Ceftobiprole medocaril: the new generation of cephalosporins

There is an increasing awareness in the community regarding multidrug resistant organisms and the burden they place on health care.

Multi-drug resistant organisms are defined as microorganisms that have developed resistance to one or more classes of antibiotics.

Methicillin-resistant Staphylococcus aureus, penicillin-resistant pneumococcus, Pseudomonas species, and extended spectrum beta lactamase positive gram-negative pathogens are the most well known multi-drug resistant organisms. These types of pathogens have been publicized heavily within the last several years. The public’s knowledge has placed demands on inpatient health care settings to control the spread and prevent the emergence of these pathogens in hospitals. This is a task not taken lightly by most health care facilities. Constant evaluation, control measures and prudent use of antimicrobials are the steps being taken to reassure the public that health care settings are safe.

Burdens on health care

The overwhelming burden on health care to address the exponential rise in resistant organisms, which significantly affect morbidity and mortality, is only part of the issue.

The other side is the decreasing research and development for new classes of anti-infectives or anti-infectives that can help combat pathogens like MRSA and other multi-drug resistant organisms.

Research and development on new products can take approximately 10 years to bring a new agent to market. The price tag ranges between $800 million to $1.7 billion dollars – a large investment for a pharmaceutical company to endure without a guarantee for return on that investment.

In the late 1990s to early 2000s, 225 new molecular entities were presented to the FDA for approval. Only seven of those agents were antimicrobials. A large area of research and development for antimicrobials has focused on anti-MRSA treatments.

New agents

Several novel agents to treat MRSA infections have been approved within the last decade, including quinapristin/dalfopristin (Synercid, King), approved in 1999; linezolid (Zyvox, Phamacia, Upjohn), approved in 2000l; daptomycin (Cubicin, Cubist), approved in 2003; and tigecylcine (Tygacil, Wyeth), approved in 2005.

Development of agents to target particular pathogens, such as MRSA or Pseudomonas species, has left practioners no option but to treat infections with multiple antibiotics. Infections in hospitalized patients can range from hospital-acquired pneumonia or ventilator associated pneumonia, urinary tract infections, wound infections and many more. These types of infections can be polymicrobial in nature. It is clear that treating with multiple antibiotics is not the most optimal strategy but the only available option to adequately cover patients.

On the horizon

A new agent is on the horizon. Ceftobiprole medocaril (BAL5788, Basilea Pharmaceutica, Johnson & Johnson- Ortho McNeill) is currently in Phase 3 registration trails. In June 2004, this agent was granted fast-track status by the FDA for the treatment of both complicated skin and skin structure infections due to MRSA and hospital-acquired pneumonia, including ventilator associated pneumonia due to suspected or proven MRSA infections. Ceftobiprole medocaril has been approved for use in Canada and Switzerland for the treatment of complicated skin and skin structure infections, including diabetic foot infections. It will be marketed under the trade name of Zaftera/Zavtera. This agent has been reviewed for approval and entrance into the U.S. market, but was only issued an approvable letter in March 2008. The FDA is requesting additional information before it will be approved for the use in the United States.

This agent is expected to launch in the United States within the next year. Therefore, an early introduction to Ceftobiprole medocaril is warranted. This agent is different than others on the market. Its predicted spectrum of coverage makes it a desirable antimicrobial for nosocomial organisms. Ceftobiprole is the first, broad-spectrum, anti-MRSA cephalosporin. It is also the first of antimicrobials to include anti-MRSA and anti-Pseudomonas activity in the spectrum of its coverage. It seemingly provides the best of both worlds.

The cephalosporins are a broad class of beta-lactam antibiotics. They are divided into four generations. It is often taught that the first generation cephalosporins provide more gram-positive coverage. As the generations progress, the spectrum of coverage changes from gram positive to gram negative. Ceftobiprole has been labeled the “fifth generation” cephalosporin with coverage for gram positives, including MRSA and gram negatives, including Pseudomonas species. The research strategy has focused heavily on this agent’s anti-MRSA coverage.

