Done by: Neetu ojha Pharm.D III yr

Definition, Structure• These are group of natural and semisynthetic antibiotics having

polybasic amino groups linked glycosidically to two or more animosugar

CLASSIFICATIONSystemic Topical

Streptomycin NeomycinGentamicin FramycetinKanamycin AmikacinSisomicin TobramycinNetilimicin

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

Properties1. All are sulfate salts which are highly soluble in water and

solutions are stable for months2. They ionize in solution, not absorbed orally, distribute only

extracellularly and do not penetrate in brain and CSF3. All are excreted unchanged in urine4. All are bactericidal and more active at alkaline pH5. Act by interfering bacterial protein synthesis6. Active against aerobic gm –ve bacteria, but spectrum

differs7. Partial cross resistance, organisms resistant to one amino

glycoside may still respond to another8. Narrow margin of safety9. All exhibit ototoxity and nephrotoxicity.

Post antibiotic effectAminoglycosides exhibit concentration dependent killingincreased conc. Can kill more bacteria at rapid rateThey also possess significant Post-antibiotic effect continue to suppress bacterial growth several hours after fall in MIC(Minimum Inhibitary Concentration)Single daily dosing at least as effective as and no more toxic than multiple dosing renal cortical uptake is a capacity dependent saturable processenhanced bactericidal activity

Antibacterial spectrum• Aerobic G-ve bacteria ( Citrobacter, Enterobacter, E. coli, proteus, shigella,

proteus, Pseudomonas, Enterococci and Staph aureus )• Streptomycin and kanamicin are active against mycobacterium

tuberculosis while amikacin, gentamicin and tobramycin are active against S. faecalis and P. aeruginosa.

• They are not effective against G+ve bacilli, G-ve cocci and anaerobes• Aminoglycosides are not effective against anaerobes

because the penetration of aminoglycoside across porin channel depend upon polarized membrane and oxygen dependent active process, since lack of oxygen make them ineffective against anaerobes

• Sometimes even facultative anaerobes are resistant in oxygen supply deficient

Mechanism of Action• The aminoglycosides are bactericidal antibiotics and all having

same general pattern of action. It is described in two ways1. Transport of amino glycoside through the bacterial cell wall

and cytoplasmic membrane depending upon polarity and oxygen dependent active process

2. 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.

RESISTANCEMay be plasmid mediated inactivation by microbial enzymes orFailure of drug penetration mutation of porin channel , so

decrease in aminoglycoside transport mechanism (decrease in premeability of pores in outer coat if bacteria)

Synthesis of metabolizing enzymesAcetyl transferaseacetylationPhosphotransferase phosphorylationAdenyltransferase adenylation

Mutation may alter ribosomal binding site for the aminoglycosidesprevent binding to 30S

• Cross resistance is observed.

Pharmacokinetics ABSORPTION: highly ionised, not absorbed or destroyed by G.I.T ,

I.M- rapid, plasma peak concentration-30-60 mins. DISTRIBUTION: Extracellularly -20-30%, High concentration in

endolymph and renal cortex , do not cross b.b.b. , may cross placenta , they get distributed in serous fluids like synovial, pleural , peritoneal etc

EXCRETION: Excreted unchanged in urine . Main channel of excretion is glomerular filtration , plasma T half : 2-4 hrs

After chronic dosing : 2-3 weeks drug persists in urine In elderly people and neonates , the drug dosing should be low as

they low glomerular filtration rate Renal clearance of aminoglycosides parallels creatinine . So an

creatinine clearance of 70ml/ min indicates no reduction of daily dose of aminoglycosides.

Shared toxicities1. 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 .

Cochlear damage: Hearing defect, deafness, tinnitus appears, on stopping drug

tinnitus disappers. Vestibular damage: Headache, nausea, vomiting, dizziness, nystagmus, ataxia,

vertigo.2. Nephrotoxicity: Tubular damage resulting in loss of urinary concentrating

power, low GFR, nitrogen retention, albuminuria and casts.

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.

3. Neuromuscular blockade:• 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• 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• 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, Yersinia pestis, F.tularensis,

Nocardia, M. tuberculosis, E. coli, Klebsiella, enterococci, Shigella• Resistance• Many organisms develop rapid resistance. E. coli, S.aureus.

