Aminoglycosides (gentamicin, tobramycin, amikacin, netilmicin, kanamycin, streptomycin, paromomycin, and neomycin) are used primarily to treat infections caused by aerobic gram-negative bacteria. Streptomycin is an important agent for the treatment of tuberculosis, and paromomycin is used orally for intestinal amebiasis and in the management of hepatic coma. Aminoglycosides are bactericidal inhibitors of protein synthesis. Mutations affecting proteins in the bacterial ribosome can confer marked resistance to their action. Most commonly resistance is due to acquisition of plasmids or transposon-encoding genes for aminoglycoside-metabolizing enzymes or from impaired transport of drug into the cell. Thus, there can be cross-resistance between members of the class.
Aminoglycosides are natural products or semisynthetic derivatives of compounds produced by a variety of soil actinomycetes. Amikacin, a derivative of kanamycin, and netilmicin, a derivative of sisomicin, are semisynthetic products. These agents contain amino sugars linked to an aminocyclitol ring by glycosidic bonds (Figure 54-1). They are polycations, and their polarity is responsible in part for pharmacokinetic properties shared by all members of the group. For example, none is absorbed adequately after oral administration, inadequate concentrations are found in cerebrospinal fluid (CSF), and all are excreted relatively rapidly by the normal kidney. All members of the group share the same spectrum of toxicity, most notably nephrotoxicity and ototoxicity, which can involve the auditory and vestibular functions of the eighth cranial nerve.
Sites of activity of various plasmid-mediated enzymes capable of inactivating aminoglycosides. The red X indicates regions of the molecules that are protected from the designated enzyme. In gentamicin C1, R1=R2=CH3; in gentamicin C2, R1=CH3, R2=H; in gentamicin C1a, R1=R2=H. (Reproduced with permission from Moellering RC Jr. Microbiological considerations in the use of tobramycin and related aninoglycosidic aminocyclitol antibiotics. Med J Aust, 1977;2S:4–8. Copyright 1977. The Medical Journal of Australia.)
MECHANISM OF ACTION. The aminoglycoside antibiotics are rapidly bactericidal. Bacterial killing is concentration dependent: the higher the concentration, the greater the rate of bacterial killing. The bactericidal activity persists after the serum concentration has fallen below the minimum inhibitory concentration (MIC). These properties probably account for the efficacy of high-dose, extended-interval dosing regimens.
Aminoglycosides diffuse through aqueous channels formed by porin proteins in the outer membrane of gram-negative bacteria to enter the periplasmic space. Transport of aminoglycosides across the cytoplasmic (inner) membrane depends on a transmembrane electrical gradient coupled to electron transport to drive permeation of these antibiotics. This energy-dependent phase is rate-limiting and can be blocked or inhibited by divalent cations (e.g., Ca2+ and Mg2+), hyperosmolarity, a reduction in pH, and anaerobic conditions. Thus, the antimicrobial activity of aminoglycosides is reduced markedly in the anaerobic environment of ...