AMINOGLYCOSIDES

AMINOGLYCOSIDES

Aminoglycosides (Aminocylitols) are a group of natural and semi-synthetic antibiotics having amino sugars linked to an aminocyclitol ring by glycosidic bond.

History:

Streptomycin was the first member of amino glycoside antibiotics discovered in 1944 by Walks man and co-workers from a strain of Streptomyces griseus.

Chemistry and source.

The aminoglycosides consist of two or more amino sugars joined in glycosidec linkages to a hexose (aminogyclitol) nucleus.The presence of amino group on the glycosides and the hydroxyl group on the sugars provide high water solubility ( or poor lipid solubility) to the drugs. Aminogly- cosides prepared from Streptomyces carry the suffix-mycin, where those derived from Micromonospora have name ending with –micin.

Properties

a)                  They are water soluble and polar compounds and generally ionize in solution.

b)                  They are not absorbed orally,

c)                  They are bactericidal in action and are more active against gram – negative.

d)                 They are more active in alkaline pH.

e)                  They show synergistic antibacterial effect with beta – lactam antibiotics,

Classification

On the basis of antibacterial spectrum, amino glycosides may be classified into following groups:

I.                  Narrow-spectrum aminnoglycosides

e.g., streptomycin and dihydrostreptomycin.

      II.        Broad-spectrum amino glycosides.

                  E.g., neomycin, framycetin,kanamycin and paromomycin.

Mechanism of action

            The amino glycosides are bactericidal drugs that act by inhibiting protein synthesis in susceptible bacteria, mainly gram – negative organisms.

2.         Binding of amino glycosides to bacterial ribosomes.

            Amino glycosides can bind with both 30 S and 50 S ribosomal subunits, although their binding with 30 S subunit is stronger.

b)                  Distortion of m-RNA Condon resulting in misreading of the codon. This causes incorporation of one or more incorrect amino acid (s) into peptide chain and synthesis of abnormal proteins.

c)                  Promotion of premature termination of translation with detachment of the ribosomal complex. Binding of aminoglycosides to 30 S- 50 S juncture is probably responsible for their bactericidal effect,

iii)                Aminoglycosides show long and concentration dependent post – antibiotic effect. There fore , despite their short half – lives a single injection of the total daily dose of aminoglycosides may be effective.

Antibacterial  Spectrum

Antibacterial spectrum of aminoglycosides varies with the type of antibiotic streptomycin and dihydrostreptomycin have relatively narrow spectra mainly gram-negative species. The broad-spectrum aminoglycosides(e.g. neomycin and kanamycin) are active against many gram-negative and gram-positive organisms,

But not pseudomonas. The extended-spectrum aminoglycosides posses antibacterial spectra similar to broad-spectrum antibiotics and are also active against pseudomonas aeroginosa and a verity of aerobic bacteria. Anaerobic bacteria are only moderately sensitive to aminoglycosides .  

Side effects /Adverse effects

All aminoglycosides have potential to produce toxic effects, but the relative propensity differs . Nephrotoxicity, ototoxicity, and neuromuscular blockade are important adverse effects observed with aminoglycosides.

1.  Nephrotoxicity:    Nephrotoxicity with aminoglycosides occurs as a result of excessive accumulation of antibiotics by the proximal tubular cells in kidneys. As aminoglycosides are positively charged agents , they get attracted to negatively charged phospholipids of the renal membrane followed by their transport onside the tubular cells via pinocytosis. This transport is directly related to the membrane content of phosphatidly inositol, which is high in renal cortex and cochlear tissues.

Manifestations of nephrotoxicity include presence of enzymes of brush border urine, proteinurea, presecnces  of casts, and low GFR.Aminoglycosides , neomycin is most nephrotoxic.

Nephrotoxicity of aminoglycosides can be prevented or minimized by following some simple steps like avoiding use of potentially nephorotoxic aminoglycosides , ensuring adequate hydration status of patient, and avoiding concurrent use of other nephrotoxic drugs.

2.  Ototoxivity:         Aminoglycosides get accumulated into perilymph and endolymph of the inner ear in dose and time dependent manner.Ototoxicity is greater when the plasma concentration of drug is persistently high. Ototoxicity once occur is usually irreversible and result from progressive destruction  of vestibular or cochlear sensory cells. Vestibular injury leads to nystagmus, in coordination, vertigo, head tilt,ataxia,and loss of righting reflex in animal. Hearing impairment or deafness may be produced by permanent damage and loss of hair cells in the organ of Corti .Aminoglycosides should not be instilled into ear unless the tympanic membrane is intact because direct administration of aminoglycosides into the inner ear could cause potential damage.

