AMINOGLYCOSIDES

AMINOGLYCOSIDES
treatment of serious infections due to aerobic gram-

negative bacilli associated with serious toxicities replaced by safer antibiotics: 3rd and 4th generation Cephalosporins Fluoroquinolones Carbapenems

derived from:
STREPTOMYCES *-mycin e.g. Neomycin Streptomycin Tobramycin
Streptomycetaceae largest antibiotic-producing genus gram positive characterized by a complex secondary metabolism

MICROMONOSPORA *-micin e.g. Amikacin Gentamicin

Micromonosporaceae gram positive spore forming aerobic sources of aminoglycosides

AMINOCYCLITOL two amino sugars joined by a glycosidic linkage to a central hexose nucleus polycationic nature: easy passage across tissue membranes

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

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 bactericidal lethality: bacteriostatic

Resistance decreased uptake of drug when uptake of oxygendependent transport system is absent plasmid- associated synthesis of enzymes * modify and inactivate aminoglycosides cross-resistance: invariable

Pharmacokinetics A. Administration

highly polar and polycationic: prevent absorption route: parenteral * adequate serum levels bactericidal effect: concentration and time dependent have postantibiotic effect fewer toxicities less expensive

B. Distribution low tissue levels variable penetration in most body fluids CSF concentrations are inadequate administered intrathecally or intraventricularly cross the placental barrier accumulate in fetal plasma and amniotic fluid C. Metabolism excreted into urine by GFR accumulation with renal failure patients * dose modification

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

MACROLIDES / KETOLIDES

MACROLIDES

macrocyclic lactone structure with one or more deoxy

sugars attached drugs under this class: -Erythromycin -Clarithromycin -Azithromycin -Telithromycin

Erythromycin first DOC penicillin alternative

Clarithromycin methylated form of erythromycin do not shake vigorously do not refrigerate Azithromycin larger lactone ring

Telithromycin semisynthetic derivative of erythromycin first ketolide

Difference between a ketolide and macrolide: KETOLIDES ARE ACTIVE AGAINST MACROLIDERESISTANT GRAM POSITIVE STRAINS.

Mechanism of Action irreversibly bind to a site on 50S subunit of bacterial ribosome interfere transpeptidation bacteriostatic bactericidal at higher doses binding site: identical

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 against streptococci and staphylococci

- H. influenzae and Moraxella catarrhalis -Chlamydia trachomatis: urethritis -Mycobacterium avium-intracellulare: AIDS and disseminated infections 4. Telithromycin -neutralize resistance mechanisms e.g. methylase-mediated; efflux-mediated Resistance inability to take up the antibiotic or efflux pump decreased affinity of 50S subunit presence of plasmid-associated erythromycin esterase

Pharmacokinetics
Erythromycin destroyed by gastric acid readily absorbed ETC and esterified forms food interferes absorption absorbed upon oral administration distribute well except CNS diffuse to prostatic fluid accumulate in macrophages metabolize and inhibit through CYP450 excreted in bile partial reabsorption Clarithromycin stable in stomach readily absorbed food interaction increase widely distributed in tissues oxidized to 14hydroxy derivative eliminated in kidney and liver Azithromycin destroyed by gastric acid readily absorbed food interferes absorption IV widely distributed in tissues low serum levels longest half-life largest Vd excreted in bile
Telithromycin

stable in stomach readily absorbed widely distributed in tissues

Adverse Effects GI Disturbances Cholestatic Jaundice- hypersensitivity reaction to estolate form (Erythromycin) Ototoxicity

Contraindications with hepatic dysfunction- accumulate in liver Telithromycin hepatoxicity with congenital prolongation of QTc interval with proarrythmic conditions with myasthenia gravis

Interactions inhibit metabolism of drugs eliminate intestinal flora- greater reabsorption