1. Haramaya University
2/15/2023
1
Dr. Balisa Yusuf
Digitally signed by Dr_ Balisa
DN: C=ET, OU=Lecturer, O=Haramaya
University, CN=Dr_ Balisa,
E=balisa.yusuf@haramaya.edu.et
Reason: I am the author of this
document
Location: haramaya
Date: 2023-02-15 15:17:55
Dr_
Balisa
2. Aminoglycosides are a group of natural and semisynthetic antibiotics
Most are either natural products or derivatives of soil actinomycetes
Discovered from soil microbe Streptomyces in 1944 by Waksman
As a result of systematic search for drug active against gram -Ve organisms &
Hense, used primarily to treat infections caused by aerobic gram -Ve bacteria
They are often secreted by actinomycetes
as mixtures of closely related compounds
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Bind both to the anionic outer bacterial m/b & to
anionic phospholipids in the cell membranes of
mammalian renal proximal tubular cells
The former contributes to the bactericidal action
The latter for their toxicity.
Aminoglycosides
History and Chemistry
Spectrum of ABA & Resistance
MoA and Classifications
Pharmacokinetics (ADME)
Primary clinical indications
Drug interaction, Toxicity &
safety principles
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Aminoglycosides are hydrophilic, poly-cationic, amine containing
carbohydrates that are usually composed of three to five rings.
Because of their hydrophilicity, the transport of across the hydrophobic
lipid bilayer of eukaryotic cell membranes is impeded.
Gentamicin
4. Groups of common Aminoglycosides are: Gentamicin, Tobramycin, Amikacin,
Netilmicin, Kanamycin, Streptomycin, and Neomycin.
Streptomycin and kanamycin are used predominantly in the treatment of TB
tuberculosis
These drugs are used primarily to treat infections caused by aerobic gram -ve
bacteria: Their activity spectrum encompasses mainly gram-negative organisms.
Aminoglycosides are relatively broad spectrum in terms of type of MO
Generally active against
Bacteria
Mycoplasma and mycobacteria
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In contrast to most inhibitors of microbial protein synthesis, which are
bacteriostatic:
Aminoglycosides are bactericidal inhibitors of protein synthesis.
5. ↈAll aminoglycosides are produced by the soil actinomycetes.
Streptomycin - the first member of aminoglycoside antibiotics discovered in
1944 by Waksman and co-workers from a strain of Streptomyces griseus.
Neomycin was next to be isolated in 1949 from S. Fradiae
kanamycin is 1957 from S. kanamyceticus
Gentamicin in 1963: from Micromonospora Purpurea.
Amikacin was the first semi-synthetic aminoglycoside obtained by chemical
modification of kanamycin. E.a Its semisynthetic derivative of Kanamycin
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ↈTobramycin: from S. tenebrarius; and Framycetin: from S. Lavendulae
ↈSisomicin: Micromonospora inyoensis; Netilmicin: Semisynthetic derivative of it (smcn)
ↈWhile most aminoglycosides are obtained by natural fermentation of Streptomyces, some
members of the group (gentamicin) are prepared from actinomycetes Micromonospora
Aminoglycosides prepared from Streptomyces carry the suffix —mycin
Those from Micromonospora have name ending with —micin
HISTORY AND SOURCES:
6. Now a day, aminoglycosides have many members, some of which are
extensively used in veterinary medicine. Members includes:
Amikacin
Streptomycin
Sisomicin
Spectinomycin
Kanamycin
Ispepamycin
Netilmicin
Gentamicin
Tobramycin
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Ribostamycin
Arbekacin
Bekanamycin
Dibekacin
Hygromycin
Verdamicin
Astromicin
Paromomycin
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They are polar organic bases, bactericidal, acts by interference with the protein synthesis
Formulations are Sulfate or hydrochloric salts that are highly water soluble (stable)
Highly active in alkaline medium; presence of pus & tissue debris leads to loss of activity.
They are hydrophilic having Poor oral bioavailability as they are polycations.
Readily ionize hence unable to cross the barriers BBB even in inflammation.
Predominantly and exclusively used in the treatment gram -V bacteria
Excreted unchanged in urine through glomerular filtration.
Narrow margin of safety? ED/TD
Eighth cranial nerve toxicity and nephrotoxicity are common.
Cross resistance is incomplete
All share common toxicities (ototoxicity and nephrotoxicity)
Inhibitors of bacterial cell wall (β-lactams, vancomycin): enhance entry of
aminoglycosides and exhibit synergism.
General Characteristics of aminoglycosides
8. 8
The aminoglycosides consist of two or more amino sugars joined in glycosidic linkage
to a hexose or aminocyclitol nucleus, which usually is in a central position.
This hexose, or aminocyclitol, is either streptidine (found in streptomycin) or 2-
deoxystreptamine (found in all other available aminoglycosides).
The presence of amino group in
the structure imparts basic
nature and
hydroxyl group on the sugars
provide high water solubility (or
poor lipid solubility) to the drugs.
If these hydroxyl groups are
removed (e.g tobramycin), the
drug becomes more active.
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Chemistry and Structure of aminoglycosides
10. Because the hydroxyl groups can be substituted at more than 1 positions
on the molecule, several forms of same aminoglycoside may be obtained.
For example, neomycin is a mixture of neomycin B, C, and gentamicin is
a complex of gentamicins C1, C1a, and C2
Minor differences in the chemical structures of these drugs may lead to
differences in efficacy and toxicity.
Bacterial killing is concentration-dependent.
Have post antibiotic effect continue to suppress bacterial regrowth even after removal.
The primary intracellular site of action of the amino glycosides is the 30S
ribosomal subunit.
Aminoglycosides – contain amino sugar joined by a glycosidic linkage.
Aminocyclitols - Amino group is on cyclitol rather than sugar ring. eg. Spectinomycin, Apramycin
Thus, these compounds are, aminoglycosidic aminocyclitols
Although the simpler term aminoglycoside is commonly used to describe them.
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11. Contain amino sugar joined by a
glycosidic linkage
Amino group is on cyclitol rather than sugar ring
Aminocyclitols - eg.
Spectinomycin, Apramycin
Aminoglycosides 2/15/2023
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12. Classification is based on spectrum activity
Narrow spectrum: Streptomycin and dihydrostreptomycin.
Mainly against aerobic gram -Ve bacteria (E.coli, Salmonella, Pasturella, & Brucella spp.)
and also against Staphylococci, Actinomyces bovis and Laptospira spp.
Mycobacterium tuberculosis is sensitive to streptomycin.
