Kathleen A. Woodin and Susan H. Morrison 1994;15;440-447 DOI: 10.1542/pir.15-11-440

BACK TO BASICS: Antibiotics: Mechanisms of Action
Kathleen A. Woodin and Susan H. Morrison
Pediatr. Rev. 1994;15;440-447
DOI: 10.1542/pir.15-11-440
The online version of this article, along with updated information and services, is located on
the World Wide Web at:
http://pedsinreview.aappublications.org
Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and
trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove
Village, Illinois, 60007. Copyright © 1994 by the American Academy of Pediatrics. All rights reserved.
Print ISSN: 0191-9601. Online ISSN: 1526-3347.
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Antibiotics:
Kathleen
A. Woodin,
Mechanisms
MD* and Susan
of Action
H. Morrison,
MDt
Medical
practice
rests on the foundation
of science.
Clinicians
are constantly
making
practical
decisions
and dealing
with immediate
situations
that demand
solutions.
Time should
be taken to focus
on those scientific
principles
that
underlie
our diagnostic
and therapeutic
maneuvers.
This section
of Pediatrics
in Review
presents
selected
topics
that
are relevant
to practice
from the areas of physiology,
pharmacology,
biochemistry,
and other disciplines;
clarification
of these will augment
the pediatrician
‘s understanding
of clinical
procedures.
Introduction
Unlike
physicians
practicing
in the
1940s,
who had only sulfonamides
and penicillin
to treat infections,
practitioners
now choose
from a
broad (and sometimes
overwhelming)
number
of antibiotics.
However,
trends
in emerging
antimicrobial
resistance
may force us to take a giant
step backward
to that frightening
situation
of the past of having
bacteria
that are essentially
“untreatable”
by
any of our available
antibiotics.
This article
is an overview
of some
of the microbiology,
pharmacology,
and physiology
critical
to the rational
use of antibiotics
in today’s
practice.
It summarizes
the basic mechanisms
of action of some commonly
used
antibiotics
and briefly
discusses
the
emergence
of resistance
to several
common
pathogens.
Structures
Important
of Bacteria
to Antibiotic
Action
The outermost
component
of most
bacteria
is the cell wall, a multilayered structure
located
external
to the
cytoplasmic
membrane.
The cell wall
is composed
of an inner layer of peptidoglycan,
a complex
interwoven
lattice of linear sugars
(glycan)
that are
440
cross-linked
tidoglycan
by which
acteristic
by peptide
chains.
Pepprovides
the rigid support
the cell maintains
its charshape.
Gram-positive
and Gram-negative
bacteria
differ in their cell wall structures (Figure).
In Gram-positive
organisms,
the peptidoglycan
layer is
a thick (15 to 80 nm) multilayer
and
may have a thin layer of teichoic
acid outside
the peptidoglycan.
In
contrast,
Gram-negative
organisms
have a thin (2 nm) single layer of
peptidoglycan
covered
by a complex
outer membrane
layer composed
of
lipopolysaccharides,
lipoproteins,
and
phospholipids.
The outer membrane
of Gram-negative
bacteria
contains
porn
proteins
that act as channels
to
transport
small molecules
such as
sugars,
metals,
vitamins,
and antibiotics into the bacterial
cell.
The cytoplasm
of bacteria
contains
an inner nucleoid
region
composed
of
single-stranded
circular
DNA and
matrix
that contains
ribosomes,
nutrient granules,
metabolites,
and plasmids. Plasmids
are double-stranded
circular
DNA molecules
that can replicate independently
of the bacterial
chromosomes.
Most plasmids
are extrachromosomal,
but some are integrated
into the bacterial
chromosome.
Pediatrics
Plasmids
occur
in both Gram-negative and Gram-positive
organisms
and are an important
source
of
genetic
information
that can convey
resistance
to various
antibiotics.
Selective
Toxicity
An ideal antimicrobial
agent would
exhibit
selective
toxicity;
that is, the
drug would
be harmful
to the infecting microorganism
without
harming
the host. Because
peptidoglycan
is
present
in bacteria
but not in human
cells, it is an excellent
target for antibiotics.
Similarly,
antibiotics
that affect protein
synthesis
take advantage
of the differences
in size and chemical composition
of ribosomes
from
bacteria
and eukaryotic
organisms
(ie,
those having
a true nucleus
surrounded
by a nuclear
membrane
and
multiple
chromosomes,
as in human
cells).
Other metabolic
steps that occur in bacteria
but not humans
(eg,
synthesis
of folic acid for nucleotides) also can be inhibited
selectively by antibiotics.
BactericIdal
Bacterlostatlc
Antibiotics
Versus
Properties
A favorable
therapeutic
lowing
the administration
in Review
VoL
15
No.
of
outcome
folof a spe11
November
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1994
I
cific antibiotic
depends
on multiple
factors,
including
those related
to the
bacteria
(eg, resistance
mechanisms),
the antibiotic
(eg, mechanism
of action, ability
to penetrate
to the infected
site, and spectrum
of activity),
and the host defenses
(eg, phagocytosis, opsonization,
complement
production).
When host defenses
are
maximally
effective,
the contribution
of the antibiotic
may be less important. For example,
a bacteriostatic
agent (eg, chloramphenicol,
erythromycin,
clindamycin,
tetracycline)
that
slows or inhibits
protein
synthesis
may be adequate
when combined
with the host’s ability
to opsonize
and phagocytize
bacteria.
