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

1
500 1000 1500 2000 2300Base pairs
SSXN
1
PBP2B
679 Amino acids
Czech Republic (1987)
South Africa (1978)
United States (1983)
Papua New Guinea (1972)
Spain (1984)
Kenya (1992)
Papua New Guinea (1970)
= Streptococcus pneumoniae
14%
= Streptococcus ?
21%
= Streptococcus ?
20%
= Streptococcus mitis
Figure 53–4. Mosaic penicillin-binding protein (PBP) 2B genes
in penicillin-resistant pneumococci. The divergent regions in the
PBP2B genes of seven resistant pneumococci from different
countries are shown. These regions have been introduced from
at least three sources, one of which appears to be Streptococcus
mitis. The approximate percent sequence divergence of the divergent
regions from the PBP2B genes of susceptible pneumococci
is shown. (From Spratt BG. Resistance to antibiotics mediated
by target alterations. Science, 1994, 264:388–393. Reprinted
with permission from AAAS.)
Bacteria also can destroy β-lactam antibiotics enzymatically.
β-Lactamases are capable of inactivating certain of these antibiotics
and may be present in large quantities (Figures 53–1 and 53–3).
Different microorganisms elaborate a number of distinct β-lactamases,
although most bacteria produce only one form of the enzyme. The
substrate specificities of some of these enzymes are relatively narrow,
and these often are described as either penicillinases or cephalosporinases.
Other “extended-spectrum” enzymes are less discriminant and
Accessory
protein
Channel
Efflux
transporter
Amphiphillic
drug
Outer
membrane
Periplasm
Cytoplasmic
membrane
Figure 53–5. Antibiotic efflux pumps of gram-negative bacteria.
Multidrug efflux pumps traverse both the inner and outer membranes
of gram-negative bacteria. The pumps are composed of a
minimum of three proteins and are energized by the proton
motive force. Increased expression of these pumps is an important
cause of antibiotic resistance. (Reprinted with permission
from the University of Chicago Press. Nikaido H. Antibiotic
resistance caused by gram-negative multidrug efflux pumps. Clin
Infect Dis, 1998, 27(suppl I):S32–S41. © 1998 by the Infectious
Diseases Society of America. All rights reserved.)
can hydrolyze a variety of β-lactam antibiotics. β-Lactamases are
grouped into four classes: A through D. Class A β-lactamases include
the extended-spectrum β-lactamases (ESBLs) that degrade penicillins,
some cephalosporins, and, in some instances, carbapenems. Perhaps
most worrisome of the class A enzymes is the KPC carbapenemase
that is rapidly emerging in the Enterobacteriaceae. This enzyme confers
resistance to carbapenems, penicillins, and all of the extendedspectrum
cephalosporins (Jones et al., 2008). Some class A and D
enzymes are inhibited by the commercially available β-lactamase
inhibitors, such as clavulanate and tazobactam. Class B β-lactamases
are Zn 2+ -dependent enzymes that destroy all β-lactams except aztreonam,
whereas class C β-lactamases are active against cephalosporins.
Class D includes cloxacillin-degrading enzymes (Bush, 2001; Jacoby
and Munoz-Price, 2005; Walsh, 2008).
In general, gram-positive bacteria produce and secrete a large
amount of β-lactamase (Figure 53–3A). Most of these enzymes are
penicillinases. The information for staphylococcal penicillinase is
encoded in a plasmid, and this may be transferred by bacteriophage
to other bacteria. The enzyme is inducible by substrates, and 1% of
the dry weight of the bacterium can be penicillinase. In gram-negative
bacteria, β-lactamases are found in relatively small amounts but
are located in the periplasmic space between the inner and outer cell
membranes (Figure 53–3A). Because the enzymes of cell wall synthesis
are on the outer surface of the inner membrane, these β-lactamases
are strategically located for maximal protection of the
microbe. β-Lactamases of gram-negative bacteria are encoded either
in chromosomes or in plasmids, and they may be constitutive or
inducible. The plasmids can be transferred between bacteria by conjugation.
These enzymes can hydrolyze penicillins, cephalosporins,
or both (Bush, 2001; Jacoby and Munoz-Price, 2005; Walsh, 2008).
However, there is an inconsistent correlation between the susceptibility
of an antibiotic to inactivation by β-lactamase and the ability
of that antibiotic to kill the microorganism.
Other Factors That Influence the Activity of β-Lactam Antibiotics.
Microorganisms adhering to implanted prosthetic devices (e.g.,
catheters, artificial joints, prosthetic heart valves, etc.) produce
biofilms. Bacteria in biofilms produce extracellular polysaccharides
and, in part owing to decreased growth rates, are much less sensitive
to antibiotic therapy (Donlan, 2001). The density of the bacterial population
and the age of an infection influence the activity of β-lactam
antibiotics. The drugs may be several thousand times more potent
when tested against small bacterial inocula than when tested against a
dense culture. Many factors are involved. Among these are the greater
number of relatively resistant microorganisms in a large population,
the amount of β-lactamase produced, and the phase of growth of the
culture. The clinical significance of this effect of inoculum size is
uncertain. The intensity and duration of penicillin therapy needed to
abort or cure experimental infections in animals increase with the
duration of the infection. The primary reason is that the bacteria are no
longer multiplying as rapidly as they do in a fresh infection. These
antibiotics are most active against bacteria in the logarithmic phase of
growth and have little effect on microorganisms in the stationary
phase, when there is no need to synthesize components of the cell wall.
The presence of proteins or other constituents of pus, low
pH, or low O 2
tension does not appreciably decrease the ability of
β-lactam antibiotics to kill bacteria. However, bacteria that survive
inside viable cells of the host generally are protected from the action
of the β-lactam antibiotics.
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CHAPTER 53
PENICILLINS, CEPHALOSPORINS, AND OTHER β-LACTAM ANTIBIOTICS