Тигециклин

Описание

The emergence of drug-resistant bacteria has diminished the clinical utility of the tetracyclines. Research to circumvent the efflux and ribosomal protection mechanisms of bacteria has led to the development of the glycylcyclines. Tigecycline is the first glycylcycline antibiotic to launch for the parenteral treatment of baterial infection, including complicated intra-abdominal and skin infections. Its mechanism of action involves inhibiting 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 to effectively prevent incorporation of amino acid residues into elongating peptide chains. Presumably, ribosomal protection proteins are ineffective against tigecycline due to its higher affinity for ribosomal binding compared to tetracyclines (approximately 16-fold). In addition, tigecycline may be resistant to efflux mechanisms by either their inability to translocate it across the cytoplasmic membrane due to steric complications or simply by their failure to recognize the molecule.

Химические свойства

Orange Solid

Использование

Tigecycline is a semi-synthetic tetracycline prepared by the introduction of a tert-butylaminoacetamido group into a previously unexplored and un-substituted region of existing tetracyclines. Like other tetracyclines, tigecycline acts by reversibly binding to the 30S ribosomal subunit and inhibits protein translation by blocking entry of aminoacyl-tRNA into the ribosome A site. The enhanced activity can be attributed to stronger binding affinity, thus minimising the impact of existing mechanisms of resistance. Tigecycline is regarded as the first of a new class of glycylcyline antibiotics. Critical comparison to the tetracycline class appears to be lacking in the literature.

Определение

ChEBI: Tetracycline in which the hydroxy group at position 5 and the methyl group at position 6 are replaced by hydrogen, and with a dimethylamino substituent and an (N-tert-butylglycyl)amino substituent at positions 7 and 9, respe tively. A glycylcycline antibiotic, it has activity against a broad range of Gram-positive and Gram-negative bacteria, including tetracycline-resistant organisms. It is used for the intravenous treatment of complicated skin and skin structure infections ca sed by susceptible organisms.

Антимикробная активность

It is as potent as, or more potent than, earlier tetracyclines and activity is retained against strains expressing acquired tetracycline resistance determinants. It displays better activity than tetracycline, doxycycline or minocycline against Streptococcus spp. and against Enterococcus faecalis and E. faecium. Among Gram-negative organisms it displays improved activity against Citrobacter freundii, Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, Salmonella spp., Serratia marcescens and Shigella spp. The spectrum includes rapidly growing mycobacteria. Ps. aeruginosa, Pr. mirabilis, other Proteus spp. and some strains of Corynebacterium jeikeium are resistant. Activity against strains expressing acquired resistance to earlier tetracyclines is attributed to failure of the MFS efflux pumps to recognize tigecycline, and to a novel mechanism of ribosome binding that permits tigecycline to overcome ribosomal protection mechanisms.
Comparative susceptibility data for some atypical pathogens are not available. However, in common with earlier tetracyclines, it is active against Chlamydophila and Mycoplasma spp. and rapidly growing Mycobacteria spp. It is less active than minocycline or tetracycline against U. urealyticum.

Общее описание

Tigecycline (Tygacil) is a first-in-class (a glycylcycline) intravenousantibiotic that was designed to circumvent manyimportant bacterial resistance mechanisms. It is not affectedby resistance mechanisms such as ribosomal protection, effluxpumps, target site modifications, β-lactamases, or DNAgyrase mutations. Tigecycline binds to the 30S ribosomalsubunit and blocks peptide synthesis. The glycylcyclinesbind to the ribosome with five times the affinity of commontetracyclines. Tigecycline also possesses a novel mechanismof action, interfering with the mechanism of ribosomal protectionproteins. Tigecycline, unlike common tetracyclines,is not expelled from the bacterial cell by efflux pumpingprocesses.
Tigecycline is recommended for the treatment of complicatedskin and skin structure infections caused by E. coli,E. faecalis (vancomycin-susceptible isolates), S. aureus(methicillin-susceptible and methicillin-resistant isolates),S. pyogenes, and B. fragilis among others. Tigecycline is alsoindicated for complicated intra-abdominal infections causedby strains of Clostridium, Enterobacter, Klebsiella, andBacteroides. To reduce the development of resistance to tigecycline,it is recommended that this antibiotic be used onlyfor those infections caused by proven susceptible bacteria.Glycylcyclines are structurally similar to tetracyclines,and appear to have similar adverse effects. These mayinclude photosensitivity, pancreatitis, and pseudotumorcerebri. Nausea and vomiting have been reported.

Фармацевтические приложения

9-T-butylglycylamido-minocycline. A compound of the glycylcycline class available as a powder for intravenous infusion.

Фармакокине?тика

C_max 100 mg intravenous infusion (1 h): 0.85–1 mg/L
Plasma half-life: 37–67 h
Volume of distribution: 7–10 L/kg
Plasma protein binding: 68%
Distribution and excretion
It is widely distributed and is concentrated in the gallbladder, colon and lung. The volume of distribution is dose related and variable, but is generally greater than that of older tetracyclines. CSF penetration is poor. Tigecycline is excreted in the feces and urine predominantly as the unchanged molecule. The elimination half-life is long (37–67 h). Tigecycline clearance is decreased by 20% in patients with renal failure. No dosage adjustments are apparently necessary for tigecycline in patients with renal impairment.

Клиническое использование

Complicated skin and skin structure infections
Complicated intra-abdominal infections
Community-acquired bacterial pneumonia
Recommended principally for the treatment of infections with multiresistant organisms.

Побочные эффекты

Side effects typical of the group, including nausea, vomiting, diarrhea and headache, occur. Occasional cases of pancreatitis, hypoproteinemia, antibiotic-associated colitis and thrombocytopenia have also been reported.