In contrast,
a patient
whose
host defenses
are impaired
may require
a bactericidal
agent (eg, penicillin,
cephalosporin,
aminoglycoside)
that actually
will kill
or lyse the bacteria.
Bactericidal
agents
(Table
1) generally
are used to
treat bacterial
endocarditis,
meningitis, and osteomyelitis
as well as any
bacterial
infections
in neutropenic
patients.
Antibiotic
Susceptibility
If the concentration
of an antibiotic
required
to inhibit
or kill the organism can be achieved
safely
in the affected
tissue or fluid, a microorganism
is considered
sensitive
to a
particular
antibiotic.
However,
if the
concentration
required
is greater
than
what can be achieved
safely,
the microorganism
is considered
to be resistant to that antibiotic.
Most in vitro
sensitivity
tests are standardized
on
the basis of drug concentrations
that
can be achieved
safely
in plasma
and
may not take into account
increased
drug concentrations
that may occur at
specific
sites (eg, bladder)
or any local conditions
that may affect the activity of the antimicrobial
agent.
Mechanisms
Antibiotics
of Action
of
For many antibiotics,
the mechanism
of action
is not understood
fully.
However,
it is known
that antibiotics
can act in the following
ways:
1) inhibit cell wall synthesis,
2) alter the
permeability
of the cell membrane,
3) inhibit
protein
synthesis,
and
4) inhibit
nucleic
acid synthesis
(Table
1).
Pediatrics
in Review
VoL
15
No.
Ii
November
WEAKEN
CELL WALL BY
INHIBITING
CROSS-LINKING
PEPTIDOGLYCAN
Penicillins
and
OF
Cephalosporins
Penicillins
and cephalosporins
(betalactam
antibiotics)
are among
the
most widely
prescribed
antibiotics
because of their safety profiles.
The basic structure
of penicillin
consists
of
a five-member
thiazolidine
ring connected
to a beta-lactam
ring to which
a side chain is attached.
In contrast,
the cephalosporins
have a six-membered hydrothiazine
ring connected
to
the beta-lactam
ring. An intact betalactam
ring structure
is an essential
requirement
for the biologic
and antibacterial
activity
of both penicillins
and cephalosporins.
New derivatives
of the basic penicillin
nuclei
continue
to be produced;
each has unique
advantages.
Modification
of the various
side chains
on these structures
affects
the specific
antibacterial
spectrum
as
well as the pharmacokinetic
profile
of
these drugs.
Beta-lactam
antibiotics
kill susceptible bacteria
by interfering
with cell
wall synthesis.
They are bactericidal,
but only kill organisms
undergoing
active
cell wall synthesis.
The biosynthesis
of peptidoglycan
in the cell
wall occurs
in three stages
and involves
about 30 different
enzymes.
Beta-lactam
antibiotics
inhibit
transpeptidases,
the enzymes
that catalyze
the final cross-linking
step of peptidoglycan
synthesis.
There
also are receptors
called
penicillin
binding
proteins
(PBPs)
in
the bacterial
cell membrane
and cell
wall for the beta-lactam
antibiotics.
Each bacterium
has several
types of
1994
PBPs that vary in their affinity
for
different
penicillins
and cephalosporins. Some PBPs are transpeptidases
responsible
for peptidoglycan
crosslinking
and necessary
for bacterial
shape;
the function
of others
is
unknown.
Inhibition
of PBPs causes
abnormal
cell shape,
division,
and
eventual
lysis. Altering
the PBPs is
one mechanism
by which
bacteria
can develop
resistance
to penicillin.
This resistance
may be intrinsic
because of structural
differences
in
PBPs or a previously
sensitive
strain
may acquire
resistance
following
a
mutation
of PBPs.
Resistance
of
Streptococcus
pneumoniae
to penicillin and cephalosporins,
which
has
been reported
around
the world
as
well as in the United
States,
is due to
alterations
in PBPs (Table
2).
Activation
of cell wall autolytic
enzymes
(ie, autolysins)
is another
factor
that is important
in the degradation
of the cell wall. The relationship between
the inhibition
of PBP
activity
and the activation
of autolysis is unclear
and very complex.
Tolerance
to penicillin
occurs
when the
organism
is inhibited
but not killed
by an antibiotic
that usually
is bactericidal.
For example,
the growth
of
certain
tolerant
strains
of Staphylococcus
aureus
can be arrested
by
beta-lactam
antibiotics,
but autolytic
enzymes
are not activated.
Production
of beta-lactamases,
enzymes
that can cleave
the beta-lactam
ring, is an important
mechanism
for
the inactivation
of beta-lactam
antibiotics and development
of resistance
by many bacteria
(eg, S aureus,
Neisseria gonorrhoeae,
Pseudomonas
sp,
Bacteroides
fragilis,
and some enteric
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441
IT.
