Aminoglycoside Nd Macrolide

8/13/2019 Aminoglycoside Nd Macrolide

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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

Aminoglycoside Nd Macrolide

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