Chapter-1

Introduction
1.1 Antibiotics

Antibiotics or antibacterials are a type of antimicrobial used in the treatment and prevention of
bacterial infection.They may either kill or inhibit the growth of bacteria. Several antibiotics are also
effective against fungi and protozoans, and some are toxic to humans and animals, even when given
in therapeutic dosage. Antibiotics are not effective against viruses such as the common cold or
influenza, and may be harmful when taken inappropriately. Antibiotics revolutionized medicine in
the 20th century, and have together with vaccination led to the near eradication of diseases such as
tuberculosis in the developed world. Their effectiveness and easy access led to overuse, especially in
live-stock raising, prompting bacteria to develop resistance. This has led to widespread problems
with antimicrobial and antibiotic resistance, so much as to prompt the World Health Organization to
classify antimicrobial resistance as a "serious threat [that] is no longer a prediction for the future, it
is happening right now in every region of the world and has the potential to affect anyone, of any
age, in any country".The era of antibacterial chemotherapy began with the discovery of
arsphenamine, first synthesized by Alfred Bertheim and Paul Ehrlich in 1907, used to treat syphilis.
The first systemically active antibiotic, prontosil was discovered in 1933 by Gerhard Domagk, for
which he was awarded the 1939 Nobel Prize. Sometimes the term antibiotic is used to refer to any
substance used against microbes, synonymous to antimicrobial. Some sources distinguish between
antibacterial and antibiotic; antibacterials used in soaps and cleaners etc., but not as medicine. This
article treats the terms as synonymous and according to the most widespread definition of
antibiotics being a substance used against bacteria.

1.2 Classification of Antibiotics

Antibacterial antibiotics are commonly classified based on their mechanism of action, chemical
structure, or spectrum of activity.

1.2.1 Based on Mechanism of action

1.2.1.1 Bactericidal

Those that target the bacterial cell wall (penicillins and cephalosporins) or the cell membrane
(polymyxins), or interfere with essential bacterial enzymes (rifamycins, lipiarmycins, quinolones, and
sulfonamides) have bactericidal activities.

1.2.1.2 Bacteriostatic

Those that target protein synthesis (macrolides, lincosamides and tetracyclines) are usually
bacteriostatic (with the exception of bactericidal aminoglycosides)

1.2.2 Based on their target specificity

1.2.2.1 Narrow-spectrum

Antibacterial antibiotics target specific types of bacteria, such as Gram-negative or Gram-positive

bacteria.

1.2.2.2 Broad-spectrum

Antibiotics affect a wide range of bacteria.

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1.3 Some important antibiotic group with structure

1.3.1 β-Lactam antibiotics

O O R2
H H H H H H R3 R
2
S S
R HN R 1 HN R1 3 HN
R
N N R2 N N
O O O O R'
COOH COOH COOH

penicillins cephalosporins carbapenems monobactams

Fig1.1: β-Lactam antibiotics

1928: A. Fleming discovered that his cultures of staphylococci was contaminated  with a fungus, and
that the colonies of staphylococci immediately surrounding the fungus had been destroyed, whereas
other staphylococci colonies farther away were normal. This fungi was the Penicillium notatum which
produced a bactericidal agent. The penicillins are the oldest of the clinical antibiotics, but are still the
most widely used. The first of the many penicillins to be employed on a significant scale was
penicillin G (benzylpenicillin), obtained from the fungus Penicillium chrysogenum by fermentation in
a medium containing corn-steep liquor. The α-aminoadipyl side-chain of isopenicillin N is removed
and replaced by another acid according to its availability from the fermentation medium. Several other
penicillins are accessible by supplying different acids.

1.3.2 Aminoglycosides
OHC OH H2N
NH2
O N OH
H2N N O O O H2N
NH H2N NH2
HO O HO HO NH2 OH
O O HO O O
OH O
H2N N N O O NH2
OH OH
OH OH OH OH NH2 NH2 OH
NH2

streptomycin gentamycin tobramycin

Fig1.2: Aminoglycosides

The aminoglycosides form an important group of antibiotic agents and are immediately recognizable
as modified carbohydrate molecules. Typically, they have two or three uncommon sugars, mainly
aminosugars, attached through glycoside linkages to an aminocyclitol, i.e. an amino-substituted
cyclohexane system, which also has carbohydrate origins. The aminoglycoside antibiotics have a
wide spectrum of activity, includingactivity against some Gram-positive and many Gram-negative
bacteria. They must be administered by injection. The widespread use of aminoglycoside antibiotics is
limited by their nephrotoxicity, which results in impaired kidney function, and by their ototoxicity,
which is a serious side-effect and can lead to irreversible loss of hearing. The aminoglycoside
antibiotics interfere with protein biosynthesis.