I
MECHANISM
DRUGS
Weaken
bacterial
cell wall and cause cell death
. Inhibit
cross-linking
of peptidoglycan
. Activate
autolytic
enzymes
(ie, autolysins)
. Inhibit
other steps in peptidoglycan
synthesis
Penicillins,
Increase
cell membrane
permeability
. Cause
leakage
of cell contents
Inhibit
protein
synthesis
. Bind to 505 ribosome
. Bind
to 305
subunit
ribosome
subunit
Inhibit
nucleic
acid synthesis
. Inhibit
nucleotide
synthesis
. Inhibit
DNA-dependent
RNA polymerase
. Inhibit
DNA supercoiling
and DNA synthesis
*Note:
Bacteriostatic
agents
ORGANISM
Streptococcus
Enterococcus
Enterococcus
Neisseria
442
pneumoniae
fecalis
faecium
gonorrhoeae
may
be bactericidal
against
some
cephalosporins
Bactericidal
Vancomycin
Bactericidal
Polymyxin
NA
Chloramphenicol
Erythromycin
Clarithromycin
Clindamycin
Aminoglycosides
Tetracyclines
Bacteriostatic
Bacteriostatic
Bacteriostatic
Bacteriostatic
Bactericidal
Bacteriostatic
Sulfonamides,
Rifampin
Quinolones
organisms
ACT1ON
at high
trimethoprim
Bacteriostatic
Bactericidal
Bactericidal
concentrations.
DRUGS FOR WHICH RESISTANCE
HAS BEEN REPORTED
RECOMMENDATiONS
#{149}
Penicillin
Intermediate-level
resistance
is
increasing
High-level
resistance
has been
reported
in various
areas
worldwide
and is increasing
in the United
States
Clusters
of cases may occur (eg,
childcare
contacts)
#{149}
Cephalosporins
Treatment
failures
have prompted
susceptibility
testing
#{149}
Conduct
oxacillin
disk susceptibility
all isolates
#{149}
If resistant,
check MICs to penicillin,
cefotaxime,
ceftriaxone,
vancomyin,
or others
#{149}
If sensitive,
susceptible
to all betalactams
#{149}
If meningitis,
treat with vancomycin
PLUS
third-generation
cephalosporin
OR chloramphenicol
OR imipenem
pending
susceptibility
testing
on
#{149}
Ampicillin
#{149}
Vancomyin
Resistant
identified
#{149}
If invasive
disease,
check
MICs and
with ampicillin
PLUS
vancomycin
PLUS
aminoglycoside
(gentamicin)
pending
susceptibility
testing
treat
strains
have
been
#{149}
Penicillinase-producing
strains
common
#{149}
Tetracycline
High-level
plasmid-mediated
resistance
reported
#{149}
Fluoroquinolones
Decreased
susceptibility
reported
#{149}
Penicillin
or doxycycline
are not
recommended
empiric
therapies
#{149}
Monitor
fluoroquinolone
susceptibility
pattern
and clinical
response
#{149}
Third-generation
cephalosporins
(eg,
ceftriaxone)
still seem effective
Pediatrics
in Review
VoL
15
No.
11
November
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1994
I
Gram-negative
bacilli).
The information for producing
beta-lactamases
can be coded
in chromosomes
or on
a plasmid.
The beta-lactamases
can
be constitutive
(produced
all the
time) or inducible
(only produced
at
certain
times).
In the case of inducible
resistance,
the organism
initially
will be susceptible to a certain
antibiotic,
but after
a short period
of therapy,
the organism will become
resistant
because
of
the beta-lactamases
that have been
induced.
Frequently,
this is signaled
by only limited
improvement
or clinical deterioration
of the patient
after
an initial improvement.
Inducible
beta-lactamase
production
is a particular problem
with some Gramnegative
bacteria
(eg, Pseudomonas,
Enterobacter,
Citrobacter,
Acinetobacter,
Serratia
sp) treated
with
broad-spectrum
cephalosporins.
Beta-lactamase
production
by bacteria can be inhibited
by the addition
of certain
chemical
structures
that are
similar
in structure
to penicillin
(eg,
clavulanic
acid, sulbactam).
The inhibitors
bind strongly
to the beta-lactamases
and prevent
the subsequent
inactivation
of the penicillin
nucleus.
Penicillins
have good activity
against
Gram-positive
bacteria
and
oral anaerobes
and variable
activity
against
Gram-negative
bacilli.
They
are the treatment
of choice
for syphilis, leptospirosis,
or Listeria
infections. Penicillins
generally
are
classified
according
to their spectrum
of activity
as determined
by changes
in their side chains
relative
to penicillin: penicillinase-resistant
penicillin
(eg, methicillin,
nafcillin,
oxacillin,
cloxacillin,
and dicloxacillin);
aminopenicillins
(ampicillin,
amoxicillin);
antipseudomonal
penicillins
(eg, carbenicillin,
ticarcillin,
and azlocillin);
and extended-spectrum
penicillins
(eg, mezlocillin,
piperacillin).
The cephalosporins
are divided
into “generations”
based on their antimicrobial
activity.
First-generation
cephalosporins
(eg, cephalexin,
cefadroxil,
and cefazolin)
have good activity against
Gram-positive
bacteria,
including
penicillinase-producing
S
aureus,
group
A beta-hemolytic
streptococci,
group
B streptococci,
and S pneumoniae,
and modest
activity against
some Gram-negative
organisms.
The second-generation
Pediatrics
in Review
VoL
iS
No.
ii
November
cephalosporins
(eg, cefaclor,
cefuroxime, cefuroxime
axetil,
cefprozil,
cefamandole,
cefoxitin,
and cefotetan)
retain activity
against
Gram-positive
organisms
but have more activity
against
Gram-negative
organisms,
including
most strains
of Haemophilus
influenzae
and some strains
of enteric
bacteria.
