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Man vs MRSA

Tieless doctors may curb propagation, but new drugs are required to treat MRSA infection

Methicillin-resistant Staphylococcus aureus (MRSA) continues to be a major problem in many countries around the world. Despite great efforts, health systems are still struggling to control it.

The MRSA bacterium may often exist harmlessly in and around the noses of healthy people and is transmitted primarily by contact with a person harbouring an infection, or who is a carrier. It can cause a wide range of infections, from trivial to life threatening, which can be especially harmful to hospitalised patients, the elderly and those with weakened immune systems.

The first reports of resistance in S. aureus followed the introduction of penicillin in 1944; the threat of MRSA began to emerge during the 1970s.

In more recent years, a distinct variant of hospital-acquired (nosocomial) MRSA has been detected in the community setting (often referred to as community-acquired MRSA), which is an increasingly common cause of skin and soft tissue infection (SSTI) in patients who have not had any previous contact with a healthcare establishment.

Current MRSA therapies
In cases of mild-to-moderate infection of the skin, which usually appears as sores resembling insect bites, boils, abscesses and/or cellulitis, the first-line treatment is incision and drainage of the lesions.

In cases of severe infection, intravenous (IV) vancomycin therapy remains the first-line choice. However, when resistance to vancomycin is detected, two antibiotics commonly used as alternative therapies are linezolid (Zyvox) and daptomycin (Cubicin). Linezolid is available in interchangeable IV and oral formulations and is currently the only oral therapy approved by the US Food and Drug Administration (FDA) for the treatment of MRSA.

Unfortunately these therapies are associated with unwanted side effects, such as the development of myelosuppression from prolonged use of linezolid, whose initial global launch in the US in June 2000 made it the first completely new antibiotic to reach the market in more than 35 years.

Tigecycline, a first-in-class glycylcycline antibiotic from Wyeth, offers another option in the armamentarium against MRSA. This agent has been developed for IV use in the treatment of complicated intra-abdominal infections, complicated SSTIs, both nosocomial and community-acquired infections, and other serious bacterial infections in addition to MRSA.

Investigational agents
Pfizer's newly-acquired therapy, dalbavancin, is awaiting US FDA approval for the treatment of SSTIs, including MRSA.

The first global launch for this second-generation glycopeptide antibiotic is anticipated to occur during the first quarter of this year.

Therapies in phase III trials for MRSA and related indications, all of which are injectable formulations, include iclaprim (Arpida), telavancin (Theravance) and ceftobiprole (Basilea Pharmaceutica/J&J).

Other agents in clinical development for MRSA include Wockhardt's WCK 771A (phase II in India), Takeda/Cerexa's PPI 0903 (phase II in US) and aRigen's WAP 8294A2 (phase I in US).

The possibility of developing an MRSA vaccine is also under investigation. The most advanced such product seems to be Nabi Biopharmaceuticals' S. aureus polysaccharide conjugate vaccine, StaphVAX, which is designed to provide immunity against the major forms of S. aureus bacteria, including MRSA.

The company has also developed an IV formulation of S. aureus immune globulin, Altastaph, which is intended for use as a supplement to StaphVAX.

However, an EU regulatory application for StaphVAX was withdrawn in November 2005 following a batch of unsatisfactory results from its confirmatory phase III trial in end-stage renal disease patients with bacteraemia.

Further development of both StaphVAX and Altastaph is on hold pending a full assessment of the trial results.

Other new therapeutic approaches to MRSA include monoclonal antibodies, of which one promising example is NeuTec Pharma's Aurograb, which is currently undergoing phase III trials in Europe. As these agents will be used in combination with antibiotics, they are expected to have an additive effect on the MRSA market.

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Future anti-MRSA market
Despite the clear need for more powerful antibiotics, the pipeline of new therapies is drying up as major pharmaceutical companies pull out of the anti-infectives playing field or refocus R&D efforts, citing poor financial returns.

The global market for antibiotics, valued at between approximately $24bn and $26bn, has remained flat in recent years and unfortunately still faces significant revenue losses within the next 2 to 3 years as major patents are due to expire (eg, US patents covering piperacillin/tazobactam and cefepime are due to expire in 2007).

Pfizer has also recently lost American patent protection covering its blockbuster azithromycin product, Zithromax.

Nonetheless, there is still scope for the pharmaceutical industry to boost the attractiveness of this market by taking a more targeted approach to development of therapies for unmet clinical needs.

This has already been demonstrated by the renewed focus on new therapeutic agents for life-threatening infections, including MRSA. Regulatory authorities, such as the FDA in America, have in part facilitated this process through their initiatives to identify specific, clinically important pathogens to direct industry's R&D efforts.

In order to contain and eradicate MRSA effectively, infection control (eg, hand washing), prudent use of antibiotics and development of novel therapies will all be influential in the global effort to fight this superbug.

The Author
Pipeline is written by Asha Vaidya of Adis International, using information derived from Adis Clinical Trials Insight and R&D Insight.

2nd September 2008


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