Streptomycin (first one discovered; resistance now limits usage)

Gentamicin (widely used, resistance is problematic)

Tobramycin (better activity in Pseudomonas vs. other aminoglycosides)

Neomycin (highly nephrotoxic/ototoxic; topical/oral use only. Component of Neosporin.)

Amikacin: (Resistant to enzymatic inactivation, a bacterial mechanism of resistance to aminoglycosides).

Many amine groups on monosaccharides joined by glycosidic linkages.

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Among aminoglycosides, Tobramycin has the best activity against P. aeruginosa.

Neomycin is ONLY used topically (skin infections) or orally (to kill bacteria in GI tract - it is not absorbed). We do not use Neomycin parenterally due to exceptionally high nephrotoxicity and ototoxicity.

Note: Component of Neosporin

When we suspect resistance to aminoglycosides (e.g. gentamicin-resistant). Among aminoglycosides Amikacin is most resistant to enzymatic inactivation (a bacterial mechanism of resistance to aminoglycosides), and also has the broadest antimicrobial spectrum.

They bind to the 30S ribosomal subunit, interfering with protein synthesis in three ways:

1. Inhibit the initiation of protein synthesis.

2. If a protein is already being translated, aminoglycosides will terminate translation prematurely. 

3. Induce misreading and incorporation of incorrect amino acids into the protein. The can lead to compromised cell wall integrity and imbalance of ion gradients (e.g. K⁺ flowing out).

Note: This last mechanism is unique to aminoglycosides, and may account for why it is bactericidal rather than bacteriostatic like other anti-ribosomal drugs.

Diffusion through porins or lippolysaccharides in the outer/inner membranes of Gram- organisms. They are then actively transported across the plasma membrane (requires ATP, O₂) bind to cation-binding sites on bacterial cytoplasmic membrane (aminoglycosides are polar). 

Note: Poor activity against Gram+ organisms because aminoglycosides can't penetrate thick peptidoglycan cell wall (unless administered synergistically with a B-lactam).

Note: No activity against anaerobes, because transport across plasma membrane requires oxygen.

Aerobic, Gram- organisms (e.g. P. aerunginosa, Enterobacter, Klebsiella).

The effectiveness of aminoglycosides depends on its ability to penetrate the target.

-- Why only aerobic? Transport across membrane is energy-dependent; requires O₂ and ATP.

-- Why only Gram-? Aminoglycosides can't penetrate thick cell wall of Gram+ organisms.

1. Enzymatic alteration of drug (major): organisms produce enzymes that inactivate drug by acetylating, phosphorylating, and/or adenylylating it..

Note: Amikacin has long side chain which is resistant to these enzymes, so bugs are less resistant to Amikacin.

2. Decreased drug penetration into bacteria (not important)

3. Ribosomal alteration (seen in TB): Results in decreased drug binding. 

-- Administered parenterally (polar molecules, so not absorbed from GI tract).

Note: Neomycin is topical/oral due to extreme nephro- and oto toxcitity. Oral drug not absorbed, just targets GI tract.

-- Distributed in extracellular fluid.

-- Minimally metabolized.

-- Excreted renally, unchanged.

Multiple daily doses lead to increased nephrotoxicity and ototoxicity. Instead, we give a large loading dose once daily; aminoglycosides exhibit a postantibiotic effect (persistence of antibacterial activity after [drug]<MIC).

Bactericidal, unlike other protein synthesis inhibitors. This is probably due to ability to induce incorporation of incorrect amino acids during protein synthesis. Dysfunctional structural proteins compromise the bacterial membranes.

Synergistic use with B-lactams, which break down thick peptidoglycan cell wall that aminoglycosides generally can't penetrate.

Note: Clinical use: Bacterial endocarditis (usually Streptococci, Staphylococci, Enterococci).

1. Ototoxicity

-- Vestibular toxicity

-- Auditory toxicity

2. Nephrotoxicity

Note: Oto/nephrotoxicity are dose-dependent, cumulative, and potentiated by use of other oto/nephrotoxic drugs. Due to toxicity we reserve aminoglycosides for serious infections for which less toxic drugs don't work.

Note: Toxicity can be reversible if caught early and patient is taken off aminoglycosides

3. Acute muscular paralysis: rare, usually occurs in patients with pre-existing muscular dysfunction (myasthenia gravis, patients taking neuromuscular blocking agents).