Ceftolozane/tazobactam shows promise against gram-negative infections

PHILADELPHIA — Phase 3 study data indicate the novel combination antibiotic ceftolozane/tazobactam achieved high clinical and microbiological cure rates in patients with complicated urinary tract infections and complicated intra-abdominal infections caused by Pseudomonas aeruginosa and extended-spectrum beta-lactamase–producing pathogens.

According to Steven Gilman, PhD, executive vice president of research and development and chief scientific officer of Cubist, there have been no new agents approved for gram-negative infections since the Infectious Diseases Society of America’s 10 x ’20 initiative was launched in 2010. He said there are roughly 25,000 deaths in the US and Europe each year from drug-resistant bacteria.

Steven Gilman

“Serious gram-negative infections are an important unmet global health need,” Gilman told Infectious Disease News. “With potential approval, ceftolozane/tazobactam can be helpful for a lot of patients with these infections.”

The FDA has designated ceftolozane/tazobactam (Cubist) as a qualified infectious disease product, making it eligible for fast track status and priority review. Cubist is seeking approval of ceftolozane/tazobactam for the treatment of complicated urinary tract infections (UTIs) and complicated intra-abdominal infections (IAIs). A decision from the FDA on the new drug application is expected in December. The company’s marketing authorization application also has been accepted for review by the European Medicines Agency.

Efficacy of ceftolozane/tazobactam

During a poster session at IDWeek 2014, researchers presented data from phase 3 studies of ceftolozane/tazobactam in the treatment of complicated UTIs and complicated IAIs. For the study of complicated UTIs, patients were randomly assigned 7 days IV ceftolozane/tazobactam or levofloxacin. For the study of complicated IAIs, patients were given either 4 to 14 days of ceftolozane/tazobactam plus metronidazole or meropenem.

In the microbiologically evaluable population, a total of 150 patients had an extended-spectrum beta-lactamase (ESBL)–producing infection, which was genotypically verified. Most baseline characteristics were comparable with the overall population, but patients with ESBLs were more likely to be aged 65 years or older or renally impaired compared with the overall population.

Clinical cure rates for ESBL patients with complicated UTIs and IAIs were 97% in the study drug arm and 85% for the combined comparators. Microbiological eradication was achieved in 80% of patients receiving ceftolozane/tazobactam vs. 61% of patients assigned a comparator.

At a breakpoint of 8 mg/L, 90% of ESBL-producing Enterobacteriaceae were susceptible to ceftolozane/tazobactam. In the study of complicated UTIs, around 20% of these pathogens were susceptible to levofloxacin. In the study of complicated IAIs, meropenem resistance was low, at less than 5%.

Resistance to levofloxacin

In another poster presentation, researchers presented data on the efficacy of ceftolozane/tazobactam in a subset of 212 patients with complicated UTIs, including pyelonephritis, caused by levofloxacin-resistant pathogens. Patients aged 18 years or older with pyuria and clinical symptoms of complicated UTIs were randomly assigned IV ceftolozane/tazobactam 1.5 g every 8 hours or IV levofloxacin 750 mg per day for 7 days. Susceptibility data were not available until after patients were assigned a therapy.

Of the 212 patients with levofloxacin-resistant infections, 176 were susceptible to ceftolozane/tazobactam. The study drug demonstrated superior composite cure rates compared with levofloxacin in the microbiologically evaluable (64% vs. 43.4%) and the microbiological modified intent-to-treat (60% vs. 39.3%) populations. Ceftolozane/tazobactam also demonstrated higher per-pathogen microbiological eradication rates. These included Enterobacteriaceae (71.4% vs. 45.2%); Escherichia coli (72.9% vs. 44.1%); Klebsiella pneumoniae (81.8% vs. 30%); and P. aeruginosa (100% vs. 37.5%).

“Ceftolozane/tazobactam offers an important choice for patients with gram-negative infections,” Gilman said. “If you know the phenotype and resistance probability in your hospital, this drug could be effective in many patients who would otherwise have problems being treated with alternative therapies.” — by John Schoen

For more information:

Popejoy M. Abstract 260. Presented at: IDWeek 2014 ; Oct. 8-12, 2014; Philadelphia.

Sakoulas G. Abstract 1044. Presented at: IDWeek 2014 ; Oct. 8-12, 2014; Philadelphia.

Disclosure: The studies were funded by Cubist.