Tetracyclines

TetracyclinesAuthorD Byron May, PharmD, BCPSSection EditorDavid C Hooper, MDDeputy EditorElinor L Baron, MD, DTMHDisclosuresAll topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Oct 2012. | This topic last updated: May 11, 2012.

INTRODUCTION — Chlortetracycline was the first tetracycline discovered, in 1948. Since then five additional tetracyclines have been isolated or derived (oxytetracycline, tetracycline, demeclocycline, doxycycline and minocycline), but only the last four are available for systemic use in the United States. Of these four agents, doxycycline and minocycline are the most frequently prescribed. Research to find tetracycline analogues lead to the development of the glycylcyclines. Tigecycline is the first of this new class of agents and exhibits broad-spectrum antibacterial activity similar to the tetracyclines [1].

Doxycycline is one of the most active tetracyclines and is the most often used clinically since it possesses many advantages over traditional tetracycline and minocycline. Doxycycline can be administered twice daily, has both intravenous (IV) and oral (PO) formulations, achieves reasonable concentrations even if administered with food, and is less likely to cause photosensitivity [2]. Doxycycline may be an alternative for use in children since it binds calcium to a lesser extent than tetracycline, which can cause tooth discoloration and bony growth retardation.

MECHANISM OF ACTION — The tetracyclines enter the bacterial cell wall in two ways: passive diffusion and an energy-dependent active transport system, which is probably mediated in a pH-dependent fashion. Once inside the cell, tetracyclines bind reversibly to the 30S ribosomal subunit at a position that blocks the binding of the aminoacyl-tRNA to the acceptor site on the mRNA-ribosome complex. Protein synthesis is ultimately inhibited, leading to a bacteriostatic effect [3].

RESISTANCE — In contrast to many other antibiotics, tetracyclines are infrequently inactivated biologically or altered chemically by resistant bacteria. Resistance to these agents develops primarily by preventing accumulation of the drug inside the cell either by decreasing influx or increasing efflux. Once resistance develops to one of the drugs in this class, it is typically conferred to all tetracyclines.

However, there are differences in resistance among species of bacteria. Resistance genes to tetracyclines often occur on plasmids or other transferable elements such as transposons [4].

Bacteria carrying a ribosome protection type of resistance gene produce a cytoplasmic protein that interacts with the ribosomes and allows the ribosomes to proceed with protein synthesis even in the presence of high intracellular levels of the drug [4,5].

Tigecycline has a reduced potential for resistance, as it is not affected by the two major mechanisms of tetracycline resistance: ribosomal protection proteins and efflux pumps [6]. Thus, tigecycline may have activity against tetracycline-resistant organisms [7,8].