Ceftobiprole: MRSA Coverage Comes to β-Lactams at Last
Ceftobiprole: MRSA Coverage Comes to β-Lactams at Last
Abstract & Commentary
By Brian G. Blackburn, MD, Clinical Assistant Professor of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine. Dr. Blackburn reports no financial relationships relevant to this field of study. This article originally appeared in the July 2008 issue of Infectious Disease Alert. It was edited by Stan Deresinski, MD, FACP, and peer reviewed by Connie Price, MD. Dr. Deresinski is Clinical Professor of Medicine, Stanford University; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, and Dr. Price is Assistant Professor, University of Colorado School of Medicine. Dr. Deresinski serves on the speaker's bureau for Merck, Pharmacia, GlaxoSmithKline, Pfizer, Bayer, and Wyeth, and does research for Merck, and Dr. Price reports no financial relationships relevant to this field of study.
Synopsis: Ceftobiprole, a novel broad-spectrum cephalosporin with activity against MRSA, was non-inferior to vancomycin plus ceftazidime in a study of complicated skin and skin-structure infections. This is the first β-lactam with reliable activity against methicillin resistant Staphylococcus aureus (MRSA) to be evaluated in advanced-stage clinical trials.
Source: 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.
In the current era of increasing antimicrobial resistance, the need for novel antibacterial agents has become more acute than ever. While complicated skin and skin-structure infections (cSSSIs) are a common scenario, the clinician's ability to choose a single antibacterial agent with reliable activity against the most likely pathogens has become limited, particularly because of the widespread emergence of MRSA. With the exception of tigecycline, agents with anti-MRSA activity have a relatively narrow spectrum of activity, necessitating the addition of a second agent, if broader coverage is desired. Despite their otherwise broad spectrum of activity and relatively benign safety profiles, β-Lactams to this point have not had anti-MRSA activity.
Ceftobiprole is a novel cephalosporin in advanced phases of clinical development. The broad-spectrum activity of this agent includes most gram-positive cocci, many aerobic gram-negative bacilli (including Pseudomonas aeruginosa), and some gram-positive anaerobes.1,2 Because of high-affinity binding to penicillin binding protein 2a (the major determinant of methicillin resistance in Staphylococci), ceftobiprole retains activity against MRSA, unlike all previous β-Lactams.1,2
Clinical evaluation of ceftobiprole was undertaken in a non-inferiority trial designed to evaluate efficacy in patients with cSSSIs. The comparator arm received vancomycin plus ceftazidime; patients were allowed to receive metronidazole for 48 hours pending culture results in both arms if anaerobes were suspected. This randomized, double-blind, placebo-controlled trial was conducted internationally from 2005-2006. Patients included for enrollment had surgical wound infections, skin abscesses, cellulitis, or diabetic foot infections. Overall, 828 patients were included in the intent-to-treat analysis, randomized 2:1 into the ceftobiprole and comparator arms, respectively. Both arms received therapy for 7-14 days.
The two arms were well matched with regard to baseline characteristics, including the frequency of the infecting organisms. In each arm, methicillin susceptible Staphylococcus aureus (MSSA) was the most commonly identified pathogen, with MRSA second in frequency; together, these comprised 64% of infections overall. Gram-negative or mixed (gram positive plus gram negative) infections comprised 27% of the study population.
In the intent-to-treat analysis, the clinical cure rates were nearly identical in the ceftobiprole and comparator arms (82% and 81%, respectively). Among clinically evaluable patients, the clinical cure rates were also similar (91% and 90%, respectively), including among the subgroup of patients with MRSA infections (90% and 86%, respectively). Microbiological cure rates (88% vs 89%, respectively) were also similar. Cure rates were similar in both arms when analyzed with regard to type of cSSSI, receipt of adjunctive surgical therapy, and for each of the infecting organisms (although for P. aeruginosa, a non-significant trend favored the comparator arm). No significant differences were observed for any of these comparisons. In addition, there were no differences in the frequency or type of adverse events (AEs) between the two groups; though over 50% of patients experienced at least one AE in each arm (most minor).