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1.3.3 Cyclic peptide antibiotics

The cyclosporins are a group of cyclic peptides produced by fungi such as Cylindrocarpon lucidum
and Tolypocladium inflatum. These agents show a narrow range of antifungal activity , but high levels
of immunosuppressive and anti-inflammatory activities. It is now widely exploited in organ and tissue
transplant surgery to prevent rejection following bone-marrow, kidney, liver, pancreas, lung, and heart
transplants. It has revolutionized organ transplant surgery, substantially increasing survival rates in
transplant patients.

O HO
O
O N HN
N N
NH O
O
N O
O N O O
H
N N
N N
H
O O

Fig1.3: Cyclosporin A

1.3.4 Glycopeptide antibiotics

1.3.4.1 Bleomycin

Bleomycin is a mixture of glycopeptide antibiotics isolated from cultures of Streptomyces verticillus,

and used for its anticancer activity . Bleomycin is a DNA-cleaving drug, causing single and double
strand breaks in DNA.
HO
OH
OH OH
HO O O
N O
O O NH2
O
O OH HO O
N S+
NH2 O
H OH O
H H N
N N N N N
N H
HN N
H H
H2N N O O S S

NH2
H2N O

Fig1.4: Bleomycin

1.3.4.2 Vancomycin

Vancomycin is frequently the last-resort agent in the control of methicillinresistant Staphylococcus

aureus (MRSA), since many strains have become resistant to all other antibiotics. It has activity
against Gram-positive bacteria, especially resistant strains of staphylococci, streptococci, and
enterococci. OH OH
Cl
HO HO OH O
O HO
H2N O NH
O
O O NH OH
O O
O
N
O H OH
OH
Cl HN
O

NH
HO
O NH2
O NH O

N
H

Fig1.5: Vancomycin

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1.3.5 Macrocyclic lactone antibiotics

The macrolide antibiotics are macrocyclic lactones with a ring size typically 12–16 atoms, and with
extensive branching through methyl substituents. Polyene macrolides are larger in the range 26–38
atoms. The largest natural macrolide structure discovered has a 66-membered ring. Two or more
sugar units are attached through glycoside linkages; these sugars tend to be unusual 6-deoxy
structures often restricted to this class of compounds. Macrolides are protein synthesis inhibitors.

Erythromycin activity is predominantly against Gram-positive bacteria, and the antibiotic is

prescribed for penicillin allergic patients
HO
O

OH O O

HO
O O O
O
O
OH OH
N

Fig1.6: Erythromycin

1.3.5.1 Polyene macrolides

Most polyene macrolides have antifungal properties, but not antibacterial activity. The
macrolide ring size ranges from 26 to 38 atoms, and this also accommodates a conjugated
polyene of up to seven E double bonds.

1.3.6 Amphotericin

Amphotericin is active against most fungi and yeasts, but it is not absorbed from the gut, so
oral administration is

potentially life-threatening systemic fungal infections.

OH
NH2
O
OH
OO
HO
HO

O HO
OH
HO
O

OH OH OH OH O

Fig1.7: Amphotericin

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1.3.7 Tetracycline antibiotics

The tetracyclines are a group of broad-spectrum, orally active antibiotics produced by species
of Streptomyces, and several natural and semi synthetic members are used clinically. Their
antimicrobial activity arises by inhibition of protein synthesis. Although the tetracycline
antibiotics have a broad spectrum of activity spanning Gram-negative and Gram-positive
bacteria, their value has decreased as bacterial resistance has developed in pathogens such as
Pneumococcus, Staphylococcus, Streptococcus, and E. coli.

Cl OH N
OH

NH2
OH
OH O OH O O
Fig1.8: Chlortetracycline

1.3.8 Antracycline antibiotics

A number of anthracycline antibiotics, e.g. doxorubicin (one of the most successful and
widely used antitumour drugs) from Streptomyces peuceticus and daunorubicin from
Streptomyces coeruleorubicus, have structurally similar tetracyclic skeletons and would
appear to be related to the tetracyclines. However, anthraquinone derivatives are
intermediates in anthracycline biosynthesis, and the fourth ring is constructed later.
OH
O OH
OH
O

O O OH O NH2

O
OH

Fig1.9: Doxorubicin

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1.4 Ancient History

The ancient Egyptians, the Chinese, and Indians of central America all used molds to treat infected
wounds. However, they did not understand the connection of the antibacterial properties of mold and
the treatment of diseases.

