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 8,500 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?
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.
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.
General Properties of Aminoglycosides
Physical and Chemical Properties
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.
Structure of streptomycin.
Structures of several important aminoglycoside antibiotics. Ring II is 2-deoxystreptamine. The resemblance between kanamycin and amikacin and between gentamicin, netilmicin, and tobramycin can be seen. The circled numerals on the kanamycin molecule indicate points of attack of plasmid-mediated bacterial transferase enzymes that can inactivate this drug. ①, ②, and ③, acetyltransferase; ④, phosphotransferase; ⑤, adenylyltransferase. Amikacin is resistant to modification at ②, ③, ④, and ⑤.
The mode of action of streptomycin has been studied far more closely than that of other aminoglycosides, but they probably all 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 actively transported across the cell membrane into the cytoplasm by an oxygen-dependent process. The transmembrane electrochemical gradient supplies the energy for this process, and transport is coupled to a proton ...