GAITHERSBURG, Md. – Food and Drug Administration's Anti-Infective Drugs Advisory Committee on Sept. 7 voted 18-0 that ceftaroline has been shown to be safe and effective for treating complicated skin and skin structure infections, based on the results of two clinical trials.
Ceftaroline, the active metabolite of ceftaroline fosamil, is a beta-lactam of the cephalosporin class, with antibacterial activity against aerobic and anaerobic gram-positive and aerobic gram-negative bacteria, which are associated with skin and respiratory infections. Ceftaroline exhibits broad-spectrum antibacterial activity against important skin pathogens, according to its manufacturer, Cerexa Inc., a subsidiary of Forest Laboratories Inc.
Cerexa has proposed that ceftaroline fosamil for injection be approved for the treatment of adults with complicated skin and skin structure infections (cSSSI), caused by susceptible isolates of gram-positive and gram-negative microorganisms, including methicillin-resistant Staphylococcus aureus (MRSA).
Earlier in the day, the same panel also unanimously agreed that the drug had been shown to be safe and effective in treating community-acquired bacterial pneumonia (CABP). But the proposed CABP indication did not include infections caused by MRSA. These infections were not studied in the CABP trials, a fact that several panelists emphasized should be explained in the drug’s label, to avoid confusion among clinicians.
The proposed cSSSI dose is 600 mg administered intravenously every 12 hours for 5-14 days, with a lower dose for people with moderate to severe renal impairment.
In two identically designed multinational, double-blind, noninferiority phase III studies of almost 1,400 patients with a variety of cSSSI, patients were randomized to treatment with ceftaroline monotherapy (at the proposed dose for 5-14 days), or vancomycin (1 g IV every 12 hours) plus aztreonam (1 g IV every 12 hours) for 5-14 days. Criteria for enrollment included the need to be hospitalized or treated in an emergency department or urgent care setting, and the expectation that at least 5 days of intravenous antimicrobial treatment would be required. About 78% of patients had S. aureus infections; of those, 45%-49% had methicillin-sensitive S. aureus (MSSA) infections and about 29%-33% had MRSA infections.
The primary end point was the clinical cure rate (total resolution of signs and symptoms or improvement to the extent that no more antibiotics were needed) 8-15 days after the end of therapy. Among those who had received at least one dose in the two studies, the clinical cure rate was about 86% in both groups. The clinical cure rate for infections caused by S. aureus, the most common pathogen, was almost 89% among those on ceftaroline, compared with 87% of those on the comparator therapy. For methicillin-sensitive S. aureus (MSSA) infections, the cure rate was 90% in both the ceftaroline-treated patients and among those on the comparator therapy. For MRSA infections, the clinical cure rate was nearly 87% among those on ceftaroline, compared with 82% of those on vancomycin plus aztreonam.
The most common adverse events in both treatment groups were nausea, headache, and diarrhea. The rate of serious adverse events was low in both groups, at about 4%, as were the rates of adverse events resulting in discontinuation of the drug of study (3% among those on ceftaroline and almost 5% among those on the comparator treatment).
One issue raised by panelists was why a weight-based dosing regimen for vancomycin had not been used in the study.
The company is planning to conduct several pediatric studies of the drug.
The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts of interest by the FDA prior to the meeting. Occasionally, the FDA grants a waiver to a panelist with a conflict of interest, but not at this meeting.