Late 1800s
The search for antibiotics began in the late 1800s, with the growing acceptance of the germ theory of
disease , a theory which linked bacteria and other microbes to the causation of a variety of ailments.
As a result, scientists began to devote time to searching for drugs that would kill these disease-causing
bacteria.

1871
The surgeon Joseph Lister, began researching the phenomenon that urine contaminated with mold
would not allow the successful growth of bacteria.

1890s
German doctors, Rudolf Emmerich and Oscar Low were the first to make an effective medication that
they called pyocyanase from microbes. It was the first antibiotic to be used in hospitals. However, the
drug often did not work.

1928
Sir Alexander Fleming observed that colonies of the bacterium Staphylococcus aureus could be
destroyed by the mold Penicillium notatum, demonstrating antibacterial properties.

1935
Prontosil, the first sulfa drug, was discovered in 1935 by German chemist Gerhard Domagk (1895–
1964).

1942
The manufacturing process for Penicillin G Procaine was invented by Howard Florey (1898–1968)
and Ernst Chain (1906–1979). Penicillin could now be sold as a drug. Fleming, Florey, and Chain
shared the 1945 Nobel Prize for medicine for their work on penicillin.

1943
In 1943, American microbiologist Selman Waksman (1888–1973) made the drug streptomycin from
soil bacteria, the first of a new class of drugs called aminoglycosides. Streptomycin could treat
diseases like tuberculosis, however, the side effects were often too severe.

1955
Tetracycline was patented by Lloyd Conover, which became the most prescribed broad spectrum
antibiotic in the United States.

1957
Nystatin was patented and used to cure many disfiguring and disabling fungal infections.

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1981
SmithKline Beecham patented Amoxicillin or amoxicillin/clavulanate potassium tablets, and first sold
the antibiotic in 1998 under the tradenames of Amoxicillin, Amoxil, and Trimox. Amoxicillin is a
semisynthetic antibiotic.

1.5 Mechanisms of Antibiotic Action

The many modes of antibiotic action are shown schematically in the diagram below.

Fig1.10: Mechanism of antibiotic action

1.6 Some specific examples

1.6.1 -Lactam antibiotics

 Penicillin is a -lactam antibiotic.

 These antibiotics contain a -lactam ring—three carbons and one nitrogen.
 Transpeptidase crosslinks the peptidoglycan net in the cell wall of Gram-positive bacteria.
 The -lactam ring mimics a component of the cell wall to which transpeptidase binds.
 Penicillin competitively inhibits the binding of transpeptidase.

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 The affected bacterium will eventually lyse (rupture) because the unsupported cell wall
cannot withstand its growth.

1.6.2 Disrupters of nucleic acid synthesis

 RNA polymerase synthesizes RNA according to a DNA template.

 The antibiotic rifampin interferes with prokaryotic RNA polymerase and thus, interferes
with transcription.
 Fluoroquinolones inhibit DNA gyrase, a bacterial enzyme that unwinds DNA in
preparation for replication and transcription.
 Both of these disruptions prevent bacteria from dividing to make more bacteria.

1.6.3 Disrupters of protein synthesis

 Aminoglycosides inhibit nucleic acid or protein synthesis in bacteria.

 They are L-shaped molecules that fit into L-shaped pockets of bacterial ribosomal RNA.
 When they insert themselves into rRNA, they disrupt ribosomal structure.
 Aminoglycosides don’t have this effect on human cells because the L-shaped pocket is
specific to bacteria.

1.6.4 Inhibitors of metabolism

 Inhibit synthesis of purine and thymidylate precursors folic acid or tetrahydrofolate.

 Sulfonomides inhibit bacteria-specific reaction.

1.7 MECHANISM OF ACTION OF SELECTED ANTIBIOTICS

Antibiotic Mechanism

1.7.1 Inhibitors of cell wall synthesis

Carbenicillin Inhibits transpeptidation enzymes. Activates lytic enzymes of cell wall.

Pennicillin Inhibits transpeptidase enzymes. Activates lytic enzymes of cell wall. The
affected bacterium will eventually lyse because the unsupported cell wall
cannot withstand its growth.

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Vancomycin Inhibits transpeptidation in cross-linking peptidoglycans. Interferes with
bacterial cells at many levels, disrupting cell wall synthesis, interfering with
RNA, and damaging the plasma membrane.

