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

of even polar drugs (Quagliarello and Scheld, 1997).
As the infection is eradicated and the inflammatory
reaction subsides, penetration diminishes to normal.
Because this may occur while viable microorganisms
persist in the CSF, drug dosage should not be reduced
as the patient improves.
Drug penetration into the eye is especially pertinent in the
treatment of endophthalmitis (infection and inflammation of ocular
cavity and surrounding tissue) and infections of the retina. There is
generally poor penetration of drug from plasma to this compartment,
so that the standard therapy is direct instillation of antibiotics into the
ocular cavity. In fungal endophthalmitis, however, systemic administration
of amphotericin B and triazole is recommended (Pappas et
al., 2009) because these agents, especially the triazoles, have sufficient
penetration ratios into the vitreous space.
In patients with pulmonary infections such as pneumonia,
drugs must penetrate into the epithelial lining fluid, where the
pathogens are found. Among antibacterial agents, many β-lactam
antibiotics have poor epithelial lining fluid-to-plasma ratios (0.1-
0.4:1); macrolides have ratios of 2-40:1, fluoroquinolones have ratios
≥1:1; pyrazinamide has ratios of ~20:1; isoniazid, >1:1; and linezolid,
2.4-4.2:1 (Kiem and Schentag, 2008).
Other important compartments requiring special drug penetration
are endocardial vegetations and the biofilm formed by bacteria
and fungi on prosthetic devices such as artificial heart valves,
long-dwelling intravascular catheters, artificial hips, and devices for
internal fixation of bone fractures. Bacterial and fungal biofilms are
colonies of slowly growing cells that are enclosed within an exopolymer
matrix. The exopolysaccharide is negatively charged, which
restricts positively charged antibiotics from reaching their target.
This physical barrier restricts the diffusion of antimicrobial molecules
and sometimes binds them (Lewis, 2001). To be effective
against infections in these compartments, antibiotics have to be able
to penetrate the biofilm and endothelial barriers.
Pharmacokinetic Compartments. Once an antibiotic
has penetrated to the site of infection, it may be subjected
to processes of elimination and distribution that
differ from those in the blood. These sites where the
concentration-time profiles differ from each other are
considered separate pharmacokinetic compartments,
thus, the human body is viewed as multicompartmental.
The concentration of antibiotic within each compartment
is assumed to be homogeneous. If two
compartments have similar concentration profiles, then
they may be considered a single compartment.
Antibiotic concentrations can be analyzed using any
number of such compartments, with the best number of
compartments chosen based on the least number of
compartments that can adequately explain the findings.
The model is also defined as open or not open; an open
model is one in which the drug is eliminated out of the
body from the compartment (e.g., kidneys). The order
of the process must also be specified (Chapter 2): a
first-order process is directly correlated to concentration
of drug D, or [D] 1 , as opposed to zero order, which is
independent of [D] and reflects a process that is saturated
at ambient levels of D (such as the elimination of
ethanol; Chapter 23).
Suppose a patient has pneumonia with the pathogen in the
lung epithelial lining fluid (ELF). The patient ingests an antibiotic
that is absorbed via the GI tract (g) into blood or central compartment
(compartment 1), as a first-order input. In this process, the
transfer constant from the GI tract to central compartment is termed
the absorption constant and is designated k a
. The antibiotic in the
central compartment is then delivered to the lungs where it penetrates
into the ELF (compartment 2). However, it also penetrates into
other tissues of the body peripheral to the site of infection, termed the
peripheral compartment (compartment 3). Thus, we have four compartments
(including g), each with its own concentration-time profile,
as shown in Figure 48–2. The penetration of drug from
compartment 1 to 2 is based on the penetration factors discussed earlier
and is defined by the transfer constant k 12
. However, the drug
also redistributes from compartment 2 back to 1, defined by transfer
constant k 21
. A similar process between the blood and peripheral tissues
leads to transfer constants k 13
and k 31
. The drug may also be
lost from the body (i.e., open system) via the lungs and other
peripheral tissues (e.g., kidneys or liver) at a rate proportional to the
concentration.
Antibiotic concentrations within each compartment change
with time. The changes in the amount of antibiotic in each compartment
with time are described using standard differential equations
(Gibaldi and Perrier, 1975). If X is the amount of antibiotic in a compartment,
SCL the drug clearance, and V c
the volume of central
compartment, then equations for absorption compartment
(Equation 48–2), central compartment (Equation 48–3), site of
infection or compartment 2 (Equation 48–4), and peripheral compartment
(Equation 48–5) are as follows:
dX g
/dt =−K a
• X g
(Equation 48–2)
dX 1
/dt = K a
• X g
− [(SCL/V c
) + K 12
+ K 13
] • X 1
+ K 21
• X 2
+ K 31
• X 3
(Equation 48–3)
dX 2
/dt = K 12
• X 1
− K 21
• X 2
(Equation 48–4)
dX 3
/dt = K 13
• X 3
− K 31
• X 3
(Equation 48–5)
Such models have been used in conjunction with population
pharmacokinetics to describe and model a plethora of antimicrobials
used to treat bacteria, fungi, viruses, and parasites (Hope et al., 2007;
Tarning et al., 2008; Wilkins et al., 2008; Zhou et al., 1999).
In recent years, semi-mechanistic models have related
pathogen response to drug concentrations within these pharmacokinetic
compartments in preclinical disease models and in patients
(Gumbo et al., 2006; Jumbe et al., 2003; Neumann et al., 1998;
Pukrittayakamee et al., 2003; Talal et al., 2006). Pathogens
within one or more of these compartments are exposed to dynamic
drug concentrations within the compartments, as described by
Equations 48–2 to 48–5. A pathogen population (N) may be described
as consisting of at least two subpopulations, drug-susceptible (N S
)
and drug-resistant (N R
) organisms. The organisms are either killed,
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CHAPTER 48
GENERAL PRINCIPLES OF ANTIMICROBIAL THERAPY