Developed by Wyeth Pharmaceuticals, Tygacil (tigecycline) is the first in a new class of antibiotics, the glycylcyclines. It is indicated as single-agent, intravenous therapy for the treatment of serious bacterial infections, such as complicated intra-abdominal infections and skin and soft tissue infections.
Wyeth filed for worldwide regulatory approval at the end of 2004. The registration package included submission of a New Drug Application (NDA) to the US Food and Drug Administration (FDA), a Marketing Authorisation Application (MAA) to the EMEA, and additional filings with regulatory authorities in Canada, Australia, and Switzerland.
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There has been a dearth of new antibiotics in the last 20 years. FDA approval of Tygacil in June 2005 marked an important advance in anti-infective therapy, expanding the range of treatment options for serious bacterial infections. In April 2006, Tygacil was approved by the EU for complicated skin and soft-tissue infections and intra-abdominal infections. The drug was also approved in Canada, Argentina, Brazil, Colombia, Ecuador, Mexico, Peru and Philippines.
In March 2009, the FDA approved Tygacil for the treatment of community-acquired bacterial pneumonia (CABP) caused by susceptible strains of indicated pathogens. Wyeth’s supplemental New Drug Application for Tygacil for the treatment of CABP was accepted by the FDA in October 2007.
In September 2010, the FDA issued a safety alert for Tygacil after an increased rate of mortality was observed in data pooled from 13 clinical trials. The FDA recommended use of alternative drugs in patients with severe infections.
Similar recommendations were also issued by the EMEA in February 2011. Tygacil’s marketing application in the EU was due for renewal in April 2011.
The EMEA carried out a review of Tygacil and renewed the application with few recommendations. It noted an increase in the rate of mortality in patients undergoing clinical trials and recommended the use of alternatives to Tygacil. Patients taking Tygacil were also required to be monitored closely to check for superinfections such as pneumonia.
New antibiotics urgently needed
Antibiotic therapy plays a vital role in the clinical management of critically ill patients, especially those who acquire infections while in hospital (nosocomial infections). The outcome is however increasingly compromised by antibiotic resistance among pathogens responsible for serious infections.
Data from the US Centers for Disease Control and Prevention (CDC) indicate that as many as 70% of bacteria responsible for hospital-acquired infections are resistant to at least one common antibiotic and many strains now exhibit multi-drug resistance. Increasingly, gram-positive bacteria are becoming resistant to vancomycin, often regarded as the treatment of last resort for serious gram-positive infections.
Prompt administration of antibiotic therapy is essential in critically ill patients and of necessity is usually given empirically, before the causative pathogen has been identified. Given current high rates of bacterial resistance to commonly used antibiotics, new broader-spectrum agents are needed for effective empirical therapy of serious bacterial infections. Studies in patients with nosocomial pneumonia have shown that when antibiotic coverage is inadequate, mortality rates are over four times higher than rates seen with antibiotics that provide broader pathogen coverage.
A new class of antimicrobial agents
Tygacil is a glycylcycline, and the first member of this new class of tetracyclines. A semi-synthetic derivative of minocycline, Tygacil possesses potent activity against tetracycline-resistant gram-positive and gram-negative pathogens refractory by both efflux and ribosomal protection mechanisms.
Tygacil is able to overcome typical bacterial resistance to tetracyclines because of modification at position 9 of its core structure. This enables it to bind to the bacterial 30S ribosomal unit with much greater affinity than earlier generation tetracyclines. The modification at position 9 provides additional steric hindrance giving Tygacil a broader spectrum of activity than traditional tetracyclines.
Tygacil shows activity against gram-negative and gram-positive pathogens, anaerobes and both methicillin susceptible and methicillin resistant strains of Staphylococcus aureus (MSSA and MRSA), an important cause of hospital-acquired infections.
Efficacy demonstrated in four pivotal Phase III studies
Regulatory filing of Tygacil was based on data from four pivotal Phase III studies, in which its safety and efficacy was assessed in patients with complicated skin and soft tissue infections as well as those with complicated intra-abdominal infections.
A comparison of intravenously administered Tygacil with Primaxin (imipenem and cilastatin for injection) in 1,575 patients with complicated intra-abdominal infections showed study treatments were of equivalent efficacy. Among patients in whom pathogens were isolated at baseline (culture positive), bacteriological eradication rates for Tygacil with Primaxin were 91.3% and 89.9% respectively.
Injectable Tygacil monotherapy was also highly effective in patients with complicated skin and soft tissue infections. No difference in the rate of cure was observed in 1,100 patients randomised to treatment with either Tygacil or vancomycin / aztreonam.
Tygacil was well tolerated by patients enrolled in the clinical trials; nausea and vomiting were the most common adverse events following treatment with Tygacil.
Marketing commentary
In an era of rising antibiotic resistance, the need to bring new antibiotics to market is widely recognised. However, there has been little focus on the development of new antibacterial compounds.
Antibiotics constitute just five of the 31 investigational anti-infective agents currently in development at the world’s largest pharmaceutical companies.
Wyeth’s Tygacil is an important addition to the panoply of drugs available for the treatment of serious bacterial infections, especially those caused by so-called "superbugs" such as MRSA and vancomycin-resistant enterococci.
