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

  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.



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


Tetracyclines and Glycylcyclines

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.


Mechanism of Action

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.

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.

Antimicrobial Activity

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. ...

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