1.7.2 Inhibitors of nucleic acid synthesis

Ciprofloxacin Inhibits DNA gyrase; interferes with DNA replication.

Rifampin Blocks RNA synthesis by binding to and inhibiting RNA polymerase.

1.7.3 Inhibitors of protein synthesis

Chloramphenicol Blocks formation of new peptide bonds during protein synthesis by binding to
the 50S subunit of the ribosome.

Erthromycin Binds the 50S subunit and blocks translocation of the new protein on the
ribosome, thus effectively halting synthesis.

Fusidic acid Blocks translocation.

Linezolid Binds rRNA to prevent translation initiation and thus protein synthesis.

Streptomycin Binds the 30S ribosomal subunit of the tuberculosis bacterium and prevents the
ribosome from forming the complex necessary to initiate protein translation.
Streptomycin is the first line of chemical defense against Mycobacterium
tuberculosis.

Tetracyclines Binds to the 30S subunit and blocks the addition of amino acids, producing
incomplete and probably nonfunctional proteins.

`1.7.4 Metabolic inhibitors

Dapsone Interferes with synthesis of folic acid, which is required for the synthesis of
purines and thymidine and for the synthesis of the amino acids methionine and
glycine.

Sulfonamides Competitively inhibits dihydropteroate synthase, an enzyme that converts p-

aminobenzoic acid (PABA) into folic acid. These drugs can also be
incorporated into a compound that resembles dihydrofolate and that in turn can
inhibit another enzyme in the pathway, dihydrofate reductase.

Trimethoprim Inhibits dihydrofolate reductase, blocking tetrahydrofolate synthesis.

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1.8 Details on antibiotics:

Antibiotic Class Common Possible side Mechanism of

Uses effects action
Urinary tract Nausea (rare), Inhibit the
infections, irreversible damage bacterial DNA
bacterial to central nervous gyrase or the
prostatitis, system (uncommon), topoisomerase IV
Quinolones/Fluoroquinolon community- tendinosis (rare) enzyme, thereby
e acquired inhibiting DNA
pneumonia, replication and
bacterial transcription.
diarrhea,
mycoplasmal
infections,
gonorrhea

Urinary tract o Nausea, Folate synthesis

infections vomiting, and inhibition. They
(except diarrhea are competitive
Sulfonamides(Bs) sulfacetamide, o Allergy inhibitors of the
used for eye (including enzyme
infections, and skin rashes) dihydropteroate
mafenide and o Crystals in synthetase,
silver urine DHPS. DHPS
sulfadiazine, o Kidney catalyses the
used topically failure conversion of
for burns) o Decrease in PABA (para-
white blood aminobenzoate)
cell count to
o Sensitivity to dihydropteroate, a
key step in folate
sunlight.
synthesis. Folate
is necessary for
the cell to
synthesize
nucleic acids
(nucleic acids are
essential building
blocks of DNA
and RNA), and in
its absence cells
cannot divide

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Antibiotic Class Common Uses Possible side effects Mechanism of

action
Syphilis, o Gastrointestinal Inhibiting the
chlamydial upset binding of
infections, Lyme o Sensitivity to aminoacyl-tRNA
Tetracyclines(Bs) disease, sunlight to the mRNA-
mycoplasmal o Potential toxicity ribosome
infections, acne to mother and fetus complex. They do
rickettsial during pregnancy so mainly by
infections, o Enamel hypoplasia binding to the 30S
*malaria *Note: (staining of teeth; ribosomal subunit
Malaria is caused potentially in the mRNA
by a protist and not permanent) translation
a bacterium. o transient complex. But
depression of bone Tetracycline
growth cannot be taken
together with all
dairy products,
aluminium, iron
and zinc minerals
Antileprotic Reddish-orange sweat, tears, Inhibits peptide
Antileprotic and urine. synthesis
Drugs against Antituberculosis Rash, discolored urine, GI Binds to the β
mycobacteria mostly Gram- symptoms. subunit of RNA
positive and Neurotoxicity, ototoxicity polymerase to
mycobacteria inhibit
Mycobacterium transcription.
avium complex.

