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INTRODUCTION

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The aminoglycoside antibiotics are widely used for the treatment of severe gram-negative infections such as pneumonia or bacteremia, often in combination with a β-lactam antibiotic. Aminoglycosides are also used for gram-positive infections such as infective endocarditis in combination with penicillins when antibiotic synergy is required for optimal killing. Aminoglycoside antibiotics available in the United States that are in common use include gentamicin, tobramycin, netilmicin, and amikacin.

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Aminoglycoside antibiotics are bactericidal, and the drugs exhibit concentration-dependent bacterial killing. Antibiotics with concentration-dependent killing characteristically kill bacteria at a faster rate when drug concentrations are higher. Also, aminoglycosides have a concentration-dependent postantibiotic effect. The postantibiotic effect is the phenomenon of continued bacterial killing even though serum concentrations have fallen below the minimum inhibitory concentration (MIC). Because the postantibiotic effect is concentration-dependent for the aminoglycosides, higher drug concentrations lead to a longer postantibiotic effect. The mechanisms of action for aminoglycosides are binding to the 30S ribosomal subunit inhibiting protein synthesis and misreading of messenger RNA (mRNA) causing dysfunctional protein production.1

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THERAPEUTIC AND TOXIC CONCENTRATIONS

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The MIC for susceptible bacteria is higher for amikacin than it is for the other aminoglycosides. Because the pharmacokinetics are similar for all these drugs, higher doses of amikacin are needed to treat infections. The conventional method of dosing aminoglycoside antibiotics is to administer multiple daily doses (usually every 8 hours, with normal renal function).2 This method of dosing is most often used for the treatment of infective endocarditis, but it can also be considered for other patients, especially those with poor renal function.

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In order to take advantage of concentration-dependent bacterial killing and the postantibiotic effect, extended-interval (usually the total daily dose given once per day) aminoglycoside administration is another dosing option.3 This dosing method is now the predominate mode of administration, except for the treatment of endocarditis where aminoglycosides are used for their synergistic effect with penicillins or vancomycin. Because these two different methods of dosage administration have very different target concentrations, it is important to identify which is being used when discussing serum concentration monitoring.

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Conventional Dosing

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Aminoglycoside antibiotics are given as short-term (½-1 hour) infusions. If a 1-hour infusion is used, maximum end of infusion “peak” concentrations are measured when the infusion is completed (Figure 4-1). If a one-half hour infusion is used, serum concentrations exhibit a distribution phase so that drug in the blood and in the tissues are not yet in equilibrium. Because of this, a one-half hour waiting period is allowed for distribution to finish if a one-half hour infusion is used before peak concentrations are measured. Therapeutic steady-state peak concentrations for gentamicin, tobramycin, and netilmicin are generally 5-10 μg/mL for gram-negative infections. Infection sites with more susceptible bacteria, such as intra-abdominal infections usually can be treated with steady-state peak concentrations at the lower end of this range (typically 5-7 ...

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