Aminoglycosides:

• These are group of natural and semi-synthetic antibiotics having polybasic amino groups linked glycosidically to two or more amino sugars.
• They are mostly bactericidal drugs.
• Important members of this group are streptomycin, neomycin, kanamycin, gentamicin, amikacin and tobramycin.
• Streptomycin was the first member of aminoglycosides discovered in 1944 by Waksman and co-workers from a strain of Streptomyces griseus.
• Neomycin was next to be isolated in 1949, followed by kanamycin 1957 and gentamicin 1963.
• Amikacin is semi-synthetic aminoglycosides obtained by chemical modification of kanamycin.

Chemistry:

• Aminoglycosides consist of two or more amino sugars joined in glycosidic linkages to hexose (aminocyclitol) nucleus.
• Amino group in antibiotic imparts basic nature to aminoglycosides and hydroxyl group on sugars provide high water solubility to drugs.

Source:

• All aminoglycosides are produced by soil actinomycetes.
• Most aminoglycosides are obtained by natural fermentation of Streptomyces while some members like gentamicin, netilmicin and sisomicin are prepared from actinomycetes micromonospora.
• Antibiotics obtained from Streptomyces carry suffix – mycin and those obtained from Micromonospora have names ending with -micin.

Properties of aminoglycosides:

• Members of aminoglycosides group share common properties:

1. They are water soluble and polar compounds & generally ionize in solution.
2. They are not absorbed orally, distribute only extracellularly, undergo limited biotransformation and excreted mainly unchanged in urine.

• They are bactericidal in action and are more active against gram -ve bacilli.

1. They penetrate poorly into mammalian cells and are of limited value in infections caused by intracellular bacteria.
2. They act by interfering with protein synthesis in susceptible bacteria.
3. They are mainly used as sulphate salts, which are highly water soluble.

• They are more active in alkaline pH.
• They have a tendency to cause ototoxicity and nephrotoxicity.

1. They have relatively narrow margin of safety.
2. Bacterial resistance to many aminoglycosides develop rapidly. However, organism resistant to one aminoglycosides may still respond to other.
3. They show synergistic antibacterial effect with beta-lactam antibiotics but at high concentration they can complex with β-lactam antibiotics resulting in loss of activity.

Classification:

On the basis of antibacterial spectrum, aminoglycosides may be classified into following group:

Mechanism of Action:

• Bactericidal action of aminoglycosides is concentration dependent i.e. they produce greater cidal effect at high concentration.
• Action of aminoglycosides may be broadly divided into two process:

1. Entry of aminoglycosides into bacterial cells
2. Binding of aminoglycosides to bacterial ribosomes.

Aminoglycosides first diffuse through outer coat of gram-ve bacteria and reach periplasm through porin channels.

They are then carried to bacterial cytoplasm from periplasmic space through oxygen dependent process linked to electron transport chain.

Aminoglycosides then bind with bacterial ribosomes at 30S unit though they can also bind to both units.

Due to this bactericidal action is achieved by following mechanism

• Interference with formation of initiation complex of protein synthesis

• Distortion of m-RNA codon resulting in misreading of codon. This causes incorporation of one or  more incorrect amino acids into peptide chain and synthesis of abnormal protein.

• Promotion of premature termination of translation with detachment of ribosomal complex. It leads to incomplete synthesis of protein.

All these results in a membrane that is more permeable to ions, amino acid and even proteins which leak out followed by bacterial death.

Antimicrobial features:

• Bactericidal action is concentration dependent, so they should be given in a single large dose.
• They are more effective against rapidly multiplying bacteria.
• They show long and concentration dependent post-antibiotic effect due to their strong and irreversible binding to ribosomes, therefore, a single total dose may be effective.
• They show synergistic effect with beta-lactam antibiotics because cell wall injury caused by beta-lactam antibiotics facilitates increased uptake of aminoglycosides and easier accessibility to bacterial cell membrane.
• Aminoglycosides those transported more efficiently across the bacterial cell membrane tend to have greater antibacterial effect.