The third-generation
cephalosporins
(eg, cefixime,
cefoperazone,
cefotaxime,
cefpodoxime
proxetil,
ceftazidime,
ceftizoxime,
and ceftriaxone) are more active against
Gramnegative
organisms
(including
Enterobacteriaceae
and beta-lactamaseproducing
strains of H infiuenzae,
Moraxella
catarrhalLi,
and N gonorrhoeae),
but they are less active than
first-generation
cephalosporins
against
Gram-positive
organisms.
Ceftazidime
is active against Pseudomonas
sp and
has superior
central
nervous
system
penetration
compared
with aminoglycosides. Ceftriaxone
has a prolonged
half-life
that allows
for once-a-day
dosing.
None of the cephalosporins
is
effective
against
anaerobes,
enterococci, or L monocytogenes.
Because
of the structural
similarity
between
penicillin
and first- and second-generation
cephalosporins,
patients may manifest
cross-reactivity
when a member
of the other class is
administered.
Immunologic
studies
demonstrate
a 20% cross-reactivity;
more recent
clinical
studies
indicate
a
frequency
as low as 1%. Cross-reactivity between
penicillins
and cephalosporins
generally
occurs
in about
8% of patients
who have a history
of
an allergic
reaction
to penicillin.
Although
side chains
do not seem to be
a factor in allergic
reactions
to penicillins,
they may be important
in
cephalosporin
allergy.
The patient
who is allergic
to cephalosporins
may
have an allergy
to the beta-lactam
ring, the bulky side chain,
or both.
The risk of allergic
reaction
with the
newer
third-generation
cephalosporins
is not known.
WEAKEN
CELL WALL
BY
INHIBITING
PEPFIDOGLYCAN
SYNTHESIS
Vancomycin
Vancomycin
is a complex
and unusual tricyclic
glycopeptide
that inhibits cell synthesis
in sensitive
bacteria
by binding
tightly
to precursor
subunits of the cell wall and preventing
1994
their incorporation
into the growing
peptidoglycan.
The drug is rapidly
bactericidal
for dividing
microorganisms.
Because
vancomycin
may
be only bacteriostatic
for some
enterococci,
an aminoglycoside
is
added
to vancomycin
therapy
in serious
infections
known
to be caused
by this organism
(eg, infective
endocarditis).
Early preparations
of vancomycin
contained
impurities
that probably
contributed
significantly
to the toxicity associated
with its early use; this
no longer
is a problem.
In recent
years,
there has been renewed
interest
in the use of vancomycin
for several
reasons.
First, it is structurally
unrelated to other antibiotics,
so it is useful in the patient
who is allergic
to
penicillin
and cephalosporins.
Second, it is active
primarily
against
Gram-positive
bacteria
and forms
the
mainstay
of therapy
for the treatment
of infections
caused
by methicillinresistant
S aureus
(MRSA),
coagulase-negative
staphylococci
that are
resistant
to other penicillins,
and S
pneumoniae
strains
that are resistant
to penicillin
and cephalosporins
(Table 2). Vancomycin
is an important
antibiotic
for use in immunocompromised
patients
who have evidence
of catheter-related
infections.
Because
oral vancomycin
is absorbed
poorly,
high concentrations
occur
in the stool.
Thus,
it can be
used as a more expensive
alternative
to metronidazole
for the treatment
of
Clostridium
difficile
infections;
metronidazole
is not approved
by the
Food and Drug Administration
for
use in children.
Reports
of vancomycin-resistant
strains
of enterococci
and S aureus
have caused
extreme
concern
in the
medical
community.
Prudent
use of
this drug is essential
to minimize
the
development
of further
resistance.
Measurement
of serum
levels of vancomycin
is recommended
to avoid
potential
ototoxicity
and nephrotoxicity. The incidence
of both toxicities
is increased
when vancomycin
is administered
simultaneously
with an
aminoglycoside.
INCREASE
Polymyxin
CELL
PERMEABILITY
B
Polymyxin
B is a basic
orated
by various
strains
peptide
elabof Bacillus
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443
sp. It is a surface-active
agent contaming
both lipophilic
and lipophobic
groups
within
the molecule
that interact strongly
with phospholipids
and
disrupt
the integrity
of cell membranes.
The permeability
of the bacterial membrane
changes
immediately
after contact
with the drug. Polymyxin
B is prescribed
primarily
for
ophthalmic,
otic, or topical
use in
combination
with a variety
of other
compounds
(eg, bacitracin,
neomycin,
hydrocortisone).
INHIBIT
PROTEIN
SYNTHESIS
Ribosomes
are the site of protein
synthesis
in both bacterial
and eukaryotic cells, but bacterial
and eukaryotic ribosomes
differ in both size
and chemical
composition.
Bacterial
ribosomes
are 70S in size (with 50S
and 30S subunits)
compared
with
80S (with 60S and 40S subunits)
in
eukaryotic
cells. Thus, antibiotics
that
phenicol
usually
is caused
by a
plasmid
acquired
by conjugation.
Other plasmids
may transfer
resistance to multiple
antibiotics
(eg,
chloramphenicol,
tetracycline,
and
beta-lactams).
