Tigecycline

Tigecycline evades the Tet(A-E) efflux pumps, which account for most acquired resistance to tetracycline and minocycline in Enterobacteriaceae and Acinetobacter spp. Tigecycline binds to bacterial ribosomes that have been modified by the Tet(M) protein, a mechanism that compromises all available tetracyclines, and which is frequent in Gram-positive cocci and Neisseria spp. Tigecycline remains vulnerable to the chromosomally-encoded multidrug efflux pumps of Proteeae and Pseudomonas aeruginosa, and to Tet(X), a tetracycline-degrading mono-oxygenase found, albeit rarely, in Bacteroides spp. Tigecycline MICs for enterococci, staphylococci, and streptococci are mostly 0.06–0.25 mg/L, again with little or no skew to the distribution. Tigecycline is prone to oxidation, and MIC values, particularly for the most susceptible isolates, may be raised if the drug is added to broth that has become oxygenated during storage, or if drug-containing media are stored before inoculation. ^[1] Tigecycline is a poor substrate for tetracycline-specific efflux pumps, and it still attaches to ribosomes that have been modified by the Tet(M) protein. Tigecycline has demonstrated activity against a wide variety of gram-positive and gram-negative pathogens, including multidrug-resistant strains. Tigecycline is active against many gram-positive and -negative organisms, including methicillin-resistantStaphylococcus aureus, vancomycin-intermediate and -resistant enterococci, and extended-spectrum β-lactamase–producing Escherichia coli and Klebsiella pneumoniae. Tigecycline exhibits antibacterial activity against a wide spectrum of aerobic and anaerobic bacteria. ^[2] Tigecycline is a broad-spectrum, protein-inhibiting, antibacterial agent possessing activity against strains resistant to other chemotherapeutic agents. Tigecycline demonstrates in vitro activities against the GISA and the methicillin-resistant and methicillin-susceptible staphylococcal strains tested (MICs at which 90% of isolates tested are inhibited [MIC90s], 0.5 to 1 μg/ml). Tigecycline has MIC90s of 0.25 μg/ml for all of the S. pneumoniae strains and demonstrates similar activities against all of the S. pneumoniae strains tested. ^[3]

Tigecycline is bactericidal against methicillin-susceptible S. aureus (MSSA) in the rabbit osteomyelitis model and exhibits good, but not excellent, activity in Legionellapneumophila pneumonia in guinea pigs^[1]. Tigecycline at 50 mg/kg twice daily was not toxic to mice. Tigecycline is effective in inhibiting NSCLC growth in vivo through decreasing proliferation and increasing apoptosis of tumor cells^[4].

NSCLC cells were treated with DMSO (as control) or different concentrations of tigecycline for 3 days prior to 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) and apoptosis assays. After 24 h of treatment with tigecycline, cells were harvested for the measurement of mitochondrial functions.

• [1] Livermore DM, et al. J Antimicrob Chemother, 2005, 56(4), 611-614.
• [2] Stein GE, et al. Clin Infect Dis, 2006, 43(4), 518-524.
• [3] Petersen PJ, et al. Antimicrob Agents Chemother, 2002, 46(8), 2595-2601.

• [4] Jia X, et al. Fundam Clin Pharmacol. 2016, 30(4):297-306.

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