Ceftobiprole can be distinguished from other beta-lactams by its increased binding to penicillin-binding protein 2a. Penicillin-binding proteins, the targets of beta-lactam antibiotics, are enzymes found in the membrane that are the last step of peptidoglycan biosynthesis. Penicillin-binding protein 2a is the enzyme most directly related to methicillin-resistant staphylococci. Activity of ceftobiprole has been studied against both the community-acquired MRSA strains and hospital-acquired MRSA. It is suggested that ceftobiprole’s affinity of most penicillin-binding proteins is equivalent to other marketed beta-lactams for both gram positive and gram-negative organisms.

New studies

Two major Phase 3 clinical trials have addressed the treatment of complicated skin and skin structure infections. Both studies were published in Antimicrobial Agents and Chemotherapy last year by Noel, G. et al. The first study was a randomized, double-blind trial comparing ceftobiprole medocaril with vancomycin plus ceftazidime for the treatment of patients with complicated skin and skin structure infections. The second study evaluated the treatment with ceftobiprole or vancomycin for complicated skin and skin structure infections caused by gram-positive bacteria, including MRSA. Both studies were non-inferiority studies. The “fast track” designation was also for the treatment of nosocomial pneumonia due to suspected or proven MRSA. The investigators are recruiting patients for phase-3 studies in this infectious disease syndrome.

The two studies combined have enrolled more than 1,600 patients with complicated skin and skin structure infections. The first trial achieved a cure rate of 93.3%, with 91.8% of those infections due to MRSA. Vancomycin was the comparator agent with cure rates of 93.5 % with 90% of those infections due to MRSA. Of clinical importance, vancomycin was given as a standard dose of 1 gm and not dosed based on a 15 mg/kg times actual body weight – the preferred dosing method for vancomycin.

Similar results were seen in the second study. The comparator was a combination of ceftazidime plus vancomycin. The achievable cure rates for the combo or ceftobiprole were 90% and 91%, respectively.

Pharmacokinetic and pharmacodynamic principles

The pharmacokinetic and pharmacodynamic principles of ceftobiprole are fairly well understood. Ceftobiprole medocaril is the prodrug, which, is converted rapidly and almost completely to the active drug ceftobiprole. Ceftobiprole undergoes primary renal excretion and minimal hepatic metabolism. The primary metabolite is the beta-lactam ring-opened hydrolysis product. This open-ring metabolite accounts for 4% of systemic exposure after a single-dose. The pharmacokinetics of ceftobiprole are linear following infusions. Steady–state drug concentrations are attained on the first day of dosing, with no accumulation when administered three times daily. The dosing regimens studied have included 500 mg IV every 8 hours or every 12 hours. Given it is renally excreted, dosing adjustments may be necessary in patients with renal insufficiency. These dosing adjustment recommendations have not been established.

In trials, adverse effects related to ceftobiprole medocaril were evaluated. Overall, the antibiotic was well tolerated with the most common treatment emergent adverse events being nausea, taste disturbance described as a caramel taste, diarrhea and vomiting.

The past decade has seen an exponential rise in multi-drug resistant pathogens, plaguing the community and inpatient health care settings. Research and development around antimicrobial agents has decreased substantially, as well. This is not a good combination for future treatment strategies for infections caused by these multi-drug resistant organisms. Ceftobiprole, while it does not add a new, novel class to an armamentarium of antibiotics, it does add a unique spectrum of coverage to the beta-lactams, particularly the cephalosporins. Its in vitro activity against staphylococci, penicillin resistant pneumococci, combined with the broad gram-negative spectrum, the stability against the beta-lactamases, the favorable pharmacokinetic/dynamic properties and low adverse effect profile so far, is making ceftobiprole medocaril an attractive new agent. Further head-to-head studies that are not sponsored by the manufacturer, focusing on complicated skin and skin structure infections and pneumonias will prove if it has a place in the arena to treat serious nosocomial infections.

Kimberly Boeser, PharmD, is the infectious disease clinical pharmacologist at the University of Minnesota Medical Center, Fairview in Minneapolis, where she coordinates the antimicrobial stewardship program.