Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 45. Aminoglycosides

Modes of Antibacterial Action

In the treatment of microbial infections with antibiotics, multiple daily dosage regimens traditionally have been designed to maintain serum concentrations above the minimal inhibitory concentration (MIC) for as long as possible. However, the in vivo effectiveness of some antibiotics, including aminoglycosides, results from a concentration-dependent killing action. As the plasma level is increased above the MIC, aminoglycosides kill an increasing proportion of bacteria and do so at a more rapid rate. Many antibiotics, including penicillins and cephalosporins, cause time-dependent killing of microorganisms, wherein their in vivo efficacy is directly related to time above MIC and becomes independent of concentration once the MIC has been reached.

Aminoglycosides are also capable of exerting a postantibiotic effect such that their killing action continues when their plasma levels have declined below measurable levels. Consequently, aminoglycosides have greater efficacy when administered as a single large dose than when given as multiple smaller doses. The toxicity (in contrast to the antibacterial efficacy) of aminoglycosides depends both on a critical plasma concentration and on the time that such a level is exceeded. The time above such a threshold is shorter with administration of a single large dose of an aminoglycoside than when multiple smaller doses are given. These concepts form the basis for once-daily aminoglycoside dosing protocols, which can be more effective and less toxic than traditional dosing regimens.


Aminoglycosides are structurally related amino sugars attached by glycosidic linkages. They are polar compounds, not absorbed after oral administration and must be given intramuscularly, or intravenously for systemic effect. They have limited tissue penetration and do not readily cross the blood-brain barrier. Glomerular filtration is the major mode of excretion, and plasma levels of these drugs are greatly affected by changes in renal function. Excretion of aminoglycosides is directly proportional to creatinine clearance. With normal renal function, the elimination half-life of aminoglycosides is 2-3 h. Dosage adjustments must be made in renal insufficiency to prevent toxic accumulation. 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.

Mechanism of Action

Aminoglycosides are bactericidal inhibitors of protein synthesis. Their penetration through the bacterial cell envelope is partly dependent on oxygen-dependent active transport, and they have minimal activity against strict anaerobes. Aminoglycoside transport can be enhanced by cell wall synthesis inhibitors, which may be the basis of antimicrobial synergism. Inside the cell, aminoglycosides bind to the 30S ribosomal subunit and interfere with protein synthesis in at least 3 ways: (1) they block formation of the initiation complex; (2) they cause misreading of the code on the mRNA template; and (3) they inhibit translocation (Figure 45-1). Aminoglycosides may also disrupt polysomal structure, resulting in nonfunctional monosomes.


Putative mechanisms of action of the aminoglycosides. Normal protein synthesis is shown in the top panel. At least 3 aminoglycoside effects have been described, as shown in the bottom panel: block of formation of the initiation complex; miscoding of amino acids in the emerging peptide chain due to misreading of the mRNA; and block of translocation on mRNA. Block of movement of the ribosome may occur after the formation of a single initiation complex, resulting in an mRNA chain with only a single ribosome on it, a so-called monosome.

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 plasmid-mediated 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. Individual aminoglycosides have varying susceptibilities to such enzymes. For example, 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.

Clinical Uses

The main differences among the individual aminoglycosides lie in their activities against specific organisms, particularly gram-negative rods. 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 species. These aminoglycosides also have activity against strains of Haemophilus influenzae, Moraxella catarrhalis, and Shigella species, although they are not drugs of choice for infections caused by these organisms. In most cases, aminoglycosides are used in combination with a beta-lactam antibiotic. When used alone, aminoglycosides are not reliably effective in the treatment of infections caused by gram-positive cocci. Antibacterial synergy may occur when aminoglycosides are used in combination with cell wall synthesis inhibitors. Examples include their combined use with penicillins in the treatment of pseudomonal, listerial, and enterococcal infections.

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. Multidrug-resistant strains of Mycobacterium tuberculosis that are resistant to streptomycin may be susceptible to amikacin. Because of the risk of ototoxicity, streptomycin should not be used when other drugs will serve. Owing to their toxic potential, neomycin and kanamycin are usually restricted to topical or oral use (eg, to eliminate bowel flora). Gentamicin is also available for topical use.

Netilmicin has been used for treatment of serious infections caused by organisms resistant to the other aminoglycosides. However, it is no longer available in the United States.

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.



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 to outweigh risk.


Renal toxicity usually takes the form of acute tubular necrosis. This adverse effect, which is often reversible, is more common in elderly patients and in those concurrently receiving amphotericin B, cephalosporins, or vancomycin. Gentamicin and tobramycin are the most nephrotoxic.

Neuromuscular Blockade

Though rare, a curare-like block may occur at high doses of aminoglycosides and may result in respiratory paralysis. It is usually reversible by treatment with calcium and neostigmine, 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.

Skill Keeper: Nephrotoxicity

One of the characteristics of aminoglycoside antibiotics is their nephrotoxic potential. What other drugs can you identify that are known to have adverse effects on renal function? The Skill Keeper Answer appears at the end of the chapter.

Skill Keeper Answer: Nephrotoxicity

Drugs with nephrotoxic potential include ACE inhibitors, acetazolamide, aminoglycosides, aspirin, amphotericin B, cyclosporine, furosemide, gold salts, lithium, methicillin, methoxyflurane, NSAIDs, pentamidine, sulfonamides, tetracyclines (degraded), thiazides, and triamterene.


When you complete this chapter, you should be able to:

Describe 3 actions of aminoglycosides on protein synthesis and 2 mechanisms of resistance to this class of drugs.

List the major clinical applications of aminoglycosides and identify their 2 main toxicities.

Describe aminoglycoside pharmacokinetic characteristics with reference to their renal clearance and potential toxicity.

Understand time-dependent and concentration-dependent killing actions of antibiotics and what is meant by "postantibiotic effect."

Drug Summary Table: Aminoglycosides & Spectinomycin

Drugs Mechanism of Action Activity & Clinical Uses Pharmacokinetics & Interactions Toxicities Gentamicin Tobramycin Amikacin Streptomycin Neomycin Spectinomycin Bactericidal; inhibit protein synthesis via binding to 30S ribsosomal subunit; amikacin least resistance; concentration-dependent action; also exert postantibiotic effects Aerobic gram negative bacteria, H influenzae, M catarrhalis, and Shigella species; often used in combinations with beta-lactams Gonorrhea (spectinomycin, IM); tuberculosis (streptomycin, IM) IV; renal clearance with half-lives 2-4 once-daily dosing effective with less toxicity; oral and topical (neomycin, gentamicin) Nephrotoxicity (reversible), ototoxicity (irreversible), neuromuscular blockade

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