AMINOGLYCOSIDES

1. AMINOGLYCOSIDES

2. Group of antibiotics used in the treatment of bacteria infections aerobic G-ve • Consists of 2 or more amino sugars and a hexose nucleus

3. Amino sugars linked through glycosidic bonds. • Polycations: This is in part responsible for many of their shared pharmacokinetic properties

4. Streptomycin was the first to be discovered in 1943 by Schatz, Bugie and Waksman

5. OLDER Aminoglycosides: StreptomycinKanamycin • NEWERAminoglycosides:GentamicinTobramycin NeomycinAmikacinNetilmicinSisomicin Framycetin Paramomycin Spectinomycin

7. SHARED PROPERTIES OF THE AMINOGLYCOSIDES

8. MECHANISM OF ACTION • Interferes with INITIATION COMPLEX of peptide formation • Induces MISREADING OF mRNA causing incorporation of incorrect AA CAUSES BREAKUP OF POLYSOMES into nonfunctional monosomes • Requires oxygen uptake, therefore ineffective against anaerobes. • BACTERICIDAL

9. Aminoglycosides on Protein Synthesis Blocks initiation 5’ 3’ Premature termination 3’ 5’ X 3’ 5’ Incorporation of wrong amino acid Mature Protein Growing Polypeptide 50S AUG 3’ 5’ 30S + mRNA translation Amino Glycoside

11. CONCENTRATION DEPENDENT KILLING •  their increased conc. kills an increasing proportion of bacteria at a rapid rate • POST ANTIBIOTIC EFFECT •  continue to suppress the bacterial growth for several hours even when their serum conc. falls below their MIC

12. ANTIMICROBIAL SPECTRUM:1. Gram (-) Aerobic Bacilli (E coli, Klebsiella, shigella, proteus, p aeruginosa)2. Beta-lactamase producers: S. aureus N. gonorrhea3. Mycobacteria

13. MICROBIAL RESISTANCE: 1. Enzyme inactivation 2. Cell surface alteration 3. Receptor protein alteration 4. Oxygen requirement related

14. KINETICS • Minimally absorbed from the GIT, well absorbed- IM, IV • Poorly penetrate the BBB • Not significantly metabolized • Primarily excreted unchanged through GF

15. CLINICAL USES • Severe gm (-) rod infections especially those due to Pseudomonas, Enterobacter, Klebsiella, Serratiaetc. • UTI’s, bacteremia, meningitis, infected burns, pneumonia, osteomyelitis, ear infections etc. • Mycobacterial infections

16. TOXICITY • Ototoxicity (esp. with loop diuretics) • Auditory damage – Neomycin, Kanamycin & Amikacin • VestibularDamage – Streptomycin,Gentamicin

17. Nephrotoxicity(esp. with cephalosporins) • Neomycin, Tobramycin, Gentamicin- most nephrotoxic

18. STREPTOMYCIN • Ribosomal resistance to this agent develops readily, limiting its role as a single agent • Mainly used for treatment of TUBERCULOSIS • Given at 0.5-1 g/d (7.5-15 mg/kg/day for children) IM or IV should be used only in combination with other agents to prevent emergence of resistance

19. In plague, tularemia and sometimes brucellosis, 1 g/d (15 mg/kg/day for children) IM or IV + oral tetracycline + Penicillin; effective for enterococcalendocarditis and 2 week therapy of viridans streptococcal endocarditis

20. Can cause fever, skin rashes and other allergic reactions, pain at injection site, vestibular dysfunction – most serious toxic effect • If given during pregnancy, can cause deafness in the newborn

21. GENTAMICIN • Employed mainly in severe infections (sepsis and pneumonia) caused by gm(-) bacteria in combination with a cephalosporin or a Pn • May be life saving given at 5-6 mg/kg/day IV in three equal doses + Pn G for bactericidal activity in endocarditis d/t viridans streptococci or enterococci and in combination with Nafcillin in selected cases of staphylococcal endocarditis

22. Serum concentrations and renal function should be monitored if administered for more than a few days or if renal function is changing (eg. Sepsis; often complicated by ARF)

23. Gentamicin sulfate 0.1% -0.3% cream, ointment – for the treatment of infected burns, wounds, or skin lesions and the prevention of intravenous catheter infections • Topical gentamicin is partly inactivated by purulent exudates, 10mg can be injected subconjunctivally for treatment of ocular infections.

