Pharm Aminoglycosides

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Aminoglycosides
General Spectrum and Clinical Status
-effective for
-limited by

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-highly effective vs. aerobic gram-neg. bacilli
-used for hospital acquired-infections due to aerobic gram-neg. bacilli
-especially useful in immunosuppressed patients when unable to use less toxic drugs
-limited by some serious toxicities

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Chemistry and Mechanism

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-highly polar basic cations
-limited distribution to primarily extracellular space
-bactericidal inhibitor of
-bacterial protein synthesis that causes misreading of mRNA so abnormal proteins inserted in bacterial membrane
bind at 30S ribosome
-misread proteins inserted into bacterial membrane causes channels that allow influx of antibiotic

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Therapeutic Uses

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-serious aerobic gram-neg. infections in hospitalized neutropenic patients
-life-threatening infections may require combination therapy with aminoglycosides
such as pneumonias, endocarditis, septicemia, osteomyelitis

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Spectrum

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-Aerobic gram-neg. bacilli
E. coli, Klebsiella, Proteus, Enterobacter, Pseudomonas aeruginosa
-Staphylococcus aureus
(need combination therapy to avoid resistance)
-Ineffective vs anaerobic bacteria

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Resistance

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-Inactivation by bacterial enzymes
plasmid-mediated
acetylases, phosphorylases, adenylases
AMIKACIN LESS SUSCEPTIBLE
-Alteration of active transport system
energy and oxygen dependent
-Mutation of ribosomal protein binding site

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Pharmacokinetics

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-Absorption
poor oral absorption
systemic use requires intravenous admin.
-Distribution
limited to extracellular space
poor distribution into CSF
-Excretion
dependent upon renal glomerular filtration

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Adverse Effects

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-Neurotoxicity
Vestibular toxicity (vertigo, ataxia)
Auditory effects (irreversible damage to hair cells in cochlea of Organ of Corti)
-Nephrotoxicity
proximal tuberular necrosis due to release of lysosomal enzymes into cytoplasm
-Neuromuscular blockade
reversible by calcium or neostigmine

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Drug Interactions

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-Combination Therapy
broaden spectrum or enhance activity
antipseudomonal penicillins or cephalosporins synergistic vs Pseud. aerug. and some gram-neg. bacilli
-Penicillins inactivated by mixing with aminoglycosides in high concentraion
-Other nephrotoxic drugs
potent diuretics, cyclosporine, cisplatin, amphotericin B, vancomycin

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Clinical Problems

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-Monitor renal function
-Monitor plasma concentration to determine drug intervals if reduced renal function
-Single daily dosing may be utilized if good renal function
post-antibiotic effect is concentration-dependent

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Drug Prototypes

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-Gentamicin (Garamycin)
lowest cost
-Amikacin (Amikin)
expensive, but less resistance
-Neomycin
topical or orally prior to abdominal surgery
-Streptomycin
tuberculosis
-Paromomycin
amebiasis