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