Broad spectrum Gentamicin, Tobramycin, Amikacin, Sisomicin and Netilmicin.
Highly effective against a wide variety of aerobic (gram +Ve/-Ve) bacteria including P. aeroginosa
Gentamicin is more potent than streptomycin (MIC 4-8 times lower), but it is ineffective against
M. tuberculosis.
Amikacin and Netilmicin are resistant to bacterial aminoglycoside inactivating enzymes and thus
have widest spectrum of activity including against organisms resistant to other aminoglycosides.
Miscellaneous: Aparamycin and Spectinomycin.
These drugs are structurally somewhat different from typical aminoglycosides but have
similar antibacterial spectra and mechanism of action. B/c they are Aminocyclitols
Extended spectrum: Neomycin, Framycetin, Paromomycin and Kanamycin
clinically useful against gram -V infections by E.coli, Salmonella, Klebsiella & Enterobacter
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13. The aminoglycosides are bactericidal antibiotics, all having the same general pattern
of action which may be described in two steps, Involving possibly synergistic effects:
1. Transport of the aminoglycoside through the bacterial cell wall & cytoplasmic m/b
Disrupting outer membrane integrity (bactericidal effect)
2. Binding to ribosome resulting in inhibition of protein synthesis.
Disrupting the initiation of protein synthesis and inducing errors in the translation
of messenger RNA to peptides
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Mechanism of Action
Bactericidal (Gram Negative, No action on Anaerobes)
Initial entry of Aminoglycosides through bacterial cell wall to periplasmic space
Through porin channels by Passive diffusion (1)
Later on further Entry across cytoplasmic membrane is carrier mediated (linked to
electron transport chain, energy and oxygen dependent) Active transport (2)
Advantage of adding Beta lactams is antibiotics weaken the bacterial cell wall
Facilitate passive diffusion of Aminoglycoside.(Synergism)
14. Transport of aminoglycoside into bacteria: It is a multistep process.
They diffuse across the outer coat of gram -V bacteria through porin channel
Entry from the periplasmic space across the cytoplasmic membrane is carrier
mediated which is linked to the electron transport chain B/c of a requirement for:
A membrane electrical potential to drive permeation of these antibiotics.
Thus, penetration is dependent upon
maintenance of a polarized membrane and on oxygen dependent active processes.
EDP1 is rate-limiting and can be blocked or inhibited by divalent cations (e.g., Ca2+
and Mg2+), hyperosmolarity, a reduction in pH, and anaerobic conditions.
The antimicrobial activity of aminoglycosides is reduced markedly in under anaerobic
conditions; in hyperosmolar acidic urine and in other conditions that limit EDP1.
anaerobes aren’t sensitive & facultative anaerobes are more resistant inside big abscesses.
Penetration is also favored by high pH; aminoglycosides are -20 times more active in
alkaline than in acidic medium.
Bacterial cell wall inhibitors (β-lactams, Vancomycin) enhance the entry of amnglycsd
Administration of beta-lactam antibiotics will reverse the negative effects of both
low pH and low oxygen tension and exhibit synergism. 2/15/2023
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Step I termed energy-dependent phase I (EDP1) transport.
15. Source : Google image
Bacterial: killing is concentration-dependent
The primary intracellular site of action of amino glycosides is a 30S ribosomal subunit
Have post antibiotic effect continue to suppress bacterial regrowth even after removal
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16. Step II termed energy-dependent phase II (EDP2) transport
Once inside the bacterial cell
Streptomycin binds to 30S ribosomes, but other aminoglycosides are:
Bind to additional sites on 50S subunit, as well as to 30S-50S interface.
They freeze initiation of protein synthesis,
Prevent polysome formation and promote their disaggregation to monosomes
So that only one ribosome is attached to each strand of mRNA.
Binding of aminoglycoside to 30S-50S juncture causes:
Distortion of mRNA codon recognition resulting in misreading of the code:
The resulting aberrant proteins may be inserted into the cell m/b, leading to
altered permeability and further stimulation of aminoglycoside transport
One/more wrong amino acids are entered in the peptide chain and/or peptides of
abnormal length are produced. Concerned with their post antibiotic effect
Different aminoglycosides cause misreading at different levels depending
upon their selective affinity for specific ribosomal proteins. 2/15/2023
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17. Cidal action of Aminoglycoside
The cidal action - based on secondary changes in the integrity of bacterial m/b
Other protein synthesis inhibiter (ttclin, chlrmphncol erythrcin) are only static
After exposure to aminoglycosides, sensitive bacteria become more permeable;
Ions amino acids and even proteins leak out followed by cell death.
This probably result from incorporation of the defective proteins into the
cell membrane: reinforcing the lethal action.
The cidal action of aminoglycosides is concentration dependent, i.e.
Rate of bacterial cell killing is directly related to the ratio of the peak
antibiotic concentration to the MIC value.
They also exert a long and concentration dependent ‘postantibiotic effect’.
Despite their short t1/2 (2-4 hr), single injection of the total daily dose of
aminoglycoside may be more effective and possibly less toxic than its
conventional division into 2-3 doses.
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18. Ans-
Defective proteins incorporated in cell membrane.
Due to secondary changes in the integrity of bacterial cell membrane.
(Increase permeability for ions, amino acids, proteins- Leading to leaking of these out side)
Bonus of incorporation of defective protein in cell membrane
More entry of antibiotic occurs in to the cell. Further increasing affectivity
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Death Of Bacteria
How Cidal action is achieved?
19. Pharmacokinetic property
Poorly absorbed from the GIT, & given by IM to achieve adequate serum level
Absorption from IM site is rapid and complete (peak plasma conc. by 1hr/ 30-90 minutes)
Because of their polarity at physiologic pH, they are distributed primarily to
the extracellular & transcellular fluids (e.g. pleural, joint, & peritoneal fluids).
They tend to accumulate in the renal cortex and otic endolymph predisposing
these tissues to toxicity. Poorly ×BBB
Are excreted unchangedly by GF, and attain high concentrations in the urine.
Plasma half-lives are 2-5 hours in most species, but effective plasma levels are
maintained for 8-12 hours following a single injection.
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They distribute only into the extracellular fluid with minimum penetration to most of the
tissues except the kidney (nephrotoxicity) and endolymph of the internal ear (ototoxicity).
They show low tendency to bind with plasma proteins and effective levels are not reached
in CSF and milk
20. Clinical Indications & Therapeutic Uses
Aminoglycosides are commonly used in several local and systemic infections
caused by susceptible aerobic bacteria (particularly Gram negative bacteria).
