By Jessica C. Song, MA, PharmD, and Hyunah Eom, PharmD
Jessica Song is Assistant Professor of Pharmacy Practice, University of the Pacific, Stockton, CA. Pharmacy Clerkship and Coordinator, Santa Clara Valley Medical Center, is associate editor of Infections Disease Alert; and Hyunah Eom is a Resident at Santa Clara Valley Medical Center
Dr. Song and Dr. Eom report no consultants, stockholders, speaker’s bureaus, research, or other financial relationships with companies having ties to this field of study.
Over the past decade, there has been growing concern about the magnitude of antimicrobial resistance, particularly among gram-positive organisms such as penicillin-resistant Streptococcus pneumoniae, methicillin-resistant staphylococci, and vancomycin-resistant enterococci.1 In light of the fact that at least 3 cases of vancomycin-resistant Staphylococcus aureus infection have been described in the United States, the need for new antimicrobial agents is greater than ever.2,3 A recent report highlighted the slowing of antibiotic drug development expansion, as new antimicrobial agents comprised 6 of 506 drugs under development by major biotechnology and pharmaceutical companies.1 Agents such as daptomycin, linezolid, and quinupristin/dalfopristin are available for the management of drug-resistant gram-positive infections, but resistance to these agents has been reported,4,5 and serious adverse effects such as myopathy,6 myelosuppression,7 and arthralgia8 have been associated with the use of these drugs.
Although the tetracycline class of antimicrobials has been in place for 60 years, widespread development of resistance has significantly limited the use of tetracyclines in the treatment of many infections.1 Structural manipulations of the tetracycline molecule resulted in the development of a more stable class of compounds, the glycylcyclines.1 Reversible binding of glycylcyclines to the 30S subunit of the bacterial ribosome occurs following entry into the bacterial cell through either passive diffusion or energy-dependent pathways. This reversible binding blocks the incorporation of transfer RNA into the ribosome and, ultimately, disrupts protein synthesis.9 Tigecycline, the first glycylcycline agent to be marketed in the United States, was approved by the FDA on June 16, 2005, for use in the treatment of adults with complicated skin/skin structure infections and complicated intra-abdominal infections.1 This article will: 1) review the pharmacology, pharmacokinetics, and FDA indications of tigecycline, 2) review its drug interactions, dosage, and resistance patterns, and 3) review the safety and efficacy of tigecycline.
Spectrum of Activity
Tigecycline exhibits in vitro activity against the majority of gram-positive and gram-negative aerobes, as well as anaerobes and some atypical organisms.1 Table 1 lists the minimum concentrations required to inhibit 90% of clinically encountered bacteria (MIC90), as well as the FDA-established MIC breakpoints for susceptibility to tigecycline for selective organisms. Of note, tigecycline has limited activity against strains of Proteus mirabilis, Providencia, Pseudomonas aeruginosa, Serratia marcescens, and Legionella pneumophila.1
Pharmacologic/Other Clinical Properties of Tigecycline
Table 2 summarizes the mechanism of action, spectrum of activity, FDA indications, pharmacokinetics, dosing/administration, contraindications, adverse effects, drug interactions, resistance patterns, and cost of tigecycline.
Clinical Efficacy of Tigecycline
A review of the literature showed that most clinical studies to date have been presented as posters at various conferences. A pooled analysis of 2 Phase III randomized, double-blind, active-controlled, multinational, multicenter studies compared the efficacy of tigecycline with that of combined therapy with vancomycin 1 g IV q 12 h/aztreonam 2 g IV q 12h in hospitalized patients with complicated skin and skin structure infections.10,12 Patients randomized to receive tigecycline were administered a 100 mg IV loading dose, followed by 50 mg IV q 12h. Patients with complicated deep soft tissue infections including wound infections and cellulitis (10 cm, necessitating surgery/drainage or with complicated underlying disease), infected ulcers with evidence of an acute infection, infected burns, infected human, or animal bites, major abscesses (complicated or extensive), superficial infections, or abscesses with a high risk of infection due to gram-negative or anaerobic pathogens, and infected ulcers were enrolled in the studies. Deep soft tissue infection with cellulitis represented the most common diagnosis. The primary end point was the clinical response at the test of cure visit in the clinically evaluable (n = 1562) and clinical modified intent-to-treat (n = 1911) subjects. Clinical cure rates observed with tigecycline and vancomycin/aztreonam were 86.5% and 88.6% (P-value not reported), respectively, in clinically evaluable patients. Clinical cure rates observed with tigecycline and vancomycin/aztreonam were 79.7% and 81.9% (P-value not reported), respectively, in the clinical modified intent-to-treat patients.
