Aminoglycosides

All aminoglycosides are produced by soil actinomycetes. Obtained from the species of – Streptomyces (suffix mycin) – and Micromonospora (suffix micin) Semisynthetic derivatives also end up with suffix micin.

Aminoglycosides Streptomycin Gentamicin Tobramycin Amikacin Kanamycin Neomycin Paromomycin Framycetin

Spectrum Narrow spectrum – Aerobic gram negative bacilli – Not effective against gram positive cocci & bacilli gram negative cocci and anaerobes

Mechanism of action

Penetrate through the bacterial cell wall through porin channels enter the periplasmic space. Transported across the cytoplasmic membrane Once inside the cell These drugs bind to 30S ribosomal units and prevent the formation of “initiation complex” – a prerequisite for peptide synthesis.

Accumulation of abnormal initiation complexes Misreading of mRNA template Incorporation of incorrect aminoacids into the growing peptide. Aberrant proteins

How ????? Bactericidal

Secondary changes in the bacterial cell membrane – resultant aberrant proteins may be inserted into the cell membrane – Disruption of cytoplasmic membrane – Altered permeability – Sensitive bacteria become more permeable – Ions, aminoacids, and even proteins leak out followed by bacterial cell death.

Altered cell membrane – Augmentation of carrier mediated entry of the antibiotic – Reinforces the lethal action of aminoglycoside.

Aminoglycosides Bactericidal antibiotics Rapidly bactericidal Bacterial killing - concentration dependent higher the concentration greater the rate at which bacteria are killed

Penetrate through the bacterial cell wall through porin channels to enter the periplasmic space. – So  -lactam antibiotics which weaken/ inhibit bacterial cell wall synthesis Facilitate passive diffusion of aminoglycosides if given together (synergistic action) –  -lactam antibiotics + Aminoglycosides

Transported across the cytoplasmic membrane – Transport is blocked by anaerobic conditions – Anaerobes not sensitive

They also exert a long & concentration dependent post antibiotic effect that is, residual bactericidal activity persisting after the serum concentration has fallen below the minimum inhibitory concentration duration of this effect is concentration dependent. Characteristic feature

Post antibiotic effect Account for efficacy of once daily dosing regimens of aminoglycosides. Short half life(2-4 hrs)(2-3 divided doses). Single daily dose as effective as multiple dosing. No more toxic & even less toxic, Less renal accumulation, less toxic

Given as a single daily dose results in a higher peak tissue concentration than if the total daily dose were divided and administered at 8 or 12 hourly interval.

Pharmacokinetics

Highly polar drugs – very poor oral bioavailability – hence given I.V. or I.M. – Rapid absorption from i.m. sites. Poorly distributed and poorly protein bound – P/E - fail to reach intraocular fluid, or CSF, – Highly polar drugs

Gentamycin - cross BBB in meningeal inflammation. – Can be used in cerebral meningitis. Excreted through kidney, unchanged All are more active at alkaline pH than acidic.

Antibacterial resistance

Three principal mechanisms for the development of resistance: Synthesis of plasmid mediated bacterial transferase enzymes that can inactivate aminoglycosides. Mutation/deletion of porin channels resulting in decreased transport of aminoglycoside into the bacterial cytosol. By deletion or alteration of the receptor protein on 30S (Target) ribosomal unit because of mutations. Attachment of drug with 30S ribosomal unit is thus prevented.

Toxicity

OtotoxicityNephrotoxicity Neuromuscular blockade

Ototoxicity Accumulate in the endolymph and perilymph of inner ear Vestibular/cochlear sensory cells & hairs undergo concentration dependent destructive changes. leading to vestibular and cochlear damage which is irreversible.

Dose & duration of treatment related adverse effect Drugs concentrated in labrinthine fluid, slowly removed as plasma levels fall. Ototoxicity greater when plasma levels are persistently high.

Old patients more susceptible. Vestibular toxicity is more with Streptomycin & Gentamycin Cochlear toxicity is more with neomycin & amikacin.

Nephrotoxicity Attain higher concentration in the renal cortex Manifests as tubular damage resulting in – loss of urinary concentrating power – low g.f.r. – nitrogen retention – albuminuria & casts.

More in elderly & patient with pre-existing renal disease. Totally reversible (PCT cells regenertae )provided drug is promptly discontinued. An important implication of aminoglycoside induced nephrotoxicity is – reduced clearance of antibiotic – higher blood levels – enhanced Ototoxicity.

neomycin, gentamicin, amikacin and tobramycin are more nephrotoxic than streptomycin % of all renal failure cases.

Neuromuscular blockade Unusual toxic reaction Inhibit pre-junctional release of acetylcholine from cholinergic neurons. Reduce postsynaptic senstivity to the transmitter

Intrapleural/intraperitoneal instillation of large doses of AG Reaction can follow after i.v, im, oral Association with anaesthesia Co-administration of other NM blocking agents Patients with Myasthenia gravis particularly susceptible to NMB by AG

Precautions & Interactions

Pregnancy – risk of foetal ototoxicity Patients past middle age; compromised renal functions. Patients with kidney damage Avoid concurrent use of Ototoxic drugs minocycline & high ceiling diuretics Nephrotoxic drugs amphotericin B, vancomycin, cyclosporin & cisplatin Muscle relaxants. Do not mix it with any drug in the same syringe/infusion bottle.

Therapeutic uses

Gentamycin Economical & first line aminoglycoside antibiotic Low therapeutic index: use is restricted to serious gram negative bacillary infections. – Psuedomonas, Proteus, Kleibsiella infections :burns, UTI, pneumonia, lung abcesses, osteomyelitis are important areas of use of gentamycin.

SABE: Genta in combination with penicillin synergistic, 4-6 weeks treatment. Meningitis caused by g-ve bacilli. – III gen. cephalosporins preferred.

Streptomycin Bacterial Endocarditis: – Enterococcal – in combination with penicillin, synergistic, 4-6 weeks treatment – Gentamicin preferred; lesser toxicity Tuberculosis: multi drug regime Plague: effective agent for all forms of plague. Tularaemia: DOC for this rare disease.

AMIKACIN Resistance to aminoglycoside inactivating enzymes special role in serious nosocomial G-ve bacillary infections in hospitals where gentamycin and tobramycin resistant microorganisms are prevalent.

Netilmicin As it is not metabolised by aminoglycoside inactivating enzymes so active against bacteria resistant to gentamycin

Kanamycin Use declined Most toxic

NEOMYCIN Wide spectrum aminoglycoside Gram negative bacilli & some gram positive cocci Highly toxic to internal ear & kidney, not used systemically. Poorly absorbed from GIT Oral & topical administration does not cause systemic toxicity.

Topical uses – Infected wounds ulcers, burn, external ear infections, conjunctivitis etc. – Combination with polymixin, bacitracin Oral uses – Preparation of bowel before surgery – Hepatic coma.

Hepatic coma: NH 3 produced by colonic bacteria, detoxified by liver, urea. Hepatic failure detoxification does not occur blood NH 3 level rises & produces encephalopathy. Neomycin suppresses intestinal flora, diminishes NH 3 production & lowers its blood level. Clinical improvement in 2-3 days. Lactulose preferred.

Framycetin Same as neomycin Too toxic for systemic administration Used topically on skin, eye, ear in the same manner as neomycin Soframycin 1% skin cream, 0.5% eye drops or ointments

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