AMINOGLYCOSIDE ANTIBIOTICS : AMINOGLYCOSIDE ANTIBIOTICS Presented by
Maharashtra Institute of Pharmacy, Pune Contents : Contents Definition and chemical structure
History and source
Antibacterium spectrum and resistance
Mechanism of action
Precautions and interactions
Streptomycin as prototype drug
Pharmacokinetics and adverse effects
Uses and other classes.
References. Definition, Structure : Definition, Structure These are group of natural and semisynthetic antibiotics having polybasic amino groups linked glycosidically to two or more animosugar History, Source : History, Source Streptomicin was the first member discovered in 1944 by Waksman and his collegues and active against tuberculi bacilli.
Neomycin was the next to be isolated in 1949 but it coud not be used systemically.
Others have been discovered later and all aminoglycosides are produced by soil actinomecetes
Source: Most of them are prepared from natural fermentation from various species of streptomyces
The exception are gentamicin which is fermented from Micromonospora purpurea and amikacin which is first antibiotic obtained by chemical modification of kanamycin Properties : Properties All are sulfate salts which are highly soluble in water and solutions are stable for months
They ionize in solution, not absorbed orally, distribute only extracellularly and do not penetrate in brain and CSF
All are excreted unchanged in urine
All are bactericidal and more active at alkaline pH
Act by interfering bacterial protein synthesis
Active against aerobic gm –ve bacteria, but spectrum differs
Partial cross resistance, organisms resistant to one amino glycoside may still respond to another
Narrow margin of safety
All exhibit ototoxity and nephrotoxicity. Antibacterial spectrum and resistance : Antibacterial spectrum and resistance Bactericidal and active against gm +ve and gm –ve bacteria.
Streptomycin and kanamicin are active against mycobacterium tuberculosis while amikacin, gentamicin and tobramycin are active against S.faecalis and P. aeruginosa.
Several other bacterias like Gonorrhoeae, N. meningitidis, Salmonella, Shigella are also susceptible but other safer agents are used.
Serious staphylococcal infections are not been treated by aminoglycosides.
Some resistance is also observed and can be developed byribosomes which do not bind aminoglycosides or by inactivating enzymes.
Cross resistance is observed. Mechanism of Action : Mechanism of Action The aminoglycosides are bactericidal antibiotics and all having same general pattern of action. It is described in two ways
Transport of amino glycoside through the bacterial cell wall and cytoplasmic membrane
Binding to ribosome resulting in inhibition of protein synthesis
The aminoglycosides act on bacterial 30Sribosomes and distort the messenger ribonucleic acid translation of genetic code, so prevent the formation of normal complex required to initiate protein synthesis.
Different aminoglycosides cause misreading at different levels depending on their selective affinity for specific ribosomal proteins.
They also combines anionic membrane groups and damage the bacterial cell membranes (proteins, aminoacids leak out) and also block energy production of Kreb’s cycle. Pharmacokinetics : Pharmacokinetics They absorbed poorly after oral administration.
Given by injection
They are poorly bound to serum protein (20-30%) but widely distributed throughout body except CNS and eye where penetration is inadequate.
Excreted by kidneys.
They must be given in less doses in case of pre existing kidney disease. Shared toxicities : Shared toxicities Ototoxicity:
Vestibular and cochlear part affected with aminoglycosides. These drugs get concentrated in labyrinthine fluid. Ototoxicity is greater when plasma concentration of drug is high.
Vestibular/cochlear sensory cells get destructive changes, aminoglycoside ear drops are contraindicated .
Hearing defect, deafness, tinnitus appears, on stopping drug tinnitus disappers.
Headache, nausea, vomiting, dizziness, nystagmus, ataxia, vertigo.
Tubular damage resulting in loss of urinary concentrating power, low GFR, nitrogen retention, albuminuria and casts. Continued… : Continued… Aminoglycosides attain high concentration in renal cortex and toxicity is related to total amount of drug receiving drug by patient.
It is more in elderly and in those with preexisting kidney disease. However, the kidney damage is reversible if drug is discontinued.
It has been suggested that aminoglycosides interfere with production of prostaglandins in kidney and so there is reduced GFR.
All aminoglycosides reduce Ach release from motor nerve ending, they have curare like action and cause neuromuscular blockade that can cause paralysis and fatal respiratory arrest.
They may cause apnea on iv injection,the blockade if severe can be effectively treated by neostigmine. Precautions and interactions : Precautions and interactions Avoid during pregnancy, risk of foetal ototoxicity.
Avoid concurent use of other ototoxic drugs e.g. high ceiling diuretics, minocycline
Avoid concurrent use of other nephrotoxic drugs. E.g. amphotericine B, vancomycin, cephalothin, cyclosporin etc
Cautious use in patients past middle age and in those with kidney damage
Cautious use in muscle relaxants.
Do not mix aminoglycosides with any drug in same syringe or infusion bottle. STREPTOMYCIN : STREPTOMYCIN It is older antibiotics and obtained by Streptomyces griseus, used in past but now used for treatment of TB.
The antibacterium spectrum is relatively narrow.
Sensitive to H.ducrey, Brucella, Tersinia pestis, F.tularensis, Nocardia, M. tuberculosis, E. coli, Klebsiella, enterococci, Shigella
Many organisms develop rapid resistance. E. coli, S.aureus. S.pneumoniae are resistant
Certain mutants become dependant on it.
Partial or unidirectional cross resistance occur. Slide 13: Pharmacokinetics
Neither absorbed nor destroyed in git.
Absorption from injection site in muscle is rapid.
Distributed extracellularly, volume of distribution 0.3 L/kg
Attains low concentration in synovial, pleural fluid.
It is not metabolized. Excreted unchanged in urine
Plasma half life is 2-4 hrs Adverse effects
Vestibular disturbances, auditory disturbances
Hypersensitivity are rare-rashes, eosinophilia, dermatitis
Pain at injection site
Paresthesias and scotoma are occasional
Ambistryn 0.75, 1 g dry powder per vial. Uses and other classes : Uses and other classes Uses:
Subacute bacterial endocarditis
Urinary tract infections, peritonitis, septicemias Other classes:
Neomycin Preparations : Preparations GENTAMICIN : GENTAMICIN It was obtained from Micromonospora purpurea in1964 and has become most common antibiotic in acute infections
The properties include
Plasma half life 2-4 hours after i.m. injections same as streptomicin
But it has following differences from streptomycin
It is more potent
It has boarder spectrum of action and effective against P. aeruginosa and most strains of Proteus, E.coli, Klebsiella, enterobactor, Serratia
It is not effective against M.tuberculosis, Str.pyogenes, stre. Pneumoniae, and some Stre. Aureus
It is more nephrotoxic. Dose, brand names and uses : Dose, brand names and uses The dose of gentamicin must be precisely calculated according to body weight and level of renal function.
For an average adult, dose is 3-5 mg/kg/day, i.m.
Garamycin, gentasporine, genticyn 20, 60, 80, 240 mg per vial, 0.3% eye ear drops.
It is cheapest and first line aminoglycoside antibiotics but due to low therapeutic index its use should be restricted to serious gram negative bacillary infections
Respiratory infections-it is often combined with penicillin/cephalosporin or another antibiotic in thsese situations
meningitis References : References The essential of Medical Pharmacology by KD Tripathi, 5th edition, 2004, page no 678-685
Essentials of Pharmacotherapeutics by FSK Barar, 2007, Page 420-424