Page 840 - Basic _ Clinical Pharmacology ( PDFDrive )

45 Aminoglycosides &
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Spectinomycin

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Camille E. Beauduy, PharmD, & Lisa G. Winston, MD

C ASE STUD Y

A 45-year-old man with no significant medical history was pending. The ICU attending physician is concerned about a
admitted to the intensive care unit (ICU) 10 days ago after bloodstream infection and decides to treat with empiric com-
suffering third-degree burns over 40% of his body. He had bination therapy directed against Pseudomonas aeruginosa.
been relatively stable until the last 24 hours. Now, he is febrile The combination therapy includes tobramycin. The patient
(39.5°C [103.1°F]), and his white blood cell count has risen weighs 70 kg (154 lb) and has an estimated creatinine clear-
3
from 8500 to 20,000/mm . He has also had an episode of hypo- ance of 90 mL/min. How should tobramycin be dosed using
tension (86/50 mmHg) that responded to a fluid bolus. Blood once-daily and conventional dosing strategies? How should
cultures were obtained at the time of his fever and results are each regimen be monitored for efficacy and toxicity?

The drugs described in this chapter are bactericidal inhibitors of pro- which various amino sugars are attached by glycosidic linkages
tein synthesis that interfere with ribosomal function. These agents (Figures 45–1 and 45–2). They are water-soluble, stable in solu-
are useful mainly against aerobic Gram-negative microorganisms. tion, and more active at alkaline than at acid pH.

B. Mechanism of Action
■ AMINOGLYCOSIDES The mode of action of streptomycin has been studied more
closely than that of other aminoglycosides, but all aminoglyco-
The aminoglycosides include streptomycin, neomycin, kanamy- sides are thought to act similarly. Aminoglycosides are irrevers-
cin, amikacin, gentamicin, tobramycin, sisomicin, netilmicin, ible inhibitors of protein synthesis, but the precise mechanism
and others. They are used most widely in combination with other for bactericidal activity is unclear. The initial event is passive dif-
agents to treat drug-resistant organisms; for example, they are fusion via porin channels across the outer membrane (see Figure
used with a β-lactam antibiotic in serious infections with Gram- 43–3). Drug is then actively transported across the cell mem-
negative bacteria, with a β-lactam antibiotic or vancomycin for brane into the cytoplasm by an oxygen-dependent process. The
Gram-positive endocarditis, and with one or more agents for treat- transmembrane electrochemical gradient supplies the energy for
ment of mycobacterial infections, such as tuberculosis.
this process, and transport is coupled to a proton pump. Low
extracellular pH and anaerobic conditions inhibit transport by
General Properties of Aminoglycosides reducing the gradient. Transport may be enhanced by cell wall-
A. Physical and Chemical Properties active drugs such as penicillin or vancomycin; this enhancement
Aminoglycosides have a hexose ring, either streptidine (in strep- may be the basis of the synergism of those antibiotics with
tomycin) or 2-deoxystreptamine (in other aminoglycosides), to aminoglycosides.
Inside the cell, aminoglycosides bind to 30S-subunit ribosomal
* The authors thank Drs. Henry F. Chambers and Daniel H. Deck for proteins. Protein synthesis is inhibited by aminoglycosides in at
their contributions to previous editions. least three ways (Figure 45–3): (1) interference with the initiation
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