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

enzyme (Harshey and Ramakrishnan, 1976; Wehrli et al., 1968). The
PAE of the rifampin is long and concentration dependent (Gumbo et al.,
2007a). This means that administering combined doses on a more
intermittent basis (i.e., once a day) will maximize effect for these
drugs. Toxicity generated by intermittent dosing may preclude such
use for some drugs such as rifampin, whereas for others (i.e., aminoglycosides)
such infrequent dosing may actually decrease toxicity.
There is a third group of drugs for which dosing schedule has
no effect on efficacy, but where it is the cumulative dose that matters.
Thus, it is more the total concentration (AUC) to MIC ratio that matters
and not the time that concentration persists above a certain
threshold. Antibacterial agents such as daptomycin fall into this class
(Louie et al., 2001). These agents also have a good PAE. The
AUC/IC 50
explains why the nucleoside analogue reverse transcriptase
inhibitors tenofovir and emtricitabine have been combined into
one pill, administered once a day for the treatment of AIDS.
The shape of concentration-time curve that optimizes resistance
suppression is often different from that which optimizes microbial
kill. In many instances, the drug exposure associated with
resistance suppression is much higher than for optimal kill. It should
actually be this higher exposure that should be achieved by each dose
in patients for optimal effect, rather than the EC 80
as discussed earlier.
However, this is often precluded by increased drug toxicity when
doses are increased. Second, although the relationship between kill
and exposure is based on the inhibitory sigmoid E max
model, experimental
work with preclinical models demonstrates that this model
does not apply to resistance suppression (Gumbo, 2007b; Tam et al.,
2007).
The optimal dose should be designed to achieve a
high probability of exceeding the EC 80
microbial
PK/PD index, or index associated with suppression of
resistance, given the population pharmacokinetic variability
and the MIC distribution of clinical microbe isolates.
The population pharmacokinetic variability
enables integration of pharmacogenetics, anthropometric
measures, and residual variability into the decision to
choose optimal dose (Gumbo, 2008). Once that has
been achieved, the dose schedule is chosen according to
whether efficacy is driven by AUC/MIC (or
AUC/EC 95
), C Pmax
/MIC, or T > MIC. Duration of therapy
is then chosen, based on best available evidence.
TYPES AND GOALS OF
ANTIMICROBIAL THERAPY
When an infection occurs, the numbers of microorganisms
are often small in the beginning. Pathogen burden
eventually increases with replication of the organism.
Sometimes, the immune system manages to eliminate
the infection before it causes any further damage. In
other instances, the organism is not entirely eliminated
but hides inside the patient’s own cells and become dormant,
only to reactivate when immune function is compromised
in the future. In some patients, the organism
may overcome immune defenses and then cause disease.
In a subset of such patients, the disease is selflimited.
For example, many viral upper respiratory
infections are self-limited and should not be treated
with antimicrobial agents. Other diseases, however,
require antimicrobial therapy. In these patients, therapy
should be discontinued after resolution of disease. In
special cases where the immune or anatomical defect
that led to the infection is still present, suppressive or
“maintenance” therapy may be required. A useful way
to organize the types and goals of antimicrobial therapy
is to consider where along the disease progression
timetable therapy is initiated (Figure 48–5); therapy can
be prophylactic, preemptive, empirical, definitive, or
suppressive.
Prophylactic Therapy. Prophylaxis involves treating
patients who are not yet infected or have not yet
developed disease. The goal of prophylaxis is to prevent
infection in some patients or to prevent development
of a potentially dangerous disease in those who
already have evidence of infection. Ideally, a single,
effective, nontoxic drug is successful in preventing
infection by a specific microorganism or eradicating an
early infection. The main principle behind prophylaxis
is targeted therapy. However, prophylaxis to prevent
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CHAPTER 48
GENERAL PRINCIPLES OF ANTIMICROBIAL THERAPY
Prophylaxis Pre-emptive Empiric Definitive Suppressive
No infection Infection Symptoms Pathogen Resolution
isolation
Figure 48–5. Aantimicrobial therapy-disease progression timeline. Stages of disease progression are below the horizontal arrow;
categories of antimicrobial therapy are above the arrow.