Download - 45 aminoglycosides
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AMINOGLYCOSIDESAMINOGLYCOSIDES
Anita Q. Sangalang, MD, FPOGSFACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS
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AMINOGLYCOSIDESAMINOGLYCOSIDES
MODES OF ANTIBACTERIAL ACTION Treatment of microbial infection with
antibiotics
• Multiple daily dosing
• Maintain serum concentration level
above the minimum inhibitory concentration (MIC)
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AMINOGLYCOSIDESAMINOGLYCOSIDES
MODES OF ANTIBACTERIAL ACTION
CONCENTRATION DEPENDENT Some drugs and aminoglycosides
• As the plasma level is increased above
the MIC, the drug kills an increasing
proportion of bacteria at a more rapid
rate
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AMINOGLYCOSIDESAMINOGLYCOSIDES
MODES OF ANTIBACTERIAL ACTION
TIME DEPENDENT Any antibiotics, including penicillin and
cephalosporins
• Directly related to time above MIC
• Independent of concentration once
the MIC is reached
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AMINOGLYCOSIDESAMINOGLYCOSIDES
MODES OF ANTIBACTERIAL ACTION
POSTANTIBIOTIC EFFECT Aminoglycosides’ killing action continues
when the plasma levels have declined
below measurable levels
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AMINOGLYCOSIDESAMINOGLYCOSIDES
MODES OF ANTIBACTERIAL ACTION
POSTANTIBIOTIC EFFECT Greater efficacy when administered as
a single large dose than when given as multiple smaller doses
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AMINOGLYCOSIDESAMINOGLYCOSIDES
MODES OF ANTIBACTERIAL ACTION Toxicity (in contrast to antibacterial activity)
depends on a critical plasma concentration and on that time such a level is exceeded
Time above such threshold is shorter with
single large dose Basis for once-daily dosing protocols
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AMINOGLYCOSIDESAMINOGLYCOSIDES
PHARMACOKINETICS Structurally related amino sugars
attached by glycosidic linkages Polar compounds Not absorbed orally
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AMINOGLYCOSIDESAMINOGLYCOSIDES
PHARMACOKINETICS Given intramuscularly or intravenously
for systemic effects Limited tissue penetration Do not readily cross the blood-brain
barrier
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AMINOGLYCOSIDESAMINOGLYCOSIDES
PHARMACOKINETICS Major mode of excretion
• Glomerular filtration Plasma levels are affected by changes
in renal function
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AMINOGLYCOSIDESAMINOGLYCOSIDES
PHARMACOKINETICS Excretion is directly proportional to
creatinine clearance With normal renal function, elimination
half-life is 2-3 h
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AMINOGLYCOSIDESAMINOGLYCOSIDES
PHARMACOKINETICS Dosage adjustment must be made in
renal insufficiency to avoid toxic accumulation
Monitoring plasma levels is needed for
safe and effective dosage selection and adjustment
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AMINOGLYCOSIDESAMINOGLYCOSIDES
PHARMACOKINETICS For traditional dosing regimens
• 2 or 3 times daily
• Peak serum levels
•Measured at 30-60 minutes after administration
• Trough serum levels
•Measured just before the next dose
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AMINOGLYCOSIDESAMINOGLYCOSIDES
MECHANISM OF ACTION Bactericidal (irreversible) inhibitors of
protein synthesis Penetration of bacterial cell wall is partly
dependent on O2-dependent active
transport
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AMINOGLYCOSIDESAMINOGLYCOSIDES
MECHANISM OF ACTION Minimal activity against strict anaerobes Transport is enhanced by cell wall
synthesis inhibitors
• Antimicrobial synergism
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AMINOGLYCOSIDESAMINOGLYCOSIDES
MECHANISM OF ACTION Bind to 30S ribosomal unit Interfere with protein synthesis
1. Block formation of initiation complex
2. Cause misreading of the code on the
mRNA template
3. Inhibit translocation
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AMINOGLYCOSIDESAMINOGLYCOSIDES
MECHANISMS OF RESISTANCE Resistant due to failure to penetrate
into the cell
• Streptococci, including S. pneumoniae
• Enterococci
