Tigecycline offers new hope in the battle against MRSA

pharmaceuticals company Wyeth presented a range of clinical data at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in October, including Phase III data from a clinical trial in patients with complicated intra-abdominal infections and from another in complicated skin and soft tissue infections (cSSI). The first trial, which compared tigecycline to Merck & Co's carbapenem Primaxin (imipenem/cilastin), found that a twice-daily dose of tigecycline was non-inferior to a comparable regime of Primaxin. In addition, adverse events occurred as often with Primaxin as with tigecycline, with the most common being gastrointestinal in nature.

The tigecycline 305 cSSI trial compared 50mg of tigecycline, taken twice daily after an initial loading dose of 100mg, to a twice daily regimen of 1g vancomycin combined with 2g of aztreonam. Tigecycline was again found to be non-inferior to the comparator regime demonstrating a lower incidence of serious side effects, in particular raised alanine aminotransferase and aspartate aminotransferase levels.

In addition to the Phase III trial data presented, Wyeth also provided details of a number of in vitro resistance studies. The Tigecycline Evaluation Surveillance Trial (TEST) examined the activity of the drug against a number of resistant strains of bacteria, including methicillin susceptible staphylococcus aureus (MSSA) and methicillin resistant staphylococcus aureus (MRSA). One study found that tigecycline had good activity against clinical strains of community-acquired MRSA and multi-drug resistant MRSA. Furthermore, oxacillin resistant strains of staphylococcus aureus (ORSA) were also susceptible to tigecycline.

New treatment option

The development of tigecycline, the first in the novel glycylcycline class, has provided a new option in the ongoing fight against resistant pathogens, particularly in severe or hospital treated infections. Although the drug's efficacy against resistant strains of bacteria is a key advantage, Professor Peter Hawkey, Professor of Public Health Bacteriology at the West Midlands Public Health Laboratory, commented that its tolerability profile would also help to position it favorably.

Currently, there are several injectable antibacterials available for the treatment of resistant infections, such as Pfizer's Zyvox (linezolid), King Pharmaceutical's Synercid (quinupristin/dalfopristin) and Cubist's recently approved Cubicin (daptomycin). However, there are a variety of adverse effects associated with these drugs, for example the development of myelosuppression with the prolonged use of Zyvox. Professor Hawkey believes that this will ensure tigecycline will not only establish itself in the treatment of severe infections, but may also lead to it being used instead of some of the already available narrow-spectrum drugs.

Recent Datamonitor research found that some of the newer, novel antibacterials acting against drug-resistant pathogens tend to be reserved for use when other options have been exhausted. There are several reasons for this, but primarily it is due to the need to protect against the development of resistance to these products. With so few drugs in the antibacterials pipeline, especially with activity against gram-negative bacteria, physicians are wary of shortening the useful life of newly launched drugs through premature resistance development.

The future use of tigecycline

A second reason is often the cost of the drugs, with many commanding a premium price point due to the sizeable unmet need and their use in niche markets. However, Professor Hawkey commented that, in reality, the cost-effectiveness of these drugs is comparable to some other antibacterials, since associated costs, such as longer hospitalization and additional nursing time, are reduced through the drugs' rapid efficacy.

In a partial reflection of these concerns, recent Datamonitor key opinion leader research in the seven major pharmaceutical markets found there were mixed opinions regarding the future use of tigecycline in the hospital antibacterial market: "It's about the only gram-negative that's actually offering anything new just now, and even that is marginal," one opinion leader commented.

In an increasingly crowded market, Wyeth will have to strategically position tigecycline to ensure maximum uptake in the hospital treatment market. Products such as Zyvox, which offers the advantage of an IV/oral switch option enabling earlier discharge from hospital, are already established in this segment and real benefits will have to be demonstrated by tigecycline to encourage physicians to switch. However, the data presented at the 44th ICAAC has gone some way towards establishing the drug's utility in complicated bacterial infections. Subsequent studies could be crucial in cementing that position.

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