Anti - infective therapy

General
considerations
Drugs used for the treatment of infectious
diseases may be termed antibiotics,
antiinfectives, antimicrobials, or
chemotherapeutic agents.

Antibiotics are strictly defined as natural

substances produced by various
microorganisms and capable of
inhibiting the growth of other
microorganisms. The term
semisynthetic is often applied to the
product of a chemical alteration of a
naturally derived anti-infective
compound.
 CLASSIFICATIONS
SPECTRUM OF ACTIVITY
Range of spectrum of activity.
Broad Spectrum - exert their effects
against a number of different type of
bacteria and other microorganisms.
(Wider range)
Narrow Spectrum - primarily affect only
one group of microorganisms
 ANTIMICROBIAL ACTIVITY

BACTERIOSTATIC - suppress the

growth of microorganisms without
actually killing existing microbes.
BACTERICIDAL - capable of
directly destroying organisms
 MECHANISMS OF ACTION
Inhibition of Bacterial Cell Wall
synthesis - bacteria possess a rigid cell
wall composed of macromolecules
cross-linked by peptide chains. Drugs
acting by inhibiting cell wall synthesis
do so by interfering with various steps
in the assembly of the peptide chains
that impart rigidity to the cell wall. The
weakened cell wall can no longer
support the internal pressure, and the
cells undergo lysis and disintegrate.
(Penicillins, Cephalosporins, Bacitracin)
Alteration in cell membrane
functions - The semipermeable
bacterial cell membrane helps control
the internal environment of the cell by
functioning as a selective barrier to
penetration of cell constituents and
nutrients. Disruption of this membrane
by antibiotics alters its permeability, by
allowing escape of proteins,
nucleotides, sugars, amino acids and
other cell constituents resulting in
damage to the cell and ultimately
cellular death.
(amphotericin, nystatin, polymyxins)
Inhibition of protein synthesis -
certain antibiotics can interfere with
ribosomal mediated protein synthesis in
bacterial cells without affecting protein
synthesis in normal mammalian cells.
Antibiotics may disrupt bacterial protein
synthesis at several stages; for
example binding to the ribosomes,
blocking attachment of transfer RNA,
causing misreading of the genetic code,
interfering with attachment of amino
acids to the developing peptide chain.
(aminoglycoside, erythromycin,
tetracyclines)
Inhibition of nucleic acid
metabolism - Although most agents
interferring with nucleic acid
metabolism are used as antineoplastic
drugs, a few antibacterial compounds
act in this manner as well. Nalidixic acid
inhibits DNA synthesis, rifampicin
interferes with DNA-dependent RNA
synthesis, and trimethoprim can inhibit
dihydrofolate reductase, an enzyme
essential for production of
tetrahydrofolic acid, an intermediate in
the formation of DNA.
(nalidixic acid, rifampin, trimethoprim)
 Interference with intermediate cell
metabolism - All bacteria require dihydrofolic
acid for production of nucleic acid; however,
certain bacteria cannot assimilate preformed
dihydrofolic acid but must synthesize it
themselves from precursors within the cell. An
essential precursor is para-amino-benzoic acid
(PABA), and because sulfonamides are close
structural analogues of PABA, they compete
with it for active sites within bacterial cells,
impairing synthesis of dihydrofolic acid and
thus cell replication.
 (sulfonamides)
 Selection of Appropriate
Drug
The aim of anti-infective drug
therapy is to choose an agent
that is most likely active
against the offending
pathogen and has at least
potential to adverse
reactions.
 Several important considerations go into
the choice of a suitable antimicrobial drug
for use in a particular patient.

1. Necessity of Therapy - Many

infectious conditions do not
require systemic antimicrobial
therapy, and the clinician should
make a careful assessment of the
patients status and the location
and severity of the infection
before undertaking antibiotic
therapy.
2. Diagnosis of the Pathogen -
Accurate determination of the infecting
organism or organisms is the
cornerstone of safe and effective
antimicrobial therapy.
Appropriate anti-infective therapy is
best accomplished by bacteriologic
culture of the infected material
(sputum, pus, urine) subsequent
isolation and identification of the
pathogen, and selection of an antibiotic
known to be effective agaisnt the
offending organism.
While it is always desirable to have the results of
bacterial culturing before initiating
antibacterial treatment this is not always
practical or feasible. For example in life
threatening infections (septicemia, peritonitis,
pneumonia) a delay in initiating anti bacterial
treatment of 24 to 48 hours while awaiting
result of culture testing can prove fatal.
The initial choice of an antibiotic should be made
on the basis of patient history, physical
examination, clinical symptoms and most
especially awareness on the part of the
clinician as to what microorganisms are likely
to be present based on the site of infection
and the circumstances under which it
developed. In some cases the probable
organism can be determined by the attending
physician by performing a simple Grams’ stain
3. Sensitivity Testing - because many
common microorganisms exhibit
varying degrees of antibacterial
resistance once a pathogen has been
identified by bacteriologic culturing the
sensitivity of the infecting organism to
different antimicrobial drugs is often
determined. Sensitivity testing
however, is not always necessary
because some microorganisms are
uniformly susceptible to certain
antibiotics.
4. Location of the infection - generally, once
the offending organism has been identified
and its susceptibility ascertained, a selective
choice of an antimicrobial agent can be made.
However, consideration must also be given to
the location of the infection when choosing an
appropriate antibiotic. The distribution of an
antibacterial drug in the body is an important
determinant of its ultimate efficacy. Although
the concentration of an antibacterial agent in
the body is usually defined in terms of blood
or plasma levels, the critical concentration is
that which is achieved in the infected tissues
themselves.
Combined Antimicrobial Therapy

