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Aminoglycosides
Aminoglycosides are a class of bactericidal antibiotic drugs that are derived from actinomycetes bacteria. They work by binding to the bacterial ribosome and inhibiting protein synthesis. Common properties include being highly ionized and not crossing the blood brain barrier, accumulating in the renal cortex, and being excreted unchanged in urine. Adverse effects can include ototoxicity, nephrotoxicity, and neuromuscular blockade. Therapeutic uses include treating tuberculosis, bacterial endocarditis, and infections caused by gram-negative aerobic bacteria like Pseudomonas. Precautions must be taken in patients with renal impairment or when other ototoxic or nephrotoxic drugs are used concurrently.
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Aminoglycosides
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- 2. Learning objective • Describethe spectrum of activity, mechanism of action and resistance of AG • Enumerate common pharmacokinetic properties of AG • Enumerate precaution, drug interaction and therapeutic uses of AG
- 3. Introduction Bactericidal antibiotics- inhibit the synthesis of bacterial protein Active against Gram-negative bacteria. Most - natural compounds , some- produced semi-synthetically. Streptomycin - first aminoglycoside antibiotic - discovered (1943) - first antibiotic - treatment of tuberculosis.
- 4. Aminoglycosides • Produced -actinomycetes. •Obtained from the species of –Streptomyces (suffix mycin) –Micromonospora (suffix micin) • Semisynthetic derivatives also end up with suffix micin.
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- 6. History /Source • Streptomycin- discovered in 1943 Waksman - tuberculi bacilli. • Neomycin - next - 1949 - not used systemic. • Amikacin first antibiotic - chemical modification of kanamycin
- 7. Chemical structure • Aminosugars connected with cyclitol ring with the help of glycosidic bonds
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- 9. Common properties Pharmacokinetic property •Highly ionised gastric PH / lipid insoluble • Do not cross BBB • Excreted unchanged - GF • High conc in renal cortex • Reduced - acidic PH & anaerobic condition • Their sulfate salts highly water soluble - stable for months
- 10. Common properties Activity againstbacteria • Bactericidal – inhibit protein synthesis • Active against aerobic gram-ve bacilli /no activity against anaerobic • Partial cross resistance among them • Significant post antibiotic effect
- 11. Common properties Adverse effect •Narrow safety margin • Ototoxicity • Nephrotoxicity • NM blockade
- 12. Spectrum of activity •Aerobic gram-ve bacilli – E.coli, pseudomonas, proteus etc, no effect – salmonella • Aerobic gram+ve cocci – staphylococcus. aureus, epidermidis streptococcus. Viridans, faecalis No effect – strep. Pneumoniae, pyogenes • Mycobacerium tuberculosis
- 14. Mechanism of action •Penetrate -porin channels • Enter the periplasmic space. • Transported across cytoplasmic membrane Inside the cell • Bind to 30S ribosomal units • Inhibition of “initiation complex”
- 15. • Misreading ofmRNA template • Incorporation of incorrect aminoacids into the growing peptide. • Premature termination of peptide chain - Abnormal protein formation
- 16. • Secondary changesin the bacterial cell membrane – abnormal proteins may be inserted into the cell membrane –Disruption of cytoplasmic membrane –Altered permeability –Ions, aminoacids, and even proteins leak out followed by bacterial cell death
- 18. Resistance • Inactivation ofdrug - drug destroying enzymes Acetyl transferase- acetylation Phosphotransferase- phosphorylation Adenyltransferase – adenylation • Failure of drug penetration -mutation of porin channel • Mutation - alter ribosomal binding site - prevent binding to 30S
- 19. Post antibiotic effect •Prolonged PAE - Concentration dependent Killing • continue to suppress bacterial growth several hours after fall in MIC • increased conc - kill more bacteria rapid rate • single large dose better effect
- 20. Pharmacokinetics • Absorption: highlyionised, not absorbed by G.I.T , I.M - peak plasma concentration-30-60 mins. • Distribution: • High concentration in endolymph &renal cortex • do not cross BBB • cross placenta • distributed in serous fluids like synovial, pleural , peritoneal etc
- 21. Pharmacokinetics • Excretion: Excretedunchanged in urine .- glomerular filtration • Elderly people and neonates - drug dose - low GFR • Dose adjustment in renal impairment
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- 23. • Accumulate inthe endolymph and perilymph • concentration dependent destructive changes - Vestibular/cochlear sensory hair cells - • vestibular and cochlear damage • Tinnitus first sign of overdose – cochlear • Headache, N,V,vertigo, ataxia – vestibular Ototoxicity
- 24. • Dose &duration dependent adverse effect • Drugs concentrated in labrinthine fluid, slowly removed as plasma levels fall. • Ototoxicity greater when plasma levels are persistently high.
