Ceftaroline fosamil: A new FDA-approved anti-MRSA cephalosporin antibiotic

Bugs are smart. This is the most predominant lesson we have learned in the 70 years since the introduction of penicillin.

This lesson is even more true today than it was back in the infancy of antibiotic therapies. With the increasing proportion of multidrug-resistant organisms, the development of antimicrobials to treat these infections is as important as it has ever been. Unfortunately, we have been relatively unsuccessful in researching and developing new antibiotics to counter these adaptations. This lack of novel agents is a multifactorial problem, not the least of which is the exorbinant amount of money that drug companies must invest to bring a novel agent to market. The increasing rates of multidrug-resistant organisms combined with the decreasing number of novel antimicrobials (only seven of 225 new entities proposed to the FDA from the late 1990s to the 2000s were antibiotics) lead to increased excitement when one of these novel agents makes it to market.

One of the most troublesome multidrug-resistant organisms, methicillin-resistant Staphylococcus aureus, has been around since the 1960s. The difference between MRSA and S. aureus is that it produces a supplementary penicillin binding protein 2a (PBP2a). These PBPs are the target of beta-lactam antimicrobials in S. aureus, and this supplementary PBP2a confers resistance to many beta-lactam antibiotics. Although MRSA has received a lot of attention lately and has been a focal point of public health programs, antimicrobial stewardship programs and even state and federal legislation, only five novel antimicrobials have been approved to treat MRSA in the past 12 years: quinupristin/dalfopristin (Synercid, King Pharms); linezolid (Zyvox, Pharmacia and Upjohn); daptomycin (Cubicin, Cubist); tigecycline (Tygacil, Wyeth Pharms); and telavancin (Vibativ, Theravance).

Newest addition to the list

Ceftaroline (Teflaro, Cerexa) was approved by the FDA on Oct. 29 for the treatment of skin and skin structure infections (SSSI), including MRSA and community-acquired pneumonia (CAP). Ceftaroline is a broad-spectrum cephalosporin antimicrobial with extended gram-positive bacteria coverage. It exhibits greater binding affinity than ceftriaxone, oxacillin and penicillin G for PBPs in MRSA due to its increased affinity for the PBP2a. A similar effect is seen with Streptococcus pneumoniae due to its increased affinity for PBP2x.

Ceftaroline has exhibited potent activity against MRSA; S. pneumoniae (including multidrug-resistant S. pneumoniae); S. pyogenes; S. agalactiae; viridans group streptococci; Haemophilus influenzae; Moraxella catarrhalis; Enterobacter cloacae; Enterococcus faecalis; and extended-spectrum beta-lactamase–negative Escherichia coli; Klebsiella pneumoniae; and Shigella species. In vitro testing has shown that ceftaroline has similar activity to ceftriaxone, with the notable exception of MRSA. The activity of ceftaroline is limited against Enterococcus sp., beta-lactamase–producing Enterobacteriacea and Pseudomonas aeruginosa. Ceftaroline has also exhibited activity against a variety of gram-positive and gram-negative anaerobes; however, activity was limited against Bacteroides species, Clostridium difficile and beta-lactamase–producing Prevotella isolates.

Ceftaroline’s unique spectrum of activity has unofficially landed itself in the “fifth-generation” cephalosporin class. The Clinical and Laboratory Standards Institute has grouped ceftaroline with ceftobiprole (Zeftera/Zevtera, Johnson & Johnson) in a currently unnamed subclass of cephalosporins. Both ceftaroline and ceftobiprole have MRSA coverage and are being studied in SSSI and CAP. Ceftobiprole differs from ceftaroline in its gram-negative coverage and other studied indications. Ceftobiprole has MRSA and P. aeruginosa coverage and is being studied in febrile neutropenia, hospital-acquired pneumonia and ventilator-associated pneumonia.

Ceftobiprole has had a long road to the United States market. It was initially sent to the FDA for approval in 2007, but has yet to be approved due to concerns regarding the conduct of the clinical trials. Ceftaroline’s story is much different. Its new drug application was first submitted to the FDA on Dec. 30, 2009, and had a relatively smooth application process leading up to its eventual approval in October.

