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Part5-1
Aminoglycosides(氨基糖苷类) &
Polymyxins(多黏菌素类)
Huifang Tang
[email protected]
Aminoglycosides （氨基苷类）
Summarization of aminoglycosides
The aminoglycosides are compounds contanining
characteristic amino sugars joined to a hexose
nucleus in glycosidic(糖苷） linkage. Most aminoglycosides, which are prepared by natural
fermentation from various species of
streptomyces, are a group of bactericidal
drugs sharing chemical, antimicrobial,
pharmacological, and toxic characteristics.
Structure of streptomycin
Structures of several important
aminoglycoside antibiotics.
Aminoglycosides （氨基苷类）
• Natural Aminoglycosides
•
链霉素(streptomycin)
•
新霉素(neomycin)
•
妥布霉素(tobramycin)
•
卡那霉素(kanamycin)
•
大观霉素(spectinomycin)
• Semisynthetic Aminoglycosides
•
阿米卡星
(amikacin)
庆大霉素(gentamicin)
西索米星(sisomicin)
小诺米星(micronomicin)
奈替米星(netilmicin)
Aminoglycosides
• Spectrum of activity
• Aminoglycosides are effective against
aerobic gram-negative bacteria,
especially in bacteremia, sepsis, or
endocarditis.
Aminoglycosides
Mechanism of action
The mechanism of Aminoglycosides is to inhibit
protein synthesis in susceptible microorganisms .
by interfering with the initiation complex of
peptide formation.
inducing misreading of the code on the mRNA
template, which causes incorporation of
inappropriate amino acid into peptide.
by rupturing the polysomes into monosome, which
become nonfunctional.
Inhibiting protein synthesis
氨基苷类
氨基苷类
氨基苷类
大环内酯类
四环素类
氯霉素类
林可霉素类
Mechanisms of resistance
Three principal mechanisms have been established:
(1) production of a transferase enzyme or enzymes inactivates the
aminoglycoside by adenylylation, acetylation, or phosphorylation.
This is the principal type of resistance encountered clinically.
(Specific transferase enzymes are discussed below.)
(2) There is impaired entry of aminoglycoside into the cell. This
may be genotypic, ie, resulting from mutation or deletion of a
porin protein or proteins involved in transport and maintenance
of the electrochemical gradient; or phenotypic, eg, resulting
from growth conditions under which the oxygen-dependent
transport process described above is not functional.
(3) The receptor protein on the 30S ribosomal subunit may be
deleted or altered as a result of a mutation.
Aminoglycosides
Pharmacokinetics
•
poorly absorbed from the gastrointestinal tract.
•
must be given intramuscularly or intravemously for
systemic infection.
• excreted almost entirely unchanged by glomerular
filtration, which is greatly reduced in renal impairment,
causing toxic blood levels.
Aminoglycosides
Adverse effects
• Ototoxicity
Aminoglycosides are potentially toxic to branches
of the eighth cromial nerve. The
evidence
indicates that the sensory receptor portions of the
inner ear ( hair cells of the cochlea) are affected
rather than the nerve itself.
cochlear damage(耳蜗损伤):
Kanamycin>Amikacin> sisomicin>gentamicin>tobramycin
vestibular impairment(前庭受损):
Kanamycin>Streptomycin>sisomicin> gentamicin> tobramycin
Aminoglycosides
Nephrotoxicity
• Nephrotoxicity may develop during or after use of
an aminoglycosides, those elderly,
debilitated patients, and patients with preexisting
renal dysfunction.
• Nephrotoxicity is dose dependent and damage to
the proximal tubular epithelium usually begins
after five to seven days of therapy.
• The toxicity results from accumulation and retention
of aminoglycosides in the proximal tubular cells.
• The renal injury may lead to acute renal failure.
Neomycin>Kanamycin>gentamicin>Streptomycin or tobramycin>Amikacin
Aminoglycosides
Neuromuscular blockade
The aminoglycosides rarely cause neuromuscular
blockade that can lead to progressive flaccid
paralysis and potentially total respiratory
arrest.
The risk is greatest after rapid iv
administration.
Neomycin>Streptomycin >Amikacin or Kanamycin>gentamicin > tobramycin
Clinical uses
• Aminoglycosides are mostly used against gramnegative enteric bacteria, especially when the isolate
may be drug-resistant and when there is suspicion of
sepsis.
• They are almost always used in combination with a lactam antibiotic to extend coverage to include
potential gram-positive pathogens and to take
advantage of the synergism between these two
classes of drugs.
