Aminoglycosides Aminoglycosides All aminoglycosides actinomycetes are produced by

Aminoglycosides

Aminoglycosides • All aminoglycosides actinomycetes. are produced by soil • 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 30 S ribosomal units and prevent the formation of “initiation complex” – a prerequisite for peptide synthesis.

• Accumulation of abnormal initiation complexes • Misreading of m. RNA 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 p. H 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 30 S (Target) ribosomal unit because of mutations. Attachment of drug with 30 S ribosomal unit is thus prevented.

Toxicity

Ototoxicity Nephrotoxicity 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. • 10 -15% 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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