Fundamentals of CHEMOTHERAPHY

Dra. Tuano
Microbiology
Definition of Terms:
Antibiotics a drug used to treat
bacterial infections
o Have no effect on viral infections
o Originally, it was a substance
produced by one microorganism
that selectively inhibits the growth
of another
o Synthetic antibiotics, usually
chemically related to natural
antibiotics, have since been
produced that accomplish
comparable tasks.
Probiotics are microorganisms that
provide health benefits when
consumed, as claimed by some.
o the term probioticis currently
used to name ingested
microorganisms associated with
beneficial effects to humans and
animals
Chemotherapeutic agents agent
used to treat cancer administered in
regimens of one oor more cycles,
combining two or more agents over a
period of days to weeks
o Such agents are toxic to cells with
high proliferative rates e.g., to the
cancer itself, but also to the GI
tract (causing nausea and
vomiting), bone marrow (causing
various cytopenias) and hair
(resulting in baldness
Antimicrobial Chemotherapy:
introduction
Drugs have been used for the
treatment of infectious diseases since
the 17th century (e.g., quinine for
malaria, emetine for amebiasis);
However, chemotherapy as a science
began in the first decade of the 20th
century with understanding of the
principles of selective toxicity, the
specific chemical relationships
between microbial pathogens and
drugs, the development of drug
resistance and the role of combined
therapy
Experiments led to the
arsphenamines for syphilis, the first
planned chemotherapeutic regimen.
Microbiology Fundamentals of CHEMOTHERAPHY

The current era of antimicrobial

chemotherapy began in 1935 with the
discovery of the sulfonamides. In 1940,
it was demonstrated that penicillin
discovered in 1929, could be an
effective therapeutic substance.
During the next 25 years, research on
chemotherapeutic agents centered
largely around substances of microbial
origin called antibiotics
The isolation, concentration,
purification, and mass reduction of
penicillin were followed by the
development of streptomycin,
tetracyclines, chlorampehenicol, and
many other agents.
These substances were originally
isolated from filtrates of media in
which their respective molds had
grown
Synthetic modification of previously
described drugs has been prominent in
the development of new antimicrobial
agents

Antimicrobial Chemotherapy:
Mechanisms of Action of Antimicrobial
Drugs
Antimicrobial drugs act in one of
several ways: By selective toxicity, By
inhibition of cell membrane synthesis
and function, By inhibition of protein
synthesis, or By inhibition of nucleic
acid synthesis
Selective Toxicity - an ideal
antimicrobial agent exhibits selective
toxicity, which means that the drug is
harmful to a pathogen without being
harmful to the host. Often, selective
toxicity is relative rather than absolute;
this implies that a drug in a
concentration tolerated by the host
may damage an infecting
microorganism.
Selective toxicity may be a
function of a specific receptor
required for a drug attachment,
or it may depend on the
inhibition of biochemical events
essential to the pathogen but not
to the host.
The mechanisms of action of
antimicrobial drugs can be
discussed under four headings:
Inhibition of cell wall
synthesis
Page 1 of 21

Inhibition of cell
membrane function
Inhibition of protein
synthesis (ie., inhibition of
translation and
transcription of genetic
material).
Inhibition nucleic
acid synthesis.
Inhibition of Cell Wall
Synthesis
Bacteria have rigid outer
layer, the cell wall. The cell
wall maintains the shape and
size of the microorganisms,
which has a high internal
osmotic pressure
Injury to the cell wall (eg. By
lysosome) or inhibition of its
formation may lead to lysis of the
cell. In a hypertonic
environments (eg. 20% sucrose),
damaged to cell formation leads
to formation of spherical
bacterial protoplasts from
gram-positive organisms or
spheroplasts from gramnegative organisms; these forms
are limited by the fragile
cytoplasmic membrane.
If such protoplasts or
sphheroplasts are placed in an
environment of ordinary tonicity,
they take up fluid rapidly, swell,
and may explode. Specimens
from patients being treated with
cell wall-active antibiotics often
show swollen or misshapen
bacteria
The cell wall contains a
chemically distinct complex
polymer mucopeptide
(peptidoglycan) consisting of
polysaccharides and a highly
cross-linked polypeptide.
The polysaccharides regularly
contain the amino sugars Nacetylglucosamine and
acetylmuramic acid. The latter is
found only in bacteria.
To the amino sugars are attached
short peptide chains.
The final rigidity of the cell wall is
imparted by cross-linking of the
peptide chains (eg, through
pentaglycine bonds) as a result

of transpeptidation reaction
carried out by several enzymes.
The peptidoglycan layer is much
thicker in the cell wall of grampositive than of gram-negative
bacteria.
All -lactam drugs are selective e
inhibitors of bacterial cell wall
synthesis & therefore active
against growing bacteria/
This inhibition is only one of the
several different activities of
these drugs, but it is the best
understood.
The initial step in drug action
consists of binding of the drugs
to cell receptors (Penicillinbinding proteins; PBS)
There are 3 to 6 PBPs (MW 4-12 x
105 ), some of which are
transpeptidation enzymes.
Different receptors have different
affinities for a drug, and each
may mediate a different effect.
For example: attachment
of Penicillin to one PBP
may result chiefly in
abnormal elongation of the
cell, whereas attachment
to another PBP may lead
to a defect in the
periphery of the cell wall,
with resulting cell lysis.
PBPs are under
chromosomal control, &
mutations may alter their
number or their affinity for
.
After a -lactam drug has
attached to one or more
receptors, the transpepdiation
reaction is inhibited &
peptidoglycan synthesis is
blocked.
The next step probably involves
removal or inactivation of an
inhibitor of autolytic enzymes in
the cell wall.
This activates the lytic enzyme
and results in lysis if the
environment is isotonic
In a markedly hypertonic
environment, the microbes
change to protoplasts or
sphetoplast, covered only by the
fragile cell membrane.
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In such cells, synthesis of

proteins and nucleic acids may
continue for some time
The inhibition of the
transpeptidation enzymes by
Penicillins & Cephalosphorins
may be due to a similarity of
these drugs to actl-structural
alanine.
The transpeptidation reaction
involves loss a D-alanine from
the pentapeptide.
The remarkable lack of toxicity of
-lactam drugs to mammalian
cells must be attributed to the
absence, in animal cells, of a
bacterial wall, with its
peptidoglycan.
The difference in susceptibility of
gram (+) & gram (-) bacteria to
various Penicillins or
Cephalosphorins probably
depends on structural differences
in their cell walls (e.g., amount of
Peptidoglycan, presence of
receptors & lipids, nature of
crosslinking activity of autolytic
enzymes) that determine
penetration, binding, & activity
of the drugs.
Resisitance to Penicillins may be
determined by the organisms
production of penicillindestroying enzymes (lactamases).
Beta-lactamases open
the -lactam ring of
penicillins and
Cephalosphorins & abolish
their antimicrobial activity.
Beta-lactamases are
plasmid-mediated (e.g.,
penicillinase of
Staphylococcus), while
others are chromosomally
mediated (e.g., many
species of gram (-)
bacteria.
All of more than 30 plasmidmediated -lactamases are
produced constitutively & have a
high propensity to move from
one species of bacteria to
another (e.g., -lactamaseproducing Neisseria