Antibacterial spectrum:

• Varies with type of antibiotic.
• Streptomycin, dihydrostreptomycin have narrow spectra mainly gram -ve.
• Neomycin, kanamycin have broad spectrum which are active against many gram -ve and gram +ve organisms but not Pseudomonas.
• Extended spectrum antibiotics possess similar spectra to those of broad-spectrum antibiotics and also active against Pseudomonas.
• However, aminoglycosides are ineffective against fungi & viruses.

Bacterial resistance:

• Resistance to aminoglycosides by bacteria is achieved by more than one mechanism. It may be plasmid mediated or acquired through mutation.
• Susceptible microorganism acquire resistance by producing transferase enzyme like aminoglycosyl acetyltransferase, aminoglycosyl nucleotidyltransferase and aminoglycosyl phosphotransferase in periplasm.
• Impaired transport of aminoglycosides across the cell wall/membrane may produce resistance to susceptible microorganism. It may occur due to changes in porin size in cell wall that becomes less permeable to antibiotics or due to alteration in active transport system.
• Alteration in ribosomal structure also confer high degree resistance by decreasing the binding sites of aminoglycosides with their target sites.

Pharmacokinetics:

• They are poorly absorbed from G.I tract, so this route is preserved for treatment of G.I infection. Absorption is rapid from IM administration site (>90%) and peak levels are achieved in blood within 30-45 minutes.
• They are extensively distributed in ECF, but donot readily enter into cells due to their polar nature. In renal tubular cells and endolymph and perilymph of inner ear, aminoglycosides accumulate in high concentration.
• They cross placental barrier and reach foetal plasma and amniotic fluid which may cause deafness in young ones.
• They bind poorly to plasma proteins.
• They are not metabolized in the body and excreted unchanged in urine through glomerular filtration.
• Plasma half-lives may range from 2-4 hours in normal renal functioning patients. In patients with renal insufficiency, half-lives may increase to 24-48 hours.

Side effects/Adverse effects:

• Nephrotoxicity occurs as a result of their excessive accumulation by proximal tubular cells in kidneys. Manifestation includes presence of brush border in urine, proteinuria, presence of casts and low GFR. In later stage, collecting duct loose ability to concentrate urine in response to ADH resulting in polyuria.
• They can produce both vesicular and auditory dysfunctions. Vestibular injury leads to nystagmus, incoordination, vertigo, head tilt, ataxia, loss of lighting reflex.
• Neuromuscular blockade through interference with Ach release from motor nerve endings. It results in muscular weakness, apnoea, respiratory arrest etc.

Contraindications:

• In patients with hypersensitivity to aminoglycosides
• In renal disease patient
• In neonatal and geriatric animals
• In pregnant animals
• In patients who have myasthenia gravis.

Drug interactions:

• Concurrent use of aminoglycosides with loop diuretics and osmotic diuretics may potentiate the nephrotoxic and ototoxic effects of aminoglycosides.
• Concurrent use of aminoglycosides and halothane may cause cardiovascular depression
• They show synergistic effect when used with β-lactam antibiotics.
• Risk of neuromuscular blockade and respiratory paralysis increase when aminoglycosides are used with inhalant anesthetic or neuromuscular blocking drugs.

Indications:

• It is widely used to treat local and systemic infections caused by susceptible bacteria.
• It is mainly used for G.I tract, urinary tract, respiratory tract and skin infections
• It is also indicated in septicemia, osteoarthritis, mastitis and wounds.
• In endometritis caused by susceptible bacteria.

Narrow-spectrum Aminoglycosides:

Streptomycin:

• It is oldest aminoglycosides obtained from Streptomyces griseus.
• It occurs as white crystalline substance, water-soluble compounds.

Mechanism of action:

Streptomycin binds to 30S subunit of bacterial ribosome

Interfere with the binding of formyl-methionyl-tRNA to 30S subunit

It causes codon misreading

Inhibition of protein synthesis and ultimately death of microbial cells.

Antibacterial spectrum:

• It is narrow spectrum antibiotics.
• It is active against aerobic gram -ve bacilli.
• Organism susceptible to streptomycin are coli, Salmonella, Klebsiella, Pasteurella, Brucella, Campylobacter foetus & Leptospira.
• tuberculosis is also sensitive.

*Bacterial resistance develops rapidly.