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AMINOGLYCOSIDESAMINOGLYCOSIDES
MECHANISMS OF RESISTANCE Plasmid-mediated formation of inactivating
enzymes
• Primary mechanism of resistance
• Varying susceptibility to the enzyme
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AMINOGLYCOSIDES
MECHANISMS OF RESISTANCE Plasmid-mediated formation of inactivating
enzymes
• Group transferases
•Catalyze the acetylation of amine functions
•Transfer of phosphoryl or adenyl groups to the O2 atoms of hydroxyl groups on the aminoglycoside
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AMINOGLYCOSIDESAMINOGLYCOSIDES
MECHANISMS OF RESISTANCE Plasmid-mediated formation of inactivating
enzymes• Transferases produced by enterococci
can inactivate •Amikacin•Gentamicin•Tobramycin •Not streptomycin
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AMINOGLYCOSIDESAMINOGLYCOSIDES
MECHANISMS OF RESISTANCE Plasmid-mediated formation of inactivating
enzymes
• Netilmicin is less susceptible and is active against more strains of organisms
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AMINOGLYCOSIDESAMINOGLYCOSIDES
CLINICAL USES
GENTAMICIN, TOBRAMYCIN, and AMIKACIN Serious infections caused by aerobic
gram (-) bacteria
• E. coli Enterobacter
• Klebsiella Proteus
• Providencia Pseudomonas
• Serratia
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AMINOGLYCOSIDESAMINOGLYCOSIDES
CLINICAL USES
GENTAMICIN, TOBRAMYCIN, and AMIKACIN Used for the following but is not the drug of
choice
• H. influenzae
• M. catarrhalis
• Shigella species
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AMINOGLYCOSIDESAMINOGLYCOSIDES
CLINICAL USES
ANTIBACTERIAL SYNERGY Not effective for gram (+) cocci when
used alone Combination of aminoglycoside and
cell wall synthesis inhibitors
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AMINOGLYCOSIDESAMINOGLYCOSIDES
CLINICAL USES
ANTIBACTERIAL SYNERGY Combined with penicillin in the treatment
• Pseudomonal
• Listerial
• Enterococcal infections
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AMINOGLYCOSIDESAMINOGLYCOSIDES
CLINICAL USES
STREPTOMYCIN Tuberculosis Plague Tularemia Multi-drug-resistant (MDR) strains of M. tb
resistant to streptomycin maybe susceptible
to amikacin
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AMINOGLYCOSIDESAMINOGLYCOSIDES
CLINICAL USES
NEOMYCIN Used topically Locally
• In the GIT
• Eliminate bacterial flora
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AMINOGLYCOSIDESAMINOGLYCOSIDES
CLINICAL USES
NETILMICIN Reserved for serious infections resistant
to other aminoglycosides
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AMINOGLYCOSIDESAMINOGLYCOSIDES
CLINICAL USES
SPECTINOMYCIN Aminocylitol related to aminoglycosides Back-up drug Intramuscular as single dose for gonorrhea
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AMINOGLYCOSIDESAMINOGLYCOSIDES
TOXICITY
A. OTOTOXICITY Auditory or vestibular damage (or both)
maybe irreversible
• Auditory impairment
• Amikacin and kanamycin
• Vestibular dysfunction
• Gentamicin and tobramycin
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AMINOGLYCOSIDESAMINOGLYCOSIDES
TOXICITY
A. OTOTOXICITY Risk is proportionate to the plasma
levels
• High if dosage is not modified in renal dysfunction
Increased with the use of loop diuretics Contraindicated in pregnancy
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AMINOGLYCOSIDESAMINOGLYCOSIDES
TOXICITY
B. NEPHROTOXICITY Acute tubular necrosis Reversible Most nephrotoxic
• Gentamicin and tobramycin
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AMINOGLYCOSIDESAMINOGLYCOSIDES
TOXICITY
B. NEPHROTOXICITY More common in elderly patients Patients concurrently receiving
• Amphotericin B
• Cephalosporins
• Vancomycin
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AMINOGLYCOSIDESAMINOGLYCOSIDES
TOXICITY
C. NEUROMUSCULAR BLOCKADE Rare Curare-like block may occur at high doses
• Respiratory paralysis Reversible
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AMINOGLYCOSIDESAMINOGLYCOSIDES
TOXICITY
C. NEUROMUSCULAR BLOCKADE Treatment
• Calcium
• Neostigmine
• Ventilatory support
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AMINOGLYCOSIDESAMINOGLYCOSIDES
TOXICITY
D. SKIN REACTIONS Neomycin
• Allergic skin reactions like contact dermatitis