Microbiology Fundamentals of CHEMOTHERAPHY

gonorrheae, Hemophilus
influenza & Enterococci)
Chromosomally mediated lactamases may be
constitutively produced (e.g.,
Bacteriodes, Acinetobacter)
or they may be inducible (e.g.,
Enterobacter, Citrobacter,
Pseudomonas).
There is one group of lactamases that is occasionally
found in certain species of gram
(-) bacilli, usually Klebsiella
pneumonia & Escherichia coli.
These enzymes are
termed extendedspectrum -lactamases
(ESBLs) because they
confer upon the bacteria
the additional ability to
hydrolyze the -lactam
rings of Cefotaxime,
Ceftazidime, or
Aztreonam.
The classification of lactamases is complex, based
upon the genetics, biochemical
properties, and substrate affinity
for -lactamase inhibitor
(clavulanic acid).
Clavulanic acid,
sulbactam &
tazobactam are lactamase inhibitors that
have a high affinity for and
irreversibly bind some lactamases (e.g.,
penicillinase of
Staphyloccocus aureus)
but arenot hydrolyzed by
the -lactamase.
These inhibitors protect
simultaneously present
hydrolysable penicillins (e.g.,
ampicillin, amoxicillin, &
ticarcillin) from destruction
Certains penicillings (e.g.,
cloxacillin) also have a high
affinity for -lactamases.
There are two other types of
resistance mechanisms:
Due to the absence of
some penicillins
receptors (penicillinbinding proteins;
PBPs) and occurs as a
Page 3 of 21

result of chromosomal
mutation;
Results from failure of
the -lactam drug to
activate the autolytic
enzymes in the cell
wall.
As a result, the organism is
inhibited but not killed. Such
tolerance has been observed
especially with
staphylococci & certain
streptococci.
Examples of agents acting
by inhibition of cell wall
synthesis: penicillins, the
cephalosphorins,
vancomycin, and
cycloserine.
Several other drugs,
including bacitracin,
teicoplanin, vancomycin,
ristocetin, and novobiocin,
inhibit early steps in the
biosynthesis of the
peptidoglycan.
Since the early stage of
synthesis take place inside
the cytoplasmic membrane,
these drugs must penetrate
the membrane to be
effective.
Inhibition of Cell Membrane
Function
The cytoplasm of all living
cells is bounded by the
cytoplasmic membrane,
which serves as a selective
permeability barrier, carries
out active transport functions,
and thus controls the internal
composition of the cell.
If the functional integrity of
the cytoplasmic membrane is
disrupted, macromolecules
and ions escape from the cell,
and cell damage or death
ensues.
The cytoplasmic membrane of
bacteria and fungi has a
structure different form that
of animal cells, and can be
more readily disrupted by
certain agents.
Consequently, selective
chemotherapy is possible.

Examples of this mechanism

are the polymyxins acting
on the gram (-) bacteria
and polyenes acting on
fungi.
Polyenes require binding to a
sterol which is present in the
fungal cell membrane but
lacking in the bacterial cell
membrane.
Conversely, Polymyxins are
inactive against fungi and
polyenes are inactive against
bacteria a striking example
of selective toxicity.
Other examples of agents
acting by inhibition of cell
membrane function are
amphotericin B, colistin &
the imidazoles &triazoles.
Inhibition of Protein Synthesis
It is established that
erythromycins, lincomycins,
tetracyclines, aminoglycosides,
& chloramphenicol can inhibit
protein synthesis in bacteria.
The precise mechanisms of
action are not fully
established for these drugs.
Bacteria have 70s ribosomes,
whereas mammalian cells
have 80s ribosomes.
The subunits of each type of
ribosome, their chemical
composition, and their
functional specificities are
sufficiently different to
explain why antimicrobial
drugs can inhibit protein
synthesis in bacterial
ribosomes without having a
major effect on a mammal
ribosomes.
In normal microbial protein
synthesis, the mRNA message
is simultaneously read by
several ribosomes that are
strung out along the mRNA
strand. These are called
polysomes.
Examples of drug
acting by inhibition of
protein synthesis are
the erythromycins,
lincomycins,
tetracyclines,

Page 4 of 21

aminoglycosides, &
chloramphenicol.
Inhibition of Protein Synthesis:
Aminoglycosides
The mode of action of
Streptomycin has been studied far
more intensively than that of other
aminoglycosides, but all probably
act similarly.
The 1st step is the attachment
of the aminoglycoside to a
specific receptor protein (P 12
in the case of streptomycin)
on the 30S subunit of the
microbial ribosome.
2nd, the aminoglycoside
blocks the normal activity of
the initiation on complex of
peptide formation (mRNA +
formyl methicinine + tRNA)
3rd, the mRNA message is
misread on the recognition
region of the ribosome;
consequently, the wrong
amino acid is inserted into the
peptide, resulting in a
nonfunctional protein.
4th, aminoglycoside
attachment results in the
breakup of polysomes and
their separation into
monosomes incapable of
protein synthesis.
o These activities occur
more or less
simultaneously, and
the overall effect is
usually an irreversible
event killing of the
bacterium
Chromosomal resistance of
microbes to aminoglycosides
principally depends on the lack of
specific protein receptor on the 30S
subunit of the ribosome.
Plasmid-dependent resistance to
aminoglycosides depends on the
production by the microorganism of
adenylylating, phosphorylating, or
acetylating enzymes that destroy
the drugs.
A 3rd type of resistance consist of a
permeability defect, an outer
membrane change that reduces
active transport of the
Microbiology Fundamentals of CHEMOTHERAPHY

aminoglycoside into the cell so that

the drug cannot reach the ribosome.
Often this is plasmid-mediated.
Inhibition of Protein Synthesis:
Macrolides, Azalides
These drugs (erythromycins,
azithromycin, and clarithromycin)
bind to the 50S subunit of the
ribosome, and the binding site is a
23S rRNA.
They may interfere with formation of
initiation complexes for peptide
chain synthesis or may interfere
with aminoacyl translocation
reactions.
Some macrolide-resistant bacteria
lack the proper receptor on the
ribosome (through methylation of
the rRNA). This may be under
plasmid or chromosomal control.
Inhibition of Protein Synthesis:
Lincomycins
Clindamycin binds to the 50S
subunit of the microbial ribosome
and resembles macrolides in binding
site, antibacterial activity, and mode
of action.
Chromosomal mutants are resistant
because they lack the proper
binding site on the 50S subunit
Inhibition of Protein Synthesis:
Tetracyclines
Bind to the 30S subunit of the
microbial ribosomes.
They inhibit protein synthesis by
blocking the attachment of charged
aminoacyl-tRNA
Thus, they prevent introduction of
new amino acids to the nascent
peptide chain.
The action is usually inhibitory and
reversible upon withdrawal of the
drug
Resistance to tetracyclines results
from changes in permeability of the
microbial cell envelope.
In susceptible cells, the drug is
concentrated from the environment
and does not readily leave the cell.
In resistant cells, the drug is not
actively transported into the cell or
leaves it so rapidly that inhibitory
concentrations are not maintained.
Page 5 of 21

This is often plasmid-controlled.

Mammalian cells do not actively
concentrate tetracyclines.

