Chapter 58: Aminoglycosides

INTRODUCTION

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.

ABBREVIATIONS

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 ratio of the peak concentration to the organism’s MIC is thus a key predictor of aminoglycoside ...