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 Protein Synthesizing machinery Ribosome Drugs inhibiting Protein Synthesis bacteria has 50S and 30 S subunit which forms 70 S polysome that slides on mRNA Aminoglycosides and Macrolides has A P and E sites for binding with tRNA Teteracycline y and Chloramphenicol p mRNA forms template for protein synthesis transcribed from DNA attaches to 30s ribosomes tRNA 1 brings amino acids attaches to A P and E sites of ribosomes 2 Overview P A E 3 4 1 Transferase P A E E P A 5 6 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 7 8 2 Aminoglycosides Gentamicin Tobramicin Amikacin Netilmicin Kanamycin Streptomycin Kanamycin composed of amino sugars water soluble hydrophillic highly polarized Kanamycin A B Tobramycin amikacin y p 2 deoxystreptamine streptidine Streptomycin 9 Aminoglycosides Entry 10 II Mechanism of Action AG a binds to A site of 30s of ribosome subunit PG Energy Dependent gy p Phase 1 EDP1 rate limiting requires inner potential Periplasmic P i l i space PBP i iinterfere i t f with ith the th formation f ti off the th initiation i iti ti complex l ii induce misreading of the mRNA template PBP iii Premature termination of mRNA translation iv cause polysomes to break up into monosomes 11 12 3 Effectiveness b Create fissure inducing bacterial damage contrast from Tetra or Chloram further enhancing AG uptake EDP2 phase Entry to the inner membrane requires Transmembrane electrical potential pH g2 Ca2 Mg Hyperosmolarity Anearobic conditions Abcess yp hyperosmolar acidic urine 13 14 VIII Mechanisms of Resistance Bacterial killing concentration dependent Post antibiotic effect persists after the serum conc minimum inhibitory concentration MIC Intracellular penetration Once daily dose of aminoglycosides is therefore efficacious Group t transferases f Drug inactivation 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 15 16 4 Cross resistance by other aminoglycosides i e gentamicin tobramicin amikamicin kanamycin and netilmycin No effect on Steptomicin AAC acetylases ANT adenylase APH phosphorylase 17 18 Enzyme Genes Selected Aminoglycoside Substrates aac 3 Ia aac 3 Ib aac 3 Iia aac 3 Iib aac 3 Iic aac 3 IIIa aac 3 IIIb aac 3 IIIc 3 III Gm AAC 3 IV aac 3 Iva Gm Tob AAC 3 VI aac 3 Via Gm Acetylation AAC 3 I AAC 3 II AAC 3 III 19 Comments Gm Tob Gm Tob Km Neo Prm Commonly found in Pseudomonas spp R l seen iin Rarely Enterobacteriaceae Commonly found in Salmonella spp Resistance to Tob and Km not conferred however a low level of enzymatic activity has been detected Rare among 20 Enterobacteriaceae 5 AAC 6 I AAC 6 II AAC 6 II AAC 6 APH 2 AAC 2 I aac 6 Ia aac 6 Ib aac 6 Ic aac 6 Id aac 6 Ie aac 6 If aac 6 Ig aac 6 Ih aac 6 Ii aac 6 Iia aac 6 Iia aac 6 Iib aac 6 aph 2 aac 2 Ia Adenylylation Tob Amk Gm Tob Gm Gm Tob Amk Observed only in P P aeruginosa Bifunctional enzyme thought to be restricted to gram positive bacteria staphylococci and enterococci ANT 2 I ant 2 Ia ant 2 Ib ant 2 Ic Gm Tob Km ANT 3 II ANT 3 ant 3 Ia ant 3 Ia Sm Spcm Sm ANT 4 I ant 4 Ia Tob Amk ANT 4 II ant 4 Iia Tob Amk ANT 6 I ant 6 Ia Sm Widespread among all gramnegative bacteria Found in grampositive organisms Gm Tob 21 Phosphorylation APH 2 I aph 2 Ia Gm Tob Amk APH 3 I aph 3 Ia aph 3 Ib aph 3 Ic Km Neo Prm APH 3 II aph 3 Iia Km Neo Prm GmB APH 3 III aph 3 IIIa Km Neo Prm Amk GmB APH 3 IV aph 3 Iva Km Neo Prm APH 3 V aph 3 Va aph 3 Vb aph 3 Vc Commonly found in S aureus and E faecalis 23 22 APH 3 VI aph 3 Via aph 3 Vib Km Neo Prm Amk GmB Primarily isolated from Acinetobacter spp APH 3 VII aph 3 VIIa Km Neo Cloned from Campylobacter jejuni APH 3 I aph 3 Ia aph 3 Ib Sm Cloned from Streptomyces griseus APH 6 I aph 6 Ia aph 6 Ib aph 6 Ic aph 6 Id Sm Cloned from Streptomyces spp 24 6 VI Absorption q24h 30 Oral or rectal administration 1 of dose is abosorbed g ml 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 1 5 2 q8h threshold 20 10 0 0 4 8 12 hours 16 20 24 Plasma concentrations after IV injection of 5 1 mg kg to a hypothetical patient either as a single q24h or as three divided doses q8h 25 Distribution 26 Excretion Do not cross BBB and do not achieve high distribution in body fluids Excreted entirely via the kidneys and urine conc of 50 200 ug ml are acheived Can cross placenta 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 27 28 7 Spectrum Side Effects Aerobic Gram bacilli Kanamycin and Streptomycin limited spectrum Should not be used for infections caused by Serratia or P aeruginosa Ototoxicity vestibular and auditory dysfunction Largely irreversible Ist pseudomonas line drug for pseudomonas May be given with penicillin in infections caused by streptococci Listeria sp Anaerobic or facultative anaerobic bacteria are resistant 29 30 amikacin kanamycin neomycin 1 cochlear damage 2 3 l loss off high hi h frequency f tones t 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 31 32 8 Rotoxicity reversible streptomycin and gentamicin vestibular damage loss of low frequency tones Loop diuretics furosemide and ethacrynic acid potentiate the ototoxicity 33 34 Muscular blockade tobra genta amika kana neomy mild rise in serum creatinine AG curare like proteinuria casts Leakage of enzymes alkaline
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