Ceftaroline: Broad-spectrum β-lactam with Anti-MRSA Activity for Skin Infections and Beyond?
Abstract & Commentary
By Brian G. Blackburn, MD, Clinical Associate Professor, Division of Infectious and Geographic Medicine, Stanford University School of Medicine, is Associate Editor for Infectious Disease Alert.
Dr. Blackburn reports no financial relationships relevant to this field of study.
Synopsis: Ceftaroline, a broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA), was non-inferior to vancomycin plus aztreonam in a study of complicated skin and skin-structure infections (cSSSIs). Ceftaroline is among the first of the ß-lactams with reliable activity against MRSA.
Source: Corey GR, et al. 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;51:641-650.
With antimicrobial resistance among clinical bacterial isolates becoming a greater problem with each passing year, the need for novel antibacterial agents has become more urgent than ever. The clinical situations in which one can employ a single antibacterial agent with reliable activity against most of the likely pathogens continue to diminish, particularly because of the widespread emergence of MRSA. Most anti-MRSA agents have a relatively narrow anti-infective spectrum predominantly limited to gram-positive organisms, necessitating the addition of a second agent if broader coverage is desired. Despite their otherwise broad spectrum of activity and relatively benign safety profiles, U.S. Food and Drug Administration (FDA)-approved ß-lactams have lacked anti-MRSA activity to date.
Ceftaroline is a novel cephalosporin and, after ceftobiprole, the second ß-lactam to reach late-stage clinical trials with anti-MRSA activity.1 The spectrum of activity of ceftaroline includes most gram-positive cocci (although not Enterococcus faecium), many aerobic gram-negative bacilli (generally excluding Pseudomonas aeruginosa and extended spectrum- and AmpC- ß-lactamase-producing organisms), and some anaerobes (although generally not Bacteroides spp.).2,3 Because of high-affinity binding to penicillin-binding protein 2a (the major determinant of methicillin resistance in Staphylococci), ceftaroline retains activity against MRSA.2,3
Clinical evaluation of ceftaroline was undertaken by the developing pharmaceutical company in two non-inferiority trials designed to evaluate efficacy in patients with cSSSIs; this paper reported the pooled analysis of the two trials. The comparator arm received vancomycin plus aztreonam. Patients included for enrollment were adults that had surgical wound infections, skin abscesses, or cellulitis severe enough to warrant emergency department evaluation or hospital admission and at least five days of intravenous antibiotics. Exclusion criteria included renal failure, necrotizing fasciitis, diabetic foot ulcer or decubitus ulcer infections, and patients with infections known or suspected to be due to a bacterial pathogen resistant to vancomycin or aztreonam, P. aeruginosa, anaerobes, or fungi. Overall, 1,378 patients were included in the modified intent-to-treat analysis, randomized 1:1 into the ceftaroline and comparator arms, respectively. Both arms received therapy for 5-14 days.
The two arms were well matched with regard to baseline characteristics; the patient population was mostly male and Caucasian. In each arm, methicillin-susceptible S. aureus (MSSA) was the most commonly identified pathogen, and MRSA second in frequency, with the latter comprising 40% of infections in the ceftaroline group, and 34% in the comparator group. Gram-negative infections comprised less than 20% of the recovered isolates in both arms. Most patients had cellulitis (36% and 40% in the ceftaroline and comparator arms, respectively), skin abscess (34% in both arms), or an infected wound (15% and 12%, respectively).
In the modified intent-to-treat analysis (MITT), the clinical cure rates were nearly identical in the ceftaroline and comparator arms (86% in both). Among clinically evaluable patients, the cure rates also were similar (92% and 93%, respectively). In the subgroup of patients with MRSA isolated, the cure rates also were similar (93% vs. 94%, respectively). However, among patients in the microbiologically evaluable subgroup with an identified gram-negative (only) infection, significantly fewer patients were cured in the ceftaroline arm (85%) than in the comparator arm (100%). A trend toward lower cure rates in the ceftaroline group than in the comparator group was seen for patients with Proteus mirabilis (69% vs. 87%, respectively), P. aeruginosa (80% vs. 88%, respectively), and E. faecalis (71% vs. 82%, respectively) isolated. A trend toward higher cure rates with ceftaroline than comparator was seen for patients with Klebsiella pneumoniae (94% vs. 74%, respectively) isolated. Cure rates were similar in both arms when analyzed with regard to clinical type of cSSSI. In addition, there were no significant differences in the frequency or type of adverse events (AEs) between the two groups.
