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The agents discussed in this chapter are grouped by their antibacterial mechanism as
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bacteriostatic protein synthesis inhibitors that target the ribosome, such as tetracyclines, macrolides, lincosamides, streptogramins (quinupristin/dalfopristin), and oxazolidinones (e.g., linezolid);
bactericidal agents acting on the cell wall or cell membrane, such as polymyxins, glycopeptides (e.g., vancomycin), and lipopeptides (daptomycin); and
miscellaneous agents acting by diverse mechanisms, such as metronidazole, bacitracin, and mupirocin.
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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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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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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. ...