Aminoglycosides.ppt

Biochemistry

1. Aminoglycosides
Elias Fondo

2. Introduction to aminoglycosides
•Are mainly useful against aerobic Gram negati
ve bacteria
•Compounds derived from streptomyces are cal
led mycins (eg streptomycin):whereas those d
erived from micromonospora are called

3. Aminoglycosides cont'd
•micins (eg gentamicin)
•Aminoglycosides have certain features in com
mon:
•a) chemically, they are polycations containing aminosug
ars in glycoside linkage
•b) they are bactericidal and their activity is maximum in
an alkaline medium
•c) they have similar spectrum of activity; highly effectiv
e in infections caused by Gram negative organisms, not
effective in anaerobic infections

4. Aminoglycosides cont'd
•d) they are highly polar ( water soluble) and are not abs
orbed orally. Their distribution is essentially extracellula
r and penetration into CSF (except in neonates) and int
o the eye is poor on systemic administration
•e) they are excreted unchanged relatively rapidly by the
kidneys by glomerular filtration and dosage adjustment
is a must in patients with renal insufficiency and in old
people

5. Aminoglycosides cont'd
•f) bacteria develop resistance to them fairly rapidly and
may even exhibit cross resistance among different amin
oglycosides
•g) they exhibit synergism when combined with a beta la
ctum antibiotic such a penicillin or a cephalosporin; ho
wever, they should not be added to an infusion containi
ng these drugs, as aminoglycosides tend to be inactivat
ed by them
•h) high concentrations are found in the renal cortex and
in the endolymph and perilymph of the inner ear.

6. Aminoglycosides cont'd
•This contributes to their nephrotoxicity and ototoxicity
( 8th cranial nerve damage) and should be avoided in pr
egnancy
•I) they are also toxicity to the neuromuscular junction

7. Mechanism of action
•Aminoglycosides diffuse through the outer cyt
oplasmic membrane and are transported to th
e ribosomes.
•Ribosomes manufacture enzymes as per the di
rection of the messenger RNA
•Aminoglycosides bind mainly to the 30s riboso
mes and interfere with protein synthesis, bloc
k the translation of mRNA

8. Mechanism of action cont'd
•prematurely terminate the synthesis.
•Incorrect amino acids are incorporated into th
e protein chain leading to production of abnor
mal proteins
•These proteins get inserted into the cell memb
rane, causing its disruption.

9. Mechanism of action cont'd
•They exhibit concentration-dependent killing a
nd also has a post-antibiotic effect, depending
on concentration.
•Hence the present trend to administer these a
ntibiotics in a single daily high dose which pro
bably reduces the incidence of oto-and renal t
oxicity

10. Aminoglycosides resistance
•Some important examples of microorganisms t
hat readily develop resistance to aminoglycosi
des are S pneumoniae, M tuberculosis, Proteu
s, E Coli,Aerobacter, H influenzae, Brucella,sta
ph aureus and strep fecalis.
•Resistance to aminoglycosides arises from diff
erent mechanisms:

11. Aminoglycosides resistance cont'd
•a) low level resistance is due to decreased cell permeab
ility to the antibiotic. The bacteria becomes impermeab
le, preventing the drug reaching the drug sensitive ribo
somes
•b) high level resistance results from a single step mutati
on which affect the ribosomal proteins. This is uncomm
on and is specific for streptomycin
•c) 'R' factor mediated resistance is clinically significant.
The genetic material transferred during conjugation con
fers on the recipient cell the capacity to synthesize spec
ific enzymes

12. Aminoglycosides resistance cont'd
•which destroy the aminoglycoside. There is cross resistan
ce among various aminoglycosides

13. Streptomycin
•Obtained from streptomyces griseus, which is
an organic base
•Its stable in dry state at room temperature
•The aqueous solution of the salt retains its acti
vity at pH 3 to 7 for three months, if kept at 28
°C or below

14. Antibacterial activity
•Its sensitive to M tuberculosis, shigella, E Coli,
Proteus, Pseudomonas aeruginosa, Aerobacte
r aerogenes,H influenzae, Brucellar
•Its moderately sensitive to staphylococci, strep
pyogens, strep fecalis, strep viridans, S pneum
oniae, vibrio and salmonella species

15. Antibacterial activity cont'd
•The gonococci and meningococci exhibit varia
ble response
•Streptomycin is bacteriostatic in low and bacte
ricidal in high concentrations
•Its bactericidal action increases progressively
with rise in concentration

16. Absorption, fate excretion
•Given IM , peak plasma level is reached within
30 to 60 minutes and the activity persist for 6
to 8 hours.
•The drug is is well absorbed when instilled intr
apleurally.
•About 30 to 35% of the drug is bound to plas
ma proteins

17. •It diffuses into the synovial, pericardial and pe
ritoneal fluids but repeated systemic administr
ation is required to produce a high concentrati
on in the pleural fluid
•It does not readily cross the BBB; however, in t
he presence of meningeal inflammation, highe
r CSF concentrations are achieved

18. •Its mainly concentrated in kidneys, liver and sk
eletal muscles
•It crosses the placental barrier and the cord bl
ood concentration is similar to the maternal bl
ood
•Its excreted unchanged through glomerular filt
ration

19. •Approximately 50 to 60% of the drug is elimin
ated in urine in active form within 24 hours

20. Adverse reactions
•Local irritation; pain at the site of injection
•Allergy; skin rash, eosinophilia,lymphoadenop
athy. Serious manifestation like angioedema, p
ericarditis, exfoliative dermatitis are rare.
•8 the cranial nerve damage; the most serious
adverse effect.

