Lecture 7: Inhibitors of protein synthesis II

Aminoglycoside Drugs

Gentamicin: G-, IV/IM, topical

Tobramycin: Mycobacteria, second line agent G-, IV/IM, topical

Amikacin: Mycobacteria, second line agent G-, IV/IM

Streptomycin: Mycobacteria, second line agent G–, IV/IM

Neomycin: G-, oral, topical

Aminoglycosides

irreversibly inhibit protein synthesis

30S subunit

Bactericidal

polarity and size

Aminoglycosides must be actively transported (oxygen requiring process) into cell

Aminoglycosides Spectrum & Use

aerobic G- enteric bacteria

sepsis or endocarditis

Gentamicin/tobramycin/amikacin: effective against P. aeruginosa and part of the DOC combination (antipseudomonal penicillin + aminoglycoside)

Concentration-dependent killing

Post-antibiotic effect

None absorbed adequately orally administration

None penetrates CSF readily

Normal kidney rapidly excretes all

DOC Enterococcus

aminoglycoside + penicillin

Aminoglycosides Adverse Effects

ototoxicity

nephrotoxicity

neuromuscular weakness

Aminoglycosides Resistance

Deficiency of ribosomal receptors, mutation in 30S subunit

Enzymatic modification of drug by the bacteria (acetylate)

Lack of permeability of the drug molecule into the bacteria

Drug efflux

Broad Spectrum Antibiotics

Chloramphenicol

Tetraclycines

Glycylcyclines

Chloramphenicol

Reversibly binds the 50S subunit

protein synthesis and cell growth is inhibited (bacteriostatic)

can inhibit mitochondrial protein synthesis in mammalian cells

Parenteral

Distributed widely in the body, including eyes and CNS (best CNS penetration @ 100%!)

Metabolized in the liver to an inactive metabolite which is secreted in kidney

Potent inhibitor of CYP3A4 and CYP2C19

Chloramphenicol Spectrum & Use

Gram-, Gram+, anaerobes, aerobes, atypicals (spirochetes, rickettsiae, chlamydiae)

Not first choice – restricted to life threatening infections

Chloramphenicol Adverse Effects

Dose dependent bone marrow suppression

Dose-independent Fatal aplastic anemia

Gray baby syndrome in infants - inadequate activity of glucuronyl transferase in premature or newborn liver

rash, angioedema, urticaria

rarely anaphylactic reactions

Chloramphenicol Resistance

acetyl transferase produced by the resistant organisms, acetylates and inactivates chloramphenicol

50S ribosomal subunit modified (acetylated)

Efflux pumps

Tetracyclines Drugs

Tetracycline – oral, topical

Doxycycline– oral

Minocycline – oral

Tetracyclines

30S subunit

Bacteriostatic

Broad spectrum

Organisms Resistant to Tetracyclines: B. fragilis, Proteus, Pseudomonas

Mycoplasma pneumonia (DOC)

Rickettsial infection (some) (DOC)

Rocky mountain spotted fever (doxy)

Lyme disease (Borrelia burgdorferi) (early, DOC)

Vibrio species (DOC)

Tetracyclines Resistance

Resistance to tetracycline usually conferred by efflux pumps

Tetracycline resistant strains may be susceptible to doxycycline, minocycline and tigecycline – all of which are poor substrates for the efflux pumps

Tetracyclines Pharmacokinetics

Oral

Tetracyclines chelate Ca++, Fe++, Al++

Tetracyclines deposit themselves in bone and teeth

Tetracyclines Adverse effects

normal flora changes

Photosensitivity

bone (inhibit bone elongation) and Teeth (Dental Discoloration)

Tetracyclines should not be given to pregnant women or children below age of 8 years

Tigecycline

Glycylcyclines

MRSA, MRSE, PRSP, VRE

30S ribosomal subunits, bacteriostatic

IV

tigecycline shows activity against tetracycline-resistant organisms