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

suggest this approach may be as efficacious as universal prophylaxis
while using far less antiviral medications (Gerna et al., 2008;
Singh et al., 2008).
Empirical Therapy in the Symptomatic Patient. Once
a patient is symptomatic, should the patient be treated
immediately? The first consideration in selecting an
antimicrobial is to determine if the drug is indicated.
The reflex action to associate fever with treatable
infections and prescribe antimicrobial therapy without
further evaluation is irrational and potentially
dangerous.
The diagnosis may be masked if therapy is started and appropriate
cultures are not obtained. Antimicrobial agents are potentially
toxic and may promote selection of resistant microorganisms. For
some diseases, the cost of waiting a few days is low. These patients
can wait for microbiological evidence of infection without empirical
treatment. In a second group of patients, the risks of waiting are high,
based either on the patient’s immune status or other known risk factors
for poor outcome with therapy delay. Initiation of optimal empirical
antimicrobial therapy should rely on the clinical presentation,
which may suggest the specific microorganism, and knowledge of
the microorganisms most likely to cause specific infections in a given
host. In addition, simple and rapid laboratory techniques are available
for the examination of infected tissues.
The most valuable and time-tested method for immediate
identification of bacteria is examination of the infected secretion or
body fluid with Gram stain. In malaria-endemic areas, or in travelers
returning from such an area, a simple thick and thin blood smear
may mean the difference between a patient’s receiving appropriate
therapy and surviving or death while on wrong therapy for presumed
bacterial infection. Such tests help to narrow the list of potential
pathogens and permit more rational selection of initial antibiotic
therapy. Similarly, neutropenic patients with fever have high risks
of mortality, and, when febrile, they are presumed to have either a
bacterial or fungal infection; thus a broad-spectrum combination of
antibacterial and antifungal agents that cover common infections
encountered in granulocytopenic patients are given. Performance of
cultures is still mandatory with a view to modify antimicrobial therapy
with culture results.
Definitive Therapy with Known Pathogen. Once a
pathogen has been isolated and susceptibilities results
are available, therapy should be streamlined to a narrow
targeted antibiotic. Monotherapy is preferred to
decrease the risk of antimicrobial toxicity and selection
of antimicrobial-resistant pathogens. Proper antimicrobial
doses and dose schedules are crucial to maximizing
efficacy and minimizing toxicity. In addition, the
duration of therapy should be as short as is necessary.
The practice of keeping a patient indefinitely on antimicrobial
therapy without a particular reason is discouraged.
In fact, both experimental and clinical evidence have
shown that unnecessarily prolonged therapies lead to
the emergence of resistance.
Combination therapy is an exception, rather than a rule. Once
a pathogen has been isolated, there should be no reason to use
multiple antibiotics, except when evidence overwhelmingly suggests
otherwise. Using two antimicrobial agents where one is required
leads to increased toxicity and unnecessary damage to the patient’s
otherwise protective fungal and bacterial flora. This is true, even
when intuition suggests use of two agents. As an example, Cosgrove
and colleagues recently demonstrated increased nephrotoxicity of
low-dose gentamicin administered only for 4 days as “synergistic
therapy” with vancomycin or an antistaphylococcal penicillin for
S. aureus bacteremia and endocarditis, without improving efficacy
(Cosgrove et al., 2009).
However, there are special circumstances where evidence is
unequivocal in favor of combination therapy. The principles behind
such antimicrobial use include:
• preventing resistance to monotherapy
• accelerating the rapidity of microbial kill
• enhancing therapeutic efficacy by use of synergistic interactions
or enhancing kill by a drug based on a mutation generated by
resistance to another drug
• paradoxically, reducing toxicity (i.e., when full efficacy of a standard
antibacterial agent can only be achieved at doses that are
toxic to the patient, and a second drug is co-administered to
exert additive effects)
Clinical situations for which combination therapy is advised
are discussed in the relevant chapters but include antiretroviral therapy
for AIDS, antiviral therapy for hepatitis B and C, the treatment
of tuberculosis, Mycobacterium avium-intracellulare and leprosy,
fixed-dose combinations of antimalarial drugs, the treatment of
Cryptococcus neoformans with flucytosine and amphotericin B, during
empirical therapy for patients with febrile neutropenia, and
advanced AIDS with fever. The combination of a sulfonamide and an
inhibitor of dihydrofolate reductase, such as trimethoprim, is synergistic
owing to the blocking of sequential steps in microbial folate
synthesis. A fixed combination of sulfamethoxazole and trimethoprim
is active against organisms that may be resistant to sulfonamides
alone, is effective for many infections, and is rarely given as
its separate components.
Post-treatment suppressive therapy. In some patients, after the initial
disease is controlled by the antimicrobial agent, therapy is continued
at a lower dose. This is because in these patients the infection is not
completely eradicated and the immunological or anatomical defect
that led to the original infection is still present. This is common in
AIDS patients and post-transplant patients, for example. The goal is
more as secondary prophylaxis. Nevertheless, risks of toxicity from
long durations of the therapy are still real. In this group of patients,
the suppressive therapy is eventually discontinued if the patient’s
immune system improves.
MECHANISMS OF RESISTANCE
TO ANTIMICROBIAL AGENTS
Antimicrobial agents were viewed as miracle cures
when first introduced into clinical practice. However,
it became evident rather soon after the discovery of
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CHAPTER 48
GENERAL PRINCIPLES OF ANTIMICROBIAL THERAPY