aminoglycosides 07

8/14/2019 AMINOGLYCOSIDES 07

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AMINOGLYCOSIDESAMINOGLYCOSIDES


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Streptomycin Neomycin Kanamycin

Amikacin GentamicinTobramycin Sisomycin Netilmicin

AminoglycosidesAminoglycosides


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Are amino sugars bound by glycosidicbridges to a hexose nucleus

They are used widely against gram-negative enteric bacteria (bacteremia andsepsis, in combination with vancomycin ora penicillin for endocarditis for thetreatment of tuberculosis)



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Have a hexose ring, either streptidine or 2-deoxystreptamine to which various aminosugars are attached by glycosidic linkages

They are water-soluble Stable in solution More active at alkaline than at acidic pH



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Mechanism of ActionMechanism of Action

Irreversible inhibitors of protein synthesis Generally bactericidal and their efficacy in

several cases can be greatly enhanced bythe concomitant use of cell wall inhibiting

-lactams and glycopeptides Activity: primarily directed toward gram-

negative bacilli and mycobacteria


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1. Interference with the initiation complex ofpeptide formation

2. Misreading of mRNA, which causesincorporation of incorrect amino acids intothe peptide, resulting in a nonfunctional ortoxic protein

3. Breakup of polysomes into nonfunctionalmonosomes

* Occurs more or less simultaneously, overalleffect is irreversible and lethal for the cell

Protein synthesis is inhibited byProtein synthesis is inhibited byaminoglycosides in 3 waysaminoglycosides in 3 ways


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Ribosomal mutations Reduced intracellular transport Plasmid-mediated aminoglycosides-

modifying enzymes (acethyltransferases,aenyltransferases andphosphotransferases)

Mechanism of ResistanceMechanism of Resistance


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Poorly absorbed orallyDo not penetrate well into the CNS,

bronchial secretions or certain microbialcells but are effective intracellularly in the

treatment of tuberculosis, plaque,brucellosis, and tularemia

Administered in high parenteral dosesNormal elimination half-lives are 2-3 hrs.

which can be extended to 24-100 hrs. inend-stage renal diseaseExcreted primarily by glomerular filtration

PharmacokineticsPharmacokinetics


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Parental aminoglycosides currentlyavailable include amikacin, gantamicin,kanamycin, netilmicin, streptomycin andtobramycin

Kanamycin and neomycin are available fororal use for gastointestinal infections

Aminoglycosides are indicated forinfections caused by gram-negativeaerobic bacteria

Often combined with a penicillin orcephalosporin for various infections

General therapeutic usesGeneral therapeutic uses


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Renal toxicity and both auditory andvestibular ototoxicity

Nephrotoxicity is caused by inhibition ofanintracellular lysosomal phospholipase inthe renal proximal tubules resulting inaminoglycoside accumulation andsubsequent reduced glomerular filtration,reduces water and Na transport, reducedmitochondrial respiration and reducedprotein synthesis resulting in renalnecrosis

Adverse effectsAdverse effects


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Nephrotoxicity of aminglycosides isincreased by vancomycin, cephalosporinand methoxyflurane

Loop diuretics increase auditory toxicity

Drug interactionsDrug interactions


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Produced by Streptomyces griseus Mainly used as a second-line agent for

treatment of tuberculosis Given intramuscularly or intravenously Used only in combination with other agents

to prevent emergence of resistance Given intramuscularly in combination with

an oral tetracycline Most serious toxic effect is disturbance of

vestibular function-vertigo and loss ofbalance

A.A.StreptomycinStreptomycin


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B. GentamicinB. Gentamicin

Isolated from Micromonospora purpurea Effective against both gram-negative

organism Inhibits in vitro many strains of staphylococci

and coliforms and other gram-negativebacteria

Active alone, but also as a synergisticcompanion with -lactam antibiotics

In combination with vancomycin or apenicillin produces a potent bactericidaleffect, which in part is due to enhanceduptake of drug that occurs with inhibition of

cell wall synthesis


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C. TobramycinC. Tobramycin

Has an antibacterial spectrum similar tothat gentamicin

Given intramuscularly or intravenously Adverse reaction: ototoxic and nephrotoxic


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E. Neomycin andE. Neomycin andKanamycinKanamycin Active against gram-negative and gram-

positive bacteria and some mycobacteria Poorly absorbed from the GIT Limited to topical and oral use Neomycin is too toxic for parenteral use Adverse reaction: nephrotoxicity and

ototoxicity

Auditory function is affected more thanvestibular

Deafness has occurred


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endend


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aminoglycosides 07

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