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AMINOGLYCOSIDES
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AMINOGLYCOSIDES
treatment of serious infections due to aerobic gram-negative bacilliassociated with serious toxicities
replaced by safer antibiotics:
3rdand 4thgeneration Cephalosporins
FluoroquinolonesCarbapenems
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derived from:
STREPTOMYCES
*-mycin
e.g.
Neomycin
Streptomycin
Tobramycin
MICROMONOSPORA
*-micin
e.g.
Amikacin
Gentamicin
Streptomycetaceae
largest antibiotic-producinggenus
gram positive
characterized by a complex
secondary metabolism
Micromonosporaceae
gram positivespore forming
aerobic
sources of aminoglycosides
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AMINOCYCLITOL
two amino sugars joined by a glycosidic linkage to a
central hexose nucleus
polycationic nature: easy passage across tissue
membranes
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MECHANISM OF ACTION
gram negative: diffuse through porin channels in outer
membrane* oxygen- dependent and transport drug across cytoplasmic
membrane
binds to 30S ribosomal subunit
interrupt process of polysome disaggregation and assembly
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Antibacterial Spectrum
treatment of infections caused by Pseudomonas
aeruginosa
for aerobic organisms
reason: anaerobes lack oxygen- requiring drug transport
system
synergistic effect: beta-lactams and vancomycin
bactericidallethality: bacteriostatic
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Resistance
decreased uptake of drug when uptake of oxygen-
dependent transport system is absentplasmid- associated synthesis of enzymes
* modify and inactivate aminoglycosides
cross-resistance: invariable
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Pharmacokinetics
A. Administration
highly polar and polycationic: prevent absorption
route: parenteral
* adequate serum levelsbactericidal effect: concentration and time dependent
have postantibiotic effect
fewer toxicitiesless expensive
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B. Distribution
low tissue levels
variable penetration in most body fluidsCSF concentrations are inadequate
administered intrathecally or intraventricularly
cross the placental barrieraccumulate in fetal plasma and amniotic fluid
C. Metabolismexcreted into urine by GFR
accumulation with renal failure patients
* dose modification
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Adverse Effects
*Peak levels: 30 mins-1 hr after infusion
*Trough levels: immediately before the next dose (OD)
*Factors triggering AE:a. Old age
b. Previous exposure to aminoglycosides
c. Liver disease
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MACROLIDES / KETOLIDES
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MACROLIDES
macrocyclic lactone structure with one or more deoxy
sugars attached
drugs under this class:
-Erythromycin
-Clarithromycin-Azithromycin
-Telithromycin
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Erythromycin
first DOC
penicillin alternative
Clarithromycin
methylated form oferythromycin
do not shake vigorously
do not refrigerate
Azithromycin
larger lactone ring
Telithromycin
semisynthetic derivative of
erythromycinfirst ketolide
Difference between a ketolide
and macrolide:
KETOLIDES ARE ACTIVE
AGAINST MACROLIDE-
RESISTANT GRAM POSITIVESTRAINS.
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Mechanism of Action
irreversibly bind to a site on 50S subunit of bacterial
ribosomeinterfere transpeptidation
bacteriostatic
bactericidal at higher dosesbinding site: identical
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A ib i l S
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Antibacterial Spectrum
1. Erythromycin
-same as penicillin G-allergic to penicillin
2. Clarithromycin-effective against Hemophilus infuenzae
-higher activity against intracellular pathogens
e.g. Chlamydia, Legionella, Moraxella, Ureaplasma,Helicobacter pylori
3. Azithromycin
-less active a ainst stre tococci and sta h lococci
H i fl d M ll t h li
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- H. influenzae and Moraxella catarrhalis
-Chlamydia trachomatis: urethritis
-Mycobacterium avium-intracellulare: AIDS and
disseminated infections
4. Telithromycin
-neutralize resistance mechanismse.g. methylase-mediated; efflux-mediated
Resistanceinability to take up the antibiotic or efflux pump
decreased affinity of 50S subunit
presence of plasmid-associated erythromycin esterase
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Ph ki ti
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Pharmacokinetics
Erythromycin Clarithromycin Azithromycin Telithromycin
destroyed by gastric
acidreadily absorbed
ETC and esterified
forms
food interferes
absorptionabsorbed upon oral
administration
distribute well except
CNS
diffuse to prostatic fluid
accumulate in
macrophages
metabolize and inhibit
through CYP450
excreted in bile
partial reabsorption
stable in stomach
readily absorbedfood interaction
increase
widely distributed
in tissues
oxidized to 14-hydroxy derivative
eliminated in
kidney and liver
destroyed by
gastric acidreadily absorbed
food interferes
absorption
IV
widely distributedin tissues
low serum levels
longest half-life
largest Vd
excreted in bile
stable in stomach
readily absorbedwidely distributed in
tissues
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Ad Eff t
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Adverse Effects
GI Disturbances
Cholestatic Jaundice- hypersensitivity reaction to estolate
form (Erythromycin)Ototoxicity
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Contraindications
with hepatic dysfunction- accumulate in liver
Telithromycin
hepatoxicity
with congenital prolongation of QTc interval
with proarrythmic conditionswith myasthenia gravis
I t ti
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Interactions
inhibit metabolism of drugs
eliminate intestinal flora- greater reabsorption