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

viability assay (Hanna and D’Aquila, 2001; Hertogs
et al., 1998; Petropoulos et al., 2000). Growth is compared
to a standardized wild-type control virus. For
HIV reverse transcriptase, e.g., <4-fold increase in IC 50
is defined as “sensitive,” 4- to 10-fold increase in IC 50
is “intermediate,” and >10-fold increase is “resistant”
(Hanna and D’Aquila, 2001). Further use has been
made of the viral IC 50
to establish the inhibitory quotient
(IQ). The IQ is the ratio of plasma concentration
of antiviral drug to the IC 50
. The phenotypic IQ is the
ratio of plasma trough concentration to the IC 50
.
Genotypic tests are now a standard part of HIV care in many
parts of the world, although the tests are rarely used in clinical practice
in resource-poor settings. The simplest tests measure presence
of mutations associated with loss of function of a drug. This loss of
function means that the organism is “resistant” to drug and the drug
should not be used to treat that patient. The absence of mutation
means the drug has an increased likelihood of working against the
pathogen. There are some situations with antiretroviral therapy, however,
when presence of such mutations may paradoxically lead to
choice of the drug to be part of combination therapy. A famous
example is that of the reverse transcriptase inhibitors zidovudine
(AZT) and lamivudine (3TC) in the treatment of HIV-1, in which an
M184V mutation that causes resistance to 3TC increases viral sensitivity
to AZT up to 10-fold. Therefore, although presence of a
mutation in a genotype assay may strongly argue for exclusion of
some drugs in a regimen, the interpretation can be complex. Indeed,
this is one of the limitations of this method in that the true meaning
of a mutation may be unclear and interpreted differently by healthcare
practitioners.
Parasites. Susceptibility testing for parasites, especially
malaria, has been performed in the laboratory. The tests
are similar to the broth tests for bacteria, fungi, and
viruses. Plasmodium species in the patient’s blood are
cultured ex vivo in the presence of different dilutions of
antimalarial drug (Stepniewska et al., 2007). A sigmoid
E max
curve for effect versus drug concentration is used
to identify IC 50
and E max
. These susceptibility tests are
usually field tests at sentinel sites that are used to determine
if there is drug resistance in a particular area or
not, and they are not used as a routine test for clinical
decision making for individual patients. In general, susceptibility
tests for parasitic infections are not standardized.
These tests are primarily used in the research
setting and not for individualization of therapy.
BASIS FOR SELECTION OF DOSE AND
DOSING SCHEDULE
Even though susceptibility testing is central to decision
making, it does not completely predict patient response.
Unlike in susceptibility tests in the laboratory where
drug concentrations are static by design, microorganisms
in patients are exposed to dynamic concentrations
of drug. In addition, the antibiotics are prescribed at a
certain schedule (e.g., three times a day) so that there is
a periodicity in the fluctuations of drug at the site of
infection. Therefore, the microbe is exposed to a particular
shape of the concentration-time curve. Harry Eagle
performed studies on penicillin and discovered that the
shape of the concentration-time profile was an important
determinant of the efficacy of the antibiotic (Eagle
et al., 1950). This important observation was forgotten
until William Craig and colleagues rediscovered it and
performed systematic studies on several classes of
antibiotics (Craig, 1998, 2007; Vogelman et al., 1988),
initiating the era of antimicrobial pharmacokineticspharmacodynamics
(PK/PD) (Ambrose et al., 2007;
Craig, 1998).
The first basic lesson is based on susceptibility
(MIC or EC 90
) of the organism to the antimicrobial
agent. The response of the microbe to a fixed dose of
antibiotic differs based on susceptibility of the organism.
As an example, vancomycin resistance is said to
be present when MIC >2.0 mg/L. When patients with
MRSA infection were treated with vancomycin, the
success rate was 61% in patients infected with isolates
that had an MIC of 0.5 mg/L, 28% for MIC of 1.0 mg/L,
and only 11% for MIC of 2.0 mg/L (Moise-Broder et al.,
2004). As expected, outcomes were poorer with
increasing MIC. This is not a surprise because the
IC 50
shifts to the right with decrease in susceptibility
(Figure 48–3A). The important point is that in determining
therapeutic outcomes, it is important to index
drug exposure to MIC.
Second, dose itself is a poor measure of drug
exposure, given between-patient and within-patient
pharmacokinetic variability. Rather, actual drug concentration
achieved at site of infection is the important
measure. The shape of the relationship between nonprotein-bound
antibiotic concentration (exposure) versus
microbial kill is the inhibitory sigmoid E max
curve
of Figure 48–1 (Craig, 2007; Craig and Kunin, 1976).
Maximal kill is actually on an asymptote, so that nonprotein-bound
antimicrobial exposures associated with
80-90% of E max
are termed “optimal” concentrations.
The optimal dose of the antibiotic for a patient is the
dose that achieves IC 80
to IC 90
exposures at the site of
infection. This exposure can often be easily identified in
preclinical models and directly applied to patient populations,
provided interspecies differences in protein
binding and pharmacokinetic variability are taken into
account.
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CHAPTER 48
GENERAL PRINCIPLES OF ANTIMICROBIAL THERAPY