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.
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.