Inhibition of Protein Synthesis:

Chloramphenicol
Binds to the 50S subunit of the
ribosome.
It interferes with the binding of new
amino acids to the nascent peptide
chain, largely because
chloramphenicol inhibits peptidyl
transferase.
Chloramphenicol is mainly
bacteriostatic, and growth of
microoganisms resumes when the
drug is withdrawn.
Microorganisms resistant to
chloramphenicol produce the enzyme
chloramphenicol acetyltransferase,
which destroys drug activity
The production of this enzyme is
usually under control of a plasmid.
Inhibition of Nucleic Acid Synthesis
Examples of a drug acting by
inhibition of nucleic acid synthesis are
the quinolones, pyrimethamine,
rifampin, sulfonamides,
trimethoprim, and trimetrexate.
Rifampin inhibits bacterial growth by
binding strongly to the DNA-

dependent RNA polymerase of

bacteria.
Thus, it inhibits bacterial RNA
synthesis.
Rifampin resistance results
from a change in RNA
polymerase due to a
chromosomal mutation that
occurs with high frequency.
The mechanism rifampicin
action on viruses is different. It

blocks a late stage in the

assembly of poxviruses
All quinolones and
fluoroquinolones inhibit microbial
DNA synthesis by blocking DNA
gyrase.
For many microorganisms, paminobnzoic (PABA) is an
essential metabolite.
The specific mode of acion of
PABA involves an adenosine
triphosphate (ATP)-dependent
condensation of a peptide with
PABA to yield dihyropteoic acid,
which is subsequently converted
to folic acid.
PABA is involved in the synthesis
of folic acid, an important
precursor to the synthesis of
nucleic acids.

Inhibition of Nucleic Acid Synthesis:

Sulfonamides
Sulfonamides are structural analog
of PABA and inhibit dihydrioteroate
synthetase
can enter into the reaction in place of
PABA and compete for the active
center of the enzyme.
As a result, nonfunctional analogs of
folic acid are formed, preventing
further growth of the bacterial cell.
The inhibiting action of sulfonamides
on bacterial growth can be
counteracted by an excess of PABA in
the environment (competitive
inhibition).
Animal cell cannot synthesize folic
acid and must depend upon
exogenous sources. Some bacteria,
like animal cells, are not inhibited by
sulfonamides. Many other bacteria,
however, synthesize folic acid as
mentioned above and consequently
are susceptible to action by
sulfonamides.
Inhibition of Nucleic Acid Synthesis:
Trimethoprim
(3,4,5trimethoxybenzylpyrimidine)i
nhibits dihydrofolic acid
reductase 50,000 times more
efficiently in bacteria than in
mammalian cells.
Page 6 of 21

This enzyme reduces dihydrofolic

to tetrahydrofolic acid, a stage in
the sequence leading to the
synthesis of purines and
ultimately of DNA.
Sulfonamides and trimethoprim
each can be used alone to inhibit
bacterial growth.
If used together, they produce
sequential blocking, resulting in
a marked enhancement
(synergism) of activity.
Such mixtures of sulfonamide
(five pats) plus trimethoprim
(one part) have been used in
the treatment of
pneumocystis pneumonia,
malaria, shigella enteritis,
systemic salmonella
infections, urinary tract
infections, and many others.

Inhibition of Nucleic Acid Synthesis:

Pyrimethamine
also inhibits dihydrofolate reductase,
but it is more active against the
enzyme in mammalian cells and
therefore I more toxic than
trimethoprim
pyrimethamine + sulfonamide or
Clindamycin is the current
treatment of choice in
toxoplasmosis and some other
protozoal infections.

Resistance to Antimicrobial Drugs

there are many different mechanisms by
which microorganisms might exhibit
resistance to drugs:
microorganisms produce enzymes
that destroy the active
microorganism might exhibit
resistance to drugs
Examples: staphylococci
resistant to penicillin G
produce a -lactamase that
destroys the drug. Other lactamases are produced by
gram (-) rods.
Gram (-) bacteria
resistant to
aminoglycoside (by
virtue of a plasmid)
produce adenylylating,
phosphorylating, or
Microbiology Fundamentals of CHEMOTHERAPHY

acetylating enzymes
that destroy drug.
Microorganisms change their
permeability to the drug
Examples: tetracylines
accumulate in succeptible
bacteria but not in resistant
bacteria.
Resistance to polymyxins is
also associated with change
in permeability to the drugs.
Streptococci have a natural
permeability barrier to
aminoglycosides.
This can be partly overcome
by the simultaneous presence
of a cell wall-active drug.
E.g., a penicillin
Resistance to amikacin and to
some other aminglycsides
may depend on a lack of
permeability to the drugs,
apparently due to an outer
membrane change that
impairs active transport into
the cell.
Microorganisms develop an altered
structural target for the rig
Examples: erythromycinresistant organisms have an
altered receptors on the 50S
subunit of the ribosome,
resulting from methylation of
a 23S riboso,al RNA
Resistance to some
penicillins and
cephalosphorons may
be a function of the
loss or alteration of
PBPs.
Penicillin resistance n
Streptococcus
pneumonia and
enterococcie is due to
altered PBPs.
Microorganisms develop an altered
metabolic pathway that bypasses
the reaction inhibited by the drug.
Example: Some sulfonamineresistant bacteria do not
require extracellular PABA
but, like mammalian cells,
can utilize preformed folic
acid.
Microorganisms develop an altered
enzyme that can still perform its
Page 7 of 21

metabolic function but is much less

affected by the drug.
Example: in trimethoprimresistant bacteria, the
dihydrofolic acid reductase is
inhibited far less efficiently
than in trimethoprimsusceptible bacteria.
Origin of Drug Resistance: Nongenetic
Origin of Drug Resistance
Active replication of bacteria is
required for most antibacterial drug
actions.
Consequently, microorganisms that
are metabolically inactive
(nonmultiplying) may be
phenotypically resistant to drugs.
However, their offspring are fully
susceptible.
Example: Mycobacteria often
survive in tissues for many
years after infection yet are
restrained by the hosts
defenses and do not multiply.
Such persisting organisms are
resistant to treatment and cannot
be eradicated by drugs. Yet if they
start to multiply (e.g., following
suppression of cellular immunity in
the patient) they are fully
susceptible to the same drugs.
Microorganisms may lose the
specific target structure for a drug
for several generations and thus be
resistant.
Example: Penicillinsusceptible organisms may
change to cell wall-deficient L
forms during penicillin
administration.
Lacking cell walls, they are resistant
to cell wall-inhibitor drugs (penicillin,
cephalosphorins) and may remain
so for several generations.
When these organisms revert to
their bacterial parent forms by
resuming cell wall production, they
are again susceptible to penicillin.
Microorganisms may infect the host
at sites where antimicrobials are
excluded or are not active.
Examples: Aminoglycosides
such as gentamicin are not
effective in treating
salmonella enteric fevers
because the salmonellae are

intracellular and the

aminoglycosides do enter the
cells.
Similarly, only drugs that
enter cells are effective in
treating legionnaires disease
because of the intracellular
location of Legionella
pneumophila.

