ANTIMICROBIAL AGENTS
AN OVERVIEW AND MECHANISM OF ACTIONS.
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LEARNING OBJECTIVE
At the end of lecture students should be able to know,
What are antibiotics.
Different antimicrobial agents.
Combination of antimicrobial drugs.
Drug resistance.
Complication of antibiotic therapy.
Patient factors.
ANTIMICROBIAL DRUGS
Chemotherapy is defined as the use of synthetic, semisynthetic and
naturally occurring chemicals to kill or suppress the growth of specific
organism causing infectious disease or the agent that shows effectiveness
in the treatment of cancer.
ANTIMICROBIAL DRUGS
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Drugs used for the treatment of bacterial infection are the anti-bacterial
agents.
Drugs derived from living organisms (fungi) used to kill or suppress the
growth of microorganisms (bacteria) are known as antibiotics.
The terms antimicrobial and antibiotic are often used interchangeably.
ANTIMICROBIAL DRUGS
The ideal antimicrobial usually exhibits selective toxicity i.e.
they are harmful to microorganism but have little or no harmful
effect on the host (patient).
In many cases selective toxicity is relative, meaning that drugs
damage the microorganisms but may produce some damage to
the host cells.
The extent to which antibiotics are selectively toxic is mainly
determined by their mechanism of action.
Selective toxicity is achieved in two major ways:
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The antibiotic blocks a reaction, which is vital to invading microorganism but
not to the host, for example cell wall synthesis inhibition. Bacterial cell wall
synthesis inhibitors exhibit maximum selective toxicity as mammalian cells
are devoid of cell wall.
The antibiotic blocks a reaction, which is vital to both the host and microbe,
but because of differences in pathways involved; the effects are exerted
predominantly on microbial cells, for example inhibition of folic acid synthesis
and protein synthesis by microbes.
BACTERIA:
Bacteria are the rapidly growing unicellular microorganisms about 1
micrometer in diameter, usually having rigid cell wall; they usually have no
true nucleus and other cytoplasmic organelles.
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They also differ from the normal nucleated cell biochemically.
Bacteria are generally divided according to their shape into:
COCCI:
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Round shaped, they are further divided in Gram positive and Gram negative.
BACILLI:
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Rod shaped, they are further divided in Gram positive and Gram negative.
On the basis of staining properties bacteria are either gram positive (they
retain the stain and resist decolorization by alcohol) or gam negative (they
lose stain or decolorize by alcohol).
Some bacteria even resist the decolorization by acid and are known as acid
fast bacilli, e.g. Tubercle bacilli and Mycobacterium leprae.
GRAM POSITIVE COCCI:
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Streptococci, Staphylococci, Pneumococci and Enterococci.
GRAM NEGATIVE COCCI:
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Meningococci and Gonococci.
GRAM POSITIVE BACILLI:
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Corynebacterium diphtheria, Bacillus anthrax.
GRAM NEGATIVE BACILLI:
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E.coli, Salmonellae, Vibro cholrae, Pseudomonas, Shigella, Proteus, H.
influenza and Klebsella.
Bacteria growing in the presence of oxygen are aerobes, growing in absence
of oxygen are anaerobes, e.g. Bacteriodes & clostridia.
Most of the dental infections are caused by gram +ve aerobic and gram –ve
anaerobic bacteria.
Not all bacteria produce diseases, therefore bacteria may be non-pathogenic
(normal flora or commensal), the disease producing bacteria are pathogenic.
NORMAL FLORA OR COMMENSAL:
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A large number bacteria are present on skin, nasopharynx, mouth, GIT, lower
genitourinary tract. They do not produce disease but produce beneficial
effects. They prevent the growth of the pathogenic microorganisms. When
immunity is suppressed or anatomical site of commensal is changed they can
produce infection. For example E.coli are normally present in lower GIT, when
they reach urinary bladder, they can produce urinary tract infections.
Antibacterial drugs are either bacteriostatic (they suppress the growth of
bacteria) or bactericidal (they kill the bacteria).
BACTERIOSTATIC:
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Tetracyclines, Sulfonamides, Trimethoprim, Lincomycin.
They are more effective against rapidly growing bacteria.
BACTERICIDAL:
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Penicillin, cephalosporins, Vancomycin, Aminoglycosides, Co-trimoxazole.
