Aminoglycoside antibiotics

Aminoglycosides
• Streptomycin – 1944
• Actinomycetes – Streptomyces
• griseus
• Bactericidal antibiotics
• Interfere
Used with
to treat proteinGram
aerobic synthesis
–ve bacteria
• Resemble each other in MOA, pharmacokinetic
therapeutic and toxic properties
• Relatively low margin of safety
• Exhibit ototoxicity and nephrotoxicity
 Aminoglycosides
• Systemic • Topical
– Streptomycin – Neomycin
– Gentamicin – Framyceti
– Kanamycin n
– Amikacin
– Sisomicin
– Tobramycin
– Netilimicin
Mechanism of Protein synthesis
 Mechanism of Action

• Bind 30S ribosomal subunits and interfere

the initiation complex induce misreading of genetic code
on mRNA
• This leads to inhibition of protein synthesis

•
 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
– Proteus, pseudomonas
– E.Coli,enterobacter
– Klebsiella
– Shigella
• Only few Gm +ve cocci:
– staph aureus, strepto viridans
• Not effective against Gm bacilli, Gm-ve
+ve
cocci and anaerobes
 Pharmacokinetics
• Highly polar basic drugs: poor oral Bioavailability
• 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
Pharmacokinetics
Dose for a case of renal insufficiency

• Cockroft gault formula:

CrCl = (140-age) x weight [kg]
(sCr x 72)

– For females multiply above value by 0.85

• Corrected dose = Normal dose x pt CrCl
Normal CrCl
 Clinical uses
• Gram –ve bacillary infection
– Septicaemia, pelvic & abdominal sepsis
• Bacterial endocarditis –
– enterococcal, streptococcal or staphylococcal infection of
heart valves
• Pneumonias, Tuberculosis
• Tularemia
• Plague, Brucellosis
• Topical – Neomycin, Framycetin.
• Infections of conjunctiva or external ear
• To sterilize the bowel of patients who receive
immunosuppressive therapy, before surgery &
in
 Shared toxicities

• Ototoxicity
– Vestibular damage
– Cochlear damage
• Nephrotoxicity
• Neuromuscular
blockade
 Ototoxicity
• Impairment of VIII cranial nerve function
• May be irreversible
• Cochlear damage
– Hearing loss and tinnitus
– More with neomycin , amikacin and kanamycin
• Vestibular damage
– Vertigo, ataxia, loss of balance
– More with Streptomycin, gentamycin
• Tobramycin has both types of toxicity
• Netilimycin claimed to have low
ototoxicity
 Nephrotoxicity
• Gentamicin, amikacin and tobramycin are
more toxic than streptomycin
• Responsible for 10-15% of all renal failure
cases
• Reversible if drug promptly discontinued
• ↓ GFR, ↑ sr creatinine
• ↓clearance of antibiotic → ↑ ototoxicity
 Neuromuscular blockade
• Cause N-M junction blockade by
– Displacing Ca2+ from NM junction
– By blocking post synaptic NM receptors
– Inhibiting Ach release from motor nerve
• Neomycin & streptomycin: more propensity
• Tobramycin least likely to produce it
• Myasthenic weakness ↑by these drugs
 Precautions / Contraindications
• Pregnancy: foetal ototoxicity
• With other ototoxic drugs: furosemide,
minocycline
• With nephrotoxic drugs: vancomycin ,cisplatin

• Elderly patients
• Those with kidney disease
• Cautious use of muscle relaxants
• Do not mix with any other drug in same
syringe
 Streptomycin
• Ribosomal resistance develops fast
• Limited usefulness as single agent
• Plague, tularemia and brucellosis
– In combination with tetracycline
• SABE: due to Streptococcus & faecalis
Viridans
– With penicillin but gentamicin preferred
• Reserve first line drug for tuberculosis used
only in combination
 Gentamicin
• Obtained from Micromonospora purpurea
• Most commonly used aminoglycoside
– More potent than Streptomycin
– Broader spectrum: pseudomonas, proteus, E.coli,
klebsiella, enterobacter, serratia
– Low cost, reliability of use, long experience
– Acts synergistically with ampicillin, penicillin G,
Ticarcillin, ceftriaxone, Vancomycin
• Ineffective against M.tuberculosis
• Relatively more nephrotoxic
 Gentamicin (Uses)
• Use restricted to serious Gm-ve bacillary infections
• Septicaemia, sepsis, fever in immunocompromised
patients
– Used with penicillins
• Pelvic infections : with metronidazole
• SABE: with Penicillin G or ampicillin or vancomycin
• Coliform infection: with ampicillin or ceftriaxone
• Pseudomonal infections: with ticarcillin
• Meningitis by Gm-ve bacilli : III generation
cephalosporin alone or with gentamicin
Guideline for adjustment of dose in
renal insufficiency
 Tobramycin
• Identical to gentamicin
• Used in pseudomonas and proteus
• infections
Ototoxicty and nephrotoxicity probably lower

Sisomicin
• Identical to gentamicin
• More potent on pseudomonas and -hemolytic
streptococci
• Used interchangeably with gentamicin
 Amikacin
• Less toxic semisynthetic derivative of kanamycin
• Resistant to enzymes that inactivate gentamicin
and tobramcyin
• Widest spectrum of activity
• Uses:
– Same as gentamicin
– Reserve drug for hospital Gm-ve bacillary
acquired infections
– Multidrug resistant TB along with other drugs
• Dose : 15mg/kg/day in 1-3 doses
 Neomycin
• wide spectrum active against Gm-ve bacilli
and some gm+ve cocci
• Pseudomonas and strep.pyogenes not
sensitive
• Too toxic for parenteral use , limited to topical
use
 Neomycin (uses)
• Topically used in skin, eye and external ear infections
combined with bacitracin or polymyxin-B to widen
antibacterial spectrum and to prevent emergence of
resistant strains
• Orally
– Preparation of bowel before surgery 1 gm TDS
– Hepatic coma: Supresses ammonia forming
coliforms prevents encephalopathy (Lactulose
more preferred)
• Bladder irrigation along with polymyxin B