Once acetylated,
choramphenicol
cannot
attach
to the
bacterial
ribosome.
Use of chloramphenicol
must be
limited
to infections
for which
the
benefits
of the drug outweigh
the risk
of the potential
toxicities
(eg, reversible, dose-related
bone marrow
suppression,
potentially
fatal idiosyncratic aplastic
anemia,
and “gray
baby”
syndrome).
When
antimicrobials that have equivalent
activity
but
are potentially
less toxic are available, they should
be used. In addition,
it is necessary
to monitor
serum
levels when treating
a patient
with chloramphenicol.
Chloramphenicol
is a broad-spectrum antibiotic
that is active
against
Gram-positive
and Gram-negative
bacteria differ in their cell
wall structures;
the peptidoglycan
layer is thick in Gram-positive
organisms
and thin in Gram-negative
organisms.
Resistance
to erythromycin
can occur by at least three plasmid-mediated mechanisms:
failure
of the drug
to penetrate
the cell, modification
of
the target sites on the 505 ribosome
so that the drug fails to bind, and
production
of an esterase
by the bacteria to hydrolyze
the drug.
Gram-positive
bacteria
accumulate
about
100 times more erythromycin
than do Gram-negative
organisms.
Although
erythromycin
generally
is
classified
as a bacteriostatic
agent,
it
can have bactericidal
activity
against
a small number
of rapidly
dividing
bacteria,
especially
in an alkaline
environment.
In patients
who have penicillin
allergy, erythromycin
is an effective
alternative
agent against
Gram-positive
bacteria
such as group
A streptococci, S pneumoniae,
and S aureus.
However,
the emergence
of resistant
strains
must be monitored.
Erythromycin
also has good antimicrobial
activity
against
Bordetella
pertussis,
Borrelia
sp, Campylobacter
sp, Chlamydia
trachomatis,
C pneumoniae
(TWAR
strain),
Mycoplasma
pneumoniae,
and Legionella
pneumophila.
Clanthromycin
affect protein
synthesis
can have a
selective
effect on sensitive
bacteria
without
affecting
human
cells.
Chloramphenicol
Chloramphenicol,
a nitrobenzene
moiety,
penetrates
bacterial
cells by
facilitated
diffusion
and binds reversibly to the bacterial
505 ribosomal
subunit. This drug (like tetracycline’s
effect on the 305 ribosome
subunit)
blocks
the binding
of the aminoacyl
transfer
RNA (tRNA)
to the acceptor
site on the ribosome.
Chloramphenicol has less of an effect on protein
synthesis
in eukaryotic
cells than in
bacterial
cells. Chloramphenicol
is
primarily
a bacteriostatic
agent,
but it
may be bactericidal
to certain
species
(eg, H influenzae,
S pneumoniae,
N
meningiditis).
Mechanisms
of resistance
to chloramphenicol
include
production
of an
acetyltransferase
by the bacteria
that
inactivates
chloramphenicol
and inability
of chloramphenicol
to enter
selected
bacteria.
Resistance
of
Gram-negative
bacteria
to chloram444
many Gram-positive
and -negative
bacteria
as well as against
rickettsiae.
In particular,
it is effective
against
most anaerobic
bacteria,
including
B
fragilis,
and the majority
of Salmonella sp and H influenzae
strains.
It
is a recommended
alternative
therapy
for infections
caused
by Brucella
and
Pasteurella
sp as well as for Rocky
Mountain
spotted
fever. Chloramphenicol
has been effective
in some S
pneumoniae
infections
resistant
to
penicillins
and cephalosporins.
Erythromycin
Erythromycin
has a macrolide
structure composed
of a large 13-carbon
ring to which
two sugars
are attached
by glycosidic
linkages.
Erythromycin
and other macrolides
inhibit
protein
synthesis
by reversibly
binding
to the
50S ribosome
subunit
of sensitive
microorganisms.
It blocks
the translocation
step in protein
synthesis
by
preventing
the release
of the tRNA
from the acceptor
to the donor
site
on the ribosome
after the peptide
bond is formed.
Pediatrics
Clarithromycin,
recently
approved
for
pediatric
use, differs
chemically
from
erythromycin
by having
a methyl
substitution
on the macrolide
ring. Its
spectrum
of activity
is similar
to that
of erythromycin
except
for enhanced
H influenzae
activity
(including
betalactamase-producing
strains),
and its
longer
half-life
allows
for twice-a-day
dosing.
Clarithromycin
and its active
metabolite
penetrate
well into body
fluids and tissues
(eg, lung tissue,
tonsils),
resulting
in intracellular
and
tissue concentrations
that are higher
than serum
concentrations.
Gastrointestinal
side effects
occur
less frequently
in patients
receiving
clarithromycin
(8% to 16%) than in
those treated
with erythromycin
(20%
to 40%).
Because
it reaches
excellent
levels in serum,
alveoli,
macrophages,
and lung tissue,
other important
uses
of clarithromycin
will be in the therapy of Mycobacterium
avium and C
pnewnoniae
(TWAR)
infections.
Clindamycin
Clindamycin,
amino
acid
in Review
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of an
attached
to a sulfur-conVol.