Origin of Drug Resistance: Genetic

Origin of Drug Resistance
Most drug-resistant microbes
emerge as a result of genetic
change and subsequent selection
processes by antimicrobial drugs
Origin of Drug Resistance:
Chromosomal Resistance
This develops as a result of
spontaneous mutation in a locus that
controls susceptibility to a given
antimicrobial drug.
The presence of the antimicrobial drug
serves as a selecting mechanism to
suppress susceptible organisms and
favor the growth of drug-resistant
mutants
Spontaneous mutation occurs with a
frequency of 10-12 to 10-7 and thus is an
infrequent cause of the emergence of
clinical drug resistance in a given
patient.
However, chromosomal mutants
resistant to rifampin occur with high
frequency (about 10-7 to 10-5).
Consequently, treatment of bacterial
infections wit rifampin as the sole drug
often falls.
Chromosomal mutants are most
commonly resistant by virtue of a
change in a structural receptor for a
drug.
Thus, the P12 protein on the 30S
subunit of the bacterial ribosome
serves as a receptor for streptomycin
attachment.
Mutation in the gene controlling that
structural protein results in
streptomycin resistant to -lactam
drugs.
Origin of Drug Resistance:
Extrachromosomal Resistance

Page 8 of 21

Bacteria often contain

extrachromosomal genetic elements
called plasmids
Some plasmids carry genes for
resistance to one and often several
antimicrobial drugs.
Plasmid genes for antimicrobial
resistance often control the
formation of enzymes capable of
destroying the antimicrobial drugs.
Thus, plasmids determine resistance
to penicillins and and
cephalosporins by carrying genes
for the formation of lactamases.
Plasmids code for enzymes that
acetylate, adenylylate, or
phosphorylate various
aminoglycosides:
For enzymes that determine
the active transport of
tetracyclines across the cell
membrane; and for others.
Genetic material and plasmids can
be transferred by transduction,
transformation, and conjugation.

Origin of Drug Resistance: CrossResistance

Microorganisms resistant to a
certain drug may also be resistant
to other drugs that share a
mechanism of action.
Such relationship exist mainly
between agents that are closely
related chemically (e.g., different
aminoglycosides) or that have a
similar mode of binding or action
(e.g., macrolides-lincomycins).
In certain classes of drugs, the
active nucleus of the chemical is so
similar among many congeners
(e.g., tetracyclines) that extensive
cross-resistance is to be expected.
Emergence of drug resistance in
infections may be minimized in the
following ways:
(1.) by maintaining
sufficiently high levels of the
drug in the tissues to inhibit
both the original population
and first-step mutants;
(2) by simultaneously
administering two drugs that
do not give cross-resistance,
each of which delays the
Microbiology Fundamentals of CHEMOTHERAPHY

emergence of mutants
resistant to the other drug
(e.g., rifampin and isoniazid in
the treatment of
tuberculosis);
(3) by avoiding exposure if
microorganisms to a
particularly valuable drug by
limiting its use, especially in
hospitals

Clinical Implications of Drug

Resistance: Gonococci
When sulfonamides were first
employed in the late 1930s for the
treatment of gonorrhea, virtually all
isolates of gonococci were
susceptible and most infections
were cured.
A few years later, most strains had
become resistant to sulfonamides,
and gonorrhea was rarely curable by
these drugs.
Most gonococci were still highly
susceptible to penicillin
Over the next decades, there was a
gradual increase in resistance to
penicillin, but large doses of that
drug were still curative.
In the 1970s, -lactamase-producing
gonococci appeared, first in the
Philippines and in West Africa, and
then spread to form endemic foci
worldwide.
Such infections could not be treated
effectively by penicillin but were
treated with spectinomycin.
Resistance to spectinomycin hhas
appeared.
Third-generation cephalosporins or
quinolones are recommended to
treat gonorrhea.
Clinical Implications of Drug
Resistance: Meningococci
Until 1962, meningococci were
uniformly susceptible to
sulfonamides, and these drugs were
effective for both prophylaxis and
therapy.
Subsequently, sulfonamide-resistant
meningococci spread widely, and
the sulfonamides have bow lost
their usefulness against
meningococcal infections.
Page 9 of 21

Penicilllins remain effective for

therapy and rifampin is employed
for prophylaxis.
However, rifampin-resistant
meningococci persist in about 1% of
individuals who have received rifampin
for prophylaxis.
Clinical Implications of Drug
Resistance: Staphylococci
In 1944, most staphylococci were
susceptible to penicillin G, though a
few resistant strains had been
observed.
After massive use of penicillin, 6585% of staphylococci isolated from
hospitals in 1948 were -lactamase
producers and thus resistant to
penicillin G.
The advent of -lactamase-resistant
penicillins, (e.g., nafcillin) provided a
temporary respite, but infections
due to nafcillin-resistant
staphylococci are common.
Presently, penicillin-resistant
staphylococci include not only those
acquired in hospitals but also 8090% of those isolated in the
community.
These organisms also tend to be
resistant other drugs, e.g.,
tetracyclines.
Nafcillin-resistant staphylococci ae
common in tertiary hospitals.
Vancomycin has been the major
drug used for treatment of nafcillinresistant S aureus infetions, but
some strains of S aureus have
become of intermediate
susceptibility to vancomycin in vitro
and may be clinically resistant in
vivo.
Clinical Implications of Drug
Resistance: Pneumococci
Streptococcus pneumonia was
uniformly susceptible to penicillin G
until 1963, when relatively penicillinresistant strains were found in New
Guinea.
Penicillin-resistant pneumococci
subsequently were found in South
Africa, Japan, Spain, and later
worldwide.
In the United States, 5-10% of
pneumococci are resistant to

penicillin G (MICs of >2 g/mL) and

approximately 20% are moderately
resistant (MICs of 0.2-2 g/mL).
The penicillin resistance is due to
altered penicillin-binding proteins.
Penicillin resistance in pneumococci
tends to be clonal.
Pneumococci also are frequently
resistant to trimethoprimsulfamethoxazole and sometimes to
erythromycin and tetracycline.

Clinical Implications of Drug

Resistance: Enterococci
The enterococci have intrinsic
resistance to multiple
antimicrobials: Penicillin G and
ampicillin with high MICSs;
cephalosporins with very high MICs;
low-level resistance to
aminoglycosides; and resistance to
trimethoprim-sulfamethoxazole in
vivo.
The enterococci also have shown
acquired resistance to almost all if
not all other antimicrobials as
follows: altered PBPs and resistane
to -lactams; high-level resistance
to aminoglycosides; and resistance
to fluoroquinolones, macrolides,
azalides, and tetracyclines.
Some enterococci have acquired a
plasmid that encodes for -lactamse
and are fully resistant to penicillin
and ampicillin.
Of greatest importance is the
development of resistance to
vancomycin, which has become
common in Europe and North
America though there is geographic
variation in the percentages of
enterococci that are vancomycinresistant.
Enterococcus faecium is the species
that is most commonly vancomycinresistant in outbreaks of infections
due to vacomycin-resistant
enterococci, the isolates may be
clonal genetically diverse.
Resistance to the streptogramins.
(quinupristin-dalfopristin) aslo
occurs in enterococci.
Clinical Implications of Drug
Resistance: Gram-Negative Enteric
Bacteria
Page 10 of 21

Most drug resistance in enteric

bacteria is attribute to the
widespread transmission of
resistance plasmids among different
genera.
About half the strains of shigella
species in many parts of the world
are now resistant to multiple drugs.
Salmonallae carried by animals
have developed resistance also,
particularly to drugs (especially
tetracycines) incorporated into
animal feeds.
The practice of incorporating drugs
unto animals feeds causes farm
animals to grow mor rapidly but is
associated with an increase in drugresistant enteric organisms in the
fecal flora of farm workers.
A concomitant rise in drug-resistant
salmonella infections in Britain led
to a restriction on antibiotic
supplements in animal feeds.
Continued use of tetracycline
supplements in animal feeds in the
United States may contribute to the
spread of resistance plasmids, and
drug-resistant salmonellae.
Plasmids carrying drug resistance
genes occur in may gram-negative
bacteria of the normal gut flora.
The abundant use of anti-microbial
drugs particularly in hospitalized
patients leads to the suppression
of drug susceptible organisms in
the gut flora and favors the
persistence and growth of drugresistant bacteria, including
enterobacter, klebsiella, proteus,
pseudomonas, and serratia and
fungi.
Such organisms present particularly
difficult problems in
granulocytopenic and
immunocompromised patients.
The closed environments of
hospitals favor transmission of such
resistant organisms through
personnel and fomites as well as by
direct contact.

