Aminoglycosides

Dr Salman

Ami nogl ycosi des • Chemically they consist of a glycoside and an amino-sugar. Gentamicin is produced by Micromonospora Purpurea while other are produced by Streptomyces griseus.Cognition • Useful primarily in the treatment of infections caused by ‘aerobic gram-negative Bacteria’

Cl assi fi cati on • • • • • • • Streptomycin: Gentamicin Tobramycin: Amikacin: Neomycin: Netilmicin: Spectinomycin:

Aminoglycosid es: Mechanism of A ction
• Aminoglycosides are bactericidal. They irreversibly inhibit protein synthesis. Initially they passively diffuse via porin channels across the outer membrane of gram negative bacteria to enter the periplasmic space. Then the drug is actively transported across the cytoplasmic membrane (inner) into cytoplasm by an oxygen dependant electron transport process. Therefore they have no activity against anaerobic bacteria. Penicillins and Vancomycin which are cell wall active drugs, enhance the transport of aminoglycosides hence they are synergistic. After entering into the cell-wall, the aminoglycosides bind to specific 30S-subunits\ ribosomal proteins. Protein synthesis is inhibited in the following ways:

Mechani sm of Act ion

Mechani sm Conti nued… After entering into the cell-wall, the aminoglycosides bind to specific 30S-subunits\ ribosomal proteins. Protein synthesis is inhibited in the following ways:
• • • • They block the formation of “initiation complex” of peptide formation. They cause miscoding of amino-acids in the emerging peptide chain due to miscoding of the code of mRNA template. They block translocation on mRNA They block the movement of ribosome after formation of a single initiation complex, resulting in an mRNA chain, with only a single ribosome on it, a so-called monosome. In other words they disrupt polysomal structure.

Mechani sm conti nued… • The aberrant protein produced may be inserted in the cell membrane, leading to altered permeability and influx of more drug “Energy Dependant Phase II” (EDP2 )

Spectrum • • • • • • • • •

of Acti vi ty

Citrobacter Freundii Enterobacter E-coli Klebsiella pneumoniae Proteus mirabilis Providencia staurtii Serratia (nosocomial) Enterococcus Faecalis Staphylococcus Aureus
Mycobacterium TB (Kenamycin, Amikacin, streptomycin)

Spectrum

wi th Peni ci lli ns

• Gram +ve Cocci
– Streptococcus viridans: endocarditis bacteremia and dental caries – Streptococcus agalactiae: bacteremia, meningitis, neonatal abscess – Enterococcus faecalis: endocarditis, bacteremia

• Gram +ve bacilli
– Corynaebacterium species: Diphtheroids causing endocarditis and bacteremia – Listeria monocytogenes: meningitis, bacteremia

Conti nued
• Gram negative Bacilli:
– E-coli: UTI Traveler’s diarrhea, bacteremia, meningitis – Proteus: UTI, other infections – Pseudomonas aeroginosa: pneumonia – Klebsiella pneumonae: pneumonia – Serratia: Pneumonia, Bacteremia & nosocomial infections – Acinetobacter: nosocomial infection – Campylobacter fetus: bacteremia, meningitis – Enterobacter

Toxi ci ties
• Ototoxicity – auditory or vestibular damage or both, and may be irreversible. Auditory damage is more likely with Amikacin and Kenamycin. Vestibular damage is more likely with Gentamicin and Tobramicin. Ototoxicity may be increased with the use of Loop-Diuretics Nephrotoxicity – Usually acute tubular necrosis occurs. Nephrotoxicity is more common in elderly patients and in those concurrently receiving Amphotericin B, Cephalosporins or Vancomycin. Gentamicin and Tobramicin are most nephrotoxic

Cont inued
• Neuromuscular blockade – at high doses of aminoglycosides, a curare-like block may occur (inhibit the prejunctional release of acetylcholine and postsynaptic sensitivity to the neurotransmitter) and may result in respiratory paralysis. It may be treated with calcium and Neostigmine. • Skin rashes: Allergic skin reactions and contact dermatitis may occur. Neomycin is more likely to cause contact dermatitis.

• Other Effects on CNS:
– Streptomycin( in particular) – dysfunction of optic nerve – Paresthesia (perioral) other areas of face may be involved , occurs after 30-60mins after injection, remains for several hours.

• • • • • •

• •

• Streptomycin: Tuberculosis – as a second line agent Plague, Tularemia, Brucellosis With penicillins used for Enterococcal Endocarditis • Gentamicin: With penicillins it has a synergistic action against: Pseudomonas, Proteus, Enterobacter, Klebsiella, Serratia, Stenotrophomonas It is given I/M, for severe infections (Sepsis, pneumonia) caused by gram negative bacteria such as pseudomonas, Enterobacter, Serratia, Proteus, Acinetobacter and Klebsiella. Gentamicin is combined with penicillins or cephalosprins fro life threatening infections. It has been used intrathecally for meningitis caused by gram negative bacteria but 3rd generation cephalosprins are preferred. Topically it is used for infected burns, wounds and skin lesions. For ocular infections it can be injected sub-conjunctively.

• • •

• • • •

• Tobramycin: Spectrum: As compared to gentamicin, tobramycin is more active against Pseudomonas. Enterococcus faecium is resistant to tobramycin. • Amikacin: It is resistant to many enzymes that inactivate gentamicin or Tobramicin. Many gram negative enteric bacteria, including Proteus, Pseudomonas, Enterobacter and Serratia are susceptible. Strains of Multidrug-resistant Mycobacterium Tuberculosis are also susceptible. • Neomycin: Only used topically and locally for example in GIT Netilmicin: Serious infections caused by organisms resistant to other aminoglycosides. • Spectinomycin: It is an amino cyclitol related to aminoglycosides. Given intra-muscularly for Gonorrhea.