Pharmacokinetics:

• They are not absorbed from G.I tract
• Absorbed gradually after IM administration with peak plasma concentration occurring in 60-90 minutes.
• Distributed extracellularly and attains poor concentration in CNS, eyes, other tissues and fluids.
• Excreted unchanged in urine
• Half-life ranges between 3-4 hours.

Side effects/Adverse effects:

• Nephrotoxicity
• Ototoxicity
• Neuromuscular blockade

Indications:

• It is used in combinations with penicillin for treatment of shipping fever, foot rot, mastitis and other infections.
• Also indicated for coliform infections.

Dose:

For enteric infections:

Dogs and other species: 15mg/kg, PO, once daily

For systemic infections:

Dogs: 5-10 mg/kg, IM, once daily

Cattle, sheep, goat, horses: 10mg/kg, once daily

For mastitis:

Lactating cows: 100mg/quarter, intramammary infusion

Dry cows: 500 mg/quarter

Broad-spectrum antibiotics:

Neomycin:

• It is broad-spectrum aminoglycosides obtained from Streptomyces
• It is combination of three compounds; Neomycin A (neamine), Neomycin B (framycetin) & Neomycin C. Neomycin A is biologically inactive whereas other two are active.

Antibacterial spectrum:

• It is broad spectrum antibiotics.
• It is active against gram -ve aerobic bacteria as well as gram +ve organism
• Pseudomonas aeruginosa & Streptococcus pyogenes are not sensitive.

Pharmacokinetics:

• Poorly absorbed from G.I tract
• Excreted largely unchanged in urine.
• Orally administered drugs remain unmetabolized in G.I tract & excreted unchanged in faeces.

Side effects/Adverse effects:

• Highly toxic to internal ear and kidneys
• Loss of hearing
• Albuminuria, hematuria
• Formation of renal casts.
• Diarrhoea, loss of digestive enzymes and flattening of intestinal villi on prolonged oral administration.

Contraindications:

• In renal failure patient
• In pregnant animals
• Oral neomycin is contraindicated in intestinal obstruction or constipation.

Indications:

• For treatment of systemic infections caused by susceptible bacteria
• Enteric infections
• Sterilizing the colon prior to surgery
• Used topically for skin, eye or ear infections.
• Mastitis

Dose:

For enteric infections:

Dogs & cats: 10mg/kg, PO, in divided dose

Cattle: 10-20 mg/kg, PO, 2 times daily

Horses: 5-15 mg/kg, PO, once daily

Sheep: 22 mg/kg, PO, for 4 days

Extended spectrum Aminoglycosides:

Gentamicin:

• It is most widely used aminoglycosides with extended spectrum of antibacterial activity.
• Obtained from Micromonospora purpurea, genus of gram +ve bacteria widely present in environment (water & soil).
• It is mixture of 3 compounds- gentamicin C₁, C_1a and C₂
• It is commercially available as gentamicin sulphate.

Antibacterial spectrum:

• It is extended spectrum aminoglycosides
• It is active against a wide range of gram -ve and gram +ve bacteria including Staphylococcus, Streptococcus, Pseudomonas, Proteus, E.coli, Klebsiella & Aerobacter

Pharmacokinetics:

• Poorly absorbed from G.I tract after oral administration
• After IM injection, peak plasma concentration is attained in 30-40 minutes.
• Bioavailability after IM or SC administration is greater than 90%
• Distributed largely in ECF, some also enters CSF, prostrate and eye
• Binding to plasma proteins is low
• Excreted mainly unchanged in urine
• Elimination half-lives is 1-3 hours.

Side effects/Adverse effects:

• It has potential to cause nephrotoxicity, ototoxicity & neuromuscular blockade.

Contraindications:

• In patients with hypersensitivity to aminoglycosides
• In renal disease patient
• In neonatal and geriatric animals
• In pregnant animals

Indications:

• For treatment of respiratory tract, urinary tract, G.I tract, bones, soft tissues & skin infections
• In metritis & mastitis
• Also used topically for skin, ear & eye infections.

Dose:

For susceptible infections:

Dogs & cats: 5 mg/kg, IM or SC, 2 times daily on first day followed by once daily

Cattle: 2.5-5 mg/kg, IM, 2-3 times daily

Horses: 2-4 mg/kg, IM, 2-3 times daily