The novel combination antibiotic ceftolozane/tazobactam demonstrated activity against several pathogens causing urinary tract infections and intra-abdominal infections in adult patients, according to data from two phase 3 clinical trials presented at the 2014 European Congress of Clinical Microbiology and Infectious Diseases, or ECCMID.
“We are delighted by the growing body of evidence indicating that ceftolozane/tazobactam may prove to be an important treatment option to address three of the most difficult to treat gram-negative pathogens — specifically Pseudomonas aeruginosa and [extended-spectrum beta-lactamase–producing Escherichia coli] and Klebsiella pneumoniae — in [complicated urinary tract infections] and [complicated intra-abdominal infections],” Steven Gilman, PhD, executive vice president of research and development and chief scientific officer of Cubist Pharmaceuticals Inc., said in a press release.
In the first study, 1,083 adult patients with pyuria and clinical symptoms of complicated urinary tract infections were randomly assigned to 1.5 mg ceftolozane/tazobactam (Cubist) every 8 hours or a daily dose of 750 mg levofloxacin for 7 days. The primary endpoint was a composite of microbiological eradication and clinical cure rates 5 to 9 days after therapy. Ceftolozane/tazobactam demonstrated significantly higher composite cure rates for microbiological modified intent-to-treat patients (76.9% vs. 68.4%; difference=8.5%; 95% CI, 2.3-14.6) and for microbiologically evaluable patients (83.3% vs. 75.4%; difference=8%; 95% CI, 2-14).
In microbiologically evaluable patients, microbiological eradication rates for ceftolozane/tazobactam and levofloxacin were 90.5% vs. 79.6% (difference=10.9%; 95% CI, 4.9-16.8) for E. coli, 84% vs. 60.9% (difference=23.1%; 95% CI, –2.1 to 45.4) for K. pneumonia, and 85.7% vs. 58.3% (difference=27.4%; 95% CI, –15.9 to 56.3) for P. aeruginosa.
Drug-related adverse events occurred in 10.3% of patients who received ceftolozane/tazobactam vs. 12% of those who received levofloxacin. The most commonly reported adverse event was headache (5.8% for ceftolozane/tazobactam and 4.9% for levofloxacin). Other adverse events in the ceftolozane/tazobactam group included constipation (3.9%), hypertension (3%), nausea (2.8%) and diarrhea (1.9%).
Researchers reported one death in the ceftolozane/tazobactam group, which was attributed to bladder cancer and unrelated to treatment, and two serious drug-related adverse events, both of which resulted in Clostridium difficile infection and eventually resolved. No deaths or serious adverse events were reported in patients taking levofloxacin.
“Pseudomonas aeruginosa and ESBL-producing Enterobacteriaceae are resistant pathogens we see in patients with complicated urinary tract infections,” study researcher Florian Wagenlehner, MD, PhD, of Justus-Liebig University of Giessen, Germany, said in a press release. “The data presented during ECCMID demonstrate the activity of ceftolozane/tazobactam against these problematic pathogens.”
Another randomized trial investigated the efficacy and safety of ceftolozane/tazobactam plus metronidazole in patients with complicated intra-abdominal infections. A total of 993 patients with complicated intra-abdominal infections received 1.5 g ceftolozane/tazobactam plus 500 mg metronidazole or 1 g meropenem every 8 hours for 4 to 10 days. The primary endpoint was to demonstrate the noninferiority of ceftolozane/tazobactam plus metronidazole to meropenem based on clinical cure rates 26 to 30 days after the initiation of therapy.
The difference in treatment response between the two groups fell within the pre-specified noninferiority margins established by the FDA (10%) and the European Medicines Agency (EMA; 12.5%).
For the FDA, the researchers looked at the modified intent-to-treat population, which had overall cure rates of 83% for ceftolozane/tazobactam plus metronidazole and 87.3% for meropenem (difference=–4.2%; 95% CI, –8.9 to 0.5).
For the EMA, the researchers examined clinical cure rates in the clinically evaluable population, which were 94.1% for ceftolozane/tazobactam plus metronidazole and 94% for meropenem (difference=0; 95% CI, –4.2 to 4.3).
In the microbiologically evaluable population, ceftolozane/tazobactam plus metronidazole demonstrated microbiological eradication rates of 96% vs. 95.1% (difference=0.9%; 95% CI, –3.3 to 4.5) for E. coli, 100% vs. 88% (difference=12%; 95% CI, –2.4 to 30) for K. pneumonia, and 100% vs. 100% (difference=0%; 95% CI, –13.3 to 12.1) for P. aeruginosa.
“Ceftolozane/tazobactam is a novel antibacterial candidate being developed for the potential treatment of common and problematic gram-negative pathogens that cause infections in patients following a broad range of surgical procedures,” Christian Eckmann, MD, chief of surgery at the Academic Hospital of Medical University Hannover, Germany, said in the release. “These clinical trial data suggest that ceftolozane/tazobactam is a potential useful treatment for patients with complicated intra-abdominal infections.”
For more information:
Eckmann C. Abstract #P0266a.
Wagenlehner F. Abstract #eP449.
Both presented at: European Congress of Clinical Microbiology and Infectious Diseases; May 10-13, 2014; Barcelona, Spain.
Disclosure: The studies were sponsored by Cubist.