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

1366
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Organism burden (log10 CFU/ml)
8
6
4
2
0
0
EC 50
[Antimicrobial]
Figure 48–1. Inhibitory sigmoid E max
curve.
CFU, colony-forming units.
Figure 48–1), where E is effect as measured by microbial
burden.
E = E con
− E max
× [IC] H /([IC] H + [IC 50
] H )
(Equation 48–1)
THE PHARMACOKINETIC BASIS
OF ANTIMICROBIAL THERAPY
E max
Penetration of Antimicrobial Agents into Anatomic
Compartments. In many infections, the pathogen causes
disease not in the whole body, but in specific organs.
Moreover, only specific pathological compartments
may be infected within these organs. Antibiotics are
often administered far away from these sites of infection.
To be effective, each antibiotic has to get to where
the pathogen is, to penetrate into the infected compartment.
Therefore, in choosing an antimicrobial agent for
therapy, a crucial consideration is whether the drug can
penetrate to the site of infection.
For example, the antibiotic levofloxacin achieves
skin tissue/plasma peak concentration ratio of 1.4,
epithelial lining fluid to plasma ratio of 2.8, and urine
to plasma ratios of 67 (Chow et al., 2002; Conte et al.,
2006; Wagenlehner et al., 2006). In a clinical trial on
patients treated with levofloxacin, the two most important
factors in predicting successful clinical and microbiological
outcomes in the patients were a sufficient
maximal plasma concentration of the drug (C Pmax
),
which needed to achieve a level of 12 times the minimum
inhibitory concentration (MIC) (C Pmax
/MIC ≥12),
and the site of infection. The failure rate of therapy was
0% in patients with urinary tract infections, 3% in
patients with pulmonary infections, and 16% in patients
with skin and soft tissue infections (Preston et al., 1998).
Clearly, the poorer the penetration into the anatomical
compartment, the higher the likelihood of failure.
The penetration of a drug into an anatomical compartment
depends on the physical barriers that the molecule
must traverse, the chemical properties of the drug,
and the presence of multidrug transporters. The physical
barriers are usually due to layers of epithelial and
endothelial cells, and the type of junctions formed
between these cells. Penetration across this physical
barrier generally correlates with the octanol-water partition
coefficient of the antimicrobial agent, a measure
of the hydrophilicity or hydrophobicity of a chemical.
Hydrophobic molecules get concentrated in the bi-lipid
cell membrane bi-layer, whereas hydrophilic molecules
tend to concentrate in the blood, the cytosol, and other
aqueous compartments. Thus, the higher the octanolwater
partition coefficient (P), the greater the likelihood
that an antimicrobial agent will cross physical barriers
erected by layers of cells. Conversely, the more charged
a molecule is, and the larger it is, the poorer its penetration
across membranes and other physical barriers
(see Figure 2–3).
Another barrier is due to membrane transporters,
which actively export drugs from the cellular or tissue
compartment back into the blood (Chapter 5). A wellknown
example is the P-glycoprotein. Although the
octanol-water partition coefficient would favor
lipophilic molecules to transverse across cell barriers,
P-glycoprotein exports structurally unrelated amphiphilic
and lipophilic molecules of 3-4 kDa, reducing their
effective penetration. Examples of antimicrobial agents
that are P-glycoprotein substrates include HIV protease
inhibitors, the antiparasitic agent ivermectin, the antibacterial
agent telithromycin, and the antifungal agent
itraconazole.
The central nervous system (CNS) is guarded by
the blood-brain barrier. The movement of antibiotics
across the blood-brain barrier is restricted by tight junctions
that connect endothelial cells of cerebral microvessels
to one another in the brain parenchyma, as well
as by protein transporters (Miller et al., 2008).
Antimicrobial agents that are polar at physiological pH
generally penetrate poorly; some, such as penicillin G,
are actively transported out of the cerebrospinal fluid
(CSF) and achieve CSF concentrations of only 0.5-5%
of that achieved in plasma. However, the integrity of
the blood-brain barrier is diminished during active bacterial
infection; tight junctions in cerebral capillaries
open, leading to a marked increase in the penetration