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New agents for gram-positive pathogens
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With an increasing incidence of resistant gram-positive pathogens such as methicillin-resistant Staphylococcus aureus, conventional antibiotics have been rendered less effective. These organisms have become a major medical threat, and the need for safe and effective therapeutic alternatives is imperative.
Of the 2 million nosocomial infections that occur in the United States each year, it is estimated that more than 50% are caused by antimicrobial-resistant strains. It is for this reason that clinicians are anxiously awaiting the availability of new agents such as telavancin (Vibativ, Theravance) and ceftobiprole (Zeftera, Johnson & Johnson).
The first of the two agents that will be available for clinical use is telavancin, which was the topic of Infectious Disease News’s November Pharmacology Consult column.
Ceftobiprole
The second of these agents is ceftobiprole, a new cephalosporin, that, similar to other cephalosporins, interferes with the final step of cell wall synthesis by covalently binding to the active site of bacterial penicillin binding proteins (PBP). Unlike other cephalosporins, it has molecular substitutions at the beta lactam ring that confer increased stability and affinity for PBPs. This allows activity against resistant gram-positive resistant organisms such as MRSA, penicillin resistant S. pneumonia and routine gram-negative pathogens. Unfortunately, it has no activity against Pseudomonas auruginosa. In addition, ceftobiprole likely has low selection for resistance, thus rendering ceftobiprole a promising therapeutic option for infection.
Srinivasan and colleagues investigated the use of this drug against 11,784 S. aureus isolates with 42.1% identified as MRSA. Ceftobiprole was found to be bactericidal against these strains with a minimum inhibitory concentration <2mcg/mL. Furthermore, Lodise and colleagues, in 2008, described time above MIC as the main parameter predictive of efficacy with this agent.
Interestingly, the IV form of ceftobiprole contains a prodrug, medocardil, that allows greater water solubility. Upon administration, the prodrug is rapidly hydrolyzed by plasma esterases to the active cephalosporin form. Ceftobiprole has a linear pharmacokinetic profile reminiscent of other cephalosporins. Ceftobiprole is not extensively protein bound, and glomerular filtration via the kidney is the primary elimination mechanism. Therefore, dose adjustment will likely be required in patients with impaired renal function. Ceftobiprole has a low expectation for major drug interactions, as it neither induced nor inhibited cytochrome P450 isoenzymes in hepatocytes.
Ongoing approval process
Ceftobiprole recently received approval letters for the use in skin and skin structure infections (SSSI) in Switzerland and Canada, but has not yet been approved for use in the United States. Two recently published large clinical trials have showcased the efficacy of ceftobiprole against invading pathogens in SSSI.
In a recent randomized, double blind, control trial, 784 patients with SSSI caused by gram-positive organisms were treated with ceftobiprole at 500 mg every 12 hours or vancomycin at 1 g every 12 hours; the study’s endpoint was cure rates seven to 14 days after the completion of therapy. This study’s results showed that ceftobiprole is effective and non-inferior to vancomycin. In the ceftobiprole and vancomycin groups, the clinical cure rates were 93.3% and 93.5%, respectively. The results of this trial support the use of ceftobiprole as an effective treatment option for patients with SSSI caused by a spectrum of gram-positive bacteria.
Another randomized, double blind, control trial enrolled 828 patients with a broad range of SSSI due to either gram-positive or gram-negative bacteria; this trial compared treatment with ceftobiprole at 500 mg every 12 hours to treatment with ceftazidime at 1 g every 12 hours and vancomycin at 1 g every 12 hours. This study also measured cure rates seven to 14 days after completion of therapy. Clinical cure rates were found to be similar between the ceftobiprole and the ceftazidime/vancomycin arms (90.5% vs. 90.2%) and also when gram-positive or gram-negative pathogens were evaluated separately. Cure rates in the ceftobiprole and ceftazidime/vancomycin arms were also comparable. Ceftobiprole was found to be similar in efficacy in treating various organisms such as MRSA, E. coli and S. pyogenes.
Ceftobiprole is also undergoing phase 3 trials to evaluate its use in community-acquired pneumonia (CAP). A randomized trial conducted by Nicholson et al evaluated ceftobiprole against ceftriaxone with or without linezolid in 666 patients with CAP. Therapy for patients treated with ceftobiprole consisted of ceftobiprole at 500 mg infusion every eight hours with or without placebo every 12 hours. The other group was treated with ceftriaxone at 2,000 mg every 24 hours plus linezolid at 600 mg every 12 hours or placebo every 12 hours. Comparison of clinical cure rates and microbiologic eradication were found to be similar for both gram-positive and gram-negative infections. This study concluded that ceftobiprole as compared with ceftriaxone with or without linezolid in CAP patients exhibited non-inferiority.
Adverse events
Ceftobiprole’s adverse effect profile has also been evaluated. In the above-mentioned studies, multiple doses of ceftobiprole were well-tolerated with no severe local or systemic adverse events. Occurrences of adverse effects between the two treatment arms were similar. No electrocardiogram abnormalities or adverse changes in vital signs were found. Nausea, headaches and a caramel-like taste disturbance were among the most frequent adverse effects reported by patients who received the infusion. Collectively, these clinical trials suggest that the adverse event profiles of ceftobiprole compared with vancomycin and with ceftazidime/vancomycin combination are similar.
With the increase in resistant gram-positive pathogens, the approval for more effective antibiotics is essential. This surge in resistant strains, coupled with the scarcity of new antimicrobials, threatens to expand an already existing crisis. Telavancin and ceftobiprole have emerged as promising potent antibiotics covering a number of resistant gram-positive pathogens. With the pending trials of ceftobiprole and the recent approval of telavancin, we are better able to treat patients with resistant gram positive organisms.
For more information:
- Jones R. Resistance patterns among nosocomial pathogens: trends over the past few years. Chest. 2001;119:397s-404s.
- Livermore DM. Can b-lactams be re-engineered to beat MRSA. Clin Microbiol Infect. 2006;12(Suppl. 2):11–16.
- Lodise T. Pharmacokinetic and pharmocodynamic profile of ceftobiprole. Diagn Microbiol Infect Dis.
- Murthy B. Pharmacokinetics and pharmacodynamics of ceftobiprole, an anti-MRSA cephalosporin with broad-spectrum activity. Clin Pharmacokinet. 2008;47:21–33.
- Nicholson S. Efficacy of ceftobiprole compared to ceftriaxone ± linezolid for the treatment of subjects hospitalized with community-acquired pneumoniae. Presented at: The International Conference of the American Thoracic Society; May 16–21, 2008; Toronto.
- Noel G. 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.
- Noel GJ. Results of a double-blind, randomized trial of ceftobiprole treatment of complicated skin and skin structure infections caused by gram-positive bacteria. Antimicrob Agents Chemother. 2008;52:37–44.
- Schmitt-Hoffmann A. Multiple-dose pharmacokinetics and safety of a novel broad-spectrum cephalosporin (BAL5788) in healthy volunteers. Antimicrob Agents Chemother. 2004;48:2576–2580.
- Srinivasan V. In vitro activity of ceftobiprole against coagulase-negative staphylococci isolated in the USA. Int J Antimicrob Agents. 2008;31:294–296.
- Stein R. Ceftobiprole: a new ß-lsctam antibiotic. Int J Clin Pract. 2009;63:930-943.