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INTRODUCTION

The agents discussed in this chapter are bacteriostatic protein synthesis inhibitors that target the ribosome, including tetracyclines and their modern derivatives; macrolides; lincosamides; streptogramins (quinupristin/dalfopristin); oxazolidinones; and pleuromutilins.

ABBREVIATIONS

Abbreviations

CYP: cytochrome P450

HIV: human immunodeficiency virus

MAI: Mycobacterium avium-intracellulare

MRSA: methicillin-resistant Staphylococcus aureus

MSSA: methicillin-sensitive Staphylococcus aureus

TETRACYCLINES AND DERIVATIVES

The tetracyclines are a series of derivatives of a basic four-ring structure (shown for doxycycline). Demeclocycline, tetracycline, minocycline, and doxycycline are available in the U.S. for systemic use. In the last two decades, tetracycline derivatives engineered to overcome resistance mechanisms have been introduced. Glycylcyclines (tigecycline), fluorocyclines (eravacycline), and aminomethylcyclines (omadacycline) are tetracycline congeners with substituents that confer broad-spectrum activity including against tetracycline-resistant bacteria.

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Mechanism of Action

Tetracyclines and their derivatives inhibit bacterial protein synthesis by binding to the 30S bacterial ribosome and preventing access of aminoacyl tRNA to the acceptor (A) site on the mRNA-ribosome complex (Figure 60–1). These drugs enter gram-negative bacteria by passive diffusion through channels formed by porins in the outer cell membrane and by active transport that pumps tetracyclines across the cytoplasmic membrane.

Figure 60–1

Inhibition of bacterial protein synthesis by tetracyclines. mRNA attaches to the 30S subunit of bacterial ribosomal RNA. The P (peptidyl) site of the 50S ribosomal RNA subunit contains the nascent polypeptide chain; normally, the aminoacyl tRNA charged with the next amino acid (aa) to be added moves into the A (acceptor) site, with complementary base pairing between the anticodon sequence of tRNA and the codon sequence of mRNA. Tetracyclines bind to the 30S subunit, block tRNA binding to the A site, and thereby inhibit protein synthesis.

Antimicrobial Activity

Tetracyclines are typically bacteriostatic antibiotics with a spectrum of activity that encompasses a wide array of bacteria. Tetracyclines are intrinsically more active against gram-positive than gram-negative microorganisms, largely due to the ability of gram-negatives to efflux tetracyclines. Recent data from the U.S. on the activity of tetracyclines and other agents are displayed in Table 60–1. Activity against Streptococcus pyogenes and penicillin-susceptible Streptococcus pneumoniae is good, but resistance is common among group B streptococci and penicillin-resistant S. pneumoniae. Good activity is maintained against both methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA). Activity against enterococci improves with later-generation agents; tigecycline and eravacycline have good activity against multidrug-resistant enterococcal isolates. Bacillus anthracis is typically susceptible.

TABLE 60–1ACTIVITY OF SELECTED ANTIMICROBIALS AGAINST KEY GRAM-POSITIVE PATHOGENS

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