Download Chapter 40 Aminoglycosides and Polymyxins

Chapter 40 Aminoglycosides
and Polymyxins
Department of pharmacology
Liu xiaokang(刘小康）
2010,3
Aminoglycosides
• Members:
• Streptomycin, kanamycin , tobramycin,
neomycin, gentamicin, sisomicin,
netilmicin, Amikacin.
• Structure:
Common properties of
aminoglycosides
• Antibacterial activity:
• Bactericidal antibiotics with special
properties as follows: (1) Concentration
dependent bactericidal effect; (2) only
acting aerobes; (3) significant PAE; (4)
First exposure effect (FEE); (5) increased
activity in alkalescent environment.
• Antibacterial spectrum:
• Gram-negative aerobic rods, E. coli,
Pseud. aeruginosa, Protues, Klebsiella,
Eterobacter, Shigella, Citrobacter.
Aminoglycosides and β-lactams are
synergistic and nearly always used in
combination with a ß-lactam to extend
coverage to possibly gram-positive
microbes.
• Mechanisms:
• (1) interference with "initiation complex" of
peptide formation; (2) causing misreading of
mRNA which results in incorrect amino acid
incorporation; (3) blocking the release of
synthesized polypeptide; (4) promotion of
polysomal dissociation into nonfunctional
monosome. These combined effects, occurring
at the same time, are probably responsible for
aminoglycoside bactericidal properties.
• Pharmacokinetics:
• Cannot absorb by oral administration.
Distributed in most tissues, especially
high concentration in kidney, cochlea,
vestibular apparatus. No metabolism and
Excreted by glomerular filtration.
• Clinical uses:
• (1) used in most gram-negative aerobic
bacillary infection, septicaemia, pelvic
and abdominal sepsis. (2) Bacterial
endocarditis, (3) other infections:
tuberculosis.
• Adverse reactions:
• (1) Ototoxicity: both vestibular and
auditory damage may occur;
• (2) Nephrotoxicity: dose-related, usually
reversible;
• (3) Neuromuscular blockade, may impair
neuromuscular transmission and
aggravate myasthenia gravis, or cause a
transient myasthenic syndrome in
patients whose neuromuscular
transmission is normal;
• (4) Allergic reactions: rashes, fever and
angioedema.
• Resistance:
• (1) plasmid-mediated aminoglycoside
inactivating enzymes.
• (2) Membrane permeability changed,
caused failure of aminoglycosides to
penetrate the cytoplasmic (inner)
membrane, the porin protein changed or
the oxygen dependent active transport
reduced;
• (3) target modification, 30s subunit
modified, hence reduced the affinity of
streptomycin with rRNA.
Properties and uses of
commonly used
aminoglycosides
• Streptomycin:
• (1) main use: second-line treatment for
tuberculosis, used only in combination with
other antimicrobials (otherwise rapid
emergence of resistance);
• (2) In combination with oral tetracycline, i.m.
streptomycin may be used in treating: plague
and tularemia;
• (3) In combination with penicillin: treatment
for enterococcal endocarditis and viridans
streptococcal endocarditis (two-week regimen).
• Adverse Reactions:
• Fever, rash (hypersensitivity), Most
serious toxic effect: vestibular toxicity
which tends to be irreversible.
Streptomycin administration during
pregnancy may result in deafness in the
newborn.
• Kanamycin & Neomycin:
• (1) Kanamycin and Neomycin: Active
against gram-positive, gram-negative and
some mycobacteria. Pseudomonas and
streptococci are resistant to kanamycin
and neomycin. (2) Mechanisms of action
and resistance follow that of other
aminoglycosides; (3) Cross-resistance
between these agents and kanamycin and
neomycin;
• (4) clinical uses: Kanamycin: Only used
to drug resistant tuberculosis. Neomycin:
topical and oral use only due to toxicity
associated with parenteral administration;
Given prior to elective bowel surgery,
reducing aerobic bowel flora.
• (5) Adverse efeccts: Ototoxicity (auditory)
and nephrotoxicity.
• Gentamicin:
• Antibacterial activity: Gentamicin is
effective against gram-positive and gramnegative microbes, mainly used for G－
bacteria infection. Active alone but shows
synergism with β-lactam antimicrobials
in managing Pseudomonas, Proteus,
Enterobacter, Klebsiella, Serratia,
Stenotrophomonas and other gramnegative rods. No activity against
anaerobes.
• Clinical uses:
• (1) Primary clinical use: Treatment of severe
gram-negative bacterial infections
(sepsis/pneumonia) when the bacteria is likely
resistant to other antibiotics.
• (2) The combination of gentamicin and a
cephalosporin or penicillin may be life-saving
in the immunocompromised patient.
• (3) Gentamicin + penicillin G: viridans
streptococcal endocarditis
• (4) Gentamicin + nafcillin in some cases of
staphylococcal endocarditis.
• (5) Gentamicin should not be used as a single
agent due to rapid development of resistance.
• (6) Aminoglycosides should not be used as
single therapy in pneumonia due to poor tissue
penetration.
• (7) Nephrotoxicity: requires serum gentamicin
monitoring if administration exceeds a few
days.
• Adverse Reactions:
• (1) Nephrotoxicity;
• (2) Deafness;
• (3) Vestibular toxicity which tends to be
irreversible.
• Tobramycin:
• Similar antimicrobial spectrum to
gentamicin. Some cross-resistance
possible.
• Clinical use: Stronger acting than
gentamicin to Pseudomonas, Proteus,
Enterobacter and Klebsiella.
• Adverse Reactions: Nephrotoxicity,
Deafness and Vestibular toxicity that
tends to be irreversible, but lighter than
gentamicin.
• Sisomicin:
• similar with gentamicin.
• Amikacin:
• Semisynthetic derivative of kanamycin,
but less toxic. Amikacin has the broadest
antibacterial spectrum in
aminoglycosides, and may be used
against microbes resistant to gentamicin
or tobramycin, because it is resistant to
enzymes that inactivate those agents.
• Amikacin is often effective in treating
multi-drug resistant strains of
Mycobacterium tuberculosis. Kanamycin
resistant isolates are likely to exhibit
cross-resistance to amikacin. Amikacin is
ototoxic (auditory component especially)
and nephrotoxic, as are all
aminoglycosides.
• Netilmicin:
• Antibacterial spectrum: Enterobacter
and some G+ cocci. Clinical use is similar
with amikacin. Ototoxicity and
nephrotoxicity are lower than other
aminoglycosides.
Polymyxins
• polymyxin B
• Antibacterial activity: narrow
spectrum, acting on some gram-negative
rods.
• Mechanism:
• impair plasmamembrane, leading the
leakage of life dependent material, hence
destroy the cell.
• Clinical uses: (1) drug resistance Pseud
aeruginosa infection; (2) drug resistance G–
rods infection; (3) topical use.
• Adverse reaction: Nephrotoxicity;
neurotoxicity; allergic reaction.
• Resistance: Very few resistant strains have
been found.
•
(The end)