Clinical Implications of Drug

Resistance: Mycobacterium
Tuberculosis
Microbiology Fundamentals of CHEMOTHERAPHY

Primary drug resistance in M

tuberculosis occurs in about 10%
isolates and most commonly is to
isoniazid or streptomycin.
Resistance to rifampin or
ethambutol is less common.
Isoniazid and rifampin or ethambitol
is less common. Isoniazid and
rifampin are the primary drugs used
in most standard treatment
regimen; other first-line drugs are
pyrazinamide, ethambutol, and
streptomycin.
Resistance to isoniazid and rifampin
is considered multiple drug
resistance.
In the United States, multiple drug
resistance of M tuberculosis ranges
from nil to 30%
Worldwide, the highest rates of
multidrug-resistant tuberculosis
have been reported from Nepal
(48%), Gujarat, India (33.8%), New
York (30.1%), Bolivia (15.3%), and
Korea (14.5%)
Poor compliance with drug
treatment is a major factor in the
development of drug resistance
during therapy.
Control of multidrug-resistant
tuberculosis is a significant
worldwide problem.

Antimicrobial Activity in Vitro

Antimicrobial activity is measured in
vitro in order to determine:
o The potency of an
antibacterial agent in solution
o Its concentration in body
fluids or tissue, and
o The susceptibility of a given,
microorganism to known
concentrations of the drug
Factors affecting Antimicrobial
Activity
1. pH of environment
o Some drugs are more active at
acid pH (eg, nitrofurantion);
other, at alkaline pH (eg,
aminoglycosides, sulfonamides)
2. Components of Medium
o Sodium polyanetholsufonate (in
blood culture media) and other
anionic detergents inhibits
aminoglycosides
Page 11 of 21

PABA in tissues extracts

antagonizes sulphonamides.
Serum proteins bind penicillins in
varying degrees, ranging from
40% for methicillin to 98% for
dicloxacillin
o Addition of NaCl to the medium
enhances the detection of
methicillin resistance in S. aures
Stability of Drug
o At incubator temperature,
several antimicrobial agents lose
their activity
o Peniciilins are inactivated slowly,
whereas aminoglycosides and
ciprofloxacin are quite stable for
long periods
Size of Inoculum
o In general, the larger the
bacterial inoculum, the lower the
apparent susceptibility of
the organism
o Large bacterial populations are
less promptly and completely
inhibited than smaller ones
o In addition, a resistant mutant is
more likely to emerge in large
populations
Length of Incubation
o In many instances,
microorganisms are not killed but
only inhibited upon short
exposure to antimicrobial agents
o The longer incubation continues,
the greater the chance for
resistant mutants to emerge or
for the least susceptible
members of the antimicrobial
population to begin multiplying
as the drug deteriorates
Metabolic activity of
Microorganisms
o In general, actively and rapidly
growing organisms are more
susceptible to drug action than
those in the resting phase
o Metabolically inactive organisms
that survive long exposure to a
drug may have offspring that are
fully susceptible to the same
drug
o

3.

4.

5.

6.

Measurement of Antimicrobial Activity

Determination of the susceptibility
of a bacterial pathogen to
antimicrobial can be done by one of

2 principal methods: dilution or

diffusion
It is important to use a standardized
method that controls for all the
factors that affect antimicrobial
activity; in the United States, the
tests are performed according to the
methods of the National Committee
for Clinical Laboratory Standards
(NCCLS)
Using an appropriate standard test
organism & a known sample of drug
for comparison, these methods can
be employed to estimate either the
potency of antibiotic in the sample
or the susceptibility of the
microorganism

Dilution Method:
Graded amounts of antimicrobial
substances are incorporated into
liquid or solid bacteriologic media
Commonly, twofold (log2) dilutions
of the antimicrobial substances are
used
The media are subsequently
inoculated with test bacteria and
incubated
The end point is taken as that
amount of antimicrobial substance
required to inhibit the growth of or
to kill the test bacteria
Agar dilution susceptibility tests are
time-consuming, and their use is
limited to special circumstances
Broth dilution tests were
cumbersome and little used when
dilutions had to be made in test
tubes; however, the advent of
prepared broth dilution series for
many different drugs in
microdilution plates has greatly
enhanced and simplified the method
The advantage of microdilution
broth dilution tests:
o They permit a quantitative
result to be reported,
indicating the amount of a
given drug necessary to
inhibit (or kill) the
microorganisms tested
Diffusion Method:
Disk diffusion test the most widely
used method
A filter paper disk containing a
measured quantity of a drug is
placed on the surface of a solid
Page 12 of 21

medium that has been inoculated on

the surface of a solid medium that
has been inoculated on the surface
with the test organism
After incubation, the diameter of the
clear zone of inhibition surrounding
the disk is taken as a measure of the
inhibitory power of the drug against
the particular test organism
This method is subject to many
physical and chemical factors in
addition to the simple interaction of
drug and organisms (eg, the nature
of the medium and diffusibility,
molecular size, and the stability of
the drug)
Nevertheless, standardization of
conditions permits determination of
the susceptibility of the organism
Interpretation of the results of
diffusion tests must be based on
comparisons between dilution and
diffusion methods
Such comparisons have led to the
establishment of reference
standards
Linear regression lines can express
the relationship between log of
minimum inhibitory concentration in
dilution tests and diameter of
inhibition zones in diffusion tests
Use of a single disk for each
antibiotic with careful
standardization of the test
conditions permits the report of
susceptibility or resistant for a
microorganism by comparing the
size of the inhibition zone against a
standard of the same drug
Inhibition around a disk containing a
certain amount of antimicrobial drug
does not imply susceptibility to the
same concentration of drug per
millilitre of medium, blood, or urine

Drug-Pathogen Relationships
Environment
o In the host, varying
environmental influences affect
microorganisms located in
different tissues and in different
parts of the body in contrast to
the test tube or Petri dish, where
the environment is constant for
all members of a microbial
population
Microbiology Fundamentals of CHEMOTHERAPHY