Meningitis, Inhibits bacterial

MRSA, topical protein synthesis
use, or for low-cost Rarely: aplastic anemia. by binding to the
Chloramphenicol(Bs internal treatment. 50S subunit of the
) Historic: typhus, ribosome.
cholera. Gram-
negative, Gram-
positive, anaerobes

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Antibiotic Common Uses Possible side effects Mechanism

Class of action

Infections caused o Hearing loss Binding to the

by Gram-negative bacterial 30S
bacteria, such as o Vertigo ribosomal
Escherichia coli o Kidney damage subunit (some
and Klebsiella work by binding
particularly to the 50S
Pseudomonas subunit),
Aminoglycosides aeruginosa. inhibiting the
Effective against translocation of
Aerobic bacteria the peptidyl-
(not tRNA from the
obligate/facultative A-site to the P-
anaerobes) and site and also
tularemia. All causing
aminoglicocydes misreading of
are ineffective to be mRNA, leaving
taken orally. the bacterium
Intravenous, unable to
intramuscular and synthesize
topical should be proteins vital to
applied. its growth.
Bactericidal for o Gastrointestinal upset
both Gram-positive and diarrhea
Carbapenems and Gram-negative o Nausea
organisms and o Seizures Inhibition of
therefore useful for o Headache cell wall
empiric broad- o Rash and allergic synthesis
spectrum reactions
antibacterial
coverage.
Good coverage o Gastrointestinal upset Same mode of
Cephalosporins against Gram- and diarrhea action as other
(First generation) positive infections. o Nausea (if alcohol beta-lactam
taken concurrently) antibiotics:
o Allergic reactions disrupt the
synthesis of the
peptidoglycan
layer of
bacterial cell
walls

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Antibiotic Common Uses Possible side effects Mechanism

Class of action

o Gastrointestinal upset Same mode of

Less Gram-positive and diarrhea action as other
Cephalosporins cover, improved o Nausea (if alcohol beta-lactam
(Second Gram-negative taken concurrently) antibiotics:
generation) cover o Allergic reactions disrupt the
synthesis of the
peptidoglycan
layer of
bacterial cell
walls.
Improved coverage o Gastrointestinal upset Same mode of
of Gram-negative and diarrhea action as other
Cephalosporins organisms, except o Nausea (if alcohol beta-lactam
(Third generation) Pseudomonas taken concurrently) antibiotics:
Reduced Gram- o Allergic reactions disrupt the
positive cover. But synthesis of the
still not cover peptidoglycan
Mycoplasma and layer of
Chlamydia bacterial cell
walls.
o Gastrointestinal upset Same mode of
Cephalosporins Covers and diarrhea action as other
(Fourth pseudomonal o Nausea (if alcohol beta-lactam
generation) infections. taken concurrently) antibiotics:
o Allergic reactions. disrupt the
synthesis of the
peptidoglycan
layer of
bacterial cell
walls.
Used to treat o Gastrointestinal upset Same mode of
MRSA and diarrhea action as other
(methicillin- o Nausea (if alcohol beta-lactam
Cephalosporins resistant taken concurrently) antibiotics:
(Fifth generation) Staphylococcus o Allergic reactions. disrupt the
aureus), penicillin- synthesis of the
resistant peptidoglycan
Streptococcus layer of
pneumoniae, bacterial cell
Pseudomonas walls.
aeruginosa, and
enterococci.

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Antibiotic Class Common Uses Possible side effects Mechanism

of action
Active against o Gastrointestinal upset
aerobic and and diarrhea Inhibiting
anaerobic Gram- o Allergic reaction. peptidoglycan
Glycopeptides positive bacteria synthesis
including MRSA;
Vancomycin is
used orally for the
treatment of C.
difficile
Serious staph-,
pneumo-, and Possible C. difficile-related Bind to 50S
streptococcal pseudomembranous subunit of
infections in enterocolitis bacterial
Lincosamides(Bs) penicillin-allergic ribosomal RNA
patients, also thereby
anaerobic inhibiting protein
infections; synthesis.
clindamycin
topically for acne.
Bind to the
membrane and
cause rapid
Gram-positive Possible C. difficile-related depolarization,
Lipopeptide organisms pseudomembranous resulting in a
enterocolitis. loss of
membrane
potential leading
to inhibition of
protein, DNA
and RNA
synthesis
Streptococcal o Nausea, vomiting, and Inhibition of
infections, diarrhea (especially at bacterial protein
syphilis, upper higher doses) biosynthesis by
Macrolides(Bs) respiratory tract o Prolonged cardiac QT binding
infections, lower interval. reversibly to the
respiratory tract o Hearing loss subunit 50S of
infections, (especially at higher the bacterial
mycoplasmal doses) ribosome,
infections, Lyme o Jaundice. thereby
disease. inhibiting
Pneumonia translocation of
Mouth infections peptidyl tRNA.

