Gram-negative: Ceftolozane/tazobactam

cUTI (complicated urinary tract infection)
Phase 3
cIAI (complicated intra abdominal infection)
Phase 3
HABP/VABP (hospital-acquired / ventilator-associated bacterial pneumonia)
Phase 2
Ceftolozane/tazobactam

Ceftolozane/Tazobactam Overview

Ceftolozane/tazobactam (formerly known as CXA-201) is a novel, antipseudomonal cephalosporin and a well-established β-lactamase inhibitor in development for the treatment of complicated urinary tract infections (cUTIs), complicated intra-abdominal infections (cIAIs), and ventilator-associated pneumonia (VAP).1-5 Ceftolozane exerts its bactericidal activity by inhibiting essential penicillin-binding proteins (PBPs),6 resulting in inhibition of cell-wall synthesis and subsequent cell death. Tazobactam is an inhibitor of most class A β-lactamases and some class C β-lactamases that, by binding to the active site of these enzymes, protects ceftolozane from hydrolysis and broadens coverage to include most extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae.7-10

Ceftolozane/tazobactam has a spectrum of activity that includes many key Gram-negative pathogens. It has shown activity against Escherichia coli and Klebsiella pneumoniae, including strains producing ESBL enzymes.10,11 Ceftolozane/tazobactam has also demonstrated activity against Pseudomonas aeruginosa, including strains resistant to carbapenems, piperacillin/tazobactam, and other cephalosporins as well as strains that are multidrug resistant.

Based on the success of Phase 3 trials of ceftolozane/tazobactam in complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI), Cubist expects to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) in the first half of 2014 for approval in both of these indications. In the second half of 2014, the Company plans to submit a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA).

Additionally, ceftolozane/tazobactam is being developed for the potential treatment of Hospital-Acquired Bacterial Pneumonia (HABP)/Ventilator-Associated Bacterial Pneumonia (VABP). The Company expects to initiate a pivotal Phase 3 trial to assess the safety and efficacy of ceftolozane/tazobactam in this indication during the first half of 2014.

References

  • Clinicaltrials.gov. Study comparing the safety and efficacy of intravenous CXA-201 and intravenous levofloxacin in complicated urinary tract infection, including pyelonephritis. Identifier NCT01345929. Accessed September 24, 2013.
  • Clinicaltrials.gov. Study comparing the safety and efficacy of intravenous CXA-201 and intravenous levofloxacin in complicated urinary tract infection, including pyelonephritis. Identifier NCT01345955. Accessed September 24, 2013.
  • Clinicaltrials.gov. Study comparing the safety and efficacy of intravenous CXA-201 and intravenous meropenem in complicated intraabdominal infections. Identifier NCT01445678. Accessed September 24, 2013.
  • Clinicaltrials.gov. Safety and efficacy of intravenous CXA-201 and intravenous meropenem in complicated intra-abdominal infections. Identifier NCT01445665. Accessed on September 24, 2013.
  • Clinicaltrials.gov. Study of intravenous ceftolozane/tazobactam vs. piperacillin/tazobactam in ventilator associated pneumonia. Identifier NCT01853982. Accessed on September 24, 2013
  • Moya B, Zamorano L, Juan C, et al. Affinity of the new cephalosporin CXA-101 to penicillin-binding proteins of Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2010;54:3933-3937.
  • Drawz SM, Bonomo RA. Three decades of ß-lactamase inhibitors. Clin Microbiol Rev. 2010;23:160-201.
  • Bonomo RA, Liu J, Chen Y, et al. Inactivation of CMY-2 ß-lactamase by tazobactam: initial mass spectroscopic characterization. Biochim Biophys Acta. 2001;1547:196-205.
  • Bush K, Macalintal C, Rasmussen BA, et al. Kinetic interactions of tazobactam with beta-lactamases from all major structural classes. Antimicrob Agents Chemother. 1993;37:851-858.
  • Livermore DM, Mushtaq S, Ge Y. Chequerboard titration of cephalosporin CXA-101 (FR264205) and tazobactam versus ß-lactamase-producing Enterobacteriaceae. J Antimicrob Chemother. 2010;65:1972-1974.
  • Titelman E, Karlsson IM, Ge Y, Giske CG. In vitro activity of CXA-101 plus tazobactam (CXA-201) against CTX-M-14- and CTX-M-15-producing Escherichia coli and Klebsiella pneumoniae. Diagn Microbiol Infect Dis. 2011;70:137-141.
  • Sader HS, Rhomberg PR, Farrell DJ, Jones RN. Antimicrobial activity of CXA-101, a novel cephalosporin tested in combination with tazobactam against Enterobacteriaceae, Pseudomonas aeruginosa, and Bacteroides fragilis strains having various resistance phenotypes. Antimicrob Agents Chemother. 2011;55:2390-2394.