What are aminoglycoside antibiotics?
Aminoglycoside antibiotics are a class of antibacterial drugs first discovered in the mid-20th century. The first, streptomycin, was isolated from the bacterium Streptomyces griseus in 1944. Later agents like gentamicin and tobramycin were derived from the genus Micromonospora. These agents are structurally characterized by amino sugars linked by glycosidic bonds, which gives them their name and their bactericidal properties.
Unlike most other antibiotics that might be taken orally, aminoglycosides are poorly absorbed from the gastrointestinal tract and must be administered parenterally (intravenously or intramuscularly) for systemic infections. Due to their hydrophilic nature, they distribute primarily within the extracellular fluid.
Types of Aminoglycosides
The aminoglycoside class includes several important drugs, each with a unique profile and use:
- Streptomycin: The first discovered, historically used for tuberculosis.
- Gentamicin: One of the most commonly used, effective against a wide range of Gram-negative aerobic bacteria.
- Tobramycin: Often preferred for Pseudomonas aeruginosa infections, particularly in cystic fibrosis patients via inhalation.
- Amikacin: Used for infections resistant to other aminoglycosides because its chemical structure is less susceptible to bacterial inactivating enzymes.
- Neomycin: Too toxic for systemic use, typically limited to topical or oral applications for gut decontamination.
- Plazomicin: A newer agent developed to combat multi-drug resistant strains.
Mechanism of action
Aminoglycosides function as potent bactericidal agents by inhibiting bacterial protein synthesis. They enter bacterial cells and bind to the 16S ribosomal RNA on the 30S ribosomal subunit. This binding causes a misreading of messenger RNA (mRNA), resulting in the production of non-functional proteins and ultimately leading to cell death. The transport of aminoglycosides into the bacterial cell is oxygen-dependent, which explains their ineffectiveness against anaerobic bacteria. Some faulty proteins can increase cell membrane permeability, accelerating drug uptake and cell death. Aminoglycosides also exhibit a post-antibiotic effect, continuing to kill bacteria even after drug levels drop below the minimum inhibitory concentration.
Clinical uses and administration
Aminoglycosides are typically reserved for serious bacterial infections, often used initially for severe illnesses like sepsis or meningitis before switching to less toxic alternatives. They are administered parenterally for systemic effect. Key uses include treating severe systemic infections caused by Gram-negative organisms like Pseudomonas aeruginosa, combined with other antibiotics for endocarditis, inhaled for chronic P. aeruginosa lung infections in cystic fibrosis, as part of multi-drug regimens for tuberculosis, and orally for bowel decontamination.
Key side effects and toxicity
Aminoglycosides have a narrow therapeutic index, meaning the effective dose is close to a toxic dose. The most significant side effects are ototoxicity and nephrotoxicity.
Ototoxicity
Ototoxicity is damage to the inner ear, affecting hearing (cochleotoxicity) or balance (vestibulotoxicity). Damage to inner ear hair cells can result in irreversible hearing loss. Vestibular damage can cause vertigo and balance issues. Gentamicin and streptomycin are mainly vestibulotoxic, while amikacin and neomycin are more cochleotoxic.
Nephrotoxicity
Nephrotoxicity affects the kidneys, potentially causing acute tubular necrosis. The drugs accumulate in kidney cells, leading to damage and decreased kidney function, indicated by a rise in serum creatinine. Unlike ototoxicity, this is often reversible after stopping the drug.
Neuromuscular Blockade
Rarely, aminoglycosides can cause neuromuscular blockade, leading to muscle weakness or respiratory paralysis, especially in susceptible individuals.
Mechanisms of bacterial resistance
Bacteria can develop resistance through several means:
- Enzymatic Modification: Enzymes can chemically alter and inactivate the antibiotic.
- Ribosomal Modification: Changes in the ribosomal target site reduce drug binding.
- Efflux Pumps: Proteins pump the drug out of the cell.
- Reduced Permeability: Alterations decrease drug entry into the cell.
Comparison of Common Aminoglycosides
| Feature | Gentamicin | Tobramycin | Amikacin |
|---|---|---|---|
| Spectrum of Activity | Broad against Gram-negative aerobes, including Enterobacteriaceae and P. aeruginosa. | Excellent against P. aeruginosa; similar to gentamicin for other Gram-negative aerobes. | Broadest spectrum, less susceptible to inactivating enzymes, effective against some resistant bacteria. |
| Primary Clinical Use | Empiric therapy for severe sepsis, complicated UTIs, synergistic for endocarditis. | Preferred for P. aeruginosa, inhaled for cystic fibrosis. | Serious nosocomial infections, suspected resistance to other aminoglycosides. |
| Toxicity Profile | Nephrotoxicity and significant vestibulotoxicity. | Similar to gentamicin but higher risk of cochleotoxicity. | Less enzymatic resistance, higher risk of cochleotoxicity than gentamicin. |
Conclusion
While newer antibiotics exist, aminoglycoside antibiotics remain crucial for treating serious bacterial infections, particularly those involving multi-drug resistance. Their potent activity and concentration-dependent killing are effective against many aerobic Gram-negative pathogens and in synergistic combinations. However, their use requires careful monitoring of kidney and auditory function due to risks of irreversible ototoxicity and potentially reversible nephrotoxicity. Managing the balance between their benefits and toxicities is vital in modern medicine.
Optimizing Safety and Efficacy
Several strategies are used to enhance the safety and effectiveness of aminoglycosides:
- Therapeutic Drug Monitoring (TDM): Helps keep drug levels within the effective yet safe range.
- Once-Daily Dosing (ODD): High peak levels for killing and low trough levels to reduce toxicity.
- Synergy in Combination Therapy: Combining with other antibiotics like beta-lactams can boost effectiveness, potentially allowing lower aminoglycoside doses.
- Patient Risk Assessment: Identifying factors like kidney issues or age to manage toxicity risks.
- Antibiotic Stewardship: Promoting responsible use to maintain effectiveness and limit resistance.
For more detailed information on specific aminoglycoside drugs and their clinical applications, consult authoritative resources such as the Merck Manual.
