Adult Patients

A total of 726 adult patients hospitalized with HABP/VABP were enrolled in a multinational, double-blind study (NCT02070757) comparing ZERBAXA 3 g (ceftolozane 2 g and tazobactam 1 g) intravenously every 8 hours to meropenem (1 g intravenously every 8 hours) for 8 to 14 days of therapy. All patients had to be intubated and on mechanical ventilation at randomization.

Efficacy was assessed based on all-cause mortality at Day 28 and clinical cure, defined as complete resolution or significant improvement in signs and symptoms of the index infection at the test-of-cure (TOC) visit which occurred 7 to 14 days after the end of treatment. The analysis population was the intent-to-treat (ITT) population, which included all randomized patients.

Following a diagnosis of HABP/VABP and prior to receipt of first dose of study drug, if required, patients could have received up to a maximum of 24 hours of active non-study antibacterial drug therapy in the 72 hours preceding the first dose of study drug. Patients who had failed prior antibacterial drug therapy for the current episode of HABP/VABP could be enrolled if the baseline lower respiratory tract (LRT) culture showed growth of a Gram-negative pathogen while the patient was on the antibacterial therapy and all other eligibility criteria were met. Empiric therapy at baseline with linezolid or other approved therapy for Gram-positive coverage was required in all patients pending baseline LRT culture results. Adjunctive Gram-negative therapy was optional and allowed for a maximum of 72 hours in centers with a prevalence of meropenem-resistant P. aeruginosa more than 15%.

Of the 726 patients in the ITT population, the median age was 62 years and 44% of the population was 65 years of age and older, with 22% of the population 75 years of age and older. The majority of patients were White (83%), male (71%) and were from Eastern Europe (64%). The median APACHE II score was 17 and 33% of subjects had a baseline APACHE II score of greater than or equal to 20. All subjects were on mechanical ventilation and 519 (71%) had VABP. At randomization, 92% of subjects were in the ICU, 77% had been hospitalized for 5 days or longer, and 49% were ventilated for 5 days or longer. A total of 258 of 726 (36%) patients had CrCl less than 80 mL/min at baseline; among these, 99 (14%) had CrCl less than 50 mL/min. Patients with end-stage renal disease (CrCl less than 15 mL/min) were excluded from the trial. Approximately 13% of subjects were failing their current antibacterial drug therapy for HABP/VABP, and bacteremia was present at baseline in 15% of patients. Key comorbidities included diabetes mellitus, congestive heart failure, and chronic obstructive pulmonary disease at rates of 22%, 16%, and 12%, respectively. In both treatment groups, most subjects (63.1%) received between 8 and 14 days of study therapy as specified in the protocol.

Table 18 presents the results for Day 28 all-cause mortality and clinical cure at the TOC visit overall and by ventilated HABP and VABP.

In the ITT population, Day 28 all-cause mortality and clinical cure rates in patients with CrCl greater than or equal to 150 mL/min were similar between ZERBAXA and meropenem. In patients with bacteremia at baseline, Day 28 all-cause mortality rates were 23/64 (35.9%) for ZERBAXA-treated patients and 13/41 (31.7%) for meropenem-treated patients; clinical cure rates were 30/64 (46.9%) and 15/41 (36.6%), respectively.

Per pathogen Day 28 all-cause mortality and clinical cure at TOC were assessed in the microbiologic intention to treat population (mITT), which consisted of all randomized subjects who had a baseline lower respiratory tract (LRT) pathogen that was susceptible to both study treatments. In the mITT population, Klebsiella pneumoniae (113/425, 26.6%) and Pseudomonas aeruginosa (103/425, 24.2%) were the most prevalent pathogens isolated from baseline LRT cultures. 

Day 28 all-cause mortality and clinical cure rates at TOC by pathogen in the mITT population are presented in Table 19. In the mITT population, clinical cure rates in patients with a Gram-negative pathogen at baseline were 139/215 (64.7%) for ZERBAXA and 115/204 (56.4%) for meropenem, respectively.

In a subset of Enterobacteriaceae isolates from both arms of the trial that met pre-specified criteria for beta-lactam susceptibility, genotypic testing identified certain ESBL groups (e.g., TEM, SHV, CTX-M, OXA) in 101/425 (23.8%). Day 28 all-cause mortality and clinical cure rates in this subset were similar to the overall trial results.