- 25. • Old patientsmore susceptible. • Vestibular toxicity - more with Streptomycin & Gentamycin • Cochlear toxicity - more with neomycin & amikacin.
- 26. • Attain higherconcentration in the renal cortex • Manifests as tubular damage – loss of urinary concentrating power – low GFR – nitrogen retention – albuminuria & casts. Nephrotoxicity
- 27. • More inelderly & patient with pre-existing renal disease. • Totally reversible - drug is discontinued. • Implication of nephrotoxicity –reduced clearance of antibiotic –higher blood levels
- 28. • At highconc produce – apnoea- paralysis of respiratory muscles • Inhibit pre-junctional release of acetylcholine from cholinergic neurons. • Reduce postsynaptic senstivity of nicotinic receptors to action of Ach. Neuromuscular blockade
- 29. • NM blockadeis more- • intraperitoneal during bowel surgery, pleural cavity • Co-administration of other NM blocking agents • Patients with Myasthenia gravis • Reversed by calcium gluconate as iv infusion
- 30. Precaution and interaction •Avoid during pregnancy • Elderly & renal impairment adjust the dose • Avoid in myasthenia - aggravate • Avoid concurrent use of other ototoxic drugs e.g. high ceiling diuretics, minocycline
- 31. Precaution and interaction •Avoid concurrent use - nephrotoxic drugs. E.g. amphotericine B, vancomycin, Cisplatin • Avoid/ reduce dose with SMrelaxant • Do not mix aminoglycosides - same syringe or infusion bottle. • Cell wall synthesis inhibitor – synergestic effect
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- 33. Streptomycin • It isolder antibiotics • used for treatment of TB, bacterial endocarditis, plague, tularemia • Dose - 15mg/kg in divided dose – TB – 0.75gm -1gm/ day
- 34. Streptomycin • Bacterial Endocarditis: –Enterococcal – in combination with penicillin, synergistic, 4-6 weeks treatment – Gentamicin preferred; lesser toxicity • Tuberculosis: multi drug regime • Plague: effective agent for all forms of plague. • Tularaemia: DOC for this rare disease.
- 35. Gentamicin • Low therapeuticindex • serious gram negative aerobic infections. Pneumonia Endocarditis Gram negative meningitis Septicemia UTI, OM, ASOM • Topical
- 36. • Dosing schedule Dose–adults- loading dose 2mg/kg 3-5mg/kg/day in divided dose
- 37. Kanamycin • Second linedrug in TB • More ototoxic and nephrotoxic • DOSE : 0.5 g i.m BD
- 38. Amikacin • Less toxic- semisynthetic derivative of kanamycin • Broadest spectrum activity • Gentamicin and tobramcyin resistant organisms
- 39. Amikacin • Reserve drugfor hospital acquired Gm-ve • MDR- TB - resistant to streptomycin • Disseminated atypical mycobacterial infection • Dose : 15mg/kg/day in 1-3 doses
- 40. Tobramycin • Identical togentamicin • pseudomonas and proteus infections • Lesser Ototoxicty and nephrotoxicity • Used as nebulizer - treatment of cystic fibrosis – pseudomonas or enterobacteriae • Opthalmic solution/oinment • Dose: 3-5mg/kg I.M in 1-3 doses
- 41. Sisomicin • Similar togentamicin • More potent on pseudomonas and b- hemolytic streptococci • Uses – endocarditis with penicillins
- 42. Netilmicin • Derivative ofsisomicin • Resistant to AG inactivating enzyme • Lowest toxicity among aminoglycosides • More active -klebsiella, enterobacter & staphylococci • Less active against pseudomonas aeruginosa • Uses-Septicemia, Lower respiratory tract infection UTI, peritonitis and endometritis
- 43. Neomycin • Highly toxicinner ear & kidney - not used systemically. • Poorly absorbed from GIT • Oral & topical administration - NO systemic toxicity.
- 44. • Topical uses –Bladderirrigation –Infected wounds ulcers, burn, external ear infections, conjunctivitis –Combination with polymixin, bacitracin • Oral uses –Preparation of bowel before surgery –Hepatic coma
- 45. Framycetin • Same asneomycin • toxic- systemic administration • Used topically on skin, eye, ear
- 46. Paromomycin • Properties similarto neomycin • Effective against visceral leishmainiasis by parentral route • Uses – protozoal infection
- 47. Palzomicin • Newer AGunder evaluation • Chronic UTI, Acute pyelonephritis
- 48. Stay home staysafe msg • Spectrum of activity • Common property • Mechanism of action & resistance • Adverse effect • Drug interaction • Therapeutic uses
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