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INTRODUCTION

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The agents discussed in this chapter are grouped by their antibacterial mechanism as

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  1. bacteriostatic protein synthesis inhibitors that target the ribosome, such as tetracyclines, macrolides, lincosamides, streptogramins (quinupristin/dalfopristin), and oxazolidinones (e.g., linezolid);

  2. bactericidal agents acting on the cell wall or cell membrane, such as polymyxins, glycopeptides (e.g., vancomycin), and lipopeptides (daptomycin); and

  3. miscellaneous agents acting by diverse mechanisms, such as metronidazole, bacitracin, and mupirocin.

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ABBREVIATIONS

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Abbreviations

ADME: absorption, distribution, metabolism, excretion

AUC: area under the curve

CMS: colistin methanesulfonate

CNS: central nervous system

CYP: cytochrome P450

FDA: Food and Drug Administration

HIV: human immunodeficiency virus

IV: intravenous

MAI: Mycobacterium avium-intracellulare

MAO: monoamine oxidase

MIC: minimum inhibitory concentration

MRSA: methicillin-resistant Staphylococcus aureus

MSSA: methicillin-sensitive Staphylococcus aureus

PCN-R: penicillin-resistant

PCN-S: penicillin-susceptible

PO: by mouth

SSRI: selective serotonin reuptake inhibitor

USP: U.S. Pharmacopeia

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PROTEIN SYNTHESIS INHIBITORS THAT TARGET THE RIBOSOME

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Tetracyclines and Glycylcyclines

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The tetracyclines are a series of derivatives of a basic four-ring structure shown next for doxycycline. Demeclocycline, tetracycline, minocycline, and doxycycline are available in the U.S. for systemic use. Glycylcyclines are tetracycline congers with substituents that confer broad-spectrum activity and activity against tetracycline-resistant bacteria; the currently available glycylcycline is tigecycline.

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Mechanism of Action
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Tetracyclines and glycylcyclines 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 59–1). 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.

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Figure 59–1

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.

Graphic Jump Location
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Antimicrobial Activity
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Tetracyclines are bacteriostatic antibiotics with activity against a wide range of bacteria. Tetracyclines intrinsically are more active against gram-positive than gram-negative microorganisms. Recent data from the U.S. on the activity of tetracycline and other agents are displayed in Table 59–1. Activity against Streptococcus pyogenes and penicillin-susceptible Streptococcus pneumoniae is good, but resistance is common in group B streptococci and penicillin-resistant S. pneumoniae. Excellent activity is maintained against both MSSA and MRSA. Activity against enterococci is limited. Doxycycline and minocycline can be active against some tetracycline-resistant isolates. Bacillus anthracis and Listeria ...

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