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Aminoglycoside by sumit
- 1. Aminoglycoside Dr. Sumit KumarMahato Senior Resident Department of Pharmacology
- 2. • Streptomycin wasthe first member discovered in 1944 by Waksman and his colleagues. • These are a group of natural and semisynthetic antibiotics containing amino sugars(streptidine, 2-deoxy streptamine, garosamine) linked to an aminocyclitol ring by glycosidic bond. • Obtained from variety of soil actinomycetes • Streptomycin derived from Streptomyces griseus Natural • Gentamicin from Micromonospora • Amikacin is a derivative of Kanamycin Semi-synthetic • Netilmicin a derivative of sisomicin
- 3. Mechanism of action •Aminoglycosides are rapidly acting bactericidal agent, and have concentration dependent killing • A post antibiotic effect i.e residual bactericidal effect persist even after serum concentration has fallen below minimum inhibitory concentration. • Aminoglycoside diffuse across the outer coat of gram-negative bacteria through porin channels. Entry from the periplasmic space across the cytoplasmic membranes is carrier mediated which is linked to the electron transport chain. Thus, penetration is dependent upon maintenance of a polarized membrane and on oxygen dependent active processes (energy dependent phase I or EDP1 entry).
- 4. • Aminoglycoside aqueous channelPorin Protein in outer membrane of gram negative bacteria Periplasmic space Inhibited by divalent cations Energy dependent phase 1(EDP-1) Ca2+ , Mg2+, hyperosmolarity, Decrease Ph, Anaerobic condition Cytoplasmic space • Anaerobes are not sensitive and facultative anaerobes are more resistant when O2 supply is deficient, e.g. inside big abscesses. • Penetration is also favoured by high pH; aminoglycosides are ~20 times more active in alkaline than in acidic medium. • Inhibitors of bacterial cell wall (β-lactams, vancomycin) enhance entry of aminoglycosides and exhibit synergism
- 5. • Inside thebacterial cell, streptomycin binds to 30S ribosomes, but other aminoglycosides bind to additional sites on 50S subunit, as well as to 30S-50S interface. • They freeze initiation of protein synthesis, • Prevent polysome formation and promote their disaggregation to monosomes so that only one ribosome is attached to each strand of mRNA. • Binding of aminoglycoside to 30S-50S juncture causes distortion of mRNA codon recognition resulting in misreading of the code. • Wrong amino acids are entered in the peptide chain and peptides of abnormal lengths are produced
- 7. How cidal? • Thecidal action is due to secondary changes in the bacterial cell membrane. • This probably results from incorporation of the defective proteins into the cell membrane. • After exposure to aminoglycosides, bacteria become more permeable to ions, amino acids and even proteins leak out followed by cell death.
- 8.
- 9. MECHANISM OF RESISTANCE Resistanceto aminoglycosides is acquired by one of the following mechanisms: (a) Acquisition of cell membrane bound inactivating enzymes which phosphorylate/ adenylate or acetylate the antibiotic. The conjugated aminoglycosides do not bind to the target ribosomes. • This is the most important mechanism of development of resistance to aminoglycosides. • These enzymes are acquired mainly by conjugation and transfer of plasmids. • Susceptibility of different aminoglycosides to these enzymes differs.
- 10. (b) Mutation decreasingthe affinity of ribosomal proteins that normally bind the aminoglycoside. • 50% of streptomycin resistance strain of E.coli is due to this ribosomal mutation. • 5% of Pseudomonas aerginosa exhibit similar kind of streptomycin resistance. (c) Decreased efficiency of the aminoglycoside transporting mechanism: • Either the pores in the outer coat become less permeable or • The active transport is interfered
- 11. Absorption: • These arehighly polar basic compounds and are poorly absorbed from G.I tract. (<1%). • Long term oral and rectal administration of aminoglycoside can lead to accumulation to toxic level in patient with renal impairment. • All aminoglycoside are absorbed rapidly from intramuscular injection site reaching peak concentration within 30-90min.
- 12. Distribution • Due topolar nature these don’t penetrate into most of the cells, eye, CNS. • These do not bind to plasma albumin, except streptomycin. • Apparent volume of distribution is only 25% of lean body mass. • Concentration of aminoglycoside in tissue and secretion are low, but high concentration is found only in renal cortex, endolymph, perilymph of inner ear. • This high concentration is most likely cause of ototoxicity and nephrotoxicity. • Inflammation increases the penetration into peritoneal and pericardial spaces
- 13. • Streptomycin andtobramycin can lead to hearing loss in children born to those women who receives these drugs during pregnancy. Excretion • Aminoglycoside are excreted almost entirely by glomerular filtration, a high urinary concentration is achieved i.e. 50- 200µg/ml. • A large fraction of the parentrally administered dose is excreted unchanged in the urine within 24 hrs , of which most is excreted within 12 hrs. • Half life is about 2-3 hrs in patient with normal renal function.