3.  Neuromuscular blockade:            All amino-glycosides have potential to produce neuromuscular blockade with curare-like action. The effect is produced mainly by interference with acetylcholine release from motor nerve endings, probably by antagonism of Ca ++ that is normally required for exocytosis.However, concomitant administration of neuromuscular blocking agents and general anesthetics with aminoglycosides may substantially increase the risk of neuromuscular blockade .

Contraindications and precautions

     Pre-existing renal disease. Aminoglycosides may impair neuromuscular transmission and so are not given to animals with myasthenia gravis. They cause adverse effects on fetus, so their use during pregnancy is not recommended unless considered mandatory.

Drug interactions

            Aminoglycosides show interaction with drugs that cause ototxicity , nephrotoxicity and neurotoxicity , Concurrent use of aminoglycosides with loop diuretics ( e.g.,, frusemide and osmotic diuretics (e.g., mannitol ) may aggravate the nephrototoxic or ototoxic effects of aminoglycosides. Risk of neuromuscular blockade and respiratory  paralysis increases when aminoglysosides are used with inhalant anesthetics or neuromuscular blocking drugs .

Clinical uses

Septicamemia, osteoarthritis, and mastits.endometritis.

Side effect/Adverse effects

Adverse effects of streptomycin are similar to other aminoglycosides  antibiotics, but it is less nephrotoxic than many aminoglycosides .Hypersensitivity reaction are rare.

TETRACYCLINES AND AMPHENICOLS

TETRACYCLINES

Tetracyclines are a group of broad – spectrum antibiotics having a nucleus of four cyclic rings.

History

The first member of the group was chlortetracycline derived from soil actinomycete Streptomyces aureofaciens introduced in 1948.

Chemistry and properties

As a group, tetracyclines are acidic and hygroscopoic compounds. They chatacteristically fluorescence  when exposed to ultraviolet light. Physical and chemical properties of tetracyclines permit them to be formulated as infection, boluses capsules, powders, feed additives, and ointments for veterinary use.

Classification

 Tetracyclines are classified according to their duration of action.

I.          Short-acting tetracyclines(t1/2=<8houres)

            Oxytetracycline, tetracycline and chlortetracycline.

II       Intermediate acting tetracycline’s(t1/2=8-16houres)

          Demeclocycline and methacycline.

III     Long-acting tetracyclines (t1/2=<16houres)

          Doxycycline and minocycline.

Mechanism of action

            Tetracyclines inhibit bacterial protein synthesis and are primarily bacteriostatic.

Antimicrobial spectrum

          The tetracyclines are broad – spectrum antibiotics. They ate active against a wide range of aerobic and anaerobic gram- positive and gram-negative bacteria. They are also active against Mycoplasma Rickettsia, Chlamydia, and some protozoa like anplasma, haemobartonella, and amoebae, Presently  strains of pseudomonas aeruginosa, Proteus, Serratia, Klebsilla, Salmonella , staphylococcus, and

corynaebacterium species appear to have become resistant to tetracyclines. Tetracyclines are infective against fungi and viruses.

Effect on bones /teeth:      Tetracyclines are deposited in growing teeth and bones due to their chelating properties with calcium .They from tetracycline – calcium orthophosphate complex, which inhibits calcification e.g. hypoplastic dental enamel and results in permanent discoloration (first yellowish) then brownish of the teeth. The stained and hypoplastic teeth are more prone to various degeneration. Delay fracture healing. Pregnancy in neonates.Tetracyclin may cause temporary suppression.

Hepatotoxicity:  Tetracyclines in excessive doses can produce fatty  in flirtation of liver.Hepatotoxicity with jaundice due to large doses of tetracyclines has been reported in pregnant woman and in some animals

Contraindication and precautions

Tetracyclines are contraindicated in hepatic insufficiency,

Drug interaction

Antacids decrease the absorption of tetracycline’s from GI tract.

Clinical uses:      Used for treating mycoplasma , chlamydiae and rickettsiae, anaplasma, hemobratonella, ehrlichia, and borrelia, In birds, they are used in the treatment of psittacosis. For treating bronchopneumonia, metritis, mastitis, pyodermatitis.

Administration

 Tetracyclines may be administered by oral, parenteral , topical, or intramammary route, The choice of route of administration depends on the species involved , type of action desired and compound to be used,