Toxicity of aminoglycoside antibioticsPresentation Transcript
TOXICITY OF AMINOGLYCOSIDE ANTIBIOTICS
INTRODUCTION• Group of natural and semisynthetic antibiotics.• Amino sugar + aminocyclitol via glycoside bond.• Streptomycin – 1st discovered – 1944 – Waksman & co-workers from Streptomyces griseus ( actinobacterium )• Amikacin – 1st semi synthetic – from Kanamycin• Bactericidal drug – Inhibit protein synthesis – Formation of aberrant proteins – streptomycin (bind with 30S subunit) – others (bind with 50S subunit) – Bacteria more permeable – leakage – cell death
• Excellent water solubility – Poor lipid soluble.• Nephrotoxicity – due to increased no: of amino groups Eg :- Neomycin – 6 amino group – more toxic Streptomycin – 3 amino group – less toxic• They are not absorbed from the gut. So I/m or I/v• Uses : Local & Systemic infection – Mainly Gram –ve• In Vet practice, Neomycin – toxic – so topical only Gentamicin – Broad spectrum antibiotic
I. NEPHROTOXICITY• Excessive accumulation in PCT cells ( 40 – 50 times than in blood )• Basic polycation, attract to membrane phospholipids• High Phosphatidyl inositol content – PCT & Cochlea• Pinocytosis – sequestrate in lysosomes –interact with organelles - cell death – cell necrosis• Inhibit phospholipidases, ATPases - reduced PG synthesis – direct effect on GFR.
• Toxicity reversible initially- renewable PCT cells• Manifestations : Enzymes of brush border in urine, proteinuria, casts, low GFR etc..• Reduced antibiotic clearance – lead to ototoxicity• Later stages - polyuria – loss of response to ADH• Neomycin – 6 amino group – more toxic DihydroStreptomycin – 3 amino group – less toxic
II. OTOTOXICITY• Both Vestibular & auditory dysfunction• Accumulate in perilymph & endolymph• Ototoxicity – irreversible – Non renewable cells• Cochlear damage – Hearing loss (high frequency sound first) – loss of hair cells in Organ of Corti• Vestibular damage – Affect balance of body – Nystagmus, incoordination, vertigo, head tilt, ataxia, loss of righting reflex etc...
• Vestibulotoxicity – Streptomycin > Gentamicin• Ototoxicity – Neomycin > Kanamycin & Amikacin• Cats are more susceptible than dogs.• Renal dysfunction increase ototoxicity
III NEUROMUSCULAR BLOCKAGE• Interfere Acetyl Choline release from motor nerve ending – antagonism of Calcium ( exocytosis )• Decrease sensitivity of post synaptic membrane• Toxicity only when administer along with neuromuscular blocking agent & general anesthetic• Muscular weakness, apnea, respiratory arrest• Neomycin & Streptomycin high side effect
IV OTHER EFFECTS• Less allergic reactions• Peripheral neuritis & optic nerve damage• Intestinal malabsorption syndrome• Diarrhea, Flattening of intestinal villi etc…
DRUG INTERACTIONS• Loop diuretics or Osmotic diuretics => Enhanced nephrotoxicity & ototoxicity• Inhalant anesthetics or neuromuscular blocking agents => respiratory paralysis• Halothane => Cardiovascular depression• Cephalosporin => additive nephrotoxicity• Carbenicillin or Ticarcillin => inactivate
CONTRAINDICATIONS & PRECAUTIONS• In hypersensitive animals, Animals with renal diseases, Neonatal & Geriatrics - dose rate reduced & treatment interval increased.• Not recommended in pregnants – adverse effect on foetus
TREATMENT• Infusion of neurotropic factor , neurotropin 3 (NT-3) in membraneous labrynth• Dialysis• Administration of carbenicillin or ticarcillin (12- 20g/day) to complex with aminoglycosides• Ca salts or neostigmine given I/v, to treat neuromuscular blockage• Avoiding concurrent use of nephrotoxic drugs