Lecture 13 Aminoglycosides Dolly Mehta Ph D Knowledge Objectives 1 Know the basic processes of bacterial protein synthesis 2 Know the mechanism of antimicrobial activity for aminoglycosides 4 Know the most common adverse effects 5 Know the mechanisms of bacterial resistance 6 Know the most common applications of these antibiotics for the treatment of disease Which drugs are broad spectrum and which have specific or unique uses Drug List Aminoglycosides neomycin gentamicin streptomycin amikacin tobramycin kanamycin 1 Drugs inhibiting Protein Synthesis Aminoglycosides and Macrolides Teteracycline and Chloramphenicol Protein Synthesizing machinery Ribosome bacteria has 50S and 30 S subunit which forms 70 S polysome that slides on mRNA has A P and E sites for binding with tRNA mRNA forms template for protein synthesis transcribed from DNA attaches to 30s ribosomes tRNA brings amino acids attaches to A P and E sites of ribosomes 1 Overview P A E 2 Transferase P A E E P A 3 Why antibiotic drugs do not inhibit mammalian protein synthesis Eukaryotes 60S and 40 S subunit Difference in ribosomal units is the basis of selectivity of antimicrobial drugs against bacteria 4 Aminoglycosides Gentamicin Tobramicin Amikacin Netilmicin Kanamycin Streptomycin composed of amino sugars water soluble hydrophillic highly polarized Kanamycin Kanamycin A B Tobramycin amikacin 2 deoxystreptamine streptidine Streptomycin 5 Bacterial killing concentration dependent Post antibiotic effect persists after the serum conc minimum inhibitory concentration MIC Once daily dose of aminoglycosides is therefore efficacious Aminoglycosides Entry AG a Diffusion through porins b Energy Dependent Phase 1 EDP1 rate limiting requires negative inner membrane potential electron transport chain PG Periplasmic space PBP PBP 6 c Create fissure inducing bacterial damage contrast from Tetra or Chloram further enhancing AG uptake EDP2 phase Entry effectiveness pH Ca2 Mg2 Hyperosmolarity Anearobic conditions Abcess hyperosmolar acidic urine 7 Mechanism of Action a binds to A site of 30s of ribosome subunit i interfere with the formation of the initiation complex ii induce misreading of the mRNA template iii P iii Premature t ttermination i ti off mRNA RNA translation t l ti iv cause polysomes to break up into monosomes Mechanisms of Resistance Intracellular penetration Group transferases D Drug iinactivation ti ti Low affinity of drug for bacterial ribosomes Modification of the ribosomal binding site acetylation phosphorylation adenylation of OH or NH2 gr Metabolites can also compete with AG 8 Cross resistance by other aminoglycosides i e gentamicin tobramicin amikamicin kanamycin and netilmycin No effect on Steptomicin AAC acetylases ANT adenylase APH phosphorylase 9 VI Absorption Oral or rectal administration 1 of dose is abosorbed Rapidly absorbed from I M peak conc in plasma occur after 30 90 min period 4 12 ug ml following 1 5 2 mg kg dose 10 q24h q8h threshold 30 g ml 20 10 0 0 4 8 12 hours 16 20 24 Plasma concentrations Pl t ti after ft IV injection i j ti off 5 1 5 1 mg kg k to a hypothetical patient either as a single q24h or as three divided doses q8h Distribution Do not cross BBB and do not achieve high distribution in body fluids Can cross placenta 11 Excretion Excreted entirely via the kidneys and urine conc of 50 200 ug ml are acheived Clearance faster from plasma as compared to tissues Clearance similar in adults and children older than 6 months half life is prolonged in The dosage must be adjusted for renal function Should not be administered to patients in renal failure V Spectrum Aerobic Gram bacilli Kanamycin and Streptomycin limited spectrum Should not be used for infections caused by Serratia or P aeruginosa Ist line drug for pseudomonas May be given with penicillin in infections caused by y streptococci p Listeria sp p Anaerobic or facultative anaerobic bacteria are resistant 12 IX Side Effects Ototoxicity vestibular and auditory dysfunction Largely irreversible 1 2 3 Cochlea normally lined with hair cells that are destroyed by high concentrations of aminoglycosides Aminoglycosides damage hair cells especially in turn No 1 and part of turn No 2 Hairs are shed by the damaged cells to give loss of high frequency response first associated with turn No 1 and low frequency loss later associated with turn to 3 13 amikacin kanamycin neomycin cochlear damage loss of high frequency tones streptomycin and gentamicin vestibular damage loss of low frequency tones Loop di diuretics retics furosemide f rosemide and ethacr ethacrynic nic acid potentiate the ototoxicity 14 Rotoxicity reversible mild rise in serum creatinine proteinuria casts Leakage of enzymes alkaline phosphatase and aminopeptidase In severe cases produces renal tubular necrosis Nephrotoxic potencies Neomycin tobramicin gentamicin t i i streptomycin t t i antagonize factor V resulting in bleeding 15 Muscular blockade tobra genta amika kana neomy AG curare like Caution C ti Myasthenia gravis patients calcium gluconate or neostigmine reverses this effect VII Therapeutic Use Streptomycin unusal mycobacterial infections in combination with other antimicrobial agents toxic 1000 mg single or 500 mg double dose serum concentration of 50 60 and 15 30 hg ml Tuberculosis Plague Bacterial endocarditis strep Penn G replaced by genta PennG Tularemia Strep or Genta 16 Gentamicin Ist choice low cost and reliable activity agnst all Gram bacilli including infections caused by pseudomonas aeruginosa IT or IV used rarely as cuases local inflammation lactum insensitive UTI s Bacterial endocarditis Sepsis Topical as in burn patients Tobramycin Tobrex Gentamicin Amikacin Broadest spectrum absobed rapidly after IM injection Peak plasma concentration 20ug ml after 7 5 mg kg injection Nosocomial Gram infections Netilmicin Gentamicin can be used for Gentamicin resistant bacteria Neomycin frequently used in topical ointments administered oral to clean the bowel prior to bowel surgery not absorbed eliminated in the feces very toxic if administered I M 17 Summary Aminoglycosides Requires oxygen and changes in trasmembrane potential to act on 30S ribosome Most toxic ototoxicity y rototoxicity y muscular blockade conc in serum should be monitored Limited spectrum Gram Aerobes ineffective in anerobes will work in facultative bact in aerobe enviroment Use diminished as other Antibts became avl Use for historical dis Plague TB 18
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