24. Nephrotoxicity is reversible and usually mild; • Irreversible ototoxicitymanifested as vestibular dysfunction, hypersensitivity reactions are uncommon

25. TOBRAMYCIN • Antimicrobial spectrum and p/k properties virtually identical to gentamicin • Blood levels should be monitored in renal insufficiency • Slightly more active against pseudomonas but not E. faecium • Ototoxic and nephrotoxic

26. AMIKACIN • Semisynthetic derivative of kanamycinresistant to many inactivating enzymes for tuberculosis; • Given at 7.5 – 15 mg/kg/d as a once daily or 2-3x weekly, Serum concentrations should be monitored • Nephrotoxic and ototoxic

27. KANAMYCIN & NEOMYCIN • Used for bowel preparation for elective surgery • There is completecross-resistance between kanamycin and neomycin • Not significantly absorbed from the GIT; excretion of any absorbed drug is mainly through GF into the urine

28. Too toxic for parenteral use, now limited to topical and oral use • Solutions 1-5 mg/ml – used on infected surfaces or injected into joints, pleural cavity, tissue spaces or abscess cavities where infection is present (15 mg/kg/day)

29. Ointments (Neomycin-Polymyxin-Bacitracin combination) applied to infected skin lesions or in the nares for suppression of staphylococci • In preparation for elective bowel surgery, 1 g of Neomycin given orally q 6-8 hours + 1 g of erythromycin base;

30. Sudden absorption of postoperatively instilled kanamycinfrom the peritoneal cavity (3-5 g) has resulted in curare-like neuromuscular blockade and respiratory arrest (Calcium gluconate and neostigmine can act as antidotes) • Prolonged application to skin and eyes-severe allergic reactions

31. FRAMYCETIN • Ointment is used for skin infections, otitisexterna, furunculosis, burns & scalds • Eye drops used for ophthalmic infections

32. SPECTINOMYCIN • Chemically related to the AG’s binds at the 30 S subunit (bacteriostatic) • Dispensed as the dihydrochloridepentahydrate for IM injection • Used almost solely as an alternativetreatment for gonorrhea in patients who are allergic to penicillin or whose gonococci are resistant to other drugs • Single dose of 2 g ( 40 mg/kg )

33. PAROMOMYCIN • Intestinal amoebiasis • Orally to treat cryptosporidiosis in immunocompramised patients

34. NEPHROTOXICITY • C/b inhibition of an intracellular lysosomal phospholipase-A2 in the renal brush border  lysosomal distension, rupture & release of acid hydrolases & the free AG into the cytosol • This free drug then binds to other cellular organelles, e.g, in mitochondria it displaces Ca2+  mitochondrial degeneration & necrosis • Neomycin, Gentamicin, Amikacin & Tobramycin

36. OTOTOXICITY • Impairment of 8th cranial nerve • Accumulate in endolymph & perilymphof inner ear  vestibular (vertigo, ataxia, loss of balance – streptomycin, gentamicin) & cochlear damage (hearing loss & tinnitus – neomycin, amikacin)

38. NEUROMUSCULAR BLOCKADE • By displacing Ca2+ from NMJ, by blocking postsynaptic Nm receptor & by inhibiting Ca2+ mediated release of Ach from cholinergic neurons • Can be reversed byI/V Ca gluconate or I/M neostigmine • More with neomycin & streptomycin as compared to amikacin, gentamicin, tobramicin & netilmicin

39. Amino Glycosides

40. Contraindications: • Hypersensitivity to AGL • Pregnancy (AGL is class D during pregnancy ) • Myasthenia gravis • Parkinsonism (AGL may cause neuromuscular blockade, resulting in further skeletal muscle weakness ) • Fetal Eight Nerve Damage ( AGL may cause auditory and vestibular toxicity )