- 14. DOSING REGIMENS: • Ithave low safety margin, • Daily dose of aminoglycosides must be precisely calculated accordingly to body weight and level of renal function. • For an average adult with normal renal function (CLcr >70 ml/min), the usual doses are: • Gentamicin/tobramycin/sisomicin/netilmicin - 3–5 mg/kg/day • Streptomycin/ kanamycin/amikacin 7.5–15 mg/kg/day
- 15. SHARED TOXICITIES The aminoglycosidesproduce toxic effects which are common to all members, but the relative propensity differ. 1. Ototoxicity: This is the most important and related to dose and duration of treatment. • The vestibular or the cochlear part may be primarily affected by a particular aminoglycoside. • These drugs are concentrated in the labyrinthine fluid and are slowly removed from it when the plasma concentration falls. • Ototoxicity is greater when plasma concentration of the drug is persistently high and above a threshold value. • Ototoxicity can happen when it is instilled in patients with perforated eardrum, so it is contraindicated in them.
- 16. Cochlear damage: It startsfrom the base and spreads to the apex; hearing loss affects the high frequency sound first, then the lower frequencies are affected. • Initially, the cochlear toxicity is asymptomatic and can be detected only by audiometry then Tinnitus appears, followed by progressive hearing loss. • No regeneration of the sensory cells occurs. • Deafness is permanent. Vestibular damage: • Headache appears first , followed by nausea, vomiting, dizziness, nystagmus, vertigo and ataxia. • Most symptoms subside in two weeks except ataxia which may persist for 1–2 years. KAN (Kanamycin, Amikacin, Neomycin) mainly damage cochlea rest vestibular damage
- 17. 2. Nephrotoxicity: • Aminoglycosidesattain high concentration in the renal cortex (proximal tubules) and toxicity is related to the total amount of the drug received by the patient. • More common in the elderly and in those with preexisting kidney disease. • It manifests as tubular damage resulting in loss of urinary concentrating power, low g.f.r, nitrogen retention, albuminuria and casts. • Renal damage caused by aminoglycosides is totally reversible. • It has been postulated that aminoglycosides interfere with the production of PGs in the kidney which is causally related to the reduced g.f.r Verapamil and Ca++ can Reduce nephrotoxic potential But Also reduce antibacterial effect
- 18. 3. Neuromuscular blockade: •Aminoglycosides reduce ACh release from the motor nerve endings. • They interfere with mobilization of centrally located synaptic vesicles to fuse with the terminal membrane. • Decrease the sensitivity of the muscle endplates to ACh. • The neuromuscular block produced by aminoglycosides can be partially antagonized by i.v. injection of a calcium salt. • More with Neomycin and Streptomycin Dangerous in Myasthenia gravis Direct administration of Aminoglycosides into pleural and peritoneal cavities If patient received curare like muscle relaxant during surgical procedure
- 19. Systemic aminoglycosides Topicalaminoglycosides Streptomycin Neomycin Amikacin Framycetin Gentamicin Sisomicin Kanamycin Netilmicin Tobramycin Paromomycin
- 20. Gentamicin: • Obtained fromMicromonospora purpurea in 1964. • Aminoglycoside of first choice because of lower cost and reliable activity against all but most resistant gram negative aerobes • It is active mainly against aerobic gram negative bacilli, including E. coli, Klebsiella pneumoniae, Enterobacter, H.influenzae, Proteus, Serratia and Pseudomonas aeruginosa. • Many strains of Brucella, Campylobacter, Citrobacter, Fransisella and Yersinia are also sensitive. • It has low therapeutic index, so its use is restricted to serious gram- negative bacillary infections.
