Antimicrobial
Definitions
Antibiotic—antimicrobials of microbial origin, most of which are
produced by fungi or by bacteria of the genus Streptomyces.
•
• Antimicrobial, antimicrobic—any substance with sufficient
antimicrobial activity that it can be used in the treatment of infectious
diseases.
• Bactericidal—an antimicrobial that not only inhibits growth but is
lethal to bacteria.
• Bacteriostatic—an antimicrobial that inhibits growth but does not kill
the organisms.
Sources of Antimicrobial Agents
There are several sources of antimicrobial agents. The antibiotics are of
biological origin and probably play an important part in microbial
ecology in the natural environment. Penicillin, for example, is produced
by several molds of the genus Penicillium, and the prototype
cephalosporin antibiotics were derived from other molds. The largest
source of naturally occurring antibiotics is the genus Streptomyces, the
members of which are Gram-positive, branching bacteria found in soils
and freshwater sediments, which produce several antibiotic as
Streptomycin, the tetracyclines, chloramphenicol, erythromycin.
Chemically synthesized antimicrobial agents were initially discovered
among compounds synthesized for other purposes and tested for their
therapeutic effectiveness in animals. The sulfonamides, for example,
were discovered as a result of routine screening of aniline dyes.
 Antimicrobics that act on cell wall synthesis.
The peptidoglycan (murein sac) component of the bacterial cell wall
gives it its shape and rigidity. This giant molecule is formed by weaving
the linear glycans N-acetylglucosamine and N-acetylmuramic acid into a
basket-like
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structure. This cross-linking process is the target of two of the most
important groups of antimicrobics, the B-lactams and the glycopeptides
(vancomycin and teicoplanin)
1.B-Lactam Antimicrobics
The B-lactam antimicrobics comprise the penicillins, cephalosporins,
carbapenems, and monobactams. Their name derives from the presence
of a B-lactam ring in their structure; this ring is essential for antibacterial
activity.
A-Penicillins Penicillins differ primarily in their spectrum of activity
against Gram negative bacteria and resistance to staphylococcal
penicillinase. This penicillinase is one of a family of bacterial enzymes
called B-lactamases that inactivate B-lactam antimicrobics
Penicillin G is active primarily against Gram-positive organisms, Gramnegative cocci, and some spirochetes, They have little action against
most Gram-negative bacilli, because the outer membrane prevents
passage of these antibiotics to their sites of action on cell wall synthesis.
Penicillin G is the least toxic and least expensive of all the penicillins. Its
modification as penicillin V confers acid stability, so it can be given
orally.
The penicillinase-resistant penicillins (methicillin, nafcillin, oxacillin) also
have narrow spectra, but are active against penicillinase-producing S.
aureus. The broader spectrum penicillins owe their expanded activity to
the ability to traverse the outer membrane of some Gram-negative
bacteria. Some, such as ampicillin, have excellent activity against a range
of Gram-negative pathogens but not P. aeruginosa.
B-Cephalosporins The structure of the cephalosporins confers resistance
to hydrolysis by staphylococcal penicillinase and to the B-lactamases of
groups of Gram-negative bacilli, which vary with each cephalosporin.
The cephalosporins are classified by generation— first, second, third, or
fourth. The “generation” term relates to historical breakthroughs in
expanding their spectrum through modification of the side chains.as
cefoxitin , cefaclor, ceftriaxone, cefotaxime, and ceftazidime
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C-Carbapenems The carbapenems imipenem and meropenem have the
broadest spectrum of all B-lactam antibiotics. penetration of Gramnegative and Gram-positive bacterial cells and high level of resistance to
Blactamases.
D-Monobactams ,Aztreonam, the first monobactam licensed in the
United States, has a spectrum limited to aerobic and facultatively
anaerobic Gram-negative bacteria, including Enterobacteriaceae, P.
aeruginosa, Haemophilus, and Neisseria.
2.Glycopeptide Antimicrobics
Two agents, vancomycin and teicoplanin, belong to this group. Each of
these antimicrobics inhibit assembly of the linear peptidoglycan
molecule by binding directly to the terminal amino acids of the peptide
side chains.
 Polypeptide Antibiotics Affect the Cell Membrane
Both bacitracin and polymyxin B are polypeptide antibiotics
produced by Bacillus species. These antibiotics are quite toxic
internally and can cause kidney damage. Therefore, they generally
are restricted to topical use, such as on the skin.