Anti bacterial drugs are divided into:
NARROW SPECTRUM:
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Drugs effective against single or limited type of microorganisms, e.g.
Penicillin-G & V, Methicillin, Oxacillin, Vancomycin, Isoniazid, & Fusidic acid.
They are more effective against sensitive bacteria than broad spectrum
antibiotics.
EXTENDED SPECTRUM:
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Drugs are effective against gram-positive bacteria and also against significant
number of gram-negative bacteria, e.g. Ampicillin, amoxicillin,
Cephalosporins, Carbenicillin, Amikacin & Gentamicin.
Anti bacterial drugs are divided into:
BROAD SPECTRUM:
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Drugs are effective against wide variety of microorganisms, e.g.
Tetracyclines, Co-trimoxazole and Chloramphenicol.
Broad-spectrum antibiotics destroy the normal flora and may produce
superinfection, (introduction of new infection due to absence of normal
flora).
GENERAL RULES FOR ANTIBIOTIC USE
While treating infection it is essential to identify the microorganism, its
culture and sensitivity (C/S) is done prior to beginning antimicrobial therapy.
When ever possible, treatment should be started with narrow spectrum
antibiotics to which bacteria are sensitive, to avoid the chances of
superinfection and resistance.
Narrow spectrum antibiotics are more effective against susceptible
microorganisms than broad-spectrum antibiotics and they have little effect
on normal flora.
GENERAL RULES FOR ANTIBIOTIC USE
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While waiting the results of C/S if the infection is severe antibiotics coverage
for gram negative, positive and anaerobes should be given, and after getting
the results of C/S specific antibiotics should be started. Penicillins are suitable
to cover dental infections caused by gram +ve aerobic and gram –ve
anaerobic bacteria.
Antibiotics should be given in proper dosage for appropriate time.
GENERAL RULES FOR ANTIBIOTIC USE
When Pus is present it must be drained if possible or if a foreign body or any
necrotic tissue is present; they should be removed, as they favor the growth
of microorganisms.
When host defense mechanisms are inadequate to control or eradicate
infection, bactericidal drugs should be given.
When immune (defense) mechanisms are intact bacteriostatic agent may also
prove useful.
GENERAL RULES FOR ANTIBIOTIC USE
When infection is severe or microorganisms develop resistance to one drug, it
may require two or more drugs.
Drugs should be properly selected for combination therapy. Generally
combination of bacteriostatic and bactericidal drugs are avoided, as
bactericidal drugs are effective against rapidly growing microorganisms,
bacteriostatic agents reduce their efficacy.
CONCENTRATION OF ANTIBIOTIC AT THE SITE OF INFECTION:
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To be effective, an antibiotic must reach the site of infection in amounts
above the MLC or MIC for the infecting organism. Effective concentration of
antibiotic at the site of infection is influenced by:
DOSE AND DURATION:
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Effective antibiotic concentration depends upon the adequate dose of the
drugs given for proper duration. Duration of therapy varies with the type of
infection and status of patient, as a rule antibiotic coverage should last for at-
least 48 hours after complete remission of clinical symptoms. Treatment of
usual oral bacterial infection requires an average of 5–7 days of antibiotic
therapy.
ROUTE & TIME OF ADMINISTRATION:
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Absorption of antibiotics is usually affected by food; therefore antibiotics
are preferably given either 1 hour before or 2–3 hours after meals. Some
antibiotics like penicillin G, aminoglycosides are not effective when given
orally. Penicillin G is destroyed by gastric acid & aminoglycosides are not
absorbed from G.I.T, therefore these antibiotics are given parenterally.
When predictable and high systemic concentration required, antibiotic
should be given parenterally.
PATIENT COMPLIANCE:
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Patients usually stop taking antibiotics once their symptoms are
diminished; this reduces effective antibiotic concentration.
DISTRIBUTION OF THE DRUG:
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Chemotherapeutic agents differ in their ability to reach certain body
compartment. For infections of CNS drug must cross BBB, otherwise drug
has to be given intrathecally.
Infections in the areas of low blood supply like abscesses and infection in
necrotic areas are difficult to treat because of less antibiotics are
distributed to these areas.
Most antibiotics have good distribution in soft tissues, however, bony
penetration constitutes another problem, lincomycin and clindamycin
have good bony penetration and are suitable for treatment of bony
infections.
