The increasing prevalence of community-acquired strains of the MRSA virus stood as one of the key issues at this year’s Interscience Conference on Antimicrobial Agents and Chemotherapy. The severity of MRSA disease, and its ability to accumulate resistance to antibiotics, illustrates the high unmet need for suitable treatment, particularly drugs that can be administered orally.

Datamonitor attended this year’s Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in San Francisco, the world’s largest gathering of infectious diseases specialists with over 10,000 attendees. Methicillin-resistant Staphylococcus aureus (MRSA), an increasingly common bacterial pathogen that is a major source of morbidity and mortality, was one of the main talking points. MRSA, often associated with skin and soft tissue infections (SSTIs), pneumonia, bacteremia, endocarditis and sepsis, used to be limited to the hospital and extended-care settings.

Market overview

Vancomycin is still the most commonly used drug for the treatment of MRSA infections. This intravenous glycopeptide drug was launched by Eli Lilly in the US in 1958. Significant competition to vancomycin finally appeared in 2000 with the launch of Pfizer’s Zyvox (linezolid), and later Cubist’s Cubicin (daptomycin) in 2004, Wyeth’s Tygacil (tigecycline) in 2005 and Theravance/Astellas’ Vibatif (telavancin) in 2009. However, the low cost of vancomycin and strong physician familiarity have restricted uptake of these new therapies. Recently though, the old drug’s utility against MRSA has increasingly been called into question because of its poor tissue penetration for systemic use, slow bactericidal activity, and the reduced susceptibility of MRSA to the drug: a trend in using higher doses of vancomycin for MRSA infections to respond to the so-called "MIC creep" has consequently seen increased nephrotoxicity in patients.

Zyvox (linezolid) is the first and only approved antibiotic from the oxazolidinone class having been launched by Pharmacia (now Pfizer) in the US in 2000. It achieved total sales across the seven major pharmaceutical markets of $968.8 million in 2008 (according to IMS Health), making it the biggest-selling anti-MRSA drug. Unlike its competitors, Zyvox is available in intravenous as well as oral form, giving it a notable advantage. However, the drug’s clinical usefulness is now threatened by first case reports of linezolid resistance from a number of countries. At ICAAC, Gomez-Gil and colleagues from Madrid, Spain, reported six cases of linezolid-resistant MRSA affecting critically ill patients (both with and without previous linezolid use) in two surgical intensive care units in their hospital in January 2008. Three of the patients had contracted nosocomial pneumonia, and one subsequently died, with the authors stating that the death seemed to be directly related to the infection.

A more promising recent development was the FDA approval of Theravance/Astellas’ Vibativ (telavancin), a lipoglycopeptide derivative of vancomycin, which coincided with the first day of ICAAC. The drug is indicated for the treatment of complicated SSTIs, including those caused by MRSA. Vibativ’s approval follows a number of previous regulatory setbacks since its initial New Drug Application (NDA) was filed in December 2006. Physicians at ICAAC welcomed the drug as a valuable new treatment option given the fact that it is bactericidal. The developers hope that telavancin’s dual mechanism of action of inhibiting both bacterial cell wall synthesis and disrupting bacterial cell membrane function will translate into a low potential for resistance development and cross-resistance with other antibiotics.

Moving forward

A number of new anti-MRSA drugs are in late-stage clinical development, the most highly anticipated of which is Basilea/Johnson & Johnson’s ceftobiprole, a novel fifth generation cephalosporin antibiotic with broad-spectrum gram-positive activity. Physicians spoken to by Datamonitor at ICAAC see ceftobiprole as potentially the most valuable of the new anti-MRSA therapies, principally due to its high rate of bacterial killing and favorable toxicity profile. The drug is already launched in Canada and Switzerland, and Datamonitor expects the drug to receive US approval in late 2009 or early 2010. Johnson & Johnson’s complete response submission was recently accepted by the FDA, after the agency had previously cited concerns over clinical and microbiological data integrity at several study sites. New data presented on the activity of ceftobiprole, vancomycin, teicoplanin, and linezolid against 1,007 MRSA isolates collected from 108 centers across 19 European countries showed that ceftobiprole is as effective in-vitro as linezolid and vancomycin.

Trius Therapeutics is developing torezolid, a new second generation oxazolidinone with activity against linezolid-resistant strains. The oral form of the drug has completed Phase II clinical trials in complicated SSTIs and the intravenous form is due to complete Phase I testing by the end of the year. The company plans to merge the oral and intravenous programs in Phase III trials in early 2010.

Morales and colleagues from Hospital Clinico San Carlos in Madrid, Spain, presented data from a study investigating the activity of torezolid against linezolid-resistant MRSA strains with resistance mediated by the chloramphenicol-florfenicol resistance (cfr) gene. Torezolid showed high in-vitro activity against linezolid-resistant MRSA (with MICs ranging from 0.5-1.0 mg/L), and all of the 18 linezolid-resistant strains were susceptible to torezolid. Activity against resistance mediated by the cfr gene is notable given that it has been reported that this gene appears to be capable of horizontal transfer between staphylococci (Arias et al., 2008). These encouraging data mean that the progress of the drug will be followed with much interest, particularly if the emergence of linezolid-resistant MRSA becomes widespread in key markets.

Pipeline potential

Despite the availability of a number of therapies, there remains a high unmet need for new antibacterial drugs to treat infections caused by MRSA. Resistance is an increasingly critical issue and serves to limit the efficacy of treatments and reduce drug lifecycles. The emergence of MRSA strains resistant to linezolid - deemed by some physicians to be the most effective therapy for MRSA infections - further highlights the challenges facing the infectious diseases community and drug developers.

The late-stage pipeline nevertheless contains a number of drugs which show good promise. Physicians await the launch of ceftobiprole with much anticipation, and, albeit much further away from commercialization, torezolid has shown strong potential in Phase II trials. Since the evolution of MRSA resistance patterns is difficult to predict, maintaining effective treatment options is crucial to fighting the threat. Both new classes of antibacterials and new drugs within those classes must be developed in order to give physicians the best chance of treating infections caused by this deadly ’superbug’.