1) Aminoglycosides are polybasic amino groups linked glycosidically to aminosugar compounds. They are highly water soluble and excreted unchanged in urine.
2) They are bactericidal, inhibiting protein synthesis by binding to the 30S/50S interface of bacterial ribosomes. This causes misreading of mRNA and nonfunctional protein formation.
3) Common adverse effects include ototoxicity (hearing loss) and nephrotoxicity. Individual drugs vary in their specific toxicities.
3. GENERAL PROPERTIES
Highly water soluble, so not absorbed orally.
More active at alkaline pH.
Excreted unchanged in urine.
Bactericidal, inhibit protein synthesis.
Active against gram negative bacteria.
Resemble each other in PK, therapeutic and toxic
properties.
4. MECHANISM OF ACTION
Passive diffusion via porin channels across outer
membrane
Decrease extra cellular pH
Anaerobic conditions Transport
Cell wall active drugs : (Penicillin, Vancomycin)
Transport Synergism
Active transport across cell membrane into
5. Bind to 30s/ 50s/ 30s-50s interface of
ribosome:
Interfere with initiation complex of peptide
formation.
Induce misreading of mRNA-amino acid
peptide: toxic/non functional protein.
Break up of polysomes to nonfunctional
monosomes.
MECHANISM OF ACTION
6. Irreversible inhibition of protein synthesis
Bactericidal
Concentration dependent killing.
“Post antibiotic effect” (once daily dosing)
MECHANISM OF ACTION
7. POST ANTIBIOTIC EFFECT
Antibacterial activity persists beyond the time
during which measurable conc is present.
Slow recovery after reversible nonlethal damage to
cell structures.
Drug bound to receptor-periplasmic space.
Time taken for enzyme synthesis for cell growth.
8. POST ANTIBIOTIC EFFECT
Once daily dosing of aminoglycoside.
High doses give once daily.
Less toxicity, lower monitoring costs.
9. MECHANISM OF
RESISTANCE
Drug inactivation -Bacteria elaborate
tranferase enzyme or adenylylating,
acetylating, phosphorylating enzyme: plasmid
mediated.
Impaired entry – Mutation/Deletion of porins or
oxygen dependent transport process disrupted.
Altered Binding Protein - 30s ribosomal unit
altered/ deleted:-mutation.
10. Mechanism of resistanceMechanism of resistance
produces enzymesproduces enzymes
Altered ribosomal subunitAltered ribosomal subunit
Changes of PorinsChanges of Porins
Active efflux systemActive efflux system
11. PHARMACOKINETICS
Poor oral absorption from intact GIT mucosa
After i/m. inj. peak conc. in 30-60 min.
Highly polar, mainly extra cellular
Cleared by kidneys: Excretion directly proportional
to creatinine clearance
Normal half life in serum : 2-3 hrs
Can cross placenta – fetal hearing loss.
C/I pregnancy.
14. ADVERSE DRUG REACTIONS
Cochl
ear
Vestib
ular
Nephrotoxic Clinical Uses
Streptomycin + ++ + T.B.
Gentamicin + ++ + More active
against
Pseudomonas
Tobramycin ++ ++ + ”
Netilmicin + + + In Gentamicin
resistant cases
Neomycin ++ + +++ Topical ,Oral
Framycetin ++ + +++ Topical
Kanamycin ++ + +++ T.B.
Amikacin ++ + +++ In Gentamicin
resistant Cases
15. STREPTOMYCIN
Less active against Gram –ve bacilli than others.
I/m. inj.
Inactivating enzymes, Ribosomal resistance-limited
use as single agent.
Therapeutic uses:
Bacterial Endocarditis:
Synergistic with penicillin - Enterococci, Gp.D
streptococci, Oral strept. viridans gps.
Strept + Penicillin G : 4 weeks
16. Tularemia: 1-2g (15-25mg/kg/day) ×7 -10 d
Plague: Most effective, 1-4g/day × 7-10 d
Tuberculosis:15mg/day, i/m inj 2-3 months in
combination with other A.T. drugs
ADVERSE EFFECTS:
Least nephrotoxic (not accumulated in renal cortex)
Disturbance of vestibular fn. - vertigo
Disturbance of auditory fn. – less common
Fever,Rash,Allergic Reactions.
C/I in pregnancy (deafness in newborn)
17. From micromonospora purpurea
Low cost, most reliable against resistant infections
Mostly active against Gram –ve, some gram +ve &
not against anaerobes
Alone or synergistic : Proteus, Enterobacter,
Klebsiella
Gentamicin, Amikacin, Tobramycin, Netilimicin:
used interchangeably
GENTAMICIN
18. RESISTANCE:
Streptococci & enterococci resistant to
Gentamicin (failure of drug to penetrate)
Resistance of staphylococcus due to
selection of permeability mutants
Gram-ve plasmid mediated
aminoglycoside modifying enzymes
19. THERAPEUTIC USES
Sepsis, Pneumonia: Gram-ve organisms, -
Pseudomonas, Enterobacter, Proteus.
In Immunocompromised patients can be given
with cephalosporin/ penicillin
Endocarditis Penicillin G + Genta:
Topical Adm: Creams, Ointments 0.1-0.3%,
Burns, I.V. Catheter infection
Meningitis by serious gram –ve with or without
3rd
gen cephalosporins .
Adverse effects: same as others
20. KANAMYCIN
Used in past
Toxic : Hepatoxicity ++
Auditory toxicity ++
Vestibular +
Use: Tuberculosis (2nd
line), Hepatic coma
21. TOBRAMYCIN
PK similar to Gentamicin
i/m or i/v
Superior activity against pseudomonal
infections, Proteus along with beta lactams .
Ineffective against mycobacterium.
Alternative to Gentamicin.
5-6 mg/kg i/m or i/v 3 divided doses.
S/E :Ototoxic ,Nephrotoxic (slightly less)
22. AMIKACIN
Semisynthetic derivative of Kanamycin, less toxic.
Resistant to enzyme inactivation.
Given in Genta/ Tobra resistant infections of
Gram –ve bact.-Proteus, Pseudomonas, Serriatia:-
500mg i/m 12 hourly(15 mg/kg/day)
Multi drug resistant T.B. (7.5-15mg/kg/day once
daily/2-3 ×weeks)
23. SISOMICIN
From Micromonospora inyoensis.
Similar to Genta but more potent on
Pseudomonas, Beta hemolytic Strept and
G –ve.
Sub Acute Bacterial Endocarditis (SABE)
– with Penicillin.
Susceptible to inactivating enzymes.
24. NETILMICIN
Like Gentamycin & Tobramycin
(interchangeable with these)
Resistant to most inactivating enzymes
Similar toxicity
5-7 mg/kg/day
25. PARAMOMICIN
Related to Neomycin.
Activity against protozoan parasites.
Intestinal Amoebiasis: 1g/6 hourly× 2 weeks,
orally
Alternative to Neomycin for Hepatic
Encephalopathy.
Visceral Leishmaniasis.
26. NEOMYCIN
Uses
Oral :
• 1) Hepatic coma suppresses Coliforms
• 2) Gut surgery
Topically for infected wound, buns, ulcers, external
ear infections, conjunctivitis.
Toxicity:
Malabsorption, Super infection
Nephrotoxic, Ototoxic
27. Extracted from Strept. lavendulae.
Similar to Neomycin but too toxic for systemic
use.
Used topically (same as Neomycin).
FRAMYCETIN