Ceftobiprole - Injectable Anti-MRSA Cephalosporin Antibiotic

The product of a joint development programme between the Swiss pharmaceutical company Basilea Pharmaceutica AG and Cilag AG International (a Johnson & Johnson company), ceftobiprole medocaril (BAL5788) is a novel cephalosporin antibiotic indicated for the treatment of serious bacterial infections in hospitalised patients.

Following successful completion of pivotal phase III registration trials, ceftobiprole was filed for regulatory approval in the US and Europe in July 2007. Regulatory submission was for the use of ceftobiprole as a treatment for complicated skin and skin structure infections, including diabetic foot infections.

Previously, the US FDA had granted ceftobiprole fast-track status for the treatment of both complicated skin and skin structure infections due to methicillin-resistant staphylococci (MRSA) and hospital-acquired pneumonia, including ventilator-associated pneumonia due to suspected or proven MRSA.

Ceftobiprole is seen as a potential first-line treatment for severe hospital-acquired infections and regulatory approval eagerly awaited. However, the companies received a setback from US regulators who issued only an approvable letter in March 2008, so delaying its entry to the key US market.

Given the FDA's request for additional information, analysts predict that it may be a year before ceftobiprole is given the green light to be marketed in the US.

Despite US setbacks, there was good news at the end of June 2008 when Canadian regulatory authorities gave their approval. Ceftobiprole will be marketed in Canada under the brand name Zeftera for the treatment of complicated skin and soft tissue infections, including diabetic foot infections. This development heralds the arrival of the first broad-spectrum anti-MRSA cephalosporin on the market.

Combating the rise in MRSA

Commonly used to treat infections caused by staphylococci, including S. aureus, use of methicillin is increasingly compromised by a rise in the incidence of resistant strains – so-called MRSA. While S. aureus is rarely a concern in healthy people, it can cause serious infections in hospitalised patients, the elderly and those with weakened immune systems.

Serious infections associated with S. aureus, including MRSA, can include wound infections, abscesses, septicaemia, nosocomial pneumonia, bone infections, and infections of prosthetic devices such as artificial joints and heart valves.

Pre-clinical studies on ceftobiprole, the first of a new class of broad-spectrum anti-MSRA cephalosporins, suggest it has potent activity against MRSA as well as strains of Streptococcus pneumoniae resistant to penicillin. The drug binds to the penicillin-resistant targets in Gram-positive cocci, resulting in potent bactericidal action. This new antibiotic, which is also effective against Gram-negative pathogens, also has a low propensity to induce resistance, an important factor governing the clinical utility of antibiotics.

Efficacy demonstrated in phase III trials

The clinical effectiveness of ceftobiprole in its primary indication has been demonstrated in the pivotal STRAUSS 1 and 2 trials. Involving over 1,600 patients with complicated skin and skin structure infections including diabetic foot infections, these double-blind, placebo-controlled trials showed treatment with ceftobiprole medocaril was at least as effective as standard comparator agents that included vancomycin.

In STRAUSS 1, treatment with ceftobiprole medocaril achieved a cure rate of 93.3% among clinically evaluable patients, and 91.8% in those with infections due to MRSA. This was comparable to cure rates of 93.5% and 90% respectively with vancomycin.

Similar results were seen in STRAUSS 2, where ceftobiprole was compared to standard combination therapy with ceftazidime plus vancomycin. Here, treatment with ceftobiprole achieved cure rates of 91%, compared with 90% for patients in the combination treatment arm.

Among patients with diabetic foot infections, who represented almost a third of all patients, the respective cure rates were 86% and 82%. Consistent with the cephalosporin class of antibiotics, ceftobiprole was well tolerated by patients in these studies.

Nosocomial pneumonia is among the most common infections in intensive care units accounting for about 15% of all hospital-acquired infections.

Mortality exceeds 30% and is highest among mechanically ventilated patients and those infected with MRSA. Selecting the right antibiotic is an important determinant of clinical outcome in such cases.

Ceftobiprole adds to J&J's antiinfective portfolio

Basilea's ceftobiprole medocaril is seen as an important addition to J&J's current anti-infective portfolio, which includes the antibiotics ofloxacin (Floxin) and levofloxacin (Levaquin). Under the terms of the co-development and marketing agreement, J&J's Ortho-McNeil Pharmaceutical subsidiary will market ceftobiprole in the US, while Janssen-Cilag will market the drug outside the US. Basilea has retained the option to co-promote ceftobiprole in most major markets, including the US, the major European countries, Japan and China.

Marketing commentary

The past decade has seen a dramatic rise in antibiotic resistance in the hospital setting, which is now spreading into nursing homes. MRSA is a particular problem because it displays resistance to most classes of antibiotics; reports suggest that some strains are becoming resistant to vancomycin. There is an urgent need to expand treatment options for this difficult-to-treat pathogen, for which first-line treatment currently includes vancomycin and linezolid.

Although the hospital antibacterial market represents only a third of all antibacterial sales, increasing antibiotic resistance in the hospital environment has increased the demand for more effective antibiotics making it an attractive sector for new antibacterial agents.