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
StreptomycinGentamicinTobramycinAmikacin
KanamycinNeomycinParomomycinFramycetin
Spectrum • Narrow spectrum–Aerobic gram negative bacilli
–Not effective against • gram positive cocci & bacilli • gram negative cocci • and anaerobes
• 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.
• 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.
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.
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
• 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 diureticsNephrotoxic drugs amphotericin B, vancomycin,
cyclosporin & cisplatinMuscle relaxants.
• Do not mix it with any drug in the same syringe/infusion bottle.
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: • NH3 produced by colonic bacteria, detoxified
by liver, urea. • Hepatic failure detoxification does not occur
blood NH3 level rises & produces encephalopathy.
• Neomycin suppresses intestinal flora, diminishes NH3 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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