The small-molecule agents discussed in this chapter—aminoglycosides, polymyxins, and urinary antiseptics—primarily target gram-negative bacteria and have a limited set of clinical applications due to their toxicities and pharmacokinetic properties. Additionally, we discuss the (re-)emerging application of phages in infectious diseases therapeutics.
AUC: area under the curve
CMS: colistin methanesulfonate
CNS: central nervous system
CsCl: cesium chloride
CSF: cerebrospinal fluid
FDA: Food and Drug Administration
G6PD: glucose-6-phosphate dehydrogenase
MIC: minimal inhibitory concentration
mRNA: messenger RNA
PFU: plaque-forming units
PO: by mouth
UTI: urinary tract infection
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 and plazomicin (derivatives of sisomicin) are semisynthetic products.
Aminoglycosides (gentamicin, tobramycin, amikacin, netilmicin, plazomicin, 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. Most commonly, resistance is due to aminoglycoside-modifying enzymes or impaired accumulation of drug at the target site; 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 59–1). 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, although the relative propensities for toxicity vary somewhat among the agents.
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. AC, acetylase; AD, adenylase.