Commentary
These data support the conclusion that ceftobiprole is non-inferior to the combination of vancomycin plus ceftazidime for the treatment of cSSSIs. This supplements a recent clinical trial (which used a lower dose of ceftobiprole) that demonstrated ceftobiprole non-inferiority to vancomycin monotherapy in a study which focused on cSSSIs caused only by gram-positive organisms.3 By including gram-negative and diabetic foot infections in the current trial, Noel and colleagues demonstrated the success of this new drug in a broader range of patients. More importantly, this trial demonstrates that monotherapy may now be possible in situations where combination therapy was previously necessary. The combination of anti-MRSA activity with a broad anti-bacterial spectrum is unique only to tigecycline and ceftobiprole to date, and only ceftobiprole among these two agents also has anti-pseudomonal activity. Clinicians are frequently confronted by the need to cover MRSA, particularly in cSSSIs. In doing this, ceftobiprole also offers the advantages of the β-lactam class, such as rapid bactericidal activity, favorable pharmacokinetics (eg, good CNS penetration), and a good safety profile.4 The most common adverse events (AEs) associated with ceftobiprole are gastrointestinal symptoms and taste disturbance; serious AEs are rare.5
Pending final data review and FDA approval, ceftobiprole appears to be a welcome addition to the therapeutic armamentarium for cSSSIs. In addition, pending data to this end, it is easy to envision subsequent use of ceftobiprole in other clinical scenarios, should its safety profile and efficacy expectations remain on track. For example, given the activity against resistant gram-positive bacteria such as MRSA and penicillin-resistant Streptococcus pneumoniae, ceftobiprole might allow monotherapy for empiric coverage in many cases of community-acquired bacterial meningitis where combination therapy with vancomycin plus ceftriaxone are currently necessary. The availability of ceftobiprole might also allow for empiric hospital-acquired pneumonia regimens which do not require the addition of a narrow-spectrum gram-positive agent (such as vancomycin or linezolid) for MRSA coverage. These advantages are significant, not only from a toxicity standpoint, but also from an efficacy standpoint, given that β-Lactams are more rapidly bactericidal than these drugs. Should clinical data and peer review subsequently support use in such scenarios, ceftobiprole (or similar agents currently in development, such as ceftaroline) would be a welcome advance.
References
1. Goldstein EJC, et al. In vitro activity of ceftobiprole against aerobic and anaerobic strains isolated from diabetic foot infections. Antimicrob Agents Chemother. 2006;50:3959-3962.
2. Fritsche TR, et al. Antimicrobial activity of ceftobiprole, a novel anti-methicillin-resistant Staphylococcus aureus cephalosporin, tested against contemporary pathogens: results from the SENTRY Antimicrobial Surveillance Program (2005-2006). Diagn Microbiol Infect Dis. 2008;61:86-95.
3. Noel GJ, et al. 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.
4. Cottagnoud M, et al. Ceftobiprole is superior to cefepime against a Klebsiella Pneumoniae strain in experimental meningitis. Presented at the 18th European Congress of Clinical Microbiology and Infectious Diseases. April 19-22, 2008; Barcelona, Spain. Abstract number: P1933
5. Anderson SD, et al. Ceftobiprole: an extended-spectrum anti-methicillin-resistant Staphylococcus aureus cephalosporin. Ann Pharmacother. 2008;42:806-816.
Ceftobiprole, a novel broad-spectrum cephalosporin with activity against MRSA, was non-inferior to vancomycin plus ceftazidime in a study of complicated skin and skin-structure infections. This is the first β-lactam with reliable activity against methicillin resistant Staphylococcus aureus (MRSA) to be evaluated in advanced-stage clinical trials.Subscribe Now for Access
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