Therefore, the response of the

microbial population is much less
uniform within the host than in
the test tube
State of metabolic activity
o In the body, the state of
metabolic activity is diverse
undoubtedly, many organisms
exist at a low level of
biosynthetic activity and are thus
relatively insusceptible to drug
action
o These dormant
microorganisms often survive
exposure to high concentrations
of drugs and subsequently may
produce a clinical relapse of the
infection
Distribution of Drug
o In the body, the antimicrobial
agent is unequally distributed in
tissues and fluids
o Many drugs do not reach the
central nervous system
effectively
o The concentration in urine is
often much greater than the
concentration in blood or other
tissue
o The tissue response induced by
the microorganism may protect it
from the drug
o Necrotic tissue or pus may
adsorb the drug and thus
prevent its contact with bacteria
Location of organisms
o In the body, microorganisms
often are located within tissue
cells
o Drugs enter tissue cells at
different rates. Some (eg,
tetracylcines) reach about the
same concentration inside
monocytes as in the extracellular
fluid
o With others (eg, gentamicin), the
drug probably does not enter
host cells at all
o This is in contrast to the test
tube, where microorganisms
come into direct contact with the
drug
Interfering subtances
o The biochemical environmental
of microorganisms in the body is
very complex and results in
Page 13 of 21
o

significant interference with drug

action
o The drug may be bound by blood
and tissue proteins or
phospholipids; it may also react
with nucleic acids in pus and
may be physically adsorbed onto
exudated, cells, and necrotic
debris
o In necrotic tissue, the pH may be
highly acid and thus
unfavourable for drug action (eg,
aminoglycosides)
o The biochemical environment of
microorganisms in the body is
very complex and results in
significant interference with drug
action
o The drug may be bound by blood
and tissue proteins or
phospholipids; it may also react
with nucleic acids in pus and
may be physically adsorbed onto
exudates, cells, and necrotic
debris
o In necrotic tissue, the pH may be
highly acid and thus
unfavourable for drug action (eg,
aminoglycosides)
Concentration
o In the body, microorganisms are
not exposed to a constant
concentration of drug; in the test
tube they are
Absorption
o The absorption of drugs from the
intestinal tract (if taken by
mouth) or from tissues (if
injected) is irregular
o There is also a continuous
excretion as well as inactivation
of the drug
o Consequently, the levels of drug
in body compartments fluctuate
continually, and the
microorganisms are exposed to
varying concentrations of the
antimicrobial agent
Distribution
o The distribution of drugs varies
greatly with different tissues.
Some drugs penetrate certain
tissues poorly (eg, CNS, prostate)
o Drug concentrations following
systemic administration may
therefore be inadequate for
effective treatment

On surface wounds or mucous

membranes such as the
conjunctivas, local (topical)
application of poorly absorbed
drugs permits highly effective
local concentrations without toxic
side effects
o Alternatively, some drugs applied
topically on surface wounds are
well absorbed
o Drug concentrations in urine are
often much higher than in blood
Variability of concentration
o It is critical to maintain an
effective concentration of a drug
where the infecting
microorganisms proliferate
o This concentration must be
maintained for a sufficient length
of time to eradicate the
microorganisms
o Because the drug is administered
intermittently and is absorbed
and excreted irregularly, the
levels constantly fluctuate at the
site of infection
o In order to maintain sufficient
drug concentrations for a
sufficient time, the time-dose
relationship must be considered
o The larger each individual drug
dose, the longer the permissible
interval between doses
o The smaller the individual dose,
the shorter the interval that will
ensure adequate drug levels
o

Post antibiotic effect

o The post antibiotic effect is the
delayed regrowth of bacteria
after exposure to antimicrobial
agents
o It is properly of most
antimicrobials, except that most
-lactams do not show the post
antibiotic effect with gram
negative bacilli
o The carbapenems do have a post
antibiotic effect with the gram
negative bacilli

Host-Pathogen Relationship
Alteration of tissue response
o The inflammatory response of
the tissue to infections may be
altered if the drug suppresses
the multiplication of
Page 14 of 21

o
o

microorganisms but does not

eliminate the from the body
And acute process may in this
way be transformed into a
chronic one
Conversely, the suppression of
inflammatory reactions in tissues
by impairment of cell-mediated
immunity in recipients of tissue
transplants or antineoplastic
therapy or by immune
compromise as a result disease
(eg, AIDS) cause enhanced
susceptibility to infection and
impaired responsiveness to
antimicrobial drugs

Alteration of immune reponse

o If an infection is modified by an
antimicrobial drug, the immune
response of the host may also be
altered
- One example illustrates this
phenomenon: Pharyngeal
infection with haemolytic
group A streptococci is
followed frequently by the
development of antistreptococcal antibodies, and
if there is a hyper immune
response the infection may be
followed by rheumatic fever
o If the infective process can be
interrupted early and completely
with antimicrobial drugs, the
development of an immune
response and of rheumatic fever
can be prevented (presumably
by rapid elimination of the
antigen)
o Drugs and dosages that rapidly
eradicate the infecting
streptococci (eg, penicillin) are
more effective in preventing
rheumatic fever than those
which merely suppress the
microorganisms temporarily (eg,
tetracycline)
Alteration of microbial flora
o Antimicrobial drugs affect not
only the microorganisms causing
disease but also susceptible
members of the normal microbial
flora

Microbiology Fundamentals of CHEMOTHERAPHY

An imbalance is thus created

that in itself may lead to disease.
A few examples are of interest
1. In hospitalized patients who
receive antimicrobials, the
normal microbial flora Is
suppressed
This creates a partial void
that Is filled by the
organisms most prevalent
in the environment,
particularly drug resistant
gram negative aerobic
bacteria (eg,
pseudomonads,
staphylococci)
Such superinfecting
organisms subsequently
may produce serious drugresistant infections
2. In women taking antibiotics
by mouth, the normal vaginal
flora may be suppressed,
permitting marked
overgrowth of candida
This leads to unpleasant
local inflammation (vulvo
vaginitis) and itching that
are difficult to control
3. In the presence of urinary
tract obstruction, the
tendency to bladder infection
is great
When such urinary tract
infection due to a sensitive
microorganism (eg,
Escherichia coli) is treated
with an appropriate drug,
the organism may be
eradicated
However, it often happens
that reinfection due to
another drug-resistant
gram negative bacillus
occurs after the drug
sensitive microorganisms
are eliminated
A similar process accounts
for respiratory tract super
infections in patients given
antimicrobials for chronic
bronchitis
4. In persons receiving
antimicrobial drugs for
several days, parts of the
Page 15 of 21

normal intense flora may be

suppressed
Drug resistant organisms
may establish themselves
in the bowel in great
numbers and may
precipitate serious
enterocolitis (Clostridium
difficile, etc)
Clinical Use of Antibiotics
Selection of antibiotics
o Diagnosis
o A specific etiologic diagnosis
must be formulated
o This can often be done on the
basis of a clinical impression
o Thus, in typical lobar pneumonia
or acute urinary tract infection,
the relationship between clinical
picture and causative agent is
sufficiently constant to permit
selection of the antibiotic of
choice on the basis of clinical
impression alone
o Even in these cases, however, as
a safeguard against diagnostic
error, it is preferable to obtain a
representative specimen for
bacteriologic study before giving
antimicrobial drugs
o In most infections, the
relationship between causative
agent and clinical picture is not
constant
o It is therefore important to obtain
proper specimens for
bacteriologic identification of the
causative agent
o As soon as such specimens have
been secured, chemotherapy can
be started on the basis of the
best guess
o Once the causative agent has
been identified by laboratory
procedures, the initial regimen
can be modified as necessary
o The best guess of a causative
organism is based on the
following considerations, among
others:
1. The site of infection (eg,
pneumonia, UTI)
2. The age of the patient (eg,
meningitis: neonatal, young
child, adult)

3. The place where the infection

was acquired (hospital vs
community)
4. Mechanical predisposing
factors (intravenous drip,
urinary catheter, respirator,
exposure to vector)
5. Predisposing host factors
(immunodeficiency,
corticosteroids, transplant,
cancerchemotherapy)
o

