A 45-year-old man with no significant 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 mmHg) 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 a bloodstream infection and decides to treat with empiric combination therapy directed against Pseudomonas aeruginosa. 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, plazomicin, and others. They are used most widely in combination with other agents to treat drug-resistant organisms; for example, they are used with a β-lactam antibiotic in serious infections with gram-negative bacteria, with a β-lactam antibiotic or vancomycin for gram-positive endocarditis, and with one or several other agents for treatment of mycobacterial infections such as tuberculosis.
General Properties of Aminoglycosides
A. 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 aminoglycoside antibiotics. Ring II is 2-deoxystreptamine. The resemblance between kanamycin and amikacin and between gentamicin, netilmicin, and tobramycin can be seen. Plazomicin’s ring II and III are similar to the other structures; it shares the same hydroxyl-aminobutyric acid R group as amikacin. Its ring I differs from amikacin in that it is unsaturated. The circled numerals on the kanamycin molecule indicate points of attack of plasmid-mediated bacterial transferase enzymes that can inactivate this drug. ➀, ➁, and ➂, acetyltransferase; ➃, phosphotransferase; ➄, adenylyltransferase. Amikacin is resistant to modification at ➁, ➂, ➃, and ➄, whereas plazomicin is resistant to modification at ➀, ➁, ➃, and ➄.