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Antibiotic Class Common Uses Possible side effects Mechanism

of action
Same mode of
action as other
beta-lactam
Monobactams Gram-negative Visual Disturbance, Liver antibiotics:
bacteria. Toxicity. disrupt the
synthesis of the
peptidoglycan
layer of bacterial
cell walls.
o Thrombocytopenia Protein synthesis
o Peripheral neuropathy inhibitor;
Oxazolidinones(Bs) VRSA o Serotonin Syndrome prevents the
initiation step.

Wide range of o Gastrointestinal upset Same mode of

infections; and diarrhea action as other
Penicillins penicillin used for o Allergy with serious beta-lactam
streptococcal anaphylactic reactions antibiotics:
infections, o Brain and kidney disrupt the
syphilis, and Lyme damage. synthesis of the
disease. peptidoglycan
layer of bacterial
cell walls
Eye, ear or bladder Kidney and nerve damage Inhibits
infections; usually (when given by injection) isoprenyl
applied directly to pyrophosphate, a
the eye or inhaled molecule that
into the lungs; carries the
rarely given by building blocks
Polypeptides injection, although of the
the use of peptidoglycan
intravenous bacterial cell
colistin is wall outside of
experiencing a the inner
resurgence due to membrane
the emergence of
multi drug
resistant
organisms.

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1.9 Bacterial Resistance and Health

Many bacterial strains now resist the effects of antibiotics that once could destroy them. Every
population of bacteria may have some individuals that are resistant. The proliferation of antibiotics
and careless use of the drugs have given some resistant bacteria the upper hand in the fight against
disease.

A patient who is prescribed a 10-day course of antibiotics, but who quits taking them after a couple of
days because the symptoms have subsided, leaves behind bacteria that resisted the antibiotic effect.
Growth of these bacteria may have slowed in the presence of the antibiotic, but the bacteria are not
completely wiped out. Some resistant bacteria may survive an even longer course of antibiotics if the
dosage of the drug is not high enough. Typically, after a complete, full-strength antibiotic course, so
few resistant bacteria remain that the body’s own immune system can handle them; however, a short
course may leave behind so many resistant bacteria that they proliferate. These resistant bacteria also
have a better chance to flourish because the other, weaker, bacteria have died. It’s the scenario for a
medical crisis.

1.10 History of Devolopment of Resistance

Resistant bacteria have always been around and existed long before humans began using antibiotics
therapeutically. What is new in the world of resistance is how quickly new resistant strains arise. The
widespread use and misuse of antibiotics contribute to the problem. For the first time in decades,
people in the United States are dying of bacterial infections that cannot be treated.

 Right after we began using penicillin, some Staphylococcus strains were identified as resistant
to it.
o Today, 80 percent of Staphylococcus strains do not respond to penicillin.
 In the 1940s and early 1950s, streptomycin, chloramphenicol, and tetracycline were
discovered.
o By 1953, a strain of Shigella was found that resisted these antibiotics and
sulfanilamides.
o By the 1970s, resistant strains of gonorrhea arose.
 The 1990s saw the development of true superbugs, bacteria that resist all known antibiotics.
o One antibiotic of last resort is Vancomycin, a powerful antibiotic that attacks bacteria
on many fronts.
o Now there are Enterococci strains that resist Vancomycin.
 Multi-drug resistant tuberculosis strains have arisen.
o By the 1940s and 1950s, a single antibiotic, such as Streptomycin, no longer cured
tuberculosis, as it had in the past.
o Tuberculosis is the leading cause of death by infectious disease in the world.

1.11 Mechanisms of Resistence

Bacteria either have preexisting resistance to drugs, or they develop resistance. Human activity has
contributed greatly to the increase in resistant strains of bacteria. Often, when bacteria acquire
resistance to a certain drug from a particular class (e.g., the penicillins), the bacteria also acquire
resistance to all other drugs in that class.

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1.12 Some of the many mechanisms of resistance are indicated schematically in the
following diagram:

Fig1.11: Mchanisms of Resistance of Antibiotics

1.13.1 Inherent Resistance

The principles of Darwinian evolution act on bacteria with inherent resistance: those bacteria that
resist an antibiotic's effects are better suited to survive in an environment that contains the antibiotic.
In the case of inherent resistance and vertical evolution, the genes that confer resistance are found on
bacterial chromosomes and are transferred to the bacterial progeny every time the cell divides.

