Ceftaroline: A New Agent For cSSSIs?

For a number of years, many felt that ceftobiprole would be the first of the new so-called “fifth-generation” of anti-methicillin Staphylococcus aureus (MRSA) cephalosporins. This drug, a joint venture by the Swiss company Basilea Pharmaceutica and Johnson & Johnson, had come under some fire from the Food and Drug Administration (FDA) and now looks like it has pretty much been abandoned, at least here in the United States. Even in Canada, where ceftobiprole had been approved for complicated skin and skin structure infections (cSSSI), sales have been discontinued as of April 2010.

While all of the hoopla surrounded ceftobiprole, another drug called ceftaroline was pretty quietly making its way through the clinical trial process. Ceftaroline is being developed by Cerexa Inc., a wholly owned subsidiary of New York’s Forest Laboratories under license from Takeda in Japan. On Sept. 15, Clinical Infectious Diseases published the results of the drug’s cSSSI trial, named the CANVAS study.1 (See http://www.journals.uchicago.edu/doi/abs/10.1086/655827 .) On Sept. 8, the Anti-Infective Drug Advisory Panel of the FDA gave the drug a very positive endorsement for two indications including cSSSI.2

The CANVAS trials were two identical, phase 3, international, multicenter, randomized, double-blind studies that compared IV ceftaroline (600 mg q12h) to the combination of vancomycin plus aztreonam for cSSSI.1 The inclusion criteria pretty much followed the FDA’s Guidance for cSSSI. Unfortunately, diabetic foot ulcers were excluded.

That being said, almost a full 50 percent of all infections in both groups occurred in the lower extremity.1 (Note to Cerexa: how about a diabetic foot infection trial? We desperately need more drugs with that indication.) The study involved 1,378 patients with 693 in the ceftaroline group and 685 in the comparator group with demographics being similar in both. As expected, S. aureus was the most common pathogen with MRSA found in 40 percent of the ceftaroline group and 34 percent of the comparator group.

I would direct the reader to the full paper for all of the different efficacy measures.1 Suffice it to say that results were similar in all measured endpoints including the clinically evaluable group (91.6 percent ceftaroline versus 92.7 percent for the 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 were 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, the Advisory Panel enthusiastically and unanimously voted (18-0 for the cSSSI indication) to support the drug’s application for approval.2 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 the recommendation was as positive as this.

What is the bottom line? 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, one can use this drug for mixed gram positive and gram negative infections. One major downside is the obvious lack of coverage of extended spectrum beta lactamases (ESBLs) and Klebsiella pneumoniae (KPC) producing gram negatives. These are becoming an issue with cSSSI.

References

1. 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.

2. FDA News Daily Drug Bulletin. FDA Panel backs approval for Forest’s ceftaroline 2010; 7(179). Available at http://www.fdanews.com/newsletter/article?articleId=130203&issueId=14035

Editor’s note: This blog was originally published at http://www.leinfections.com/category/antibiotics/ and has been adapted with permission from Warren Joseph, DPM, FIDSA, and Data Trace Publishing Company. For more information about the Handbook of Lower Extremity Infections, visit www.leinfections.com/ .



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