They are potent bactericidal antibiotics that act by creating fissures in the external membrane of the bacterial cell and are particularly active against aerobic bacteria.
Gentamycin is the most commonly used aminoglycoside, amikacin but may be particularly effective against resistant organisms.
Aminoglycosides are used to treat severe infections of the abdomen and urinary tract and bacteremia and endocarditis.
They are also used for prevention, especially against endocarditis. Resistance is rare but increases in frequency. Avoiding prolonged use, volume depletion, and concomitant administration of other potentially nephrotoxic agents decreases the risk of toxicity.
The single daily dosage of aminoglycosides is possible due to its rapid death dependent on the concentration and the effect after antibiotics and has the potential to decrease toxicity. The single daily dose of aminoglycosides appears safe, effective, and cost-effective.
The standard traditional dosage is still generally recommended in specific clinical situations, such as patients with endocarditis or pediatric patients. The first aminoglycoside, streptomycin, was isolated from Streptomyces griseus in 1943.
Neomycin, isolated from Streptomyces fradiae, had better activity than streptomycin against aerobic gram-negative bacilli but, due to its formidable toxicity, could not be used systemically in a safe manner.
Gentamicin, isolated from Micromonospora in 1963, was a breakthrough in treating gram-negative bacillary infections, including those caused by Pseudomonas aeruginosa.
Subsequently, other aminoglycosides were developed, including amikacin (Amikin), netilmicin (Netromycin), and tobramycin (Nebcin), all currently available for systemic use in the United States.
Despite the introduction of newer, less toxic antimicrobial agents, aminoglycosides play a valuable role in treating severe bacterial infections and serious enterococci.
Pharmacology of Aminoglycosides
Traditionally, it was believed that the antibacterial properties of aminoglycosides were the result of the inhibition of bacterial protein synthesis by irreversible binding to the 30S bacterial ribosome.
However, this explanation does not consider the potent bactericidal properties of these agents since other antibiotics that inhibit the synthesis of proteins (such as tetracycline ) are not bactericidal.
Recent experimental studies show the initial site of action in the outer bacterial membrane. Cationic antibiotic molecules create fissures in the outer cell membrane, resulting in leakage of intracellular content and improved absorption of antibiotics.
This rapid action on the outer membrane probably accounts for most bactericidal activity.2 Energy is needed for the uptake of aminoglycosides in bacterial cells.
Anaerobes have less energy available for this absorption, so aminoglycosides are less active against anaerobes. Aminoglycosides are poorly absorbed from the gastrointestinal tract.
After parenteral administration, the aminoglycosides are distributed mainly within the extracellular fluid. Therefore, the presence of disease states or iatrogenic situations that alter the fluid balance may require dosage modifications.
When used parenterally, adequate drug concentrations are typically found in bone, synovial fluid, and peritoneal fluid.
Penetration of biological membranes is poor due to the polar structure of the drug, and intracellular concentrations are usually low, except in the proximal renal tubule.
Endotracheal administration results in higher bronchial levels than systemic administration, but differences in clinical outcomes have not been consistent.
After parenteral administration of an aminoglycoside, subtherapeutic concentrations are usually found in the cerebrospinal fluid, vitreous fluid, prostate, and brain.
Aminoglycosides are rapidly excreted by glomerular filtration, which results in a plasma half-life that varies from two hours in a patient with “normal” renal function to 30 to 60 hours in patients who are functionally aneféricos.
The half-life of the aminoglycosides in the renal cortex is approximately 100 hours, so that that repetitive dosing can cause renal accumulation and toxicity.
Aminoglycosides exhibit bactericidal, concentration-dependent killing action and are active against a broad range of aerobic gram-negative bacilli. They are also active against staphylococci and certain mycobacteria.
Aminoglycosides are effective even when the bacterial inoculum is significant, and resistance rarely develops during treatment.
These potent antimicrobials are used for prevention and treatment in various clinical situations. Gentamicin is the aminoglycoside used most frequently due to its low cost and reliable activity against gram-negative aerobes.
However, local resistance patterns should influence the choice of therapy. In general, gentamicin, tobramycin, and amikacin are used in similar circumstances, often interchangeably. Tobramycin may be the aminoglycoside of choice for use in another because it has shown more excellent in vitro activity.
However, the clinical importance of this activity has been questioned. Amikacin is particularly effective against bacteria resistant to other aminoglycosides since its chemical structure makes it less susceptible to inactive enzymes.
Depending on local resistance patterns, amikacin may be the preferred agent for severe nosocomial infections caused by gram-negative bacilli.
Resistance to drugs
Most resistance to aminoglycosides is caused by bacterial inactivation by intracellular enzymes. Due to structural differences, amikacin is not inactivated by the common enzymes that inactivate gentamicin and tobramycin.
Therefore, a large proportion of gram-negative aerobes that are resistant to gentamicin and tobramycin are sensitive to amikacin. In addition, with greater use of amikacin, a lower incidence of resistance has been observed compared to increased use of gentamicin and tobramycin.
Aeruginosa may show adaptive resistance to aminoglycosides. This occurs when previously susceptible populations become less vulnerable to the antibiotic due to decreased intracellular concentrations of the antibiotic.
This decrease may result in colonization, slow clinical response, or failure of the antibiotic despite the sensitivity in vitro tests. Aminoglycosides are often combined with a beta-lactam drug to treat Staphylococcus aureus infection.
This combination increases bactericidal activity, whereas monotherapy with aminoglycosides can allow resistant staphylococci to persist during treatment and cause a clinical relapse once the antibiotic is stopped.
The infectious endocarditis is due to enterococci with high levels of resistance to aminoglycosides is becoming more common.
All enterococci have a low-level resistance to aminoglycosides due to their anaerobic metabolism. In the treatment of bacterial endocarditis, a beta-lactam drug is also used synergistically to facilitate the penetration of aminoglycosides into the cell.
When high-level resistance occurs, it is usually due to the production of inactivating enzymes by bacteria. Due to the increasing frequency of this resistance, all enterococci must be analyzed to detect susceptibility to antibiotics.
As with all antibiotics, resistance to aminoglycosides is increasingly prevalent. The repeated use of aminoglycosides, mainly when a single type is used, leads to a higher incidence of resistance.