 Bacteria may begin life resistant to a particular antibiotic.

o Example: Gram-negative bacteria are naturally resistant to penicillins.
 Bacteria may be resistant because either
o they have no mechanism to transport the drug into the cell.
o they do not contain or rely on the antibiotic’s target process or protein.
 Specific examples of bacterial strains with known natural resistance:
o tetracycline-resistant Proteus mirabilis.
o ampicillin-resistant Klebsiella pneumoniae.

1.13.2 Acquired resistance

Bacteria that don’t begin life resistant to a certain antibiotic can

acquire that resistance. In the case of vertical evolution and
inherent resistance, mutations occur on chromosomes and are
then selected for an environment where resistance increases
fitness. In the case of horizontal evolution, genes pass from a
resistant strain to a nonresistant strain, conferring resistance on
the latter. The introduction of an antibiotic alters the
environment and acts as a selective pressure.

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1.13.3 Conjugation

Transmission of resistance genes via plasmid exchange.

 Bacteria have circles of DNA called plasmids that they can pass to other bacteria during
conjugation.
 Plasmids, the key players in conjugation, are even referred to as resistance transfer factors.
 This type of acquisition allows resistance to spread among a population of bacterial cells
much faster than simple mutation and vertical evolution would permit.

1.13.4 Transduction

A virus serves as the agent of transfer between bacterial strains.

1.13.5 Transformation

DNA released from a bacterium is picked up by a new cell.

After the new DNA is introduced—whether via conjugation, transduction, or transformation—it is

incorporated into the cell and results in the emergence of a new, resistant genotype.

Fig1.12: Different Process of Bacterial Resistance

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1.14 SOME EXAMPLES OF RESISTANCE

Type of bacteria Resistance to

Gram-negative bacteria Penicillin and other b-lactam

antibiotics

Proteus mirabilis (rheumatoid arthritis, urinary tract infections) Tetracycline

Klebsiella pneumoniae (ankylosing spondylitis, a disease of the Ampicillin

joints)

Staphylococcus aureus Methicillin

1.15 Some mechanisms of resistance

1.15.1 Enzyme-based resistance

There are a number of ways enzymes have been used by bacteria to confer antibiotic resistance:

 Resist b-lactam antibiotics through modifications in the genetic code for the proteins that bind
penicillin.
 Genes for enzymes that can destroy or disable antibiotics are acquired or arise through
mutation. For example, a b-lactamase enzyme can destroy the b-lactam ring of penicillins
through hydrolysis, and without a b-lactam ring, penicillins are ineffective against the
bacteria.

Fig1.13: Penicillin Ressistence

 Prevent aminoglycoside disruption of ribosomes. A bacterial enzyme adds a bulky substituent

to the aminoglycoside, making it impossible for the drug to fit into the rRNA pocket and
rendering it harmless.

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1.15.2 Ribosomal modifications

The ribosome can be methylated so that an antibiotic cannot bind to it.

Fig1.13: Ribosomal Modification

1.15.3 Protein modifications

For antibiotics that target DNA gyrase, the enzyme that unwinds DNA for replication, random
mutations in the bacterial DNA may alter the gyrase and make it unrecognizable to antibiotics while
still leaving it functional.

1.15.4 Metabolic resistance

In the case of sulfonamides, which operate by mimicking PABA and competing for an enzyme that
synthesizes folic acid, an increase in the amount of PABA can outcompete the sulfonamide and render
it ineffective; or an alteration in the code for the enzyme itself can prevent its sulfonamide binding.

Fig1.14: Metabolic resistance

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1.15.5 Effluxing the toxin

One particularly active way a bacterium may deal with an antibiotic is to pump it out, perhaps using
proteins encoded by acquired genes. For example, a strain of enterococcal bacteria can pump out
tetracycline. This type of pumping is called an “efflux phenomenon.”

Note: Bacteria without inherent antibiotic resistance can acquire—through conjugation, transduction,
or transformation—the genes that encode proteins that confer resistance .

1.16 Rationale of antibiotic use

1.16.1 Reasons for appropriate use

 Avoid adverse effects on the patient

 Avoid emergence of antibiotic resistance - ecological or societal aspect of antibiotics
 Avoid unnecessary increases in the cost of health care
1.16.2 Prescribing an antibiotic

 Is an antibiotic necessary ?
 What is the most appropriate antibiotic ?
 What dose, frequency, route and duration ?
 Is the treatment effective ?
1.16.3 Is an antibiotic necessary ?

