Aminoglycosides

Aminoglycosides are a potent class of bactericidal antibiotics primarily used to treat severe Gram-negative bacterial infections. They are derived from Streptomyces or Micromonospora species and are characterized by the presence of amino-modified sugars linked by glycosidic bonds. Their clinical significance lies in their rapid bactericidal action, especially in life-threatening systemic infections. However, their therapeutic use is limited by their nephrotoxicity and ototoxicity.

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Mechanism of Action

• Aminoglycosides bind irreversibly to the 30S ribosomal subunit of bacterial ribosomes.

• This binding interferes with initiation complex formation, causes misreading of mRNA, and ultimately leads to the production of nonfunctional or toxic proteins.

• The cumulative effect results in inhibition of protein synthesis and bacterial death (bactericidal effect).

• Uptake of aminoglycosides into bacteria is oxygen-dependent, which makes them ineffective against anaerobic organisms.

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Spectrum of Activity

• Effective against:

  • Aerobic Gram-negative bacilli such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterobacter, Serratia, Proteus species.

  • Some Gram-positive bacteria, especially in combination with cell wall–active agents (e.g., β-lactams, vancomycin), for synergy in Enterococcus or Staphylococcus infections.

• Not effective against:

  • Anaerobic bacteria (due to oxygen-dependent uptake mechanism).

  • Many Gram-positive organisms when used alone.

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Common Agents and Doses

• Gentamicin: 3–5 mg/kg/day IV/IM in divided doses (serious infections).

• Tobramycin: 3–5 mg/kg/day IV/IM in divided doses (especially for Pseudomonas infections).

• Amikacin: 15 mg/kg/day IV/IM in divided doses (broadest spectrum, reserved for resistant Gram-negative infections).

• Streptomycin: 15 mg/kg/day IM (used in tuberculosis, plague, tularemia).

• Neomycin: topical or oral (not systemic due to high toxicity, used for bowel decontamination).

• Kanamycin, Paromomycin: less frequently used; paromomycin is useful in intestinal amoebiasis and cryptosporidiosis.

Dosing must be individualized based on renal function and therapeutic drug monitoring (TDM) to avoid toxicity.

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Clinical Uses

• Serious Gram-negative infections: sepsis, pneumonia, urinary tract infections, intra-abdominal infections, and nosocomial infections caused by multidrug-resistant organisms.

• Endocarditis: in combination with β-lactams or vancomycin for Enterococcus or Staphylococcus aureus.

• Tuberculosis: streptomycin as a second-line agent.

• Plague and tularemia: streptomycin as drug of choice.

• Cystic fibrosis lung infections: inhaled tobramycin for Pseudomonas.

• Topical/oral uses: neomycin and paromomycin for gut sterilization, skin infections, or protozoal infections.

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Contraindications

• Hypersensitivity to aminoglycosides.

• Pre-existing hearing loss or vestibular dysfunction.

• Severe renal impairment (unless dose adjusted and drug levels monitored).

• Pregnancy: risk of fetal ototoxicity (e.g., streptomycin is contraindicated).

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Side Effects

• Nephrotoxicity: acute tubular necrosis, usually reversible but risk increases with prolonged use or in patients with renal impairment.

• Ototoxicity: auditory (hearing loss, tinnitus) and vestibular (vertigo, balance disturbances); may be irreversible.

• Neuromuscular blockade: rare, but can cause respiratory depression; risk higher in patients receiving muscle relaxants or with myasthenia gravis.

• Hypersensitivity reactions: rare skin rashes, fever.

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Precautions

• Monitor serum creatinine and adjust dose in renal impairment.

• Perform therapeutic drug monitoring (peak and trough levels) to ensure efficacy and reduce toxicity.

• Avoid prolonged use beyond 7–10 days when possible.

• Use with caution in elderly patients and those with pre-existing auditory or renal dysfunction.

• Avoid concurrent nephrotoxic (e.g., vancomycin, amphotericin B, cyclosporine, NSAIDs) or ototoxic agents (e.g., loop diuretics like furosemide).

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Drug Interactions

• Loop diuretics (furosemide, ethacrynic acid): increase ototoxicity risk.

• Vancomycin, amphotericin B, cyclosporine, cisplatin, NSAIDs: increase nephrotoxicity risk.

• Neuromuscular blocking agents: potentiation of neuromuscular blockade, risk of respiratory paralysis.

• Penicillins/cephalosporins: synergistic effect against some Gram-positive bacteria, but may inactivate aminoglycosides if mixed in same IV solution (should be given separately).