The antimicrobial agents discussed in this chapter may be grouped as:
Bacteriostatic protein-synthesis inhibitors that target the ribosome, such as tetracyclines and gly-cylcyclines, chloramphenicol, macrolides and ketolides, lincosamides (clindamycin), streptogramins (quinupristin/dalfopristin), oxazolidinones (linezolid), and aminocyclitols (spectinomycin).
Agents acting on the cell wall or cell membrane such as polymyxins, glycopeptides (vancomycin and teicoplanin), and lipopeptides (daptomycin).
Miscellaneous compounds acting by diverse mechanisms with limited indications: bacitracin and mupirocin.
TETRACYCLINES AND GLYCYLCYCLINES
The tetracyclines are a series of derivatives of a basic 4-ring structure shown below for doxycycline. Glycylcyclines are tetracycline congers with substituents that confer broad-spectrum activity and activity against bacteria that are resistant to other antibiotics; the available glycylcycline is tigecycline (Tygacil).
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 55-1). 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.
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 aerobic and anaerobic gram-positive and gram-negative bacteria.
Doxycycline, the most important member of the tetracyclines, is a drug of choice for sexually transmitted diseases, rickettsial infections, plague, brucellosis, tularemia, and spirochetal infections, and is also used for treatment of respiratory tract infections including atypical pneumonia pathogens, and for skin and soft-tissue infections caused by community strains of methicillin-resistant Staphylococcus aureus (MRSA), for which minocycline also is effective. Glycylcyclines have activity against bacteria that resistant to the first- and second-generation tetracyclines.
These agents are effective against some microorganisms, such as Rickettsia, Coxiella burnetii, Mycoplasma pneumoniae, Chlamydia spp., Legionella spp., Ureaplasma, some atypical mycobacteria, and Plasmodium spp., that are resistant to cell-wall-active antimicrobial agents. The tetracyclines are active against many spirochetes, including Borrelia recurrentis, Borrelia burgdorferi (Lyme disease), Treponema pallidum (syphilis), and Treponema pertenue. Demeclocycline, tetracycline, minocycline, and doxycycline are available in the U.S. for systemic use. Resistance of a bacterial strain to any 1 member of the class may or may not result in cross-resistance to other tetracyclines. Tigecycline ...