PROCEEDINGS P APER Tigecycline: A Review of Properties, Applications, and Analytical Methods Luce ´lia Magalha ˜es da Silva, MSc* and He ´rida Regina Nunes Salgado, PhD*† Abstract: Tigecycline is a new glycylcycline with an expanded broad-spectrum antibiotic, including inhibition of Gram-positive, Gram-negative, atypical, anaerobic, and antibiotic-resistant organ- isms. Trials have demonstrated that tigecycline is noninferior to the comparators for the treatment of complicated skin and skin structure infections as well as complicated intra-abdominal infections. Tige- cycline is only available as an intravenous preparation and analytical methods to its quantitation in pharmaceutical products has not been published to date. This review examined tigecycline characteristics, the spectrum and mechanism of action, pharmacokinetics, applica- tions, and, mainly, the instrumental conditions of published chro- matographic methods used to measure tigecycline, its metabolites, and some analogs in clinical and biologic research. Key Words: glycylcycline, tigecycline, analytical methods, broad- spectrum antibiotic (Ther Drug Monit 2010;32:282–288) INTRODUCTION Over the past several years, there has been growing con- cern about the increase prevalence of antimicrobial resistance, particularly concerning among Gram-positive pathogens are the increased rates of penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant enterococci, and methicillin- resistant Staphylococcus aureus. Among multridrug-resistant Gram-negative pathogens, extended-spectrum beta-lactamase- producing bacteria are particularly problematic because of the lack of treatment options and poor outcomes in serious infec- tions caused by such organisms. 1–4 The emergence of clinical resistance to previously active antibacterial agents among many clinically significant bacterial species has showed a sig- nificant impact on empiric therapy choices available to the prescribing clinician. 4–7 There is a need to develop new agents that overcome existing mechanisms of resistance displayed by multidrug- resistant bacteria. 8 Glycylcyclines, discovered in 1993, are structural analogs of tetracycline designed to avoid resistance mediated by efflux and ribosomal protection. 9 Tigecycline, a novel, first-in-class glycylcycline and an analog of the semi- synthetic antibiotic minocycline, is a potent, broad-spectrum antibiotic that acts by inhibition of protein translation in bacteria. 10 Several large-scale evaluations of many types of bacteria indicate that tigecycline is highly active in vitro against most common Gram-positive and Gram-negative pathogens, anae- robes, and atypical pathogens, including those frequently demonstrating resistance to multiple classes of antimicrobials such as methicillin-resistant S. aureus, vancomycin-resistant enterococci, and extended-spectrum beta-lactamase-producing Klebsiella pneumoniae, Escherichia coli, and Acinetobacter baumanii. 11,12 It is indicated for the treatment of complicated skin and skin structure infections and complicated intra- abdominal infections caused by susceptible strains of bacteria. 13 Tigecycline exhibits robust activity against bacterial isolates resistant to other antibiotic classes, including beta- lactams and fluoroquinolones, while resisting deactivation by most of the known tetracycline resistance mechanisms found in clinically significant bacteria. 14 This antibiotic has been evaluated as monotherapy for serious infections in human clinical trials as a result of its microbiologic, pharmacody- namic, and pharmacokinetic properties. 9,15 Full review summarizing the mode and spectrum of action, clinical applications, pharmacokinetics, and analytical methods to tigecycline has not been presented to date. In this context, this report describes the tigecycline properties and characteristics of the available analytical methods to evaluation of this drug. CHEMICAL STRUCTURE Research into the glycylcycline class of antibiotics, which possesses the four-ring carbocyclic skeleton of the tetracyclines, began in the early 1990s, when it was discovered that the addition of a modified (bulky) glycylamido moiety to the D ring overcame both efflux (from the added bulk of the glycycline agents) and the ribosomal-type resistant (from improved affinity to ribosomal mutations). 16–18 Tigecycline is structurally derived from minocycline by adding a tert-butyl- glycylamido side chain to carbon 9 of the D ring of the tetra- cycline backbone. 17 Figure 1 depicts the structural formulas of minocycline and tigecycline. 3 Chemically, tigecycline is ([4S,4aS,5aR,12aS]-9-[2-tert-butylaminoacetylamino]-4,7-bis- dimethylamino-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a, 5,5a,6,11,12a-octahydronaphthacene-2-carboxamide). Its Received for publication March 14, 2010; accepted March 14, 2010. From the *Postgraduate Program in Pharmaceutical Sciences; and †Department of Drugs and Medicines, Faculty of Pharmaceutical Sciences of Araraquara-UNESP, Araraquara-SP, Brazil. Correspondence: He ´rida Regina Nunes Salgado, PhD, Programa de Po ´s- graduac xa ˜o em Cie ˆncias Farmace ˆuticas, Faculdade de Cie ˆncias Farm- ace ˆuticas de Araraquara, UNESP, Rodovia Araraquara-Jau ´, km 1, CEP 14801-902, Araraquara, SP, Brazil (e-mail: salgadoh@fcfar.unesp.br). Copyright Ó 2010 by Lippincott Williams & Wilkins 282 Ther Drug Monit  Volume 32, Number 3, June 2010