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Chapter 37 Aminoglycosides History 1944 Streptomycin 1957 kanamycin 1964 gentamicin 1967 tobramycin Amikacin & netilmicin General properties of Aminoglycosides Phsical and chemical properties Structure Water-soluble, stable in solution More active at alkaline than at acid pH Antibacterial spectrum High activity against aerobic G- rods Effective on MRSA netilmicin Less active on gram-negative cocci P.aeruginosa: gentamicin,tobramycin, amikacin and netimicin Resisant to enterococci and anaerobe Mycobacteria: streptomycin, kanamycin Mechanism of Action Inhibit protein synthesis irreversibly interfering with the initiation complex of peptide formation induce misreading of mRNA,resulting in nonfunctional protein inhibit the break of 70s initiation complex Increasing the permeability of cell membrane Mechanism of resistance Produce enzyme that inactivate the aminoglycoside by adenylylation, acetylation and phosphorylation Impared entry of aminoglycoside into the cell Alteration of target protein Pharmacokinetics Absorption: po poorly, im, iv Distribution : low concentration in most tissue except renal cortex Can pass placental barrier, ×BBB Excretion: in unchanged form by glomerular filtration Clinical uses Infections caused by sensitive G- rods Topical infections Tuberculosis Infections caused by P. aeruginosa Adverse reactions Dangerous factors: Using continuously more than 5 days High dose Eldly and children Renal insufficiency Concurrent use with loop diuretics or other nephrotoxic drugs Adverse reactions Ototoxicity Auditory damage:tinnitus, hearing loss Vestibular damage:vertigo, ataxia and loss of balance Nephrotoxicity Neuromuscular blockade neostigmine and calcium gluconate Allergic reactions The commonly used aminoglycosides Streptomycin Clinical uses Tuberculosis first line Plague, tularemia and brucellosis: combination with tetracycline Enterococcal and viridans streptococcal endocarditis: combination with penicillin G Gentamicin Clinical uses Severe infections caused by gramnegative bacteria such as pseudomonas, enterobacter, serratia, proteus(变形杆菌）, acinetobacter（不动杆菌） and klebsiella P.aeruginosa infections: combination with carbenicillin Endocarditis Bowel preparation for elective surgery Kanamycin Topical administration Oral administration in preparation for elective bowel surgery Tobramycin Similar antibacterial spectrum with gentamicin More active against P.aeruginosa Treat infections caused by P.aeruginosa that are resistant to gentamicin Amikacin The most wide antibacterial spectrum Resistant to many enzyme that inactivate gentamicin and tobramycin Netilmicin Resistant to many enzyme that inactivate gentamicin and tobramycin Lowest toxicity among aminoglycosides Thanks !
