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Aminoglycosides & G-CSF

Shahd AlAli

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Aminoglycosides • Neomycin • Tobramycin • Amikacin • Gentamycin • Streptomycin; treatment of TB

NOTAGS

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Mechanism of Action: How they’re transported?They cross the outer membrane and enter the periplasmic space through aqueous channels formed porin proteins.These drugs are actively transported through the cell membrane by an oxygen-dependent processMechanism of action? They irreversibly bind to the 30S ribosomal subunit and inhibit the protein synthesis by blocking the formation of initiation complex, inhibit translocation step, misread mRNA

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Resistance

Block the entry into the cell Receptor on 30S ribosome deleted from the bacteria Production of transferase enzyme

which inactivate the aminoglycosdie

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Pharmakinetics Penetrate most of body fluids well except for CSF, they are

highly concentrated in the renal cortex and endolymph of the inner ear which could account for their nephrotoxicity and ototoxicity

They must be given IV or IM because they are not absorbed after oral administration

Not well GI absorption, polar

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Administration

Single dose is preferred 1. Concentration-dependent killing 2. Post-antibiotic effect (which can

last for several hours)

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Synergism

With b-lactum or vancomycin Synergism is important in case of endocarditis

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Therapeutic Use Ecoli, Klebsiella, Pseudomonas aeruginosa & Enterobacter

(PEEK) They don’t cover the anaerobes because oxidative metabolism

is required for the uptake of these drugs. Usually they are coadiministered with B-lactams to extend the

spectrum.

Streptomycin is very effective against

enterococcal carditis in

combination with pencillins

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Toxicity OtotoxicityAuditory may occur with any aminoglycoside and may be irreversible it’s more likely with amikacin, ototoxicity is proportional to the plasma level the toxicity is increased by the use of loop diuretics. It is contraindicated in pregnancy. Nephrotoxicity Acute tubualr necrosis it is often reversible Neuromuscular blockage at high doses (curare-

like effect)Resulting is respiratory paralysis

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Preganncy Catigoury D’ there is a + evidence of

human fetal risk based on advese reaction but poteinal benfiits may warrant the usuage of the drug

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Clinical use

Multi-drug resisitant TB Aerobic gram – bacteria Always with b-lactum combiniation for 1. Synergism 2. Extend to gram + 3. Bacterocidical in endocarditis

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Granulocyte colony-stimulating factor Filgrastim (G-CSF) stimulate the production and function of

neutrophils it also mobilize hematopoietic stem cells (ie, increase their concentration in peripheral blood)

stimulates proliferation and differentiation of progenitors already committed to the neutrophil lineage.

It also activates the phagocytic activity of mature neutrophils and prolongs their survival in the circulation.

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Clinical use Used to accelerate the recovery of neutrophils after

cancer chemotherapy aplastic anemia congenital and cyclic neutropenia Autologous stem cell transplantation multiple myeloma

Given IV/Subcutaneous It can cause bone pain

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Q’s Regarding the mechanism of action of

aminoglycosides, the drugsa) Are bacteriostatic b) Bind to 50S ribosome subunit c) Cause misreading of the codon on the mRNA

template d) Stabilize polysomes

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Amphotericin B

Is used for fungal systemic infections (flucytosin is also used) It’s a polyene macrolide which is poorly absorbed (IV)

Mechanism of action: bind to the fungal ergosterol on the cell membrane and forms pores or channels within the membrane leading to electrolyte leak out which results in the cell death

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Clinical usage

Candidia, cryptococcus, aspergillas For fungal meningitis it’s giver intrathecally Topical for occular and bladder infections

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Toxicity (Infusion reaction and cumulative toxicity) Infusion reactionFever, chills, spasm, headache and vomiting Usually test by 1 mg IV to know the severity To ameloirate it Slow the infusion rate Decrease the daily dose Give antihistamin and steroids

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Cumulative toxicity

Renal impairment (renal tubular acidosis, K and Mg wasting)

Liver function abnormality Anemia due to reduced erythropoitein

(hypochromatic normocytic anemia) Seziures after IT therapy