| aminoglycosides | Aminoglycosides are structurally related amino sugars attached by glycosidic linkages. They are polar compounds, not absorbed after oral administration, and must be given IM IV They do not readily cross the blood-brain barrier. |
| bacteriocidal or static | Aminoglycosides are bactericidal inhibitors of protein synthesis. they have minimal activity against strict anaerobes. |
| MECHANISM OF ACTION | Aminoglycoside entry can be enhanced by cell wall synthesis inhibitors, which may be the basis of antimicrobial synergism. Susceptible gram-negative organisms allow aminoglycosides to diffuse through porin channels in their outer membranes. These organisms also have an oxygen-dependent system that transports the drug across the cytoplasmic membrane. The antibiotic then binds to the 30S ribosomal subunit prior to ribosome formation There, it interferes with assembly of the functional ribosomal apparatus and/or can cause the 30S subunit of the completed ribosome to misread the genetic code. Polysomes become depleted because the aminoglycosides interrupt the process of polysome disaggregation and assembly inibit translocation Aminoglycosides may also disrupt polysomal structure, resulting in nonfunctional monosomes. |
| MECHANISMS OF RESISTANCE | Streptococci, including Streptococcus pneumoniae, and enterococci are relatively resistant to gentamicin and most other aminoglycosides owing to failure of the drugs to penetrate into the cell. However, the primary mechanism of resistance to aminoglycosides, especially in gram-negative bacteria, involves the plasmidmediated formation of inactivating enzymes. These enzymes are group transferases that catalyze the acetylation of amine functions and the transfer of phosphoryl or adenylyl groups to the oxygen atoms of hydroxyl groups on the aminoglycoside. decreased uptake also affects |
| enzyme resistances | transferases produced by enterococci can inactivate amikacin, gentamicin, and tobramycin but not streptomycin. However, amikacin is often resistant to many enzymes that inactivate gentamicin and tobramycin. In addition, resistance to streptomycin, which is common, appears to be due to changes in the ribosomal binding site. |
| gentamicin tobramicin amikacin use | Gentamicin, tobramycin, and amikacin are important drugs for the treatment of serious infections caused by aerobic gram-negative bacteria, including Escherichia coli and Enterobacter, Klebsiella, Proteus, Providencia, Pseudomonas, and Serratia,and Haemophilus influenzae, Moraxella catarrhalis, and Shigella species, although they are not drugs of choice for infections caused by these organisms. |
| gram positive | When used alone, aminoglycosides are not reliably effective in the treatment of infections caused by gram-positive cocci. Examples include their combined use with penicillins in the treatment of pseudomonal, listerial, and enterococcal infections. |
| streptomycin | Streptomycin in combination with penicillins is often more effective in enterococcal carditis than regimens that include other aminoglycosides. This combination is also used in the treatment of tuberculosis, plague, and tularemia. Other aminoglycosides are usually effective in these conditions. |
| amikacin | Multidrug-resistant strains of Mycobacterium tuberculosis that are resistant to streptomycin may be susceptible to amikacin. |
| streptomycin tox | Because of the risk of ototoxicity, streptomycin should not be used when other drugs will serve. |
| toxic | Owing to their toxic potential, neomycin and kanamycin are usually restricted to topical or oral use (eg, to eliminate bowel flora). |
| gentamicin | Gentamicin is also available for topical use. |
| netilmicin | Netilmicin has been used for treatment of serious infections caused by organisms resistant to the other aminoglycosides. Netilmicin is no longer use |
| specintomycin | Spectinomycin is an aminocyclitol related to the aminoglycosides. Its sole use is as a backup drug, administered intramuscularly as a single dose for the treatment of gonorrhea, most commonly in patients allergic to beta-lactams. There is no cross-resistance with other drugs used in gonorrhea. Spectinomycin may cause pain at the injection site. |
| ototoxic | Auditory or vestibular damage (or both) may occur with any aminoglycoside and may be irreversible. Auditory impairment is more likely with amikacin and kanamycin; vestibular dysfunction is more likely with gentamicin and tobramycin Ototoxicity risk is proportional to the plasma levels and thus is especially high if dosage is not appropriately modified in a patient with renal dysfunction. Ototoxicity may be increased by the use of loop diuretics. Because ototoxicity has been reported after fetal exposure, the aminoglycosides are contraindicated in pregnancy unless their potential benefits are judged The antibiotic accumulates in the endolymph and perilymph of the inner ear, and toxicity correlates with the number of destroyed hair cells in the organ of Corti. Patients simultaneously receiving another ototoxic drug, such as cisplatin or the loop diuretics, furosemide, bumetanide, or ethacrynic acid, are particularly at risk. Vertigo and loss of balance (especially in patients receiving streptomycin) may also occur because these drugs affect the vestibular apparatus. |
| B. Nephrotoxicity | acute tubular necrosis is more common in elderly patients and in those concurrently receiving amphotericin B, cephalosporins, or vancomycin. Gentamicin and tobramycin are the most nephrotoxic. Retention of the aminoglycosides by the proximal tubular cells disrupts calcium-mediated transport processes, and this results in kidney damage ranging from mild, reversible renal impairment to severe |
| nueromuscular blockade | Though rare, a curare-like block may occur at high doses of aminoglycosides and may result in respiratory paralysis. This side effect most often occurs after direct intraperitoneal or intrapleural application of large doses of aminoglycosides. The mechanism responsible is a decrease in both the release of acetylcholine from prejunctional nerve endings and the sensitivity of the postsynaptic site. Patients with myasthenia gravis are particularly at risk. Prompt administration of calcium gluconate or neostigmine can reverse the block that causes neuromuscular paralysis but ventilatory support may be required. |
| skin reactions | Allergic skin reactions may occur in patients, and contact dermatitis may occur in personnel handling the drug. Neomycin is the agent most likely to cause this adverse effect |
| 1. Administration: | The highly polar, polycationic structure of the aminoglycosides prevents adequate absorption after oral administration Therefore, all aminoglycosides (except neomycin must be given parenterally to achieve adequate serum levels. [Note: The severe nephrotoxicity associated with neomycin precludes parenteral administration, and its current use is limited to topical application for skin infections or oral administration to prepare the bowel prior to surgery.] The bactericidal effect of aminoglycosides is concentration and time dependent They also have a postantibiotic effect. Because of these properties, once daily dosing with the aminoglycosides can be employed. This results in less toxicity, and is less expensive to administer. The exceptions are pregnancy, neonatal infections, and bacterial endocarditis, in which these agents are administered in divided doses every 8 hours. [Note: The dose that is administered is calculated based on lean body mass, because these drugs do not distribute into fat.] |
| 2. Distribution: | Concentrations in CSF are inadequate, even when the meninges are infl amed. Except for neomycin, the aminoglycosides may be administered intrathecally or IV. High concentrations accumulate in the renal cortex and in the endolymph and perilymph of the inner ear, which may account for their nephrotoxic and ototoxic potential. All aminoglycosides cross the placental barrier and may accumulate in fetal plasma and amniotic fluid. |
| 3. Fate: | Metabolism of the aminoglycosides does not occur in the host. All are rapidly excreted into the urine, predominantly by glomerular filtration Accumulation occurs with renal failure and requires dose modification. Excretion of aminoglycosides is directly proportional to creatinine clearance. With normal renal function, the elimination half-life of aminoglycosides is 2–3h.Monitoring of plasma levels of aminoglycosides is important for safe and effective dosage selection and adjustment. For traditional dosing regimens (2 or 3 times daily), peak serum levels are measured 30–60 min after administration and trough levels just before the next dose. With once-daily dosing, peak levels are less important since they will naturally be high. |
