An aminoglycoside is a molecule composed of a
sugar group and an
amino group.
Several aminoglycosides function as
antibiotics that are effective against certain types of
bacteria. They include
amikacin,
arbekacin,
gentamicin,
kanamycin,
neomycin,
netilmicin,
paromomycin, rhodostreptomycin,
streptomycin,
tobramycin, and
apramycin.
Anthracyclines are another group of aminoglycosides. These compounds are used in
chemotherapy.
Contents
1 Nomenclature2 Mechanism of action3 Toxicity4 Routes of administrationNomenclature
Aminoglycosides that are derived from bacteria of the
Streptomyces genus are named with the suffix -mycin, while those which are derived from
Micromonospora are named with the suffix -micin.
Tom Gander (Aldridge University) says that his nomenclature system is not specific for aminoglycosides.[
citation needed] For example
vancomycin is a
glycopeptide antibiotic and
erythromycin, which is produced from a species of
Saccharopolyspora (which was previously misclassified as
Streptomyces) along with its synthetic derivatives
clarithromycin and
azithromycin are
macrolides - all of which differ in their mechanisms of action.
Mechanism of actionAminoglycosides work by binding to the bacterial
30S ribosomal subunit(some work by binding to the
50S subunit ) inhibiting the translocation of the peptidyl-tRNA from the A-site to the P-site and also causing misreading of mRNA, leaving the bacterium unable to synthesize proteins vital to its growth. They kill bacteria by inhibiting protein synthesis as they bind to the 16S rRNA and by disrupting the integrity of bacterial cell membrane.However, their exact mechanism of action is not fully known.
There is a significant relationship between the dose administered and the resultant plasma level in blood. TDM, therapeutic drug monitoring, is necessary to obtain the correct dose. These agents exhibit a post-antibiotic effect in which there is no or very little drug levels detectable in blood, but there still seems to be inhibition of bacterial re-growth. This is due to strong, irreversible binding to the ribosome, and remains intracellular long after plasma levels drop. This allows a prolonged dosage interval. Depending on their concentration they act as
bacteriostatic or
bacteriocidial agents.
The protein synthesis inhibition of aminoglycosides does not usually produce a bactericidal effect, let alone a rapid one as is frequently observed on susceptible Gram-negative bacilli. Aminoglycosides competitively displace cell biofilm-associated Mg2+ and Ca2+ that link the polysaccharides of adjacent lipopolysaccharide molecules. "The result is shedding of cell membrane blebs, with formation of transient holes in the cell wall and disruption of the normal permeability of the cell wall. This action alone may be sufficient to kill most susceptible Gram-negative bacteria before the aminoglycoside has a chance to reach the 30S ribosome."
Traditionally, the antibacterial properties of aminoglycosides were believed to result from inhibition of bacterial protein synthesis through irreversible binding to the 30S bacterial ribosome. This explanation, however, does not account for 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 that the initial site of action is the outer bacterial membrane. The cationic antibiotic molecules create fissures in the outer cell membrane, resulting in leakage of intracellular contents and enhanced antibiotic uptake. This rapid action at the outer membrane probably accounts for most of the bactericidal activity.2 Energy is needed for aminoglycoside uptake into the bacterial cell. Anaerobes have less energy available for this uptake, so aminoglycosides are less active against anaerobes. Aminoglycosides are useful primarily in infections involving
aerobic,
gram-negative bacteria, such as
Pseudomonas,
Acinetobacter, and
Enterobacter. In addition, some
Mycobacteria, including the bacteria that cause
tuberculosis, are susceptible to aminoglycosides. The most frequent use of aminoglycosides is empiric therapy for serious infections such as septicemia, complicated intraabdominal infections, complicated urinary tract infections, and nosocomial respiratory tract infections. Usually, once cultures of the causal organism are grown and their susceptibilities tested, aminoglycosides are discontinued in favor of less toxic antibiotics.
Streptomycin was the first effective drug in the treatment of tuberculosis, though the role of aminoglycosides such as streptomycin and amikacin has been eclipsed (because of their toxicity and inconvenient route of administration) except for multiple drug resistant strains.
Infections caused by
gram-positive bacteria can also be treated with aminoglycosides, but other types of antibiotics are more potent and less damaging to the host. In the past the aminoglycosides have been used in conjunction with beta-lactam antibiotics in streptococcal infections for their synergistic effects, particularly in
endocarditis. One of the most frequent combinations is ampicillin (a beta-lactam, or penicillin-related antibiotic) and gentamicin. Often, hospital staff refer to this combination as "amp and gent" or more recently called "pen and gent" for penicillin and gentamicin.
Aminoglycosides are mostly ineffective against anaerobic bacteria, fungi and viruses.
Experimentation with aminoglycosides as a treatment of
cystic fibrosis (CF) has shown some promising results. CF is caused by a mutation in the
gene coding for the
cystic fibrosis transmembrane conductance regulator (CFTR) protein. In approximately 10% of CF cases the mutation in this gene causes its early termination during
translation, leading to the formation of is truncated and non-functional CFTR protein. It is believed that
gentamicin distorts the structure of the ribosome-RNA complex, leading to a mis-reading of the
termination codon, causing the
ribosome to "skip" over the stop sequence and to continue with the normal elongation and production of the CFTR protein. The treatment is still experimental but showed improvement in cells from CF patients with susceptible mutations.
Toxicity
The toxicity of these agents is dose-related, and therefore every individual can get these side effects provided the dose is sufficiently high. Because of their potential for
ototoxicity and
nephrotoxicity (
kidney toxicity), aminoglycosides are administered in doses based on body weight. Vestibular damage, hearing loss and tinnitus are irreversible, so care must be taken not to achieve a sufficiently high dose. Concomitant administration of a
cephalosporin may lead to increased risk of nephrotoxicity while administration with a
loop diuretic increases the risk of ototoxicity. Blood drug levels and
creatinine are monitored during the course of therapy, as individuals vary widely in the relationship between dose and plasma level. Serum creatinine measurements are used to estimate how well the kidneys are functioning and as a marker for kidney damage caused by these drugs. They may react with and prolong the actions of neuromuscular agents. Impaired renal function necessitates a reduced dose.[
citation needed] Dosing and monitoring of aminoglycosides are routinely performed by hospital
clinical pharmacists.
Routes of administrationSince they are not absorbed from the gut, they are administered
intravenously and
intramuscularly. Some are used in topical preparations for wounds. Oral administration can be used for gut decontamination (e.g. in hepatic encephalopathy). Tobramycin may be administered in a nebulized form.
Anti-malarial drugs are medicines that prevent or treat malaria.