Susceptibility tests
o Laboratory tests for antibiotic
susceptibility are indicated in the
following circumstances
1. When the microorganism
recovered is of a type that is
often resistant to
antimicrobial drugs (eg, gram
negative enteric bacteria)
2. When an infectious process is
likely to be fatal unless
treated specifically (eg,
mengitis, septicaemia)
3. In certain infections where
eradication of the infectious
organisms requires the use of
drugs that are rapidly
bactericidal, not merely
bacteriostatic (eg, infective
endocarditis)

Dangers of Indiscriminate Use

o The indications for administration of
antibiotics must sometimes be
qualified by the following concerns
1. Widespread sensitization of the
population, with resulting
hypersensitivity, anaphylaxis,
rashes, fever, blood disorders,
cholestatic hepatitis,, and
perhaps collagen-vascular
diseases
2. Changes in the normal flora of
the body, with disease resulting
from superinfection due to
overgrowth of drug-resistant
organisms
3. Wala pic
4. Wala pic
5. Development of drug resistance
in microbial populations, chiefly
through the elimination of drugsensitive microorganisms from
antibiotic-saturated
environments (eg, hospitals) and
Page 16 of 21

their replacement by drugresistant microorganisms

Antimicrobial Drugs Used in
Combination
Indications:
o Possible reasons for employing two
or more antimicrobials
simultaneously instead of a single
drug are as follows:
1. To give prompt treatment in
desperately ill patients
suspected of having a serious
microbial infection
o A good guess about the most
probable two or three
pathogens is made, and drugs
are aimed at those organisms
o Before such treatment is
started, it is essential that
adequate specimens be
obtained for identifying the
etiologic agent in the
laboratory
o Suspected gram-negative or
staphylococcal sepsis in
immunocompromised
patients and bacterial
meningitis in children are
foremost indications in this
category
2. To delay the emergence of
microbial mutants resistance to
one drug in chronic infections by
the use of a second or third noncross-reacting drug. The most
prominent example is active
tuberculosis
3. To treat mixed infections,
particularly those following
massive trauma or those
involving vascular structures,
each drug is aimed at an
important pathogenic
microorganisms
4. To achieve bactericidal
synergism or to provide
bactericidal action
o In a few infections, eg,
enterococcal sepsis, a
combination of drugs is more
likely to eradicate the
infection than either drug
used alone
5. Such synergism is only partially
predictable, and a given drug
Microbiology Fundamentals of CHEMOTHERAPHY

pair may be synergistic for only a

single microbial stain
o Occasionally, simultaneous
use of two drugs permits
significant reduction in dose
and thus avoids toxicity but
still provides satisfactory
antimicrobial action
Disadvantages:
o The following disadvantages of
using antimicrobial drugs in
combinations must always be
considered:
1. The physician may feel that since
several drugs are already being
given, everything possible has
been done for the patient,
leading to relaxation of the effort
to establish a specific diagnosis.
It may also give a false sense of
security
2. The more drugs that are
administered, the greater the
chance for drug reactions to
occur or for the patient to
become sensitized to drugs
3. The cost is unnecessarily high
4. Antimicrobial combinations
usually accomplish no more than
an effective single drug
5. Very rarely, one drug may
antagonize a second drug given
simultaneously
Mechanisms:
o When two antimicrobial agents act
simultaneously on a homogenous
microbial population, the effect may
be one of the following:
1. Indifference, ie, the combined
action is no greater than that of
the more effective agent when
used alone
2. Addition, ie, the combined
action is equivalent to the sum of
the actions of each drug when
used alone
3. Synergism, ie, the combined
action is significantly greater
than the sum of both effects
4. Antagonism, ie, the combined
action is less than that of the
more effective agent when used
alone. All these effects may be
observed in vitro (particularly in
Page 17 of 21

o
o
o

terms of bactericidal rate) and in

vivo
The effects that can be achieved
with combinations of antimicrobial
drugs vary with different
combinations and are specific for
each strain of microorganism
Thus, no combination is uniformly
synergisitic
Combined therapy should be made
to employ the single antibiotic of
choice
In resistant infections, detailed
laboratory study can at times define
synergistic drug combinations that
may be essential to eradicate the
microorganisms

Mechanisms: Antimicrobialsynergism
o Can occur in several types of
situations. Synergistic drug
combinations must be selected by
complex laboratory procedures
1. Two drugs may sequentially
block a microbial metabolic
pathway. Sulfonamides inhibit
the use of extracellular paminobenzoic acid by some
microbes for the synthesis of
folic acid
o Trimethoprim or
pyrimethamine inhibits the
next metabolic step, the
reduction of dihydro- to
tetrahydrofolic acid
o The simultaneous use of a
sulphonamide plus
trimethoprim is effective in
some bacterial (shigellosis,
salmonellosis, serratia) and
some other infections
(pneumocystosis, malaria)
o Pyrimethamine plus a
sulfonamide or clindamycin is
used in toxoplasmosis
2. A drug such as a cell inhibitor (a
penicillin or cephalosporin) may
enhance the entry of an
aminoglycoside into bacteria and
thus produce synergistic effects
o Penicillins enhance the uptake
of gentamicin or streptomycin
by enterococci
o Thus, ampicillin plus
gentamicin may be essential
for the eradication of

Enterococcus faecalis,
particularly in endocarditis
o Similarly, piperacillin plus
tobramycin may be
synergistic against some
strains of pseudomonas
3. One drug may affect the cell
membrane and facilitate the
entry of the second drug
o The combined effect may
then be greater than the sum
of its parts
o For example, amphotericin
has been synergistic with
flucytosine against certain
fungi (eg, Cryptococcus,
candida)
4. One drug may prevent the
inactivation of a second drug by
microbial enzymes
o Thus, inhibitors of lactamase (eg, clavulanic
acid, sulbactam, tazobactam)
can protect amoxicillin,
ticarcilliin, or piperacillin from
inactivation by -lactamases
o In such circumstances, a form
of synergism takes place
Mechanisms: Antimicrobial antagonism
o Is sharply limited by time-dose
relationships and is therefore a rare
event in clinical antimicrobial
therapy
o Antagonism resulting in higher
morbidity and mortality rates has
been most clearly demonstrated in
bacterial meningitis
o It occurred when bacteriostatic drug
(which inhibited protein synthesis in
bacteria) such as chloramphenicol
or tetracycline was given with a
bactericidal drug such as a penicillin
or an aminoglycoside
o Antagonism occurred mainly if the
bacteriostatic drug reached the site
of infection before the bactericidal
drug; if the killing of bacteria was
essential for cure; and if only
minimal effective doses of either
drug in the pair were present
o Another example is combining lactam drugs in treatment of P
aeruginosa infections (eg, imipenem
and piperacillin, where imipenem is
a potent -lactamase inducer and
Page 18 of 21