– Penicillin-aminoglycoside combinations also are used to
achieve bactericidal activity in treatment of enterococcal
endocarditis and to shorten duration of therapy for viridans
streptococcal and staphylococcal endocarditis. Which
aminoglycoside and what dose should be used depend on the
infection being treated and the susceptibility of the isolate.
Aminoglycosides
Streptomycin （链霉素）
Spectrum of activity and therapy of Streptomycin
(1) most gram-negative bacilli and some gram-positive
cocci.
(2) organisms that cause plague(鼠疫） and in
combination with penicillin G against bacterial
endocarditis.
(3) antituberculosis agent.
A major disadvantage of streptomycin therapy is the
development of frequent bacterial resistance to the
drug.
Aminoglycosides
Untoward effects of streptomycin
 Hypersensitivity reactions can occur.
 Labyrinthine damage (迷路破坏) and vestibular
disturbances can occur. Streptomycin should not be
given with other ototoxic drugs .
 Renal effects are minimal at normal doses.
 Neuromuscular junction blockade may occur when
streptomycin is given at high doses and in combination
with curariform drugs (箭毒样药物).
Gentamicin
Gentamicin
It is effective against both gram-positive and gram-negative
organisms, and many of its properties resemble those of other
aminoglycosides.
It is active alone, but also as a synergistic companion with –lactam
antibiotics, against pseudomonas, proteus, enterobacter, klebsiella,
serratia, stenotrophomonas, and other gram-negative rods that
may be resistant to multiple other antibiotics.
Like all aminoglycosides, it has no activity against anaerobes.
Clinical uses
Gentamicin
Intramuscular or intravenous administration
• used in the treatment of a serious infections caused
by a large number of gram-negative organisms. It
usually is used in combination with a second agent,
because an aminoglycoside alone may not be effective
for infections outside the urinary tract.
• Gentamicin is of the first choice when these
infections occurs
1) urinary tract infections, bacteremia resulting
from Escherichia coli.
2) bile duct and urinary tract infections caused by
proteus mirabilis.
Gentamicin
Gentamicin
 Gentamicin combined with carbenicillin is of
the first choice for the treatment of
infected burns, bacteremia, urinary tract
infection resulting from pseudomonas
aeruginosa.
Gentamicin
• Topical administration
• Creams, ointments, and solutions containing
0.1–0.3% gentamicin sulfate have been used
for the treatment of infected burns, wounds,
or skin lesions and the prevention of
intravenous catheter infections. Topical
gentamicin is partly inactivated by purulent
exudates. Ten mg can be injected
subconjunctivally for treatment of ocular
infections.
Gentamicin
• Intrathecal administration
• Meningitis caused by gram-negative bacteria has been
treated by the intrathecal injection of gentamicin
sulfate, 1–10 mg/d. However, neither intrathecal nor
intraventricular gentamicin was beneficial in neonates
with meningitis, and intraventricular gentamicin was
toxic, raising questions about the usefulness of this
form of therapy. Moreover, the availability of thirdgeneration cephalosporins for gram-negative
meningitis has rendered this therapy obsolete in most
cases.
Gentamicin
Untoward effects of gentamicin
 Ototoxicity (耳毒性) is the most serious
effect.(The incidence of ototoxicity is in part genetically determined,
having been linked to point mutations in mitochondrial DNA, and occurs
in 1–5% for patients receiving gentamicin for more than 5 days. )
 Nephrotoxicity can occur.
 Hypersensitivity can also occur.
Tobramycin
Tobramycin 妥布霉素
Tobramycin has an antibacterial spectrum similar to
that of gentamicin.
The pharmacokinetic properties of tobramycin are
virtually identical with those of gentamicin.
Tobramycin
Tobramycin vs Gentamicin
Spectrum of activity of Tobramycin
• Tobramycin has almost the same antibacterial spectrum as
gentamicin with a few exceptions.
• Gentamicin is slightly more active against serratia, whereas
tobramycin is slightly more active against pseudomonas （假单胞
菌属）;
• Enterococcus faecalis is susceptible to both gentamicin and
tobramycin, but E faecium is resistant to tobramycin.
Adverse effects of Tobramycin
• Ototoxicity
• Nephrotoxic
– Nephrotoxicity of tobramycin may be slightly less than that
of gentamicin, but the difference is clinically inconsequential.
Tobramycin
Clinical uses
• Gentamicin and tobramycin are otherwise
interchangeable clinically.