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Streptomycin is widely used for the Rx of :
ↈBovine streptococcal and staphylococcal mastitis
(Strepto-penicillin as oily intermammary infusṉ
ↈPasteurellosis
ↈ E-coli infection (causing mastitis, metritis,
enteritis and septicemia in all species)
ↈLeptospirosis (for clearance of organism from
urine)
ↈ Tuberculosis and Vibriosis.
Gentamicin parenterally used in the Rx:
Gram negative septicemia (drug of choice)
Urinary tract, GI tract, respiratory tract
Topically in eye/ear infections.
Netilmicin is resistant to bacterial
aminoglycoside inactivating enzymes
Thus effective against gentamicin
resistant strains.
Framycetin rarely used systemically because of:
Ototoxicity and Nephrotoxicity
But used for the Rx of enteritis and topically for otitis externa in dogs
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Spectinomycin:. It is active against several gram +Ve (used as alternative to Penicillin G)
ↈAn aminocyclitol active against Wide range of Gram -Ve bacteria and Mycoplasma species.
ↈIt inhibits the protein synthesis in these organisms by binding with 30s ribosome
ↈThus produces a bacteriostatic rather than bactericidal effect.
ↈIt is poorly absorbed from GI tract but rapidly absorbed after IM administration.
ↈThe antibiotic is mainly used in the treatment of
CRD and fowl cholera in poultry, Colibacillosis in poultry and pigs & E.coli mastitis in cows.
CRD= Chronic Respiratory Disease
Apramycin It is a Bactericidal antibiotic.
Mainly used to control Gram -Ve infections, especially of E.coli and Salmonella
in calves and piglets.
It is also active against Proteus, Klebsiella, Treponema and Mycoplama species.
It is not absorbed orally but rapidly absorbed parenterally.
The drug is contraindicated in cats because of its severe toxic action, but it can be
given safely to other Animals
It is used in the treatment of Colibacillosis & Salmonellosis in calves & piglet
22. Ototoxicity
This is the most related to dose and duration of treatment .
The ototoxicity involves progressive & irreversible damage & destruction to the
sensory cells in the cochlea & vestibular apparatus of internal ear
Vestibular damage - Nystagmus, Vertigo and Ataxia.
Cochlear damage - auditory disturbances which may even lead to deafness
Other ototoxic drugs potentiates the ototoxicity of aminoglycosides.
Cats are particularly sensitive to vestibular toxicity.
Streptomycin & Gentamicin are more prone to produce vestibular toxicity
Neomycin and Amikcacin cause mainly cochlear damage.
Netilmicin is less ototoxic and therefore preferred for long term use.
Adverse reactions and Toxicity
Aminoglycosides produce toxic effect which is common to all but the relative intensity d/f.
The main toxicities are: Ototoxicity, Nephrotoxicity and Neuromuscular blockade
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23. Most commonly resistance is due to acquisition of plasmids or transposon-encoding
genes for aminoglycoside-metabolizing enzymes or from impaired transport of drug
into the cell.
Thus there can be cross-resistance between members of the class.
Plasmid-mediated expression of enzymes (more than 20 enzymes) that acetylate,
adenylate, or phosphorylate the aminoglycosides is the most important
Mutations in the proteins of the bacterial ribosomes (aerobic gram negative bacilli)
Decreased transport into the bacterial cytosol (anaerobes)
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Drug Resistance
24. Neuromuscular blockade
High doses of aminoglycosides may cause neuromuscular blockade (due to chelation of calcium
and reduction of Ach release from the motor nerve endings by aminoglycosides)
Resulting in skeletal muscle paralysis and respiratory arrest which may even lead to death.
Neomycin and Streptomycin are more prone to cause this toxic effect than Kanamycin,
Gentamicin or Amikacin.
Tobramycin is least toxic in this respect.
The blockade can be partially antagonized by IV calcium gluconate and neostigmine.
NM blockers should be used cautiously in animals receiving aminoglycoside antibiotics.
Nephrotoxicity
It is due to damage of kidney tubules and this is more common in patient with
preexisting kidney diseases.
Renal damage can be reversed by immediate discontinuation of drugs.
Hypersensitivity reactions
Contact dermatitis and sometime allergic reaction particularly to streptomycin is common.
Rapid IV injection: At high dose may cause CNS disturbances, even convulsions, respiratory
arrest, fall in BP, collapse and death. 2/15/2023
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25. Contraindications and precautions
To be avoided during pregnancy (fetal toxicity)
Along with other ototoxic drugs (high ceiling diuretics, minocycline)
To be avoided Ŵ other nephrotoxic drug (amphotericin B, Cephaloridine).
Neomycin is contraindicated in animals prone to post-perturient
hypocalcaemia.
Drug withdrawal time
Drug withdrawal time for aminoglycoside antibiotics:
Oral dosing: 20-30 days;
Parenteral; 100-200 days and
2-3 days after intermammary administration (Usually not approved for use in
food animals).
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26. Dosages of Aminoglycosides
Streptomycin and dihydrostreptomycin:
Oral: 20 mg/kg 2-3 times in a day
IM: 8-12 mg/kg twice a day;
Intramammary @ 100 mg/quarter (in dry cows).
Gentamicin: 3-6 mg/kg IM or SC 2-3 times a day
Kanamycin: 12-15 mg/kg IM or SC twice a day
Amikacin: 5-7.5 mg/kg. IM or SC once or twice daily
Netilmicin: 3-6 mg/kg, IM or SC once or twice daily.
Neomycin: Oral 20 mg/kg TD; Intramammary @ 0.5-1 gm/quarter daily.
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27. Summary
Streptomycin - the first member of aminoglycoside antibiotics
discovered in 1944 by Waksman and co-workers from a strain of
Streptomyces griseus.
The aminoglycosides are bactericidal antibiotics, all having the same
general pattern of action.
Bactericidal and more active at alkaline pH.
The cidal action - based on secondary changes in the integrity of
bacterial cell membrane.
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28. Group of natural and semisynthetic antibiotics having nucleus of four
partially unsaturated cyclohexane rings.
All are obtained from soil actinomycetes and have nearly similar ABA.
All are crystalline yellow powder and Slightly water soluble but
Their hydrochloride salts are more soluble & are used (except doxycycline)
Tetracycline is protein synthesis inhibiter Ŵ very wide AMA spectrum
including: Gram +Ve & -Ve bacteria, Mycoplasma, Rickettsia,
Chlamydia spp., spirochaetes & some protozoa (amoebae)
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They affect both eukrytc & prokaryotic cells but are selectively toxic for bacteria
It contrasted from penicillin G & streptomycin in:
Being orally active and
Broad spectrum antibiotic.
