title: Multicenter, double-blind, randomized, phase II trial to assess the safety and efficacy of ceftolozane-tazobactam plus metronidazole compared with meropenem in adult patients with complicated intra-abdominal infections.
abstract: Ceftolozane-tazobactam (TOL-TAZ) is a novel antibacterial with activity against Pseudomonas aeruginosa and other common Gram-negative pathogens, including extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae, that are associated with complicated intra-abdominal infections (cIAIs). This prospective, double-blind, randomized, multicenter, phase II trial assessed patient clinical and microbiological responses to and the safety of TOL-TAZ plus metronidazole compared with those of meropenem. Hospitalized adults with cIAIs that required surgical intervention were randomized (2:1) to receive intravenous (i.v.) TOL-TAZ (1.5 g [containing 1,000 mg TOL and 500 mg TAZ] every 8 h [q8h]) with or without i.v. metronidazole (500 mg q8h) or i.v. meropenem (1 g q8h) for 4 to 7 days. The primary endpoint was the clinical response at the test-of-cure visit in the microbiologically modified intent-to-treat (mMITT) and microbiologically evaluable (ME) populations. Secondary measures included the patients' microbiological response and safety. In total, 82 patients received TOL-TAZ (90.2% with metronidazole), and 39 received meropenem. For the mMITT population, clinical cure was seen in 83.6% of the patients (51/61; 95% confidence interval [CI], 71.9 to 91.8) who received TOL-TAZ and 96.0% of the patients (24/25; 95% CI, 79.6 to 99.9) who received meropenem (difference, -12.4%; 95% CI, -34.9% to 11.1%); in the ME population, clinical cure was seen in 88.7% and 95.8% of the patients (difference, -7.1%; 95% CI, -30.7% to 16.9%) who received TOL-TAZ and meropenem, respectively. TOL-TAZ demonstrated microbiological success against Escherichia coli (89.5%), Klebsiella pneumoniae (100%), and P. aeruginosa (100%). The adverse event rates were similar in the groups (50.0% with TOL-TAZ and 48.8% with meropenem). TOL-TAZ in combination with metronidazole was well tolerated and resulted in clinical and microbiological success rates supportive of further clinical development in patients with cIAIs. (This study has been registered at ClinicalTrials.gov under registration no. NCT01147640.).
authors: South Jersey Infectious Disease, Somers Point, New Jersey, USA infect123@aol.com.
authors: Christopher
authors: C
authors: Lucasti
authors: Cubist Pharmaceuticals, Lexington, Massachusetts, USA.
authors: Ellie
authors: E
authors: Hershberger
authors: Cubist Pharmaceuticals, Lexington, Massachusetts, USA.
authors: Benjamin
authors: B
authors: Miller
authors: Cubist Pharmaceuticals, Lexington, Massachusetts, USA.
authors: Sara
authors: S
authors: Yankelev
authors: Cubist Pharmaceuticals, Lexington, Massachusetts, USA.
authors: Judith
authors: J
authors: Steenbergen
authors: Cubist Pharmaceuticals, Lexington, Massachusetts, USA.
authors: Ian
authors: I
authors: Friedland
authors: University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors: Joseph
authors: J
authors: Solomkin
mesh_terms: D002511:Cephalosporins / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D059413:Intraabdominal Infections / Q000188:drug therapy*; D008297:Male; D000077731:Meropenem; D008795:Metronidazole / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D010397:Penicillanic Acid / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000078142:Tazobactam; D013845:Thienamycins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D002511:Cephalosporins; D013845:Thienamycins; C000594038:ceftolozane, tazobactam drug combination; D008795:Metronidazole; D010397:Penicillanic Acid; D000077731:Meropenem; D000078142:Tazobactam