Overview

Aminoglycosides

History: The first aminoglycoside antibiotic, streptomycin, was isolated in 1944 and shortly thereafter was observed to be effective in the treatment of tuberculosis. In 1949, neomycin was isolated, followed by kanamycin in 1957. In 1959, another less known aminoglycoside, paromomycin, was developed. Today, these four aminoglycoside antibiotics are seldom used due to the availability of gentamicin (1963), tobramycin (1975), and amikacin (1976). Gentamicin is most widely used since it is available as a generic formulation and, as such, is much less expensive than either tobramycin or amikacin. Also responsible for the decline in the use of streptomycin and neomycin is the risk of severe ototoxicity, although the newer agents also possess this potential. Currently, neomycin is used only orally in the treatment of hepatic encephalopathy because toxicity is too great with parenteral administration or topical irrigation. Paromomycin is primarily used today as an intestinal antiparasitic agent in the treatment of amebiasis, giardiasis, cestodiasis, cutaneous leishmaniasis, as well as cryptosporidiosis in patients with AIDS.

In the 1970s and 1980s, dozens of cephalosporin antibiotics were released, and many individuals believed aminoglycoside use would become obsolete. Some gram-negative bacteria, however, developed resistance to cephalosporins, reaffirming the usefulness of aminoglycosides and renewing interest in this class of drugs. Administration in higher doses at longer dosing intervals may simultaneously increase efficacy and decrease toxicity.

Mechanism of Action: Despite many years of investigation, it is not clear how aminoglycosides cause bacterial cell death. It is known that aminoglycosides bind irreversibly to one of two aminoglycoside-binding sites on the 30 S ribosomal subunit, subsequently inhibiting bacterial protein synthesis. This inhibition, however, does not adequately explain the bactericidal effect of aminoglycosides because other non-aminoglycoside antibiotics that also inhibit protein synthesis are only bacteriostatic. One aspect essential to aminoglycoside lethality is the need to achieve intracellular concentrations in excess of extracellular ones. Anaerobic bacteria are not susceptible to aminoglycosides due, at least in part, to a lack of an active transport mechanism for aminoglycoside uptake.

Aminoglycosides exhibit "concentration-dependent killing" and a "post-antibiotic effect" (PAE). "Concentration-dependent killing" describes the principle that bactericidal effects increase as the antibiotic concentration increases. "PAE" represents a sustained inhibitory effect on bacterial growth persisting for several hours after aminoglycoside concentrations are no longer detectable. Both of these phenomena can be exploited with dosage regimens that employ higher doses administered at longer intervals.

Distinguishing Features/Adverse Reactions: Aminoglycosides are similar in actions and adverse reactions. Two well-known adverse reactions are ototoxicity and nephrotoxicity. It is believed that certain aminoglycosides, such as neomycin and streptomycin, are more ototoxic than the others, although there has never been a clear association between aminoglycoside serum concentrations and the development of ototoxicity. While it is believed that neomycin ototoxicity is predominantly cochlear and streptomycin causes vestibular toxicity, all aminoglycosides have the potential for causing either type. Ototoxicity is believed to develop after prolonged use and may not be reversible.

Nephrotoxicity is another well-described adverse reaction to aminoglycoside therapy. Aminoglycosides are taken up by pinocytosis in cells lining the proximal nephron where the drug is concentrated within lysosomes. With no mechanism for intracellular elimination of the aminoglycoside-lysosome complex, the cell swells and bursts. There appears to be a stronger association between aminoglycoside serum concentrations and the occurrence of nephrotoxicity than with ototoxicity. Elevated trough concentrations for a sustained period of time appear to aggravate aminoglycoside nephrotoxicity. Tubular cellular uptake of drug was greater during a continuous 24-hour infusion of aminoglycoside compared with the same dose infused over 30 minutes.[266] In addition, efficacy does not appear to be compromised by administering the aminoglycoside in larger doses at extended intervals.[63]

Because the clinical differences among aminoglycoside antibiotics are subtle, it is likely that cost will remain a significant factor in selecting one agent over another.

Stan Reents, PharmD 6/23/94