Aminoglycoside

CLASSIFICATION:
Systemic
  1. Streptomycin
  2. Gentamicin
  3. Kanamycin
  4. Amikacin(outstanding feature of being little or not affected by majority of inactivating enzymes )
  5. Sisomicin
  6. Tobramycin
  7. Netilimicin 
  • Topical
  1. Neomycin
  2. Framycetin
MECHANISM OF ACTION :
  • Initially they penetrate bacterial cell wall, to reach periplasmic space through porin channels (passive diffusion)
  • Further transport across cytoplasmic membrane takes place by active transport by proton pump; an oxygen-dependent process
  • Bind 30S ribosomal subunits and interfere the initiation complex
  • Induce misreading of genetic code on mRNA
  • Breakup of polysomes into monosomes
POST ANTIBIOTIC EFFECT:
  • Aminoglycosides exhibit concentration dependent killing.
  • They also possess significant Post-antibiotic effect.
  • Single daily dosing at least as effective as and no more toxic than multiple dosing
MECHANISM OF RESISTANCE:
  • Synthesis of plasmid mediated bacterial transferase enzyme: Inactivate aminoglycosides
  • ↓ transport into bacterial cytosol
  • Deletion/alteration of receptor protein on 30 S ribosomal unit by mutation: prevents attachment
ANTIBACTERIAL SPECTRUM :
  • Primarily against Gm –ve aerobic bacilli
  1. Proteus, pseudomonas
  2. E.Coli,enterobacter
  3. Klebsiella
  4. Shigella
  5. Only few Gm +ve cocci:
  6. staph aureus, strepto viridans
  • Not effective against Gm +ve bacilli, Gm-ve cocci and anaerobes
  • Enterococcus faecalis when isolated in the blood, requires the synergistic activity of penicillin plus an aminoglycoside for appropriate therapy
  • Widest spectrum aminoglycoside is Amikacin
PHARMACOKINETICS
  • Highly polar basic drugs: poor oral BA
  • Administered parenterally or applied locally
  • Poorly distributed and poorly protein bound
  • Do not undergo any significant metabolism
  • Nearly all IV dose is excreted unchanged in urine
  • Dose adjustment is needed in renal insufficiency
USES:
  1. Gram –ve bacillary infection
  2. Septicaemia, pelvic & abdominal sepsis
  • Bacterial endocarditis –
  1. enterococcal, streptococcal or staphylococcal infection of heart valves
  2. Pneumonias, Tuberculosis
  3. Tularemia
  4. Granuloma venerum
  5. Plague, Brucellosis
  6. Topical – Neomycin, Framycetin.
  • Infections of conjunctiva or external ear
  • To sterilize the bowel of patients who receive immunosuppressive therapy, before surgery & in hepatic coma
STREPTOMYCIN:
  • Nonplant toxin
  • Ribosomal resistance develops fast
  • Limited usefulness as single agent
  • Streptomycin single dose is more effective than multiple small doses because of it's Concentration dependent lytic effect
  • Plague, tularemia and brucellosisIn combination with tetracycline
  • SABE: due to Streptococcus Viridans & faecalis With penicillin but gentamicin preferred
  • Reserve first line drug for tuberculosis used only in combination
  • Streptomycin should not be used with d-tubocurarine
GENTAMYCIN
  • Obtained from Micromonosporapurpurea
  • Most commonly used aminoglycoside
  1. More potent than Streptomycin
  2. Broader spectrum: pseudomonas, proteus, E.coli, klebsiella, enterobacter, serratia
  3. Low cost, reliability of use, long experience
  4. Acts synergistically with ampicillin, penicillin G, Ticarcillin, ceftriaxone, Vancomycin
  • Ineffective against M.tuberculosis
  • Relatively more nephrotoxic
  • USES:
  1. Use restricted to serious Gm-ve bacillary infections
  2. Septicaemia, sepsis, fever in immunocompromised patients
  3. Used with penicillins
  4. Pelvic infections : with metronidazole
  5. SABE: with Penicillin G or ampicillin or vancomycin
  6. Coliform infection: with ampicillin or ceftriaxone
  7. Pseudomonal infections: with ticarcillin
  8. Meningitis by Gm-ve bacilli : III generation cephalosporin alone or with gentamicin
SIDE EFFECTS:
  • Ototoxicity
  • Cochlear damage
  • Hearing loss ( damaging Outer hair cells of basal turn) and tinnitus
  • More with neomycin , amikacin and kanamycin 
  • Vestibular damage
  1. Vertigo, ataxia, loss of balance
  2. More with Streptomycin, gentamycin
  3. Tobramycin has both types of toxicity
  4. Netilimycin claimed to have low ototoxicity
  • Nephrotoxicity 
  1. Gentamicin, amikacin and tobramycin are more toxic than streptomycin
  2. Responsible for 10-15% of all renal failure cases
  3. Reversible if drug promptly discontinued
  4. ↓ GFR, ↑sr creatinine
  5. ↓clearance of antibiotic →↑ototoxicity
  6. Risk factors include:
  7. Old age, Hypokalemia, Aminoglycoside administration in recent past 
  • Neuromuscular blockade 
  1. Cause N-M junction blockade by
  2. Displacing Ca2+ from NM junction
  3. By blocking post synaptic NM receptors
  4. Inhibiting Ach release from motor nerve
  • Neomycin & streptomycin: more propensity
  • Tobramycin least likely to produce it
  • Myasthenic weakness ↑by these drugs
Exam Question
  • Aminoglycosides cause non-oliguric renal failure
  • Deafnessmight be seen in patient of TB, who has regularly been injecting intramuscular injection of streptomycin
  • In treatment of Pseudomonas infec­tions, carbencillin is frequently combined with Gentamycin
  • Streptomycin should not be used with d-tubocurarine
  • Old age, Hypokalemia, Aminoglycoside administration in recent past increase the risk of aminoglycoside renal toxicity
  • Enterococcus faecalis when isolated in the blood, requires the synergistic activity of penicillin plus an aminoglycoside for appropriate therapy
  • Streptomycin used in treatment of plague, brucellosis
  • Streptomycin is protein synthesis inhibitor & are nonplant toxin
  • Streptomycin single dose is more effective than multiple small doses because of it's Concentration dependent lytic effect
  • Streptomycin require dose adjustment in renal failure
  • Streptomycin is a Gycoside
  • Mechanism of action of streptomycin is inhibition of translation
  • Framycetin is not available for parenteral use
  • An aminoglycoside with an outstanding feature of being little or not affected by majority of inactivating enzymes is Amikacin
  • Widest spectrum aminoglycoside is Amikacin
  • Aminoglycoside class of drugs causes hearing loss by damaging Outer hair cells of basal turn
  • Streptomycin is useful in treatment of Granuloma venerum
Don't Forget to Solve all the previous Year Question asked on Aminoglycoside