 Inhibitors of Protein Synthesis
1.Aminoglycosides. The aminoglycosides are a group of bactericidal
antibiotic compounds that attach irreversibly to the 30S subunit of
bacterial ribosomes, thereby blocking the reading of the genetic code on
messenger RNA (mRNA).
Gentamicin and tobramycin are the major aminoglycosides; they have
an
extended
spectrum,
which
includes
staphylococci;
Enterobacteriaceae; and of particular importance
,
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P. aeruginosa. Streptomycin and amikacin are now primarily used in
combination with other antimicrobics in the therapy of tuberculosis and
other mycobacterial diseases.
Neomycin, the most toxic aminoglycoside, is used in topical
preparations and as an oral preparation before certain types of intestinal
surgery, because it is poorly absorbed.
2.Tetracyclines. The tetracyclines are a group of broadspectrum
bacteriostatic antibiotics that block attachment of the tRNA to the 30S
subunit. There are naturally occurring chlortetracyclines, isolated from
species of Streptomyces, and semisynthetic tetracyclines, such as
minocycline and doxycycline.Tetracyclines have said effect cause a
yellowgray brown discoloration of teeth and stunted bones in children,
The tetracyclines are broad-spectrum agents with a range of activity that
encompasses most common pathogenic species, including Gram-positive
and Gram-negative rods and cocci and both aerobes and anaerobes.
They are active against cell wall–deficient organisms, such as
Mycoplasma and spheroplasts, and against some obligate intracellular
bacteria, including members of the genera Rickettsia and Chlamydia.
3.Chloramphenicol. An antibiotic with a broad spectrum acts on 50s
subunit .Its discovery from Streptomyces venezuelae was hailed as a
milestone in microbiology because the drug is capable of inhibiting a
wide variety of gram positive and gram-negative bacteria, as well as
several species of rickettsiae and fungi. side effects. In the bone marrow,
it prevents hemoglobin incorporation into the red blood cells, causing a
condition called aplastic anemia and Chloramphenicol also accumulates
in the blood of newborns, causing a toxic reaction and sudden
breakdown of the cardiovascular system known as the gray syndrome.
4. Macrolides.
erythromycin, azithromycin, and clarithromycin, differ in the exact
composition of a large 14- or 15-member ring structure. They affect
protein synthesis at the ribosomal level by binding to the 50S subunit
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and blocking the translocation reaction. Their effect is primarily
bacteriostatic.
5. Clindamycin
Clindamycin is chemically unrelated to the macrolides acts on 50s
subunit but has a similar mode of action and spectrum. It has greater
activity than the macrolides against Gram-negative anaerobes, including
the important Bacteroides fragilis group.
6.Streptogramins
Quinupristin and dalfopristin are used in a fixed combination known as
quinupristin dalfopristin in a synergistic ratio. They inhibit protein
synthesis by binding to different sites on the 50S bacterial ribosome.
 Inhibitors of Nucleic Acid Synthesis
Quinolones
The quinolones have a nucleus of two fused six-member rings that when
substituted with fluorine become fluoroquinolones, which are now the
dominant quinolones for treatment of bacterial infections. Among the
fluoroquinolones, ciprofloxacin, norfloxacin, and
ofloxacin. The primary target of all quinolones is DNA topoisomerase
(gyrase), the enzyme responsible for nicking, supercoiling, and sealing
bacterial DNA during replication. The fluoroquinolones are highly active
and bactericidal against a wide range of aerobes and facultative
anaerobes
 Folate Inhibitors
Agents that interfere with synthesis of folic acid by bacteria have
selective toxicity because mammalian cells are unable to accomplish this
feat and use preformed folate rom dietary sources. Folic acid is derived
from para-aminobenzoic acid (PABA), glutamate, and a pteridine unit.
Sulfonamides and Trimethoprim-Sulfamethoxazole. Trimethoprim acts
on the folate synthesis pathway but at a point after sulfonamides.
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 Metronidazole
Metronidazole is a nitroimidazole, a family of compounds with activity
against bacteria, fungi, and parasites. The antibacterial action requires
reduction of the nitro group under anaerobic conditions
 Rifampin
asemisynthetic bactericidal drug derived from Streptomyces
mediterranei, interferes with RNA synthesis.This agent is active against
most Gram-positive bacteria and selected Gram-negative organisms,
including Neisseria and Haemophilus but not members of the
Enterobacteriaceae. The most clinically useful property of rifampin is its
antimycobacterial activity, which includes Mycobacterium tuberculosis.
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