MECHANISM OF ACTION OF ANTIMICROBIAL DRUGS:
For many antimicrobial agents exact mechanism of action is not known;
antimicrobial agent generally act by one or more by the following
mechanisms.
Inhibition of the bacterial cell wall synthesis.
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Inhibition of cell membrane.
Inhibition of protein synthesis.
Antimetabolites.
Inhibition of nucleic acid synthesis.
INHIBITION OF CELL WALL SYNTHESIS:
In contrast to mammalian cell, bacterial cell possesses a rigid outer layer,
the cell wall; which completely surrounds the cell membrane.
The cell wall consists of cross linkage of peptidoglycans, which forms
much thicker layer in gram positive than gram negative bacteria.
INHIBITION OF CELL WALL SYNTHESIS:
 Bacteria possess high internal osmotic pressure than
the mammalian body fluids, the intact cell wall prevent
movement of mammalian body fluids to inside the
bacterium and is responsible for maintaining the shape
of bacterium.
 If the cell wall has been damaged, movement of water
into the cell will be followed by swelling, extrusion of
the cellular contents through weak areas of the cell wall
and cell lysis.
 Penicillin and cephalosporins are inhibitors of cell wall synthesis.
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INHIBITION OF CELL MEMBRANE:
Bacterial cell is lined by cell membrane that serves as selective permeability
barrier and controls internal environment of cell.
Disruption of cell membrane or alteration to cell membrane permeability
leads to bacterial cell damage. Polymyxins damage cell membrane of
bacteria that leads to the escape of metabolites, ions and proteins from
bacterial cell usually leading to cell death.
As bacterial & mammalian cell membranes have minor differences, cell
membrane inhibitors show low order of selective toxicity and are
potentially destructive to mammalian cells.
INHIBITION OF PROTEIN SYNTHESIS:
Bacterial ribosomes have sedimentation coefficient of 70 Svedberg units (S)
and may be dissociated into 30–S & 50–S subunits. Various protein synthesis
inhibitors preferentially bind to these subunits.
Drugs like Aminoglycosides, Tetracyclines, Chloramphenicol inhibit
specifically the proteins synthesis in bacteria.
Generally antibiotics that prevent protein synthesis exhibit bacteriostatic
activity but some of these antibiotics are bactericidal at concentrations that
can be achieved clinically.
inhibition of protein synthesis
ANTIMETABOLITES:
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Many bacteria synthesize folic acid from PABA (Para Amino Benzoic Acid),
and folic acid is required for the synthesis of nucleic acid (DNA and RNA).
Sulfonamides and trimethoprim inhibit the synthesis and utilization of
folic acid by bacteria and thus suppress their growth.
INHIBITION OF NUCLEIC ACID SYNTHESIS:
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Rifampin blocks RNA polymerase in bacteria and interferes with nucleic
acid synthesis.
Quinolones inhibit the DNA gyrase and reduce the formation of mRNA.
RESISTANCE TO ANTI-MICROBIAL DRUGS:
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Sometimes antimicrobials fail to control the infection as microorganisms
become resistant to the drug. There are many mechanisms by which
microorganisms develop resistance.
Resistance may be:
Natural or Acquired, it may be due to
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Inability of the drug to penetrate cell wall.
Changes in the receptor proteins.
Synthesis of enzymes by microorganisms that destroy the drug.
Changes in the structure of DNA.
Changes in the metabolic pathways that bypass the reaction inhibited by
drug.
Acquired resistance is usually plasmid derived, plasmid is the extrachromosomal genetic material present in cytoplasm of the bacteria that is
not essential for viability of organism but in some way changes the organism’s
ability to adopt the environment.
Resistance is acquired by mutation of gene encoding an inactivating enzyme,
target protein or transport protein.
Resistant gene may be passed vertically to daughter cells. More commonly
resistance is acquired by horizontal transfer of resistant determinants from
one bacterium to other by transformation, transduction and conjugation.
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This type of transfer spreads rapidly and widely.
TRANSFORMATION:
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This method of transferring gene information involves incorporation of DNA
that lies free in the environment into bacteria.
TRANSDUCTION:
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Transduction takes place through bacteriophage i.e. a virus that infects
bacteria and contains bacterial DNA in its protein coat.
CONJUGATION:
It is the passage of gene from cell to cell by direct contact through sex bridge.
It mainly occurs in gram-negative bacilli. It can take place in intestine
between non-pathogenic and pathogenic microorganisms.
THE END
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