A pooled analysis of 2 Phase III randomized, double-blind, active-controlled, multinational, multicenter studies compared the efficacy of tigecycline with that of imipenem 500 mg IV q 6h in hospitalized patients with complicated intra-abdominal infections.10,13 Patients randomized to receive tigecycline were administered a 100 mg IV loading dose, followed by 50 mg IV q 12h. Patients with complicated intra-abdominal infections, including appendicitis (most common diagnosis), cholecystitis (second most common diagnosis), intra-abdominal abscess (third most common diagnosis), perforated intestine, diverticulitis, gastric/duodenal perforation, and peritonitis were enrolled in the studies. The primary end point was the clinical response at the test of cure visit in the clinically evaluable (n = 1908) and clinical modified intent-to-treat (n = 2282) subjects. Clinical cure rates observed with tigecycline and imipenem were 86.1% and 86.2% (P-value not reported), respectively, in clinically evaluable patients. Clinical cure rates observed with tigecycline and imipenem were 80.2% and 81.5% (P-value not reported), respectively, in the clinical modified intent-to-treat patients.
At present, 4 ongoing Phase III clinical trials are assessing the efficacy of tigecycline in hospitalized patients with infections caused by antibiotic-resistant gram-negative bacteria (Acinetobacter baumanii, Enterobacter spp., Klebsiella pneumoniae), infections caused by vancomycin-resistant Enterococci or methicillin-resistant Staphylococci, and in patients with community-acquired pneumonia or nosocomial pneumonia.14
There is a crucial need for well-tolerated antimicrobial agents that are effective against resistant organisms, such as vancomycin-resistant enterococci, staphylococci with reduced susceptibility to vancomycin, and resistant gram-negative pathogens. Currently, 4 antimicrobial agents, daptomycin, linezolid, quinupristin-dalfopristin, and tigecycline are available for use in the treatment of infections caused by drug-resistant gram-positive pathogens. Oral formulations of daptomycin, quinupristin-dalfopristin, and tigecycline are not available, and administration is limited to the IV route. This represents a potential disadvantage compared with linezolid, which is available as parenteral and oral formulations. However, compared with the current agents that are available for use in the treatment of infections caused by drug-resistant gram-positive pathogens, tigecycline has a superior side effect profile, as nausea and vomiting were the most commonly reported adverse events in clinical trials. Although early results from Phase III clinical trials are promising, ongoing clinical trials will help further define the potential role of tigecycline.
- Pankey GA. Tigecycline. J Antimicrob Chemother. 2005; July 27 issue accessed online on July 30, 2005.
- Sievert DM, et al. Staphylococcus aureus Resistant to Vancomycin: United States. 2002. MMWR Morb Mortal Wkly Rep. 2002;51:565-567.
- Miller D, et al. Public Health Dispatch: Vancomycin-Resistant Staphylococcus aureus: Pennsylvania, 2002 [letter]. MMWR Morb Mortal Wkly Rep. 2002;51:902.
- Shah PM. The Need for New Therapeutic Agents: What is the Pipeline? Clin Microbiol Infect. 2005; 11(Suppl 3):36-42.
- Hershberger E, et al. Quinupristin-Dalfopristin Resistance in Gram-Positive Bacteria: Mechanism of Resistance and Epidemiology. Clin Infect Dis. 2004;38:92-98.
- Tedesco KL, Rybak MJ. Daptomycin. Pharmacotherapy. 2004;24:41-57.
- Linezolid (Zyvox®) Prescribing Information. New York, NY: Pharmacia and Upjohn: September 2004.
- Carver PL, et al. Risk Factors for Arthralgias and Myalgias Associated with Quinupristin-Dalfopristin Therapy. Pharmacotherapy. 2003;23:159-164.
- Chopra I. Glycylcyclines: Third Generation Tetracycline Antibiotics. Curr Opin Pharmacol. 2001;1:464-469.
- Tigecycline (Tygacil ) Prescribing Information. Philadelphia, PA: Wyeth Pharmaceuticals Inc.June 2004.
- Muralidharan G, et al. Pharmacokinetics (PK), Safety and Tolerability of GAR-936, a Novel Glycylcycline Antibiotic, in Healthy Subjects. In: Program and Abstracts of the 39th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; September 26-29, 1999; San Francisco, Calif. Abstract F-416.
- Ellis-Grosse EJ, Loh E. Tigecycline is Safe and Effective in the Treatment of Skin and Skin Structure Infections: Results of Two Double-Blind Phase 3 Comparison Studies with Vancomycin/Aztreonam. In: Programs and Abstracts of the 9th Western Pacific Congress on Chemotherapy and Infectious Diseases, Bangkok, Thailand, 2004. Abstract FP-C-6, p. 219. Thailand Infectious Diseases Society.
- Dartois N, et al. Tigecycline vs Imipenem/Cilastatin for Treatment of Complicated Intra-Abdominal Infections. In: Programs and Abstracts of the Forty-fourth Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington DC, 2004. Abstract LB-992c, p.12. American Society for Microbiology, Washington, DC, USA.
- www.clinicaltrials.gov accessed on July 30, 2005.