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 groupsEg :- 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