Aminoglycosides Streptomycin, gentamicin, tobramycin, amikacin, netilmicin, neomycin, kanamycin, sisomycin

General features  Protein synthesis inhibitor

 Interfere with ribosomal function
 Affect gram negative bacteria
 Bactericidal
 Originally obtained from STREPTOMYCES species
 Important antibiotics
General props  Physical n chem props
# water sol
# synergism w -lactams/ vancomycin in vitro
# should not mix 4 administration w -lactams (form complex)
Mech of action  Irreversible inhibitor of protein synthesis but precise bactericidal activity x clear
 Passive diff : via porin chanels acoss outer membrane
 Active t/port: across cell membrane-oxygen dependent
 t/membrane electrochemical gradient supplies energy
 LOW extracellular pH n anaerobic condition inhibit t/port
 Cell wall active drug -> enhance t/port-> synergism
 Intracellular : binds to a specific regions of polyanionic 16S rRNA on 30S-subunit ribosomal proteins
 It inhibits
# interfere ‘initiation complex’ formation
# misreading of mRNA-forming non-functional/ toxic protein
# break up polysomes to non-functional monosomes
Mech of  Transferase enzyme prdction : inactivate aminoglycosides by adenylation, acetylation,phosphorylation
resistance  Impaired aminoglycosides entry into d cell (genotypic/phenotypic)
 Receptor protein on d 30s ribosomal subunit may be deleted/altered due 2 mutation
Pharmacokinetics  Absorped poorly by intact GIT mucosa
 Ulcer presence improve absorption
 Post IM route : aminoglycosides’re well absorbed, peak [ ] 30-60 mins
 Usually administered IV as 30-60 mins infusion
 Hv [ ] dpndent killing: increasing [ ] kill an increasing bacteria proportion at > rapid rate
 Has significant post-AB effect : significant (several hours) : antibacterial activity persist beyond measurable drug [ ], SINGLE LARGE DOSE
> effective than multiple small dose
 Eg of dosing – creatinine clearance GOAL: [ ] < than 1 mcg/mLbetween 18-24 hrs after dosing
 Distribution:
# highly polar cmpnds x enter cell readily
# excluded from CNS n eye
# nervous system inflammation mprove CNS distribution
# intrathecal n intraventricular injctn- 2 achieve higher CNS level
# low distribution of other tissue
 T ½:
# normal: 2-3 hrs
# impaired real fnction: 24-48 hrs
# only partially removed by haemodialysis,peritoneal dialysis
# important dosage adjustments 4 renal dis pt
# calculate dose with: Normogram/ estimate creatnine clearance using Cockcroft-Gault formula *refer to notes 4 explanation
Toxicity  Depends on time n concentration ( [ ] )
 [ ] : above 2mcg/mL
 Time above d threshold will be greater with multiple doses than single large dose
 advisable 2 use SINGLE LARGE DOSE in many clinical settings EXCEPT enterococcal,streptococcal,staphylococcal
 Advantage of single dosing
# Not necessary to determine serum [ ]
# < nursing time
Adverse effects  Ototoxic
# auditory damage causing TINNITUS, HIGH FREQUENCY HEARING LOSS
# vestibular damage like VERTIGO, ATAXIA, LOSS OF BALANCE
 Nephrotoxic
#risk: > than 5 days tx, elderly, renal insufficiency setting, potentiation by use of diuretic n antimicrobial agent
 Most ototoxic agent: NEOMYCIN, KANAMYCIN, AMIKACIN
 Most nephrotoxic : NEOMYCIN, TOBRAMYCIN, GENTAMICIN
 Very high dose: curare like effects : neuromuscular blockade -> result in RESPIRATORY PARALYSIS (reversible w CALCIUM GLUCONATE/
NEOSTIGMINE)
 Hypersensitivity: infrequently

Clinical uses  G-ve enteric bact : esp whe isolate is drug resistant n there is species suspicion
 Use w - lactam 2 cover G+ve orgnsm
 Achieved synergism by combining penicillin n aminoglycosides
# BACTERICIDAL 4 enterococcal endocarditis
# shorten tx 4 viridans streptococcal n staphylococcal endocarditis

Syazwani Nazri
Syazwani Nazri