead to catastrophic outcomes
such as drug-resistant pathogens and untoward
toxicity to the patients.
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