Lavoro svolto da Roberta Clari ed Alessio Testore
Description
Tigecycline is a semisynthetic derivate of minocycline; it is the first glycylcycline antibiotic to reach the clinic and has several unique features that warrant its consideration apart from the older tetracyclines.
Indications
Tigecycline is FDA for treatment of skin and skin-structure infection and intra-abdominal infections; opposite to older tetracyclines its concentrations in the urine are relatively low, so it has no indication for urinary tract infections because it may not be effective for them.
The efficacy and safety of tigecycline in the treatment of skin and skin-structure infections: results of 2 double-blind phase 3 comparison studies with vancomycin-aztreonam. 2005
The efficacy and safety of tigecycline for the treatment of complicated intra-abdominal infections: analysis of pooled clinical trial data. 2005
Should tigecycline be considered for urinary tract infections? A pharmacokinetic re-evaluation. 2010
Thanks to the substitution at the D-9 position, its spectrum is very broad and it is active against a wide variety of multidrug-resistant nosocomial pathogens: coagulase-negative staphylococci and Staphylococcus aureus (including methicillin-resistant, vancomycin -intermediate, and vancomycin-resistant strains); streptococci, penicillin-susceptible and resistant; enterococci (including vancomycin-resistant strains); gram-positive rods; enterobacteriaceae (including Klebsiella); multi-drug-resistant strains of Acinetobacter spp; anaerobes, both gram-positive and gram-negative; atypical agents, rickettsiae, chlamydia, and legionella; and rapidly growing mycobacteria all are susceptible. Proteus and P. aeruginosa, however, are intrinsically resistant.
Tigecycline activity tested against multidrug-resistant Enterobacteriaceae and Acinetobacter spp. isolated in US medical centers (2005-2009). 2011
Tigecycline may be considered a second-third choice antibiotic, useful in serious infections and in multi-drug resistance diseases.
Successful treatment of pan-resistant Klebsiella pneumoniae pneumonia and bacteraemia with a combination of high-dose tigecycline and colistin. 2010
Pharmacokinetics
Tigecycline is poorly absorbed orally and must be administered intravenously. It has an excellent tissue and intracellular penetration and a quite large volume of distribution; elimination is primarily biliary, and no dosage adjustment is needed for patients with renal insufficiency.It can cross the placenta and be excreted in milk.
It has a half-life of 36 hours and attains steady-state levels in serum by day 7.
Molecular Mechanism
As the others tetracyclines, tigecycline inhibits bacterial protein synthesis by binding to and interfering with ribosomes.
In details it enters microorganisms in part by passive diffusion and in part by an energy-dependent process of active transport. Susceptible cells concentrate the drug intracellularly. Once inside the cell, tigecycline binds reversibly to the 30S subunit of the bacterial ribosome, blocking the binding of aminoacyl-tRNA to the acceptor site on the mRNA-ribosome complex. This prevents addition of amino acids to the growing peptide.
Side Effects
The chief adverse effect of tigecycline is nausea and occasionally vomiting due to direct local irritation of the intestinal tract with modification of physiological flora; it occurs in up to one third of patients but neither nausea or vomiting usually requires discontinuation of the drug.
Because of its binding to calcium deposited in newly formed bone or teeth in young children, it may cause fluorescence, discoloration, and enamel dysplasia in teeth or deformity or growth inhibition in bones. That’s why tigecycline is usually avoided in pregnancy.
It can raise aPTT, PT and occasionally INR, and reduce Warfarin clearance.
Finally it is related to photosensitization and vestibular reactions such as dizziness and vertigo.
Intravenous injection can lead to venous thrombosis.
Toxicity
Liver toxicity has been described especially during pregnancy, in patients with preexisting hepatic insufficiency and when high doses are given intravenously.
Resistance
Because of overuse, tetracyclines’ resistance is common. Three mechanisms have been described: (1) impaired influx or increased efflux by an active transport protein pump (tetracycline resistance determinants Tet A-E in gram-negative species and Tet K efflux pump of stafilococci); (2) ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome (Tet M in gram-positives); and (3) enzymatic inactivation.
Tigecycline is not a substrate of these efflux pumps and thanks to its bulky t-butylglycylamido substituent, has a steric hindrance effect on Tet(M) binding to the ribosome, so it can be used in case of tetracyclines’ resistance.
However it is a substrate of the chromosomally encoded multidrug efflux pumps of Proteus species, and Pseudomonas aeruginosa which are actually resistant to all tetracyclines.
First case of resistance to tigecycline by Klebsiella pneumoniae in a European University Hospital. 2011