Tetracyclines
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tRNA with mRNA-
ribosome complex on
the 30S ribosome
sub-unit
Further preventing
the binding of the
aminoacyl transfer
RNA (tRNA) to the A
site (acceptor site) on
a 50S ribosomal unit
Common groups are: Chlortetracycline, Oxytetracycline, Tetracycline,
Demeclocycline, Lymecycline, Doxycycline and Minocycline.
Tetracyclines interfere with binding of
30. ↈTetracyclines are bacteriostatic antibiotics produced by different species
of Streptomyces (Streptomyces aureofasciens, Streptomyces rimosus)
The development of tetracycline antibiotics was the result of a systemic screening of soil
specimens collected from many parts of the world for antibiotic producing microorganisms.
The first member of the group was Chlortetracycline; Introduced in 1948.
Derived from soil Actinomycetes Streptomyces aureofaciens.
Introduced in 1948 under the name aureomycin (B/c of the golden colour of
S. Aureofacience colonies producing it).
This was followed by introduction of Oxytetracycline in 1950 from S.rimosus
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ↈRemoval of chlorine atom from chlortetracycline produced tetracycline introduced in 1952
ↈFurther discovery led to other semi-synthetic tetracycline's like
Methacycline, Doxycycline, and Rolitetracycline.
Demethylchlortetracycline/demeclocycline (a mutant strain of S. aureofaciens).
ↈDoxycycline and minocycline are newer tetracyclines with high lipid solubility and
longer duration of action.
HISTORY AND SOURCES:
31. 31
Tetracyclines are close congeners of polycyclic naphthacenecarboxamide
They are a family of four ringed amphoteric compounds that differ by specific
substitution at different points on the rings.
As a group, tetracyclines are acidic and hygroscopic compounds, which in aqueous
solution form salts with both acids and bases.
They characteristically fluoresce when exposed to ultraviolet light.
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Chemistry and Structure of Tetracyclines
32. Hydrochloride salts of tetracyclines are mostly used in clinics
except for doxycycline that is marketed as hyclate.
Tetracyclines form insoluble chelate with divalent and trivalent cations
like Ca++, Mg++, and Al+++.
They are stable as powder but their aqua solutions are not stable
Therefore for parenteral injection, they are formulated in:
Propylene glycol or polyvinyl pyrrolidine and
Stabilizers are added to increase stability & prolong elimination half-life.
Physical & chemical properties of tetracyclines permit them to be
formulated as:
injections, boluses, capsules, powders, feed additives, and
ointments for veterinary use.
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34. Classification is Based on Sources, Spectrum & Duration of action
Natural: Chlortetracycline, Oxytetracycline, Demethylchlorttrc or Demeclocycline.
Semisynthetic: Tetracycline, Methacycline, Rolitetracycline, Lymecycline, Doxycycline
and Minocycline.
Based on duration of action
Short acting: Tetracycline, Oxytetracycline and Chlortetracycline.
Intermediate: Demeclocycline and Methacycline.
Long acting: Doxycycline & Minocycline (highly protein bound and slowly excreted)
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35. The tetracyclines are primarily bacteriostatic; inhibit protein synthesis by
binding to 30S ribosomes in susceptible organism.
Subsequent to such binding, attachment of aminoacyl-t-RNA to the mRNA-
ribosome complex is interfered.
As a result, the peptide chain fails to grow.
The sensitive organisms have an energy dependent active transport process
which concentrates tetracyclines intracellularly.
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Mechanism of Action
In gram-negative bacteria tetracyclines diffuse through porin channels.
The more lipid-soluble members (doxycycline, minocycline) enter by passive diffusion
also (this is partly responsible for their higher potency).
Two factors are responsible for the selective toxicity of tetracyclines for the microbes:
The carrier involved in active transport of tetracyclines is absent in the host cell.
Moreover, protein synthesizing apparatus of host cell is less sensitive to tetracycline.
36. Further preventing the binding of
aminoacyl transfer RNA (tRNA) to the A site
(acceptor site) on the 50S ribosomal unit
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The peptide chain
fails to grow
37. Pharmacokinetics
Tetacyclines are administered orally (mainly to small animals), parenterally
(mostly IM and IV) and also topically.
Absorption:
Oral administration in carnivores the drugs are absorbed rapidly from GIT reaching peak plasma
concentration within 2-4hr which persists for 6-8hr.
Milk and milk products, calcium, magnesium, iron or iron preparations and antacids interfere with
the absorption of the tetracyclines in the GI tract due to chelation.
The absorption of doxycycline and minocycline is complete & highest and they in undergo
enterohepatic cycling.
Tetracycline should not be administered orally to ruminants as they are poorly absorbed and
cause disruption of ruminal microflora.
In veterinary medicine, specially buffered tetracycline solutions (to avoid irritation)
are most commonly administered by IM and sometimes by IV routes.
IM dosage gives peak blood levels after 2 hr and maintained for 12-24 hr.
Chlorteracycline should not be administered IM b/c of severe tissue irritation & damage.
The long acting tetracycline are produced by delaying their absorption from IM sites by using a
special carrier or increasing magnesium content.
Oily preparations, used for SC administration in poultry shouldn’t be administered
parenterally to mammals. 2/15/2023
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38. Distribution:
Tetracyclines are widely and extensively distributed to almost all the body
tissues and fluids, particularly after parenteral administration.
These drugs undergo chelation with calcium and are deposited
irreversibly in growing bones and teeth in young animals.
Doxycycline and minocycline readily penetrate tissues and also CSF.
Protein binding varies from 30% (Oxytetracycline) to 90% (Doxycycline).
Metabolism:
Tetracyclines undergo limited metabolism in domestic animals except
doxycycline and minocycline (partly).
Excretion:
They are chiefly excreted by kidney via Glomerular filtration and also
excreted unchanged in faeces directly or through bile.
Most tetracycline will accumulate if renal function is impaired and increases
nephrotoxicity.
Doxycycline is an exception as it is largely excreted through the GI tract.
They are also secreted in milk.
Their minimum therapeutic level is 0.5 to 1 µg per ml serum. 2/15/2023
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39. Tetracyclines can also be absorbed from the uterus and udder,
although plasma levels remain low
Tetracyclines distribute rapidly and extensively in the body,
particularly after parenteral administration.
They enter almost all tissues and body fluids; high concentrations are
found in the kidneys, liver, bile, lungs, spleen, and bone.