S.pneumoniae are resistant• Resistance occurs by: 1. 1st step mutation • 2. Acquisition of plasmid which codes for

inactivation of enzymes• Streptomycin dependence• Certain mutants become dependent on streptomycin as they promote

mutant growth bi induced misreading of genetic code which becomes normal feature for organisms . Occurs mainly in Tb

• Cross resistance:• Partial or unidirectional cross resistance occur.

PharmacokineticsNeither 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 effectsVestibular disturbances,

auditory disturbancesNephrotoxicityHypersensitivity are rare-

rashes, eosinophilia, dermatitis

Pain at injection siteParesthesias and scotoma

are occasionalPreparation:Ambistryn 0.75, 1 g dry

powder per vial.

CONTRAINDICATION: pregnancy causes foetal ototoxicityDOSE: Tb – 1g or 0.75 g i.m OD or thrice weekly for 30-60 daysAcute infection: 1g i.m OD or BD for 7-10 days USES: 1.TB2. SABE: given with pencillin/ampicillin/vancomycin for 4-6 weeks 3. Plague: rapid cure within 7-12 days 4. Tularemia: Streptomycin cures it in 7-10 days

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

streptomycin• 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.

usesUse restricted to serious Gm-ve bacillary infections Septicaemia, sepsis, fever in immunocompromised

patients used with penicillins /cephalosporinsPelvic infections : with metronidazoleSABE: with Penicillin G or ampicillin or vancomycin,

where gentamicin dose is 1mg/kg for 8 hrs i.m Coliform infection: with ampicillin or ceftriaxone Pseudomonal infections: with ticarcillin Meningitis by Gm-ve bacilli : III generation

cephalosporin alone or with gentamicin Topical-infected burns, wounds, skin lessions (with

purulent exudates

KANAMYCINObtained from S.Kanamycetius , similar to

streptomycin and even against M.tuberculosis but lack activity on pseudomonas

More toxic to cochlea and kidney , hearing loss id irreversible . Because of toxicity and narrow spectrum it is replaced by other drugs.

DOSE : 0.5 g i.m BD

TOBRAMYCINIdentical to gentamicin and obtained from S.

tenebrariusUsed in pseudomonas and proteus infectionsOtotoxicty and nephrotoxicity probably lowerDOSE: 3-5mg/kg I.M in 1-3 doses

Less toxic semisynthetic derivative of kanamycin but more hearing loss occurs

Resistant to enzymes that inactivate gentamicin and tobramcyin Widest spectrum of activity Uses: Same as gentamicinReserve drug for hospital acquired Gm-ve bacillary infections Multidrug resistant TB resistant to streptomycin, along with other drugs Dose : 15mg/kg/day in 1-3 doses

SISOMICIN• Identical to gentamicin and also equal in toxicities and susceptible to

aminoglycosides inactivating enzymes.• More potent on pseudomonas and -hemolytic streptococci and obtained

from Micromonospora inyoensis.NETILMICIN Resistant to many enzyme that inactivate gentamicin and tobramycin

additional ethyl group protects from enzymatic degradationLowest toxicity among aminoglycosidesSemisynthetic derivative of sisomicin More active against klebsiella, enterobacter & staphylococci Less active against pseudomonas aeruginosa Doses and pharmacokinetics similar to gentamicin Uses-Septicemia, Lower respiratory tract infection Urinary tract infection, peritonitis and endometritis

FramycetinObtained from S. lavendulae . Similar to

neomycin .Toxic for systemic administration , used topically on eye,skin and ear.

Paromomycin Properties similar to neomycin Effective against visceral leishmainiasis by parentral routeUses – Intestinal infectionsTreatment of hepatic encephalopathy Treatment of amoebiasis

Neomycinwide spectrum active against Gm-ve bacilli and some

gm+ve cocci and obtained from S.fradiaePseudomonas and strep.pyogenes are not sensitive Too toxic for parenteral use , limited to topical use DOSE: 0.25-1g QID oral, 0.3-0.5% topical.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

ADR: Low sensitizing potential, rashes , oral neomycin damage intestinal villi. Prolonged treatment causes malabsorption syndrome , diarrhoea

Decreasing the absorption of digoxin , bile acids , suppresses gut flora causing superinfection by candida

It is excreted unchanged in kidney causing kidney damage and ototoxicity

In serous cavity it causes apnoea due to muscle paralysing action .