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 on smear of exudate from the infected
area.
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.