Lower levels are found in serosal fluids, synovia, CSF,
prostatic fluid.
The more lipid-soluble tetracyclines (doxycycline and minocycline)
readily penetrate tissues such as the blood- brain barrier and CSF
TTC deposited irreversibly in the growing bones and in dentin and
enamel of unerupted teeth of young animals, or even the fetus if
transplacental passage occurs
Drug bound in this fashion is pharmacologically inactive
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40. Resistance to the Tetracycline
Resistance is primarily plasmid-mediated and often is inducible.
Resistance develops slowly in a multistep fashion but
Is widespread because of the extensive use of low levels of tetracyclines
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The three main resistance mechanisms are:.
Decreased accumulation of tetracycline as a result of either decreased
antibiotic influx or acquisition of an energy-dependent efflux pathway.
ↈProduction of a ribosomal protection protein that displaces tetracycline
from its target, a "protection" that also may occur by mutation
Enzymatic inactivation of tetracyclines.
Cross-resistance among tetracyclines, doxycycline and minocycline occurs
41. Antibacterial spectrum
Tetracyclines are broad spectrum antibiotics and practically inhibit all
types of pathogenic microorganism except mycobacteria, fungi and
viruses.
Some strains of E. coli, Klebsiella, proteus, Psedomonas aeroginosa
and Corynebacterium spp. are frequently resistant to tetracyclines.
Therapeutically effective level in serum is 0.5 to 4 µg / ml of serum.
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Tetracyclines are active against and used in the Rx:
Both aerobic and anaerobic Gram +Ve and Gram -Ve bacteria, in Four Quadrants
Mycoplasma, Rickettsiae, Chlamidia and
Some protozoa like
Babesia, Theileria, Anaplasma, Coccidia and Entamoeba.
42. Therapeutic Indications and Clinical uses
Rickettsiosis (especly Chlortetracycline)
Nocardiosis (especially Minocycline)
Ehrlichosis (especially Doxycycline)
Haermobartoneliosis by M. haemofelis causing fatal hemolytic anemia
Pasteurellosis (Transit fever, Hidradenitis Suppurative, Fowl Cholera )
Bacterial diseases of poultry (Blue comb in turkey, CRD, etc.
Besides chemotherapy they are used for as additives as growth promoter
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General organ infection are:
Mastitis (local + parenteral)
Coliform-salmonella enteritis
Bronchopneumonia in all species
Urinary tract infections, Metritis
Pyodermatitis Prostatitis Cholangitis
Leptospirosis, Amoebiasis
Balantidosis by balantidium coli
bacterial enteritis
Cystitis in small animals, Heartwater
Specific disease actinomycosis (A. bovis anaer)
Actinobacilosis (WT, A. Lignieresi)
Keratoconjuntivitis, Brucellosis, Chlamydiosis
Babesiosis, Anaplasmosis, Theileriasis
Tetracyclines are used in to treat both systemic & local infections.
43. Dosage
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Tetracycline Species Dosage Route Frequency
Tetracycline Cats
dogs
7 mg/kg IM or IV Bid
20 mg/kg PO Tid
Oxytetracycline Cats
dogs
7 mg/kg IM or IV Bid
20 mg/kg PO Tid
Cattle, sheep, pigs 5-10 mg/kg IM or IV Sid
Calves, foals, lambs, piglets 10-20 mg/kg PO Bid - tid
Horses 5 mg/kg IV Sid - bid
Doxycycline Dogs 5-10 mg/kg PO Sid
5 mg/kg IV Sid 158
Rolitetracycline Cattle 2 mg/kg IV once a day
Withdrawal periods
Oxytetracycline: Cattle & pig: 22 days; Poultry: 5days;
Oxytetracycline (long acting): Cattle-28 days;
Chlortetracycline: Cattle: 10 days; Pig: 7 days;
Oxytetracyclines are not to be used in lactating cows.
44. Adverse Reactions and Toxicity
Alteration in microflora in rumen or intestines oral use leads to digestive
disturbances and ruminal stasis,
Decrease in synthesis and availability of vitamin B and K particularly in monogastric.
Superinfections by fungi, yeasts and resistant bacteria may cause severe or
fatal diarrhea (horse) following oral or parenteral administration.
Tetracyclines are deposited in growing teeth and bones and should not
be used in growing animals because they cause yellowish and later
brownish discoloration of teeth and suppress bone growth.
Tetracycline should not be used with immunization program (cause immunosuppression).
Intramammary infusion of chlortetracycline is contraindicated in dry cows
(Cause severe tissue irritation and subsequent fibrosis) and if infused:
Cows fail to lactate after parturition (due to teat and udder tissue damage).
Intraarticular injection of tetracyclines are contraindicated (cause severe irritation and
inflammation).
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45. If administered by rapid IV injection, hypotension and acute collapse may occur
in cattle and horses due to chelation of blood Ca++ and
This can be avoided by slow infusion of the drug or pretreatment with IV calcium
gluconate.
Tetracyclines in high doses produce hepatotoxicity particularly in pregnant
animals or those having renal abnormality.
All tetracyclines in high doses are potentially nephrotoxic (due to decrease
in host protein synthesis and anti-anabolic effect) except doxycycline and are
contraindicated in renal insufficiency.
Phototoxic dermatitis is most common with Demeclocycline, Doxycycline
in man which is rare in animals.
Hypersensitivity is rare.
In human ingestion of outdated tetracyclines produces a syndrome charxd by
aminoaciduria, glycosuria, polyuria & polydypsia (Thrusty) due to
proximal convoluted tubular damage (Fanconi syndrome).
Demeclocycline induces diuresis (ADH antagonism).
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46. Drug Interactions
The absorption of tetracyclines from the GIT is decreased by milk and milk
products, antacids, kaolin, and iron preparations.
Tetracyclines gradually lose activity when diluted in infusion fluids and
exposed to ultraviolet light.
Vitamins of the B-complex group, especially riboflavin, hasten this loss of
activity in infusion fluids.
Methoxyflurane anesthesia combined with tetracycline therapy is nephrotoxic.
Microsomal enzyme inducers such as phenobarbital and phenytoin shorten
the plasma half-lives of minocycline and doxycycline.
Except for minocycline and doxycycline, the presence of food can substantially
delay the absorption of tetracyclines from the GI tract.
The tetracyclines are less active in alkaline urine, and urine acidification can
increase their antimicrobial efficacy.
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47. Precautions
Contraindicated in
Pregnant, Lactating and Young animals.
Must be cautiously used in animals with renal and hepatic dysfunctions.
