Tigecycline - A Novel Expanded Spectrum Antibiotic for the Treatment of Serious Infections
Correspondence Address :
Dr. Jimmy B,Department of Pharmacy Practice,Manipal College of Pharmaceutical Sciences,
Manipal University, Manipal, Karnataka, India 576 104
Ph. 91-820-2922403 Fax 91-820-2571998
E-mail : firstname.lastname@example.org
Resistance to presently available antibiotics is increasing at an alarming rate, and the same proves to be a major hurdle in the treatment of infections, especially serious infections, where organisms with a wide range of antibacterial resistance are frequently present. The drug discovery sector is concentrating on developing antibiotics with a broader antibiotic coverage to overcome the existing resistance mechanisms displayed by organisms. Tigecycline is a member of a new class of antibiotics named glycylcyclines. This is an antibiotic class related to tetracyclines and has the above mentioned properties. This new drug has been shown to confer broad antibiotic coverage and prove effective against many species of multidrug-resistant organisms. The drug was approved by the US Food and Drug Administration for the treatment of complicated skin and skin structure infections and complicated intra-abdominal infections in June 2005. Tigecycline has been efficacious and well tolerated in clinical studies. The drug is not currently available in India. It will be a welcome addition to the current armamentarium for the treatment of serious infections.
Tigecycline, expanded spectrum antibiotic, glycylcyclines, serious infections.
Highly resistant strains of both gram-positive and gram-negative bacteria are becoming commonplace in both the inpatient and the outpatient setting. The changing pattern of antimicrobial resistance among bacteria that commonly cause serious infections present difficult challenges for health care professionals (1).There is an urgent need to develop new antimicrobial agents due to increasing prevalence and spread of multidrug-resistant bacteria that are commonly responsible for serious and life threatening disease. Focus on developing agents that effectively overcome mechanisms of resistance displayed by bacteria to currently available drugs is equally important (2).
Tigecycline, the first in a new class of antibiotics, the glycylcyclines, which is an antibiotic class related to tetracylines, is an analogue of minocycline and has been designed to overcome many existing mechanisms among bacteria mediating resistance to tetracyclines. It confers broad antibiotic coverage against gram negative and gram positive bacteria with activity against vancomycin-resistant enterococci, methicillin resistant S aureus, and many species of multidrug-resistant gram negative bacteria (3).In June 2005, the US Food and Drug Administration approved the use of tigecyline for the treatment of skin, soft tissue, and intra-abdominal infections.
Chemically, the broader spectrum of activity of glycylcyclines is attributed to the substitution of an N-alkyl-glycylamido group at the 9 position on the D ring of the central 4 ring carbocyclic skeleton that is essential for antibacterial activity. The same substitution creates the ability of this group of agents to overcome most tetracycline resistance mechanisms. Tigecyclineâ€™s molecular weight is 585.65 Da and its chemical formula is C29H39N5O8 (4).
Glycylcyclines are bacteriostatic, and they act by binding to the bacterial 30S ribosomal subunit and by blocking the entry of amino-acyl tRNA molecules to the A site of the ribosome. This ultimately results in inhibition of protein synthesis (5),(6). Two major determinants of tetracycline resistance, active efflux of the drug from inside the bacterial cell and protection of ribosomes, are overcome by tigecycline as a result of steric hindrance produced by the large substituent at position 9 (6),(7),(8). Tigecycline has been reported to exhibit invitroantimicrobial activity against gram-positive bacteria, gram-negative bacteria, anaerobes and some atypical organisms.
Considering the pharmacokinetics of the drug, elimination half life of the parent compound was 42.4 hours after administration of multiple doses of tigecycline 100 mg initially, followed by 50 mg every 12 hours intravenously (IV). Studies have revealed that tigecycline has a large volume of distribution (7 to 9 l/kg). This suggests extensive distribution into the tissues. In invitro studies, plasma protein binding was 71% to 89%. Tigecycline is not extensively metabolized.
Approximately 33% of tigecycline is eliminated through the kidneys with 22% of the total dose excreted as unchanged drug. Approximately, 59% is eliminated by biliary/ fecal excretion.
Reduced systemic clearance of the drug was observed in moderateor severe hepatic impairment. Therefore, the product labeling recommends an initial 100 mg loading dose followed by a reduced maintenance dose of 25 mg every 12 hours for patients with severe hepatic impairment. No alterations in pharmacokinetics occurred in patients with severe renal impairment. The dosage adjustments are therefore not needed in this population (9).
Efficacy and safety
Data generated regarding the efficacy and safety of tigecycline during clinical trials are promising. The<
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