 Useful only for the treatment of bacterial infections

 Not all fevers are due to infection
 Not all infections are due to bacteria
o There is no evidence that antibiotics will prevent secondary bacterial infection in
patients with viral infection
 Not all bacterial infections require antibiotics
o Consider other options :
o antiseptics
o surgery
1.16.4 Principles on choosing an antibiotic for empiric therapy

 As best possible, attempt to localize the site of infection

o Do a good exam!!!
 Occam’s razor
o “Plurality must not be posited without necessity”
o Use only one diagnosis whenever possible

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1.17 Poultry farming

Poultry farming is the raising of domesticated birds such as chickens, turkeys, ducks, and geese, for
the purpose of farming meat or eggs for food. Poultry are farmed in great numbers with chickens
being the most numerous.More than 50 billion chickens are raised annually as a source of food, for
both their meat and their eggs. [1] Chickens raised for eggs are usually called laying hens whilst
chickens raised for meat are often called broilers.

In total, the UK alone consumes over 29 million eggs per day. In the US, the national organization
overseeing poultry production is the Food and Drug Administration (FDA). In the UK, the national
organization is the Department for Environment, Food and Rural Affairs (Defra).

1.17.1 Poultry Industry: Bangladesh

The poultry industry has been successfully becoming a leading industry in Bangladesh.This industry
can provide various opportunities to increase GDP growth rate plus equitable distribution through
arranging food security as well as ensuring self-employment,creating purchasing power and reducing
poverty at large scale.This sector is also growing rapidly for last two decades though it started farming
during mid-sixties in this country.

Both the government and a variety of non-governmental organization(NGO) are actively promoting
poultry development at all level.The Bangladesh Rural Advancement Commission (BRAC),the
largest,shows in its annual report that more than 70% of rural households are involved in poultry
keeping.But they face serious constraints,as the mortality rate of poultry is said to be as high as
25%,due to a combination of improper feeding practices, ignorance of management,poor distribution
of vaccine & misuse of medication.

1.17.2 Use of antibiotics in poultry

Antibiotics have been used in animal feed for about 50 years ever since the discovery not only as an
anti-microbial agent, but also as a growth-promoting agent and improvement in performance.
Tetracyclines, penicillin, streptomycin and bactrican soon began to be common additives in feed for
livestock and poultry. Currently, the following antibiotics are used in livestock and poultry feed:
chlortetracycline, procaine penicillin, oxytetracycline, tylosin, bacitracin, neomycin sulfate,
streptomycin, erythromycin, linomycin, oleandomycin, virginamycin, and bambermycins.In addition
to these antibiotics, which are of microbial origin, there are other chemically synthesized
antimicrobial agents that are also sometimes used in animal feeds. These include three major classes
of compounds: arsenical, nitro-furan, and sulfa compounds. Arsenical compounds include arsanilic
acid, 3-nitro-4-hydroxy phenylarsonic acid, and sodium arsanilate; nitro-furan compounds include
furazolidone and nitro-furazone; sulfamethazine, sulfathiazole, and sulfaquinoxaline. Other chemicals
are also used as antiprotozoal agents to prevent coccidiosis and histomaniasis in chickens and turkeys.
Antibiotics are used regularly in animal feed at a rate of 2 to 50 grams per ton for improved
performance in the animals.

1.18 History of the growth promotant antibiotics

The growth-promotant effect of low levels of antibiotics in animal feeds was first described in the late
1940s when chickens fed fermentation waste from tetracycline production grew more rapidly than
controls. Over the ensuing 50 years the production-enhancing effects of feeding sub therapeutic levels
of a wide range of antibiotics has been described. In this time, the use of growth-promotant antibiotics
became entrenched in animal production, particularly in the intensive livestock industries.

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1.19 Mode of action of growth promotant antibiotics

The mode of action of antibiotic growth promotants is not known.Most of the growth promotants are
active against Gram-positive organisms. However, the concentrations used are lower than therapeutic
levels, although they may exceed the minimal inhibitory concentration for the Gram-positive
intestinal bacteria. The agents are assumed to exert their effect by acting on the intestinal micro flora
to cause a range of beneficial changes: causing lethal or sub lethal damage to pathogens; causing a
reduction in the production of bacterial toxins; reducing bacterial utilization of essential nutrients;
allowing increased synthesis of vitamins and other growth factors; improving the absorption of
nutrients by reducing the thickness of the intestinal epithelium; reducing intestinal mucosa epithelial
cell turnover and reducing intestinal motility.It is clear that, in many cases, the effects are more
noticeable in sick animals and animals housed under conditions of poor hygiene.There are also age-
related effects, with younger animals showing a greater response to growth promotants than older
animals.

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