Injectable tetracyclines should never be mixed with penicillin
(precipitation inactivation occurs).
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49. Chloramphenicol (Chloromycetin) is a nitrobenzene derivative produced by
Streptomyces venezuelae
Affects protein synthesis by binding to the 50S & preventing peptide bond formation
Prevents the attachment of the amino acid end of aminoacyl-tRNA to the A site,
hence the association of peptidyltransferase with the amino acid substrate.
A broad spectrum antibiotic, chloramphenicol has the ability to cross the corneal
barrier and enter the anterior chamber.
Because of the potential toxicity associated with chloramphenicol to humans, Its use
in veterinary ophthalmology is becoming less widespread.
Effective against gram +ve and -ve bacteria, including Rickettsia, Mycoplasma, and
Chlamydia spp.. 2/15/2023
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51. Pharmacokinetic property
Chloramphenicol is absorbed rapidly and completely from the gastrointestinal tract.
Hepatic metabolism (glucuronosyltransferase) to the inactive glucuronide is the
major route of elimination and is rapidly excreted (80–90% of dose) in the urine.
This metabolite and chloramphenicol itself are excreted in the urine following GF & TS
Animals Ŵ cirrhosis or impaired hepatic function have decreased metabolic clearance
About 50% of chloramphenicol is bound to plasma proteins; such binding is reduced in
cirrhotic patients and in neonates.
Resistance to Chloramphenicol
Resistance to it usually is caused by a plasmid-encoded acetyl transferase that
inactivates the drug.
Acetylated derivatives of chloramphenicol fail to bind to bacterial ribosomes.
Resistance also can result from decreased permeability and from ribosomal mutation.
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52. Suggested Dosages/Precautions/Adverse Effects
For prophylaxis following surgery or for cats with Mycoplasma or
chlamydial conjunctivitis: One drop (or 1/4 inch strip if using
ointment) four times daily.
Chloramphenicol exposure in humans has resulted in fatal aplastic
anemia.
For this reason, this drug should be used with caution in veterinary
patients.
Labels (food) state to not use longer than 7 days in cats, but tid
application of ointment for 21 days to cats did not cause toxicity.
Must not be used in any food producing animal.
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53. Veterinary-Approved Products: THIAMPHENICOL AND FLORPHENICOL
Derivative of chloramphenicol where NO2 group is replaced by sulphomethyl group –CH3S2
Chloramphenicol 1% Ophthalmic Ointment in 3.5 gm; Bemacol¨-(Pfizer); Chlorbiotic¨-
(Schering); Chloricol¨ (Evsco); Generic; (Rx)
Chloramphenicol 0.5% Ophthalmic Drops in 7.5 ml btls tubes; Chlorasol¨-(Evsco); (Rx).
Approved for use in dogs and cats.
Dose dependent reversible suppression of bone marrow activity; more common in cats
and in dogs. It can be reversed on withdrawal of the drug.
Dose independent irreversible bone marrow depression aplastic and fatal anemia.
⚫ Human beings exposed to small doses through residues in food animals develop
aplastic anemia. Thus Banned by FDA.
Occasionally –Anaphylaxis, vomition and diarrhea in cats and dogs
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54. Therapeutic uses
The use of chloramphenicol should be reserved for serious infections in
which the benefit of the drug is greater than the risk of toxicity.
It is used for both local and systemic infections in animals:
Drug of choice in Salmonella and Bacteroides septicaemia.
Also used in Bacterial meningoencephalitis, and Brain abscess,
Ophthalmitis, Intraocular infections, eye infections
Mastitis (Intramammarily and/or parenterally),
Equine dermatophilus infections (haematogenus delivery)
Superficial skin and Otitis externa (as 1% topical preparation).
In human it is effective in typhoid and paratyphoid fever
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55. Toxicity
Nausea and vomiting, unpleasant taste, diarrhea, and perineal irritation
may follow the oral administration of chloramphenicol.
Chloramphenicol in man (but not florfenicol) produces two types
syndrome related to bone marrow depression.
Non regenerative anaemia:
Such blood dyscrsias may also be seen in susceptible neonatal animals
treated with adult doses of chloramphenicol.
This is the direct toxic effect of drug related to the interference with
mRNA and protein synthesis in rapidly multiplying bone marrow cells.
Reversible aplastic anaemia
It is sometimes seen in dogs and cats, much more serious and related to
idiosyncratic reaction.
Thiamphencol and florfenicol, without the nitro group, do not produce
aplastic anaemia. 2/15/2023
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56. Gray baby syndrome:
Chloramphenicol should be used with great care in newborns because
inadequate inactivation and execration of the drug result in such toxic
syndrome – vomiting flaccidity, hypothermia, and an ashen grey cyanosis
followed by CV collapse and death.
GI disturbances : Oral administration of chlormphenicol in monogastric
animals causes GI disturbances.
Hypersensitivity reactions to the antibiotic are uncommon.
The antibiotic causes immunosuppression so animal should not be
vaccinated while being treated with chloramphenicol.
In large animal rapid IV injection of preparations containing propylene
glycol may result in haemolysis, collaspse and death.
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57. Drug interactions
Chloramphenicol (a potent microsomal enzyme inhibitor)
inhibits the metabolism of many other drugs like phenytoin,
barbiturates, primidone, local anaesthetics and thereby
either prolong their action or precipitate toxicity.
Phenobarbitone and phenytoin enhance chloramphenicol
metabolism, reduce therapeutic concentration and cause
failure of chemotherapy.
It should not be combined with bactericidal drugs and
drugs that bind to 50S ribosomal subunit (macrolides and
lincosamides).
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58. Macrolide antibiotics are bacteriostatic agents that inhibit protein
synthesis by binding reversibly to 50S ribosomal subunits of sensitive
microorganisms, at/very near the site that bind chloramphenicol
Erythromycin does not inhibit peptide bond formation per se,
but rather inhibits the translocation step where in a newly synthesized
peptidyl tRNA molecule moves from the acceptor site on the ribosome
to the peptidyl donor site.
Gram +Ve bacteria accumulate about 100 times more erythromycin
than do gram -Ve bacteria.
Cells are considerably more permeable to the un-ionized form of the
drug, which probably explains the increased antimicrobial activity at
alkaline pH.
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MACROLIDES (Erythromycin, Clarithromycin and Azithromycin)
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Resistance to macrolides usually results from one of four mechanisms:
Drug efflux by an active pump mechanism in staphylococci, group A streptococci,
or S. pneumoniae, respectively);
Ribosomal protection by inducible or constitutive production of methylase
enzymes, mediated by expression of ermA, ermB, and ermC, which modify the
ribosomal target and decrease drug binding;
Macrolide hydrolysis by esterases produced by Enterobacteriaceae; and
Chromosomal mutations that alter a 50S ribosomal protein (found in B. subtilis,
Campylobacter spp., mycobacteria, and gram-positive cocci).