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I
taming
sugar,
has replaced
its parent
drug lincomycin
in clinical
use. Clindamycin
inhibits
protein
synthesis
by
reversibly
binding
to the 505 ribosome subunit
of sensitive
microrganisms. Although
bactericidal
for some
organisms,
clindamycin
generally
is
bacteriostatic.
Mechanisms
of resistance are similar
to those outlined
for
erythromycin.
Clindamycin
is active
against
pneumococci
and group
A streptococci.
It has excellent
activity
against
S aureus
and many anaerobic
bacteria, particularly
B fragilis.
Clindamycin
is an important
antibiotic
for
the treatment
of intra-abdominal
or
pelvic
infections
and as an alternative therapy
in patients
who are allergic
to penicillin.
Bacterial
strains
that are resistant
to clindamycin
generally
are resistant
to erythromycin.
Clindamycin
penetrates
well into
most body fluids,
including
sputum,
pleural
fluid, and bone.
However,
it
should
not be used for central
nervous system
infections
because
of its
poor penetration
into cerebrospinal
fluid.
the inner cytoplasmic
membrane
can
be reduced
by acidic
or anaerobic
conditions,
such as those present
in
an abscess.
Inactivation
by microbial
enzymes
is an important
cause of the
acquired
resistance
to aminoglycosides that occurs
frequently.
The genetic information
for these enzymes
is acquired
primarily
by conjugation
and the transfer
of DNA as plasmids
or resistance
factors.
Such plasmids
are widespread
and may disseminate
resistance
to other antibiotics
simultaneously.
Amikacin
may be less vulnerable
to these inactivating
enzymes
than kanamycin,
gentimicin,
and tobramycin
because
of protective
molecular
side chains.
The antibacterial
activity
of aminoglycosides
is directed
primarily
against
aerobic
Gram-negative
bacilli;
there is little activity
against
anaerobes or Gram-positive
bacteria.
Streptomycin
has been used in the
In patients who have penicillin
effective alternative
agent.
outer membrane
of bacteria.
Then it
is transported
into the inner cytoplasmic membranes
where
it is bound
mainly
to the 30S subunits
of the
bacterial
ribosomes.
The tetracyclines
inhibit
protein
synthesis
by blocking
aminoacyl
tRNA
from entering
the
acceptor
site on the mRNA
ribosome
complex.
Tetracycline’s
selective
action on bacterial
cells is based
on its
greatly
increased
uptake
in susceptible bacterial
cells compared
with
human
cells; the host cells lack the
active
transport
system
present
in
bacteria.
Resistance
to the tetracyclines
frequently
is mediated
by plasmids
and
is an inducible
trait; that is, the bacteria become
resistant
following
exposure
to the drug. A number
of
transferable
resistance
determinants
for tetracycline
have been identified.
Microrganisms
that develop
resistance to one tetracycline
usually
are
allergy,
erythromycin
is an
Aminoglycosides
The aminoglycosides
(eg, amikacin,
gentamicin,
tobramycin,
and streptomycin)
contain
amino
sugars
linked
to an aminocyclitol
ring by glycosidic bonds.
Aminoglycosides
diffuse
through
channels
formed
by porin
proteins
in the outer membrane
of
Gram-negative
bacteria
and into the
periplasmic
space (Figure).
There the
aminoglycosides
bind irreversibly
to
polysomes,
especially
the 305 ribosomal subunits,
and prevent
protein
synthesis
by inhibiting
the ‘initiation
complex.”
In addition,
aminoglycosides cause misreading
of the messenger
RNA (mRNA)
template,
which
results
in the incorporation
of
incorrect
amino
acids into the growing protein
chain.
As a result,
the
membrane
is damaged
and the bacteria die. Unlike
the other inhibitors
of
microbial
protein
synthesis,
the aminoglycosides
are bactericidal
rather
than bacteriostatic.
Bacteria
may be resistant
to the
antimicrobial
activity
of aminoglycosides if the drug fails to penetrate
the
cell, has a low affinity
for the bacterial ribosome,
or is inactivated
by
microbial
enzymes.
Transport
across
‘
Pediatrics
in Review
VoL
15
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ii
November
multiple
drug therapy
of resistant
pulmonary
tuberculosis
or disseminated mycobacterial
disease.
Gentamicin has been used in combination
with other antibiotics
for its synergistic effects
against
certain
bacteria
(eg,
with penicillin
against
enterococci,
with nafcillin
against
S aureus,
with
penicillin
against
group
B streptococci, with ampicillin
against
L monocytogenes,
and with other drugs
effective
against
Pseudomonas
sp).
The clinical
usefulness
of aminoglycosides
is limited
by the potential
for
ototoxicity
and nephrotoxicity,
poor
central
nervous
system
penetration,
and the need for monitoring
serum
levels.
Tetracycline
The structure
of tetracycline
consists
of four cyclic
rings with different
substituents
in three regions;
the latter substitutions
result in different
pharmacologic
properties
but similar
antibacterial
activity.
Initially,
the tetracycline
moiety
passively
diffuses
through
the porn
proteins
in the
1994
resistant
to the congeners
as well.
High-level
plasmid
resistance
to tetracycline
has increased
nationally
among
strains
of N gonorrhoeae;
consequently,
monotherapy
with tetracycline
or doxycycline
no longer
is
recommended
to treat a patient
who
has both gonorrhea
and chiamydial
infections
(Table
2).
