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CASE STUDY
A 45-year-old man with no medical history was admitted to the intensive care unit (ICU) 10 days ago after suffering third-degree burns over 40% of his body.∗ He had been relatively stable until the last 24 hours. Now he is febrile (39.5°C [103.1°F]), and his white blood cell count has risen from 8500 to 20,000/mm3. He has also had an episode of hypotension (86/50 mm Hg) that responded to a fluid bolus. Blood cultures were obtained at the time of his fever and results are pending. The ICU attending physician is concerned about sepsis and decides to treat with empiric combination therapy directed against Pseudomonas. The combination therapy includes tobramycin. The patient weighs 70 kg (154 lb) and has an estimated creatinine clearance of 90 mL/min. How should tobramycin be dosed using once-daily and conventional dosing strategies? How should each regimen be monitored for efficacy and toxicity?
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The drugs described in this chapter are bactericidal inhibitors of protein synthesis that interfere with ribosomal function. These agents are useful mainly against aerobic gram-negative microorganisms.
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The aminoglycosides include streptomycin, neomycin, kanamycin, amikacin, gentamicin, tobramycin, sisomicin, netilmicin, and others. They are used most widely in combination with a β-lactam antibiotic in serious infections with gram-negative bacteria, in combination with vancomycin or a β-lactam antibiotic for gram-positive endocarditis, and for treatment of tuberculosis.
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General Properties of Aminoglycosides
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A. Physical and Chemical Properties
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Aminoglycosides have a hexose ring, either streptidine (in streptomycin) or 2-deoxystreptamine (in other aminoglycosides), to which various amino sugars are attached by glycosidic linkages (Figures 45–1 and 45–2). They are water-soluble, stable in solution, and more active at alkaline than at acid pH.
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B. Mechanism of Action
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The mode of action of streptomycin has been studied more closely than that of other aminoglycosides, but all aminoglycosides act similarly. Aminoglycosides are irreversible inhibitors of protein synthesis, but the precise mechanism for bactericidal activity is not known. The initial event is passive diffusion via porin channels across the outer membrane (see Figure 43–3). Drug is then ...