Toxicity of aminoglycoside antibiotics

by ajith covas mannuthy

1. TOXICITY OF AMINOGLYCOSIDE ANTIBIOTICS

2. INTRODUCTION Group of natural and semisynthetic antibiotics. Amino sugar + aminocyclitol via glycoside bond. Streptomycin – 1 st discovered – 1944 – Waksman & co-workers from Streptomyces griseus ( actinobacterium ) Amikacin – 1 st 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

3. 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

4. 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.

5. 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

6. 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...

7. Vestibulotoxicity – Streptomycin > Gentamicin Ototoxicity – Neomycin > Kanamycin & Amikacin Cats are more susceptible than dogs. Renal dysfunction increase ototoxicity

8. 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

9. IV OTHER EFFECTS Less allergic reactions Peripheral neuritis & optic nerve damage Intestinal malabsorption syndrome Diarrhea, Flattening of intestinal villi etc…

10. 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

11. 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

12. 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