The tetracyclines
have bacteriostatic activity
against
a variety
of
Gram-positive
and Gram-negative
bacteria.
Tetracyclines
are a recommended
treatment
for early Lyme
disease,
Rocky
Mountain
spotted
fever,
and infections
caused
by M
pneumoniae,
C trachomatis
(including pelvic
inflammatory
disease),
and
C pneumoniae
(TWAR
strain).
Because
of its increased
lipophilic
properties,
doxycycline
attains
higher
central
nervous
system
concentrations
than other tetracyclines,
which
may
be important
in the treatment
of early
Lyme disease.
Tetracyclines
are not
given routinely
to children
younger
than 9 years of age because
of toxicity to teeth and bones.
However,
cx-
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445
I
I
ceptions
younger
Mountain
have been made to treat
children
who have Rocky
spotted
fever.
INHIBIT
NUCLEIC
SYNTHESIS
ACID
Sulfonamides
Sulfonamide
is a generic
name for
the derivatives
of para-aminobenzenesulfonamide.
Sulfonamides
are structural analogs
and competitive
inhibitors of the bacterial
enzyme
dihydropteroate
synthase,
which
is responsible
for incorporating
para-aminobenzoic
acid (PABA)
into dihydropteroic
acid, the precursor
of folic acid. This
results
in a decreased
pool of bacterial nucleotides,
which
are the building blocks
for DNA synthesis.
Mammalian
cells are not affected
by
this mechanism
because
they require
preformed
folic acid from their diet.
disrupted
synergistically
and less resistance
develops.
TMP-SMZ
is used
widely
for the treatment
of urinary
tract infections,
respiratory
infections,
sinusitus,
otitis media,
and gastrointestinal
infections
(eg, salmonellosis,
shigellosis,
traveler’s
diarrhea).
TMPSMZ also is the drug of choice
for
the treatment
and prophylaxis
of
Pneumocystis
carinii
infections.
Rifampin
Rifampin
inhibits
DNA-dependent
RNA polymerase
at the B subunit
of
this enzyme,
which
prevents
chain initiation
but not elongation
in RNA
synthesis.
Rifampin
is bactericidal
for
both intracellular
and extracellular
microorganisms.
Resistant
strains
of
bacteria
have altered
RNA polymerase that is not inhibited
by rifampin.
Microorganisms
may develop
resistance to rifampin
rapidly
in vitro as a
The clinical usefulness of aminoglycosides
is limited by the
potential for ototoxicity
and nephrotoxicity,
poor central nervous
system penetration,
and the need for monitoring
serum levels.
Sulfonamides
are bacteriostatic
agents;
thus, the final eradication
of
the infection
depends
on the cellular
and humoral
defense
mechanisms
of
the host.
Sulfonamides
have a wide range of
antimicrobial
activity
against
Grampositive
and Gram-negative
bacteria.
They were the first effective
chemotherapeutic
agents
used to cure bacterial diseases
(eg, puerperal
sepsis and
meningococcal
infections).
Sulfonamides frequently
are used as chemoprophylaxis
and also are recommended
for the treatment
of Toxoplasma
infections.
Tnmethoprim
Trimethoprim,
an antimetabolite
that
affects
folic acid synthesis,
is a
highly
selective
inhibitor
of dihydrofolate reductase
in lower organisms.
It prevents
the reduction
of dihydrofolate to tetrahydrofolate,
another
critical
precursor
in purine
synthesis.
By combining
trimethoprim
with sulfamethoxazole
(TMP-SMZ),
two sequential
steps of purine
synthesis
are
446
one-step
mutation;
this also occurs
in
vivo. For this reason,
rifampin
should
not be administered
alone,
except
for
short-term
chemoprophylaxis
(eg, infections
caused
by N meningiditis
or
H influenzae
type b). Rifampin
is
used in combination
with other
agents
to treat tuberculosis
and persistent
group A streptococcal
or
staphylococcal
infections.
Quinolones
Nalidixic
acid has been available
for
the treatment
of urinary
tract infections for decades,
but it has limited
usefulness
because
bacterial
resistance develops
rapidly.
Newer
synthetic fluoroquinolones
(eg, norfioxacm, ciprofloxacin,
enoxacin,
fleroxacm, lomefloxacin,
and ofloxacin)
have broad-spectrum
antimicrobial
activity
and are a therapeutic
advance.
Their use in pediatrics
has
been limited
by the potential
risk of
arthropathy
that has been documented
in several
species
of immature
animals.
The quinolones
bind to the A subPediatrics
units of DNA gyrase,
which
are responsible
for cutting
DNA strands,
thus preventing
supercoiling,
unraveling the DNA,
and halting
DNA replication.
Most quinolones
are not as
active
against
Gram-positive
bacteria
as they are against
Gram-negative
bacteria;
they are only effective
against
streptococci
and enterococci
at levels that can be reached
in the
urine.
The emergence
of resistance
to
fluoroquinolones
has been problematic for MRSA,
methicillin-sensitive
S aureus,
P aeruginosa,
and some
Serratia
infections.
Decreased
susceptibility
of N gonorrhoeae
to fluoroquinolones
recently
has been reported
(Table
2). It is believed
that widespread
and often indiscriminate
use
of fluoroquinolones
has contributed
to this resistance
problem.
