For a number of years it was widely felt that the first of the new so-called “5th Generation”, or anti-MRSA cephalosporins would be ceftobiprole. This drug, a joint venture by the Swiss company Basilea and Johnson & Johnson had come under some fire from the FDA (see my blog entry from Dec 31, 2009) and now looks like it has pretty much been abandoned, at least here in the US. Even in Canada, where it had been approved for complicated skin and skin structure infections (cSSSI), as of April 2010 sales have been discontinued.
While all of the hoopla surrounded ceftobiprole, another drug was pretty quietly making its way through the clinical trial process; ceftaroline. Ceftaroline is being developed by Cerexa Inc., a wholly owned subsidiary of New York’s Forest Pharmaceuticals under license from Takeda in Japan. This month has proven to be an important one for this antibiotic. In the September 15 issue of Clinical Infectious Diseases the results of their cSSSI trial, named the CANVAS study have been published (PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/20695801) and on September 8, the Anti-infective Drug Advisory Panel of the FDA gave the drug a very positive endorsement for 2 indications including cSSSI.
The CANVAS trials were two identical, phase 3, international, multicenter, randomized, double blind studies which compared IV ceftaroline (600mg q12h) to the combination of vancomycin + aztreonam for cSSSI. Inclusion criteria pretty much followed the FDA’s Guidance for cSSSI. Unfortunately, diabetic foot ulcers were excluded! That being said, almost a full 50% of all infections in both groups occurred in the lower extremity. (NOTE to Cerexa…how about a diabetic foot infection trial? We desperately need more drugs with that indication!) 1378 patients received study drug with 693 in the ceftaroline group and 685 in the comparator with demographics being similar in both. As expected, S. aureus was the most common pathogen with MRSA found in 40% of the ceftaroline group and 34% of the comparator group.
I would direct the reader to the full paper for all of the different efficacy measures. Suffice it to say that results were similar in all measured endpoints including the clinically evaluable group (91.6% ceftaroline vs. 92.7% comparator) as were the rates of adverse reactions and discontinuations, all really pretty low, in the single digits. One other point of interest is that although ceftaroline is not effective, in vitro, against Pseudomonas aeruginosa, the clinical cure rates when this organism was found in combination with others was still very high. Again, this brings up the issue I have addressed many times, as to the relative lack of importance of this bug as a primary pathogen.
As for the news about the FDA, a press release put out by the company and found from many sources, including Medscape reported that the Advisory Panel enthusiastically and unanimously voted (18-0 for the cSSSI indication) to support the drugs application for approval. It has frequently been repeated that the FDA itself does not have to follow the Panel’s recommendation but it almost always does. Especially when it was as positive as this. The bottom line is that I think we will see a new option for the IV treatment of cSSSI caused by mixed infections including MRSA in the next few months. It will be interesting to see the impact this has on the marketplace since many people have a very high comfort level with cephalosporins. Furthermore, this drug can be used for mixed gram positive and gram negative infections. One major downside is the obvious lack of coverage of ESBL and KPC producing gram negatives. These are becoming an issue in cSSSI.
Corey GR, Wilcox M, Talbot GH, Friedland HD, Baculik T, Witherell GW, Critchley I, Das AF, Thye D. Integrated analysis of CANVAS 1 and 2: phase 3, multicenter, randomized, double-blind studies to evaluate the safety and efficacy of ceftaroline versus vancomycin plus aztreonam in complicated skin and skin-structure infection. Clin Infect Dis. 2010 Sep 15;51(6):641-50.