61. Pharmacokinetics
Erythromycin base is incompletely absorbed from the upper small intestine
Because it is inactivated by gastric acid, the drug is administered as enteric-
coated tablets, as capsules containing enteric-coated pellets that dissolve in
a duodenum.
Food, which increases gastric acidity, may delay absorption.
Erythromycin diffuses readily into intracellular fluids, achieving antibacterial
activity in essentially all sites except the brain and CSF.
Only 2% to 5% of orally administered erythromycin is excreted in active form
in the urine; this value is from 12% to 15% after intravenous infusion.
Azithromycin administered orally is absorbed rapidly and distributes
widely throughout the body, except to the brain and CSF.
Concomitant administration of aluminum and magnesium hydroxide antacids
decreases the peak serum drug concentrations but not overall bioavailability.
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62. Azithromycin's unique pharmacokinetic properties include extensive tissue
distribution and high drug concentrations within cells (including phagocyte)
resulting in much greater concentrations of drugs in tissue or secretions compared
to simultaneous serum concentrations
Azithromycin undergoes some hepatic metabolism to inactive metabolites, but
biliary excretion is the major route of elimination.
Only 12% is excreted unchanged in the urine. The elimination half-life, 40 to 68
hours, is prolonged because of extensive tissue sequestration and binding.
Clarithromycin is absorbed rapidly from the GIT after oral administration, but
first-pass metabolism reduces its bioavailability to 50% to 55%.
Clarithromycin & its active metabolite, 14-hydroxyclarithromycin, distribute widely
and achieve high intracellular concentrations throughout the body.
Clarithromycin is eliminated by renal and nonrenal mechanisms.
It is metabolized in the liver to several metabolites, the active 14-hydroxy significant.
Primary metabolic pathways are oxidative N-demethylation and hydroxylation at the
14 position.
The elimination half-lives are 3 to 7 hours for clarithromycin and 5 to 9 hours for 14-
hydroxyclarithromycin. 2/15/2023
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63. Nitroimidazole antibiotics have been used to combat anaerobic bacterial and
parasitic(protozual) infections .
E.g metronidazole, tinidazole, nimorazole, dimetridazole
Mechanism of Action
It causes excessive breakage of DNA strand and inhibit DNA repair enzyme
DNAase – bactericidal
Resistance is rare. It involves reduced intracellular drug activation. Cross
resistance between nitro imidazole is complete and some with nitrofurans.
Pharmacokinetics
It is well absorbed in monogastrics and horses from GIT. Highly lipophilic and
excellent tissue penetration(even into blood brain barrier), oxidised and
conjugated in the liver and 2/3 excreted unchanged in urine.
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NITROIMIDAZOLES
64. Toxicity, Drug Interaction and Clinical Application
High dose- neurotoxicity and reversible bone marrow suppression
Carcinogenic- not used in food producing animals in US and not approved by FDA for use in
cattle.
Teratogenic not used in first trimester of pregnancy
Drug interaction
No interference with penicillin G, Amoxcillin+Cloxacillin, cefoxitin, clindamycin,
erythromycin.
Clinical application
Amoebiasis, Trichomoniasis, Giardiasis, Anaerobic bacterial infection,
abdominal abscess, peritonitis, genital tract infection, meningitis and necrotic
tissue.
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65. Mechanism of Action
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Inhibit the activity of DNA gyrase - an enzyme which controls the supercoiling of DNA
Which converts released covalently closed circular DNA to a super helical form by
energy dependent strand breakage and resealing.
The enzyme gyrase (topoisomerase II) permits the orderly accommodation of a
~1000 μm long bacterial chromosome in a bacterial cell of ~1 μm.
Within the chromosomal strand, double-stranded DNA has a double helical
configuration.
The former, in turn, is arranged in loops that are shortened by supercoiling.
The gyrase catalyzes this operation, as illustrated, by opening, under winding, and
closing the DNA double strand such that the full loop need not be rotated.
Derivatives of 4-quinolone-3-carboxylic acid (fluroquinolones) are inhibitors of
bacterial gyrases.
They appear to prevent specifically the resealing of opened strands and thereby act
bactericidally.
QUINOLONES
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Classification of Fluoroquinolones
First generation Quinolones Eg:
Nalidixic acid, Oxolinic acid, flumequine
Second generation Quinolones Eg:
Ciprofloxacin, Danofloxacin,
Enrofloxacin, Norfloxacin
67. Antimicrobial Action and Resistance
High activity towards Gram negative aerobes and against Gram positive
aerobes
The second generation Quinolones are active against Mycobacteria
[Ciprofloxain and ofloxacin],Mycoplasma, Rickettsia and inactive against
anaerobes
Pharmacokinetics and Drug Interactions
Better absorbed after oral administration in monogastrates, better
in parenteral administration.
Partially metabolized in liver and excreted in urine and bile.
Drug Interaction
Additive effect - lactam, Aminoglycosides, Macrolides
Antagonistic – Nitro-furans, Chloramphenicol and rifampin
Fluoroquinolones+ Metronidazole - extended spectrum
Food and antacids interfere with the absorption 2/15/2023
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68. Toxicity and Adverse Effects
Relatively safe drug
Human - Nausea, upper gastrointestinal tract discomfort, headaches
and dizziness
Skin rashes and photosensitivity - less common
Neurotoxic - sometimes prone for CNS convulsions
Pregnancy - embryonic loss and maternal toxicity
Dogs
Cartilaginous erosion leading to permanent lameness in young animals.
Hence not recommended for pups less than 8 months in small breed
and 18 months in large breeds
Horses
Not recommended because of arthralgic effect 2/15/2023
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69. Clinical Indications & Therapeutic Uses
Administered For Monogastrates – Orally and for Ruminants - Parenterally
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Fluoroquinolones are widely used for the Tx of:
ↈHuman- Urinary tract infection, bacterial enteritis, pneumonia, septicemia due to Gram
negative aerobic organisms.
ↈAlso in meningitis, prostatitis, Rickettsia, Mycoplasma and Mycobacteria infections
Cattle, sheep and goat Pneumonia
ↈMycoplasma bovis and pasteurella
ↈE.coli and salmonella enteritis
Also used for Tx of:
E.coli septicaemia
Mycoplasma, Rickettsia, chlamydia.