the -lactamase breaks down the

less stable piperacillin)
Antimicrobial Chemoprophylaxis
o Anti-infective chemoprophylaxis
implies the administration of
antimicrobial drugs to prevent
infection
o In a broader sense, it also includes
the use of antimicrobial drugs soon
after the acquisition of pathogenic
microorganisms (eg, after
compound fracture) but before the
development of signs of infection
o Useful chemoprophylaxis is limited
to the action of a specific drug on a
specific organism
o An effort to prevent all types of
microorganisms in the environment
from establishing themselves only
selects the most drug resistant
organisms as the cause of a
subsequent infection
o In all proposed uses of prophylactic
antimicrobials, the risk of the
patients acquiring an infection must
be weighed against the toxicity,
cost, inconvenience, and enhances
risk of superinfection resulting from
the prophylactic drug
Prophylaxis in persons of normal
susceptibility exposed to a specific
pathogen
In this category, a specific drug is
administered to prevent one specific
infection
o Outstanding examples are the
injection of benzathine penicillin
G intramuscularly once every 3-4
weeks to prevent reinfection with
group A haemolytic
streptococci in rheumatic
patients
o Prevention of meningitis by
eradicating the meningococcal
carrier state with rifampin
o Prevention of syphilis by the
injection of benzathine penicillin
G
o Prevention of plague pneumonia
by oral administration of
tetracycline in persons exposed
to infections droplets
o Prevention of clinical rickettsial
disease (but not of infection) by
Microbiology Fundamentals of CHEMOTHERAPHY

o
o

the daily ingestion of tetracycline

during exposure
Prevention of leptospirosis with
oral administration of
doxycycline in a hyper endemic
environment
Early treatment of an
asymptomatic infections is
sometimes called prophylaxis
Thus, administration of
isoniazid, 6-10mg/kg/day
(maximum, 300mg/day) orally
for 6-12 months, to an
asymptomatic person who
converts from a negative to a
positive tuberculin skin test may
prevent later clinically active
tuberculosis

Prophylaxis in persons of increased

susceptibility
Certain anatomic or functional
abnormalities predispose to serious
infections
It may be feasible to prevent or
abort such infections by giving a
specific drug for short period
Prophylaxis in persons of increased
susceptibility:
Heart Disease
Persons with heart valve
abnormalities or with prosthetic
heart valves are unusually
susceptible to implantation of
microorganisms circulating in the
bloodstream
This infective endocarditis can
sometimes be prevented if the
proper drug can be used during
periods of bacteremia
Large numbers of viridants
streptococci are pushed into the
circulation during dental procedures
and operations on the mouth or
throat
At such times, the increased risk
warrants the use of a prophylactic
antimicrobial during aimed at
viridans streptococci
o for example, amoxicillin taken
orally before the procedure and 2
hrs later can be effective
o persons allergic to penicillin can
take erythromycin orally
Page 19 of 21

other oral and parenteral dosage

schedules can be effective
enterococci cause 5-15% of cases if
infective endocarditis
they reach the bloodstream from the
urinary, gastrointestinal or female
genital tract
during procedures in these areas,
persons with prostheses or heart
valve abnormalities can be given
ampicillin combined with an
aminoglycoside (eg, gentamicin),
both administered intramuscularly
or intravenously 30 minutes before
the procedure
during and after cardiac
catheterization, blood cultures may
be positive in 10-20% of patients
many of these persons also have
fever, but very few acquire
endocarditis
prophylactic antimicrobials do not
appear to influence these events
o

Prophylaxis in persons of increased

susceptibility:
Respiratory Tract Disease
persons with functional and
anatomic abnormalities of the
respiratory tract eg, chronic
obstructive pulmonary disease
(COPD) or bronchiectasis are
subject to attacks of chronic
bronchitis
this is a recurrent bacterial infection,
often precipitated by acute viral
infection and resulting in respiratory
decompensation
the most common organisms are
pneumococci & H. influenza
antibiotics may be given to patients
with COPD in the following clinical
setting: as prophylaxis for patients
with frequent recurrences of chronic
bronchitis, to treat an acute episode
of bronchitis, or to treat severe
exacerbations of COPD
there is little evidence supporting
the use of prophylactic antibiotics,
but patients with acute
exacerbations of chronic bronchitis
with changes in the character or
quantity of their sputum do benefit
from antibiotic therapy
simple prophylaxis of bacterial
infection has been applied to

children with cystic fibrosis who are

not hospitalized
in spite of this, such children
contract complicating infections
caused by pseudomonads and
staphylococci
trimethoprim-sulfamethoxazole
orally or pentamidine by aerosol is
used for prophylaxis for
pneumocystis pneumonia in AIDS
patients
for certain women who are subject
to frequently recurring urinary tract
infections, the oral intake either
daily or three times weekly of
nitrofurantion or trimethoprimsulfamethoxazole cane markedly
reduce that frequency of
symptomatic recurrences over long
periods
certain women tend to develop
symptoms of cystitis after sexual
intercourse
the ingestion of a single dose of
antimicrobial drug (nitrofurantion,
trimethoprim-sulfamethoxazole, etc)
can prevent post coital cystitis by
early inhibition of growth of bacteria
moved from the introitus into the
proximal urethra or bladder during
intercourse

Prophylaxis in persons of increased

susceptibility:
Oppotunistic Infections in Severe
Granulocytopenia
immunocompromised patients
receiving organ transplants or
antineoplastic chemotherapy often
develop profound leukopenia
when the neutrophil count falls
below 1000/L, they become
unusually susceptible to
opportunistic infections, most often
gram-negative sepsis
such persons are sometimes given
a fluoroquinolone or cephalosphorin
or a drug combination (eg,
vancomycin, gentamicin,
cephalosporin) directed at the most
prevalent opportunists at the
earlieast sign or even without
clinical evidence of infection
this is continued for several days
until the granulocyte count rises
again
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Prophylaxis in Surgery
a major portion of all antimicrobial
drug used in hospitals Is employed
on surgical services with the stated
intent of prophylaxis
several general features of surgical
prophylaxis merit consideration:
1. in clean elective surgical
procedures (ie, procedures
during which no tissue bearing
normal flora is traversed other
than the prepared skin), the
disadvantages of routine
antibiotic prophylaxis (allergy,
toxicity, superinfection) may
outweigh the possible benefits
except when hardware (eg.
Artificial hip joint) is being placed
however, even in clean
herniorrhaphy, a single
preoperative dose of a
cephalosporin resulted in
measurable benefit
2. prophylactic administration of
antibiotics should generally be
considered only if the expected
rate of infectious complications is
3-5%
an exception to this rule is the
elective insertion of
prostheses (cardiovascular,
orthopaedic), where a
possible infection would have
a catastrophic effect
3. The initial dose of systemic
prophylactic antibiotic should be
given at the time of induction of
anesthesia. An exception is
elective colonic surgery, in which
case oral antibiotics should be
given before the procedure
4. Prolonged administration of
antimicrobial drugs tends to alter

Microbiology Fundamentals of CHEMOTHERAPHY

the normal flora of organ

systems, suppressing the
susceptible microorganisms and
favouring the implantation of
drug-resistant ones
Thus, antimicrobial
prophylaxis should usually
continue for no more than 1
day after the procedure and
ideally should be given only
preoperatively
5. Systemic levels of antimicrobial
drugs usually do not prevent
wound infection, pneumonia, or
urinary tract infection if
physiologic abnormalities or
foreign bodies are present
Topical antimicrobials for
prophylaxis (intravenous
catheter site, closed urinary
drainage, within a surgical
wound, acrylic bone cement,
etc) have limited usefulness
Disinfectants
Disinfectants and antiseptics differ
from systematically active
antimicrobials in that they possess
little selective toxicity: They are
toxic not only for microbial
pathogens but for host cells as
well
Therefore, they can be used only to
inactivate microorganisms in the
inanimate environment or to a
limited extent, on skin surfaces
They cannot be administered
systematically

Page 21 of 21