Although most infections can be adequately

treated with a single anti-infective agent,
simultaneous administration of two or more
antimicrobial agent is justifiable under certain
circumstances.
The primary indications for combination anti-
infective therapy are the following:
1. Treatment of mixed bacterial
infections - Some infections may be
complicated by the presence of two or
more microorganisms possessing
different antimicrobial susceptibility.
Although broad spectrum antibiotics are
occasionally successful when used alone
in such infections, combination therapy
is frequently necessary to ensure
complete eradication of all pathogens
present in mixed infections.
2. Initial treatment of severe
infections where the causative
agent is unknown - Before the results
of bacteriologic culturing in an unknown
infection are obtained, combination
therapy is often undertaken to ensure
that the widest range of possible
organism is covered. Such treatment of
course should be modified if necessary
as soon as culture and sensitivity data
are available; prolonged use of several
broad-spectrum anti-infective drug is
not only expensive but may result in
serious toxicity as well.
3. Postponement of the emergence of
resistant strains - Development of
resistance to antibiotic agents is often
delayed (but not necessarily prevented)
when a sensitive pathogen is exposed
to two drugs simultaneously. This is
particularly apparent with the combined
use of two or more antitubercular drugs
4. Enhancement of antibacterial
therapy - Increased antibacterial
activity is frequently observed with
simultaneous use of two
antibiotics, compared to that
observed with each drug alone.
5. Reduction of toxicity - In certain
instances, combined use of anti-
infective drugs may allow a reduced
dosage of one or both drugs, with a
possible corresponding reduction in
toxicity. On the other hand, the addition
of a second drug to the regimen,
especially at full dosage, can increase
the likelihood of adverse effects
compared to that seen with a single
drug.
 Adverse Effects of
Antimicrobial Drugs
1. Hypersensitivity - both acute and
delayed allergic responses have
occurred with a number of antimicrobial
drugs, most frequently with the
penicillins and sulfonamides. These may
range from mild dermatologic
manifestations, such as skin rash,
itching, and urticaria, to severe
anaphylactic reactions, which have
proved fatal in a number of instances.
2. Organ Toxicity - various classes
of antibiotics are known to exert
selective toxic effects on certain
structures or organs of the body.
For example; aminoglycosides and
vancomycin cause both renal and
eight cranial nerve damage.
3. Superinfection - development of
secondary infections is a potentially
serious problem connected with
antibiotic usage. It occurs most often as
a result of prolonged anti-infective
therapy, insufficient drug dosage,
impaired host defense mechanisms,
concurrent therapy with
immunosuppressant drugs or a
combination of these factors.Pathogens
fequently responsible for secondary
infections include Pseudomonas,
proteus, candida and drug resistant
staphylococci and fungi.
These organisms may be especially difficult to
eradicate because they often represent strains
resistant to conventional antimicrobial agents.
Although superinfection can theoretically occur
anywhere in the body, it is found most
commonly in the GI tract and may be
manifested by diarrhea, glossitis, stomatitis,
“furry” tongue and perenial irritation. Prompt
recognition of a secondary infection is critical
to its effective management. Therapy is best
accomplished by discontinuing the initial
antibiotic culturing the infected area and
administering an antimicrobial drug shown by
sensitivity testing to be effective against the
new organism.
4. Resistance - bacteria are susceptible
to elimination by some anti-infective
drugs but not others. The phenomenon
whereby certain organisms are
unaffected by a particular antimicrobial
agent is called resistance. Bacterial
resistance may be broadly categorized
into either natural or acquired
resistance. Natural resistance is
genetically determined and may be
characteristics of either an entire
species or only certain strains within a
species.
Acquired resistance on the other
hand can develop in previously
susceptible pathogens for a
number of reasons and is a major
clinical problem with many anti-
infective drugs. Development of
bacterial resistance has severely
limited the usefulness of many
antibiotics in certain infections.
 Microorganisms can develop resistance to
anti-infective drugs in a number of ways,
the most important of which are listed
below:
Elaboration of enzymes (e.g. beta-
lactamases such as penicillinase or
cephalosporins) that destroy the drug.
Decreased permeability of the
microbial cell membrane to certain
antibiotics (e.g. tetracyclines,
aminoglycosies, chloramphenicol) that
depend on penetration into the bacteria
for their effectiveness.
Development of altered binding
sites (e.g. loss of specific ribosomal
proteins) within the bacterial cell for
certain antibiotic drugs (e.g.
aminoglycosides, erythromycins) that
normally interrupt ribosomal function by
chemically binding to ribosomal
proteins.
Development of altered enzymatic
or metabolic pathways that either
entirely bypass the reaction inhibited by
the antimicrobial drug or that become
less susceptible to interruption by
antibiotic drugs such as sulfonamides.
Production by bacteria of a direct
antibiotic drug antagonist (e.g. PABA
vs sulfonamides)

To minimize this possibility, it is

essential that antimicrobial drugs be
used sensibly and that only those drugs
necessary to eliminate the organisms
known to be present should be
prescribed.
 Dosage and Duration of Therapy:
Anti-infective drug dosage should
always be high enough and duration of
treatment long enough to provide
effective drug concentrations in infected
tissues in order to render the culture
from the infected site sterile.
Although different infections require
variable treatment durations, oral anti-
microbial therapy of most common
respiratory and urinary infections
should be continued for a minimum of 7
days to 10 days.
Patients may decide to discontinue
antimicrobial drugs as soon as the overt
symptoms (e.g. fever, sore throat,
painful urination) of their disease
subside. For this reason they should be
carefully instructed to continue the
drugs for at least 48 hours to 72 hours
after symptoms disappear to ensure
that the pathogen is completely
eliminated. Follow up cultures are also
desirable to confirm the effectiveness of
therapy.