21. Adverse reactions cont'd
•Streptomycin impair the vestibular function; h
owever, the symptoms of this damage are usu
ally reversible.
•The incidence of this complication is depende
nt on the dose and duration of therapy
•Ototoxicity is greater in infants, elderly and th
ose with renal insufficiency

22. Adverse reactions cont'd
•Streptomycin causes deafness, usually preced
ed by tinnitus. Congenital hearing loss may ha
ve resulted from its administration during preg
nancy. Other rare toxic effects include optic ne
uritis and peripheral neuritis. CAF also produc
es neuritis and the two should never be combi
ned.

23. Adverse reactions cont'd
•Neuromuscular blockade; all aminoglycosides
can produce neuromuscular block and respirat
ory arrest on intrapleural or intraperitoneal ins
tillation. It acts by inhibiting the release of ace
tylcholine at the neuromuscular junction thro
ugh competition with calcium ions.

24. Adverse reactions cont'd
•Nephrotoxicity; mild albuminuria or acute tub
ular necrosis may occur in patients receiving st
reptomycin, hence dose adjustment must be
made in patients with renal insufficiency
•Superinfection; with staphylococci and candid
a has been reported

25. Dosages
•0.5 to 1 g daily by deep intramuscular injectio
n

26. Kanamycin
•Derived from streptomyces kanamyceticus. Its
antibacterial spectrum, pharmcokinetics and t
oxicity are similar to those of streptomycin.
•However, its much more toxic and is now rarel
y used.

27. Indications
•Gram negative infections (when less toxic anti
biotic are unsuitable)
•Precautions: avoid use with potent diuretics, n
ephrotoxicity and neurotoxic drugs, impaired r
enal function, myasthesia gravis

28. •Contraindication: pregnancy, lactation,myasth
esia gravis
•Dose: by im injection, and in acute infections a
dults may be given 15mg/kg, to a maximum of
1.5 g daily in 2 to 4 divided doses
•Pregnancy risk category D

29. Gentamicin
•It is produced by micromonospora purpura
•Antibacterial activityhighly effective against P
seudomonas, Proteus, E Coli, A aeruginosa, K
pneumoniae, salmonella and group A beta he
molytic streptococci
•Staphylococci are also highly effective includin
g those resistant to penicillin

30. •It is 5 to 10 times more effective than kanamy
cin against Pseudomonas aeruginosa
•M tuberculosis and mycoplasma pneumoniae
are also highly sensitive
•Resistance developed slowly
•It exerts synergistic action with beta lactum an
d metronidazole.

31. Absorption fate excretion
•Not significantly absorbed on oral administrati
on
•Given im , the peak plasma levels are reached
within 60 to 90 minutes and therapeutically ef
fective concentration persists for 6 to 8 hours
•25 to 30% bound to plasma proteins

32. •It is excreted largely unchanged by glomerular
filtration and its urinary concentration ranges f
rom 50 to 100 times that in the plasma

33. Adverse reactions
•Allergic skin reactions and possibly photosensi
tivity reactions have occurred following topical
gentamicin
•Parenteral therapy in the presence of renal im
pairment, may produce vestibular damage an
d ototoxicity
•Dizziness is the may presenting symptom
•Its less toxic than streptomycin& kanamyc

34. Dosages
•Im or iv 2 -5 mg/kg/day in divided doses, for p
ts with normal renal function. Reduce dose in
renal damage
•Higher concentration achieved by the single d
ose accounts for higher efficacy and is cost eff
ective, preferred in clinical practice except in p
regnancy, neonate and in low dose combinatio
n therapy of bacterial endocardititis

35. Therapeutic uses
•Topical usein various skin infections; burns inf
ected with Pseudomonas, bed sores, ocular inf
ections
•UTI
•Systemic infectionsalthough Gram positive ba
cteria are susceptible to gentamicin, safer and
effective agents are available.

36. •Tetracycline and CAF should not be used toget
her with gentamicin as they reduce its therape
utic efficacy
•However, effect of ampicillin is additive and ca
n be used together with gentamicin.

37. Assignment
•Read and make notes on:
a.Tobramycin
b.Amikacin
c.Neomycin
d.Framycen
e.Paromomycin