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INTRODUCTION

ORIGINS

Aminoglycosides are natural products or semisynthetic derivatives of compounds produced by a variety of soil actinomycetes. Streptomycin was first isolated from a strain of Streptomyces griseus. Gentamicin and netilmicin are derived from species of the actinomycete Micromonospora. The difference in spelling (-micin) compared with the other aminoglycoside antibiotics (-mycin) reflects this difference in origin. Tobramycin is one of several components of an aminoglycoside complex known as “nebramycin” that is produced by Streptomyces tenebrarius. It is most similar in antimicrobial activity and toxicity to gentamicin. In contrast to the other aminoglycosides, amikacin, a derivative of kanamycin, and netilmicin, a derivative of sisomicin, are semisynthetic products.

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.

Aminoglycosides (gentamicin, tobramycin, amikacin, netilmicin, kanamycin, streptomycin, paromomycin, and neomycin) are used primarily to treat infections caused by aerobic gram-negative bacteria. Streptomycin and amikacin are important agents for the treatment of mycobacterial infections, and paromomycin is used orally for intestinal amebiasis. 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 aminoglycoside-metabolizing enzymes or impaired transport of drug into the cell; these mechanisms may confer resistance to all aminoglycosides or only select agents. Resistance genes are frequently acquired via plasmids or transposons.

Aminoglycosides contain amino sugars linked to an aminocyclitol ring by glycosidic bonds (Figure 58–1). 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 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.

Figure 58–1

Aminoglycoside structure and sites of activity of plasmid-mediated enzymes capable of inactivating aminoglycosides. Tobramycin is shown as a representative; structural characteristics protect some aminoglycosides from the actions of some of these enzymes, explaining differences in spectrum of activity.

ABBREVIATIONS

Abbreviations

AC: acetylase

AD: adenylase

ADME: absorption, distribution, metabolism, excretion

CNS: central nervous system

CSF: cerebrospinal fluid

GI: gastrointestinal

IM: intramuscular

IV: intravenous

MIC: minimum inhibitory ...

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