However,
when used in selected
patients,
the
quinolones
can be life-saving,
may
allow the patient
to avoid or shorten
hospitalization,
and can be very costeffective.
Fluoroquinolones
have been used
to treat patients
who have pyelonephritis
or recurrent
urinary
tract infections,
prostatitis,
gonorrhea
(single
dose) and chlamydia
(7-day
course)
infections,
malignant
external
otitis,
osteomyelitis
caused
by Gram-negative bacteria,
respiratory
infections
including
exacerbations
of cystic
fibrosis,
and gastrointestinal
infections
(eg, Shigella,
Salmonella,
Campylobacter
infections
and traveler’s
diarrhea).
Quinolones
are not approved
by
the Food and Drug Administration
for use in patients
younger
than 18
years of age or in pregnant
or nursing women.
Children
who have cystic fibrosis
and are younger
than 18
years old have been treated
with
quinolones
without
adverse
effects
because
the benefits
were believed
to
outweigh
the risks.
Implications
Understanding
the many different
mechanisms
of action
for available
antibiotics
may help practitioners
make better clinical
decisions
regarding the use of antibiotics.
Although
the increasing
emergence
of antibiotic-resistant
pathogens
is alarming,
there are steps that each physician
can take to slow this trend (Table
3).
in Review
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1994
I
Admittedly,
some of these recommendations
are not easy or popular.
However,
the alternative
may be the
emergence
of resistant
bacteria
that
cannot
be treated
with any of our
many antibiotics.
SUGGESTED
READING
General
Brooks
OF, Butel JS, Ornston LN, Ct al.
Medical
Microbiology.
Norwalk,
Conn:
Appleton
and Lange;
1991
Craft JC, Siepman
N. Overview
of the safety
profile
of clarithromycin
suspension
in
pediatric
patients.
Pediatr
Infect Dis J.
1993;12:S142-.S147
Oilman
AG, Rail 1’W, Nies AS, et al. The
Pharmacological
Basis of Therapeutics.
New York, NY: Pergamon
Press; 1990
Kucers A, Bennett
N. The Use of Antibiotics,
4th ed. Philadelphia,
Penn: JB Lippincott
Company;
1987
Mulligan
Mi, Cobbs CO. Bacteriostatic
versus
bactericidal
activity.
Infect
Dis Clin North
Am. 1989;3:389-397
Petz LD. Immunological
reactions between
penicillins
and cephalosporins:
a review.
J
Infect Dis. 1978;137(suppl):S74-S79
Reese RE, Betts RF. Handbook
of Antibiotics,
2nd ed. Boston,
Mass: Little
Brown
and
Company;
1993
Rodriequez
Wi, Wiedermann
VL. Role of
newer oral cephalosporins,
fluoroquinolones
and macrolides
in the treatment
of pediatric
infections.
In: Aronoff
SC, ed. Advances
in
Pediatric
Infectious
Diseases,
vol 9. St.
Louis, Mo: CV Mosby;
1994:125-151
Table
3. What Practftloners
Can Do To Umft
of Antibiotlcreslstant
Pathogens
the
Emergence
#{149}
Wash hands thoroughly
to avoid spreading
resistant
organisms
to other
patients.
#{149}
Stop and think.
Is this a bacterial
disease
and is an antibiotic
needed?
#{149}
Educate
your patients
that viral illnesses
do not respond
to antibiotics.
#{149}
Always
use the narrowest-spectrum
antibiotic
possible.
#{149}
Try to limit the empiric
use of broad-spectrum
agents.
#{149}
Stay informed
about your hospital’s
antibiotic
resistance
patterns.
#{149}
Recognize
that hospitaiwide
antibiotic
control
programs
may be
implemented
in some cases to limit access
to certain
antibiotics.
AntIbiotic-resistant
Pathogens
Breiman
RF, Butler
JC, Tenover
FC, Elliott
JA, Facklam
RR. Emergence
of drugresistant
pneumococcal
infections
in the US.
JAMA.
1994;271:1831-1835
Centers
for Disease Control.
Decreased
susceptibility
of Neisseria
gonorrhoeae
to
fluoroquinolones:
Ohio and Hawaii,
19921994. MMWR.
1994;43:325-327
Leggiadro
RJ. Penicillin
and cephalosporinresistant
Streptococcus
pneumoniae:
an
emerging
microbial
threat. Pediatrics.
1994;
93:500-503
Sloas MM, Barrett FF, Chesney
PJ, et at.
Cephalosporin
treatment
failure
in penicillinand cephalosporin-resistant
Streptococcus
pneumoniae
meningitis.
Pediatr
Infect
Dis J.
1992;! 1:662-666
Smith AL. Antibiotic
resistance
in pediatric
pathogens.
Infect Dis Clin North Am. 1992;
6:177-195
ASSiSOJU
of Pediatric
Pediatrics,
NY.
Private
Diseases
Pediatrics
Professor
Infectious
University
of Pediatrics,
Divisions
Diseases
and General
of Rochester,
Rochester,
Practice,
Pediatric
Infectious
and Allergy,
Bellevile,
NJ.
in Review
VoL
15
No.
ii
November
1994
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447
BACK TO BASICS: Antibiotics: Mechanisms of Action
Kathleen A. Woodin and Susan H. Morrison
Pediatr. Rev. 1994;15;440-447
DOI: 10.1542/pir.15-11-440
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