Commentary
These data largely support the conclusion that ceftaroline is non-inferior to the combination of vancomycin plus aztreonam for the treatment of cSSSIs. Importantly, this trial raises the possibility that antibacterial monotherapy may now be possible in some situations in which combination therapy was previously necessary. Clinicians are frequently confronted by the need to cover MRSA, particularly when treating cSSSIs. The combination of anti-MRSA activity with a broad anti-bacterial spectrum is relatively unique. While achieving this, ceftaroline also offers the advantages of the ß-lactam class, such as rapid bactericidal activity, favorable pharmacokinetics, and a good safety profile.2,3
Some limitations of the trials are worthy of discussion. Although generally considered effective against many aerobic gram-negative rods, the MICs for ceftaroline against K. pneumonia and P. mirabilis isolates in the study were relatively high. Furthermore, in part because of lower clinical efficacy in patients with P. mirabilis, ceftaroline was significantly less effective than comparator in patients in whom a gram-negative bacterium was isolated. On the other hand, although not considered reliably effective against P. aeruginosa, ceftaroline appeared surprisingly effective in patients in whom this organism was isolated. This raises the question of the clinical significance of many of the cultures performed in the study, highlighting the difficulty of knowing whether an organism is a colonizer (or contaminant) vs. an invasive pathogen in patients with cSSSIs. It also is important to note that most patients in the study had either cellulitis or a skin abscess the relative lack of diabetic foot infections and other polymicrobial processes renders inconclusive the role of ceftaroline in these clinical situations. In this trial (as in most cSSSIs), gram-positive pathogens predominated; the efficacy of ceftaroline in situations where gram-negative pathogens predominate remains unclear at this time; of note, the efficacy of ceftaroline against enterococcal infections and anaerobes also is less certain. Lastly, the patient population was relatively homogeneous, and did not include large numbers of elderly, Asian, black, Hispanic, or pediatric patients; the applicability of these results to such groups is therefore currently unknown.
Recently, the FDA Anti-Infective Drugs Advisory Committee voted unanimously in favor of approval of ceftaroline for the treatment of both cSSSIs and community-acquired pneumonia, based in part on the CANVAS I and II data reviewed here and additional trial data that address pneumonia.4 Although ceftobiprole, the other ß-lactam with anti-MRSA activity, previously seemed to have the lead among the anti-MRSA cephalosporins for FDA approval, this drug has been subject to additional scrutiny by the FDA because of concerns regarding the validity of the data supporting its efficacy and safety. In late 2009, the FDA issued a complete response letter for ceftobiprole, recommending that additional new trials be conducted before approval would be granted.5 Ceftaroline may, therefore, be the first anti-MRSA ß-lactam approved. Pending final FDA approval, ceftaroline appears to be a welcome addition to the therapeutic armamentarium.
References
- Noel GJ, et al. A randomized, double-blind trial comparing ceftobiprole medocaril with vancomycin plus ceftazidime for the treatment of patients with complicated skin and skin-structure infections. Clin Infect Dis. 2008;46:647-655.
- Steed ME, Rybak MJ. Ceftaroline: A new cephalosporin with activity against resistant gram-positive pathogens. Pharmacother. 2010;30:375-389.
- Zhanel GG, et al. Ceftaroline: A novel broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus. Drugs. 2009;69:809-831.
- FDA advisory committee recommends approval of Forest Laboratories' ceftaroline fosamil for the treatment of community-acquired bacterial pneumonia and complicated skin and skin structure infections. http://www.frx.com/news/PressRelease.aspx?ID=1468014 Accessed 18 Sept 2010.
- FDA issues ceftobiprole complete response letter. http://www.basilea.com/chameleon//outbox//public/29/20091230-Final-PR-Cefto-FDA-3rd-CR-Letter-3-1-E.pdf Accessed 18 Sept 2010.
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