Swine Pneumonia of various origin
E.coli diarrhoea, salmonellosis, Mastitis Metritis Agalactia
syndrome.
70. Anti tuberculosis agents
Rifampin
Pharmacology
Rifampin acts as either a bactericidal/bacteriostatic antimicrobial dependent
upon the susceptibility of the organism and the concentration of the drug.
Rifampin acts by inhibiting DNA-dependent RNA polymerase in susceptible
organisms, thereby suppressing the initiation of chain formation for RNA synthesis.
It does not inhibit the mammalian enzyme.
It is active against a variety of mycobacterium species and S. aureus, Neisseria,
Haemophilus, and Rhodococcus equi (C. equi).
At very high levels, rifampin also has activity against poxviruses, adenoviruses, and
Chlamydia trachomatis.
Also has antifungal activity when combined with other antifungal agents
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71. Uses/Indications
At the present time, the principale use of rifampin in veterinary medicine is in the treatment of
Rhodococcus equi (Corynebacterium equi) infections (Ŵ erythromycin estolate) in young
horses.
In small animals, the drug is sometimes used in combination with other antifungal agents
(amphotericin B) in the Rx of histoplasmosis or aspergillosis with CNS involvement.
Pharmacokinetics
After oral administration, rifampin is relatively well absorbed from the GI tract.
Oral BiA is 40-70% in horses & 37% in sheep: If Ŵ food, peak plasma levels is delayed slightly .
It is very lipophilic and penetrates most body tissues (bone & prostate), cells & fluid CSF
It is 70- 90% bound to serum proteins & is distributed into milk and crosses the placenta.
It is metabolized in the liver to a deacetylated form which also has antibacterial activity.
Both this metabolite and unchanged drug are excreted primarily in the bile, but up to 30% may
be excreted in the urine.
The parent drug is substantially reabsorbed in a gut, but the metabolite is not
As it can induce hepatic microsomal enzymes, elimination rates may increase with time.
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72. Contraindications
Rifampin is contraindicated in patients hypersensitive to it or other rifamycins..
It should be used with caution in patients with preexisting hepatic dysfunction.
Adverse Effects/Warnings
Rifampin can cause red-orange colored urine, tears, sweat and saliva.
There are no harmful consequences from this effect.
Drug Interactions
Because rifampin has been documented to induce hepatic microsomal enzymes,
drugs that are metabolized by these enzymes may have their elimination half-
lives shortened and serum levels decreased.
Drugs that may be affected by this process include
Propranolol, Quinidine, Dapsone, Chloramphenicol, Corticosteroids,
Oral Anticoagulants (Warfarin), Benzodiazepines (Diazepam), and
Barbiturates (Phenobarbital).
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73. Polymyxins discovered in 1947, are a group of closely related antibiotic
elaborated by various strains of Bacillus polymyxa.
Because of the extreme nephrotoxicity associated parenteral admstrṉ of
these drugs, they are rarely if ever used except topically.
Mechanism of Action
Polymyxins are surface-active, amphipathic (both hydrophilic & phobic) agents.
They interact strongly with phospholipids and disrupt the structure of cell m/b.
The permeability of the bacterial m/b changes immediately on contact with the drug
Sensitivity to polymyxin B apparently is related to the phospholipid content of the cell
wall-membrane complex.
The cell walls of certain resistant bacteria may prevent its access to the cell m/b.
The antimicrobial activities of polymyxin B is restricted to gram -Ve bacteria, including:
Enterobacter, E. coli, Klebsiella, Salmonella, Pasteurella, Bordetella & Shigella.
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Miscellaneous antibacterial agents
74. Polymyxin B and colistin are not absorbed when given orally and are poorly
absorbed from mucous membranes and the surfaces of large burns.
They are cleared renally & dose modification is required in impaired renal function
Infections of the skin, mucous m/b, eye, and ear due to polymyxin B sensitive MOs
respond to local application of the antibiotic in solution or ointment.
External otitis due to Pseudomonas, may be cured by the topical use of the drug.
Contraindication and Untoward Effects
Polymyxin B applied to intact or denuded skin or mucous membranes produces no
systemic reactions because of its almost complete lack of absorption from these sites.
Hypersensitization is uncommon with topical application.
Polymyxins interfere with neurotransmission at the neuromuscular junction resulting
in muscle weakness and apnea.
Other neurological reactions include paresthesias and vertigo.
Polymyxins are nephrotoxic, and administration with aminoglycosides should be
avoided if possible.
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75. Bacitracin
Bacitracin inhibits the synthesis of the bacterial cell wall.
A variety of gram +Ve cocci and bacilli, Neisseria, H. influenzae, & Treponema pallidum
are sensitive to 0.1 unit or less of bacitracin per milliliter.
Actinomyces and Fusobacterium are inhibited by concentrations of 0.5 to 5 units/ml.
It is available in ophthalmic & dermatologic ointments; as a powder for the topical solutions preprṉ.
The ointments are applied directly to the involved surface one or more times daily.
A number of topical preparations of bacitracin, to which neomycin or polymyxin or both have been
added, are available, and some contain the three antibiotics plus hydrocortisone.
For open infections such as infected eczema and infected dermal ulcers, the local application of the
antibiotic may be of some help in eradicating sensitive bacteria.
Unlike several other topical antibiotics, bacitracin rarely produces hypersensitivity. Suppurative
conjunctivitis & infected corneal ulcer respond well to the topical use when causd by suptbl bacteria
Oral bacitracin has been used with some success for the treatment of antibiotic-associated diarrhea
caused by Clostridium difficile.
Bacitracin is used by neurosurgeons to irrigate the meninges intraoperatively as an alternative to
vancomycin. It has no direct toxicity on neurons. 2/15/2023
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76. Vancomycin
Mechanisms of Action
Vancomycin inhibits the synthesis of the cell wall in sensitive bacteria by binding
with high affinity to the D-alanyl-D-alanine terminus of cell wall precursor units.
Pharmacokinetics
Vancomycin is poorly absorbed after oral administration.
For parenteral therapy, the drug should be administered intravenously, never
intramuscularly.
A single intravenous dose of 1 g in adults produces plasma concentrations of 15 to
30 mg/ml 1 hour after a 1- to 2-hour infusion.
The drug has a serum elimination half-life of about 6 hours.
Approximately 30% of vancomycin is bound to plasma protein.
Vancomycin appears in various body fluids, including the CSF when the meninges
are inflamed (7% to 30%); bile; and pleural, pericardial, synovial, and ascitic fluids.
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