• Tobramycin is also formulated in solution (300 mg in 5
mL) for inhalation for treatment of Pseudomonas
aeruginosa lower respiratory tract infections
complicating cystic fibrosis.
Neomycin & Kanamycin
Neomycin & Kanamycin
• Antimicrobial Activity & Resistance
– gram-positive and gram-negative bacteria and some
mycobacteria.
– Pseudomonas and streptococci are generally
resistant.
– The widespread use of these drugs in bowel
– preparation for elective surgery has resulted in
the selection of resistant organisms and some
outbreaks of enterocolitis in hospitals.
– Cross-resistance between kanamycin and neomycin
is complete.
Neomycin & Kanamycin
Clinical Uses
• Neomycin and kanamycin are now limited to
topical and oral use.
• Neomycin is too toxic for parenteral use.
With the advent of more potent and less
toxic aminoglycosides, parenteral
administration of kanamycin has also been
largely abandoned.
• Paromomycin has recently been shown to be
effective against visceral leishmaniasis when
given parenterally, and this serious infection
may represent an important new use for this
drug.
Neomycin & Kanamycin
Kanamycin
Kanamycin has a more limited spectrum of
activity than Gentamicin has.
It is ineffective against Pseudomonas and most
gram-positive organisms.
Its clinical uses almost replaced by gentamicin.
Neomycin & Kanamycin
Neomycin新霉素
Spectrum of activity of Neomycin
Neomycin has a spectrum of activity similar
to that of kanamycin.
Untoward effects of Neomycin
Renal damage, eighth-nerve damage
resulting in nerve deafness.
Neomycin & Kanamycin
Adverse Reactions
All members of the neomycin group have significant nephrotoxicity and
ototoxicity.
Auditory function is affected more than vestibular function. Deafness
has occurred, especially in adults with impaired renal function and
prolonged elevation of drug levels.
The sudden absorption of postoperatively instilled kanamycin from the
peritoneal cavity (3–5 g) has resulted in curare-like neuromuscular blockade
and respiratory arrest. Calcium gluconate and neostigmine can act as
antidotes.
Although hypersensitivity is not common, prolonged application of neomycincontaining ointments to skin and eyes has resulted in severe allergic reactions.
Amikacin
Amikacin 阿米卡星, 丁胺卡那霉素
Specturm of activity of Amikacin
Amikacin has a spectrum of activity similar
to that of Gentamicin but often is reserved for
serratia (沙雷菌属）infections or for cases
where resistance to Gentamicin has emerged.
Adverse effects of Amikacin
Ototoxicity is the most serious side effect.
Spectinomycin(大观霉素 )
• Spectinomycin is an aminocyclitol antibiotic that is
structurally related to aminoglycosides. It lacks
amino sugars and glycosidic bonds.
Tobramycin: Intravenous; more active than gentamicin versus pseudomonas;
may also have less nephrotoxicity
Amikacin: Intravenous; resistant to many enzymes that inactivate gentamicin
and tobramycin; higher doses and target peaks and troughs than gentamicin
and tobramycin
Streptomycin: Intramuscular, widespread resistance limits use to specific
indications such as tuberculosis and enterococcal endocarditis
Neomycin: Oral or topical, poor bioavailability; used before bowel surgery to
decrease aerobic flora; also used to treat hepatic encephalopathy
Spectinomycin: Intramuscular; sole use is for treatment of antibiotic-resistant
gonococcal infections or gonococcal infections in penicillin-allergic patients
Polymyxins
Polymyxins 多粘菌素类
There are five polymyxins. A, B, C, D, E,
Polymyxin E, 多粘菌素E (Colistin,抗敌素)
is frequently used in clinics.
Polymyxins
Spectrum of activity
• Polymyxins are active mainly against gramnegative bacilli, particulary pseudomonas and
coliform organisms.
Mechanism of action of polymyxins
Polymyxins act by attaching to the cell
membranes of bacteria and other membranes
rich in phosphatidylethanolamin (磷脂酰乙醇胺)
and disrupting the osmotic properties and
transport mechanisms of the membrane. This
results in leakage of macromolecules and death
of the cell.
Polymyxins
Therapeutic uses of Polymyxins
• Infections caused by pseudomonas or
coliform bacteria resistant to other
antimicrobial drugs.
Polymyxins
Untoward effects
• Neurotoxic effects
• Polymyxin can cause paresthesias,
dizziness and incoordination.
• Nephrotoxic effects
• Some proteinuria, hematuria are the
evidence of tubular injury.