Ceftaroline is administered as a prodrug — ceftaroline fosamil — that is rapidly dephosphorylated in the blood to the active form. Ceftaroline is currently available for IV administration and is given over 1 hour. It is eliminated renally with 60% of the administered dose recovered in the urine. The recommended dose is 600 mg IV every 12 hours (for 5-14 days in SSSI, and for 5-7 days in CAP). Dose reductions for renal impairment are included in the package labeling. Common adverse effects seen with ceftaroline include nausea, diarrhea, headache and insomnia. Rare but severe adverse effects include respiratory and infectious complications, but these were not more common than in comparator groups in clinical trials.

Ceftaroline was compared with ceftriaxone in two randomized, double blind, phase 3 trials treating a total of 1,228 hospitalized patients with CAP. Patients received IV ceftaroline 600 mg every 12 hours or ceftriaxone 1 g every 24 hours for 5 to 7 days. Ceftaroline was found to be as effective as ceftriaxone in reaching clinical cure 8 to 15 days after completion of therapy. Clinical and microbiologic success rates were greater with ceftaroline than ceftriaxone in the pooled study results, but the study was not powered to determine ceftaroline superiority. Of note, no patients receiving ceftaroline had microbiologic cultures containing MRSA.

Ceftaroline was compared with vancomycin plus aztreonam for the treatment of SSSI in two identical phase 3 clinical trials. The two studies and the combined data showed ceftaroline was as effective as vancomycin and aztreonam combination therapy in the rate of clinical cure. This was also true in a subgroup analysis for MRSA isolates. One limitation to this trial is that the doses and levels of vancomycin used in the vancomycin/aztreonam group were not reported.

Ceftaroline is also being developed for use in combination with a novel beta-lactamase inhibitor (NXL 104), which will improve activity against beta-lactamase–producing organisms, including Enterobacteriaceae. This combination of ceftaroline and NXL 104 is currently being studied in patients with complicated urinary tract infections. Ceftaroline is also being studied against linezolid for SSSI and in 12- to 17-year-olds for pharmacokinetic data.

Antimicrobial stewardship

Fortunately, we have not yet reached the end of the road for new antimicrobials. Unfortunately, multidrug-resistant organisms will continue to be common in the inpatient setting, and antimicrobial stewardship remains an important role for practitioners. Ceftaroline is an antimicrobial that will require stewardship in its utilization. Although there are no currently known resistant isolates of S. aureus or S. pneumonia, it is only a matter of time before they develop. Ceftaroline has yet to find its niche in the clinical setting, but its favorable side effect profile and lack of monitoring requirements make it an attractive option.

It will be interesting to see how this medication is used clinically. The current literature suggests ceftaroline is effective in treating MRSA infections and also in treating pneumonia, but the studies did not look at patients with MRSA pneumonia. The studies also did not look at hospital-, health care- or ventilator-associated pneumonia. Until studies are available for the treatment of MRSA pneumonia and these other indications, it will be difficult to confidently treat this indication with ceftaroline alone. Initially, this medication may find a home on general medicine floors treating both CAP and SSSI. Its lack of bone marrow suppression and renal toxicity makes it a favorable alternative to linezolid and vancomycin in patients with low blood cell counts and renal dysfunction, respectively.

As the literature base grows for this antimicrobial, we will have a better idea on how it is used clinically, but for now, we are limited to the available data. Overall, ceftaroline appears to be a safe and effective antimicrobial therapy for the treatment of SSSI and CAP.

Corey J. Leinum, PharmD, is a post graduate year-1 resident with the University of Minnesota Medical Center, Fairview. Kimberly Boeser, PharmD, is an infectious diseases clinical PharmD, antimicrobial stewardship coordinator at the University of Minnesota Medical Center, Fairview.

For more information:

• ClinicalTrials.gov. US National Institutes of Health website. Available at: clinicaltrials.gov/ct2/results?term=ceftaroline. Accessed Feb. 22, 2011.
• Corey GR. Clin Infect Dis. 2010;51:641-650.
• File TM Jr. Clin Infect Dis. 2010;51:1395-1405.
• Food and Drug Administration. Department of Health and Human Services. Available at: www.accessdata.fda.gov/drugsatfda_docs/appletter/2010/200327s000ltr.pdf. Accessed Feb. 23, 2011.
• Teflaro [package insert]. St. Louis, MO: Forest Laboratories Inc; 2010.
• Woodford N. J Infect. 2009;59:S4-S16.

Disclosures: The researchers report no relevant financial disclosures.