- 21. 1. Gentamicin isvery valuable for preventing and treating respiratory infections in critically ill patients. 2. Pseudomonas, Proteus or Klebsiella infections: burns, urinary tract infection, pneumonia, lung abscesses, osteomyelitis, middle ear infection, septicaemia, etc., caused mostly by the above bacteria and are an important area of use of gentamicin. 3. Meningitis caused by gram negative bacilli. 4. Subacute bacterial endocarditis (SABE): Gentamicin (1 mg/kg 8 hourly i.m.) is generally combined with penicillin/ampicillin/vancomycin
- 22. Tobramycin: • Obtained fromS. tenebrarius in the 1970s. • The antibacterial and pharmacokinetic properties, as well as dosage are almost identical to gentamicin, but it is 2–4 times more active against Pseudomonas and Proteus. • Used only as an alternative to gentamicin, Serious infections caused by Pseudomonas and Proteus • Ototoxicity and nephrotoxicity is probably less than gentamicin. • Dose: 3–5 mg/kg day in 1–3 doses
- 23. Amikacin: It is asemisynthetic derivative of kanamycin. It resembles in pharmacokinetics, dose and toxicity to Kanamycin • Broadest spectrum of activity • Because of its resistance to many of aminoglycosides – inactivating enzymes , has a role for treatment of serious nosocomial gram negative bacillary infection. • Serratia, Proteus, Pseudomonas, Klebsiella, enterobacte and E.coli • Less active than gentamicin against Enterococci • Active against Mycobacteria, but used only for multidrug resistant infection • Dose is 15mg/kg/day as a single dose • Cochlear > vestibular
- 24. Streptomycin: • Oldest aminoglycosideantibiotic obtained from Streptomyces griseus. Used extensively in the past, but is now restricted to treatment of tuberculosis. • The antimicrobial spectrum of streptomycin is relatively narrow. About 1/5 patients given streptomycin 1 g BD i.m. experience vestibular disturbances. Auditory disturbances are less common. • Streptomycin has the lowest nephrotoxicity among aminoglycosides. Uses: 1. Tuberculosis 2. Subacute bacterial endocarditis (SABE) 3. Plague 4. Tularemia • Deep IM • Dose 15 to 25 mg/kg • Vestibular > cochlear , irreversible
- 25. Neomycin: • Obtained fromS. fradiae, • It is a wide-spectrum aminoglycoside, active against most gram negative bacilli and some gram-positive cocci. • Pseudomonas and Strep. pyogenes are not sensitive. • Spectrum of activity against E.coli, Enterobacter, Klebsiella, Proteus • Neomycin is highly toxic to the internal ear (mainly auditory) and to kidney. • It is, therefore, not used systemically. Oral neomycin has damaging effect on intestinal villi- Malabsorption syndrome. Damages colonic flora- deficiency of vit. K Superinfection
- 26. Uses: 1. Most commonuse is topical, ointment, eye and ear drops 2. Orally for: (a) Preparation of bowel before surgery: 3 doses of 1.0 g along with metronidazole 0.5 g on day before surgery) may reduce postoperative infections. (b) Hepatic coma or or Hepatic Encephalopathy 3. Neomycin with Polymyxin-B solution is used as an irrigant in urinary bladder to prevent bacteriuria associated with use of indwelling catheter
- 27. Paramomycin: • Chemically relatedto neomycin. • It is active against many protozoan parasites, including E. histolytica, Giardia lamblia, Trichomonas vaginalis, Cryptosporidium and Leishmania, in addition to many bacteria sensitive to neomycin • It can be used as an alternative to neomycin for hepatic encephalopathy. • Parenterally, it is being used for visceral leishmaniasis, topical use for cutaneous leishmaniasis
- 28. Kanamycin: • Obtained fromS. kanamyceticus (in 1957), it was the second systemically used aminoglycoside to be developed after streptomycin. • It is more toxic, both to the cochlea and to kidney. • Hearing loss, which is irreversible, is more common than vestibular disturbance. • It is similar to streptomycin in all respects including efficacy against M. tuberculosis and lack of activity on Pseudomonas. • It is occasionally used as a second line drug in resistant tuberculosis. Dose: 0.5 gm i.m. BD (15 mg/kg/day);
- 29. Precautions in usingaminoglycosides Do not mix aminoglycosides with any other drug in the same syringe. Avoid use of other ototoxic drugs like loop diuretics with aminoglycosides. Avoid use of other nephrotoxic drugs like amphotericin B, cephalothin and cisplatin with aminoglycosides. Avoid use of drugs having muscle relaxant action along with aminoglycosides. Use cautiously in the elderly, in renal damage and in combination with skeletal muscle relaxants. Contraindicated in pregnancy because of the risk of deafness in the child. Determination of plasma levels of aminoglycosides may be needed in severe infections and in patients with renal dysfunction.