The first glycylcycline---Tigecycline

Tigecycline is the first glycylcycline that became available for clinical use and is a member of the tetracycline family. The chemical name for tigecycline is (4S,4aS,5aR,12aS)-9-[2-(tert-butylamino)acetamido]- 4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide.Tigecycline is produced by Wyeth under the trade name of Tygacils. The modification of the tetracycline nucleus led to a reduction in tetracycline-specific efflux and ribosomal protection. Similar to other members of the tetracycline class, tigecycline inhibits bacterial protein synthesis through its binding action on the bacterial 30S ribosomal subunits. It is only available for parenteral admission. 

Tigecycline has a spectrum of activity that is similar to that of the tetracyclines, but with more potent in vitro activity against several Gram-positive (e.g. methicillin-resistant Staphylococcus. aureus, vancomycin-intermediate and -resistant enterococci, and penicillin-resistant Streptococcus pneumoniae) and Gram-negative bacteria [e.g. extended-spectrum b-lactamase (ESBL)- producing Enterobacteriaceae]. Furthermore, it is also active against many anaerobic bacteria, as well as atypical pathogens, including rapidly growing, nontuberculous mycobacteria. However, tigecycline has no activity against Pseudomonas aeruginosa and decreased activity to some members of the Enterobacteriaceae, in particular Proteus spp., Providencia spp., and Morganella spp.

MECHANISM OF DRUG ACTION

Tigecycline inhibits protein translation in bacteria by binding to the 30S ribosomal subunit and blocking entry of amino-acyl tRNA molecules into the A site of the ribosome. This prevents incorporation of amino acid residues into elongating peptide chains, thereby inhibiting protein synthesis. This inhibition of protein synthese may occur in wild-type ribosomes and in TetM- and TetO-protected-, tetracycline resistant ribosomes. It is thought that the product of TetM is either unable to disrupt the tight tigecycline–ribosome bond or is unable to interact with the ribosome to allow protein synthesis to occur. There is no association found between the presence of Tet(M) in S. aureus and tigecycline resistance. Additional inhibition of protein synthesis occurs in mitochondria through binding to the 70S ribosomes. This explains the antiparasitic activity, because most parasites contain mitochondria. It has been shown that the glycylcyclines bind 5-fold more strongly to the ribosome than do tetracycline or minocycline and it is likely that this enhanced binding is responsible for overcoming the ribosomal protection mechanism of tetracycline resistance . Moreover, tigecycline appears to interact with both the ribosomal binding site and the A-site in a manner distinct from that of tetracyclines. The interaction between the tetracyclines and the ribosome is reversible, providing an explanation of the bacteriostatic effect.

Drug interactions 

Tigecycline is not a substrate, inhibitor, or inducer of common cytochrome P450 enzymes, therefore such pharmocokinetic drug interactions are unlikely. However, concomitant use with warfarin can decrease the clearance of R-warfarin and S-warfarin by 40% and 25%, respectively, and increase the AUC by 68% and 29%, respectively. Significant changes in international normalized ratio (INR) values have not been shown, but since tigecycline may extend both prothrombin times (PT) and activated partial thromboplastin times (aPTT), regular control of relevant coagulation tests is necessary when tigecycline is administered together with anticoagulation. Furthermore, no significant effect of tigecycline on digoxin pharmacokinetics and pharmacodynamics was reported. Therefore, no dose adjustments are necessary when tigecycline is given together with digoxin.

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