A total of 870 hospitalized adults with HABP/VABP were randomized and received trial medications in a multinational, multi-center, double-blind trial comparing AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) intravenously every 8 hours to meropenem 1 gram intravenously every 8 hours for 7 to 14 days of therapy. Study medication dosages were adjusted per renal function. The protocol allowed for administration of prior and concomitant systemic antibacterial therapy.

Clinical efficacy was evaluated in the intent-to treat (ITT) population, which included all randomized patients who received study drug. The median age was 66 years and 74.1% were male. The median APACHE II score was 14. The majority of patients were from China (33.1%) and Eastern Europe (25.5%). There were no patients enrolled within the United States. Less than 1.0% of patients were of Pacific Island or African descent. Overall, 379 (43.6%) patients were ventilated at enrollment, including 290 (33.3%) patients with VABP and 89 (10.2%) with ventilated HABP. Bacteremia at baseline was present in 4.8% of patients. 

In the AVYCAZ and meropenem treatment groups up to 26% of patients received more than 24 hours of potentially effective systemic Gram-negative antibacterial therapy in the 3 days prior to randomization. Patients with infections only due to Gram-positive organisms were excluded from the trial, when this could be determined before enrollment. Following randomization, patients in both treatment groups could receive empiric open-label linezolid or vancomycin to cover for Gram-positive pathogens while awaiting culture results. Treatment with Gram-positive coverage continued in patients with Gram-positive pathogens. 

Adjunctive Gram-negative antibacterial therapy with amikacin or another aminoglycoside was permitted if resistance to meropenem was suspected. Systemic Gram-negative antibacterial therapy was administered to 87% and 86% of patients in the AVYCAZ and meropenem treatment groups, respectively, at any point up to the end of therapy. In either treatment group, up to 36% of patients received more than 72 hours of potentially effective concomitant therapy. 

Table 23 presents the 28-day all-cause mortality rates (28 to 32 days after randomization). Results are presented for the ITT population and for the microbiological intent-to-treat (micro-ITT) population, which included all patients with positive culture results indicating the presence of at least one Gram-negative pathogen. Clinical cure at the TOC visit (21-25 days from randomization) is also presented. Clinical cure was defined as resolution or significant improvement in signs and symptoms associated with pneumonia and cessation of antibacterial treatment for HABP/VABP. AVYCAZ was non-inferior to meropenem with regard to the primary endpoint (28-day all-cause mortality in the ITT population). The control group mortality rates were lower than that observed in other HABP/VABP trials which may impact generalizability of results. However, review of patient characteristics reflecting disease severity indicates the study enrolled a representative HABP/VABP population.

The administration of prior or concomitant Gram-negative antibacterial therapy can confound the assessment of trial results. However, a subgroup analysis of 28-day all-cause mortality in subjects who received 24 hours or less of potentially effective antibacterial therapy prior to randomization and 72 hours or less of concomitant potentially effective antibacterial therapy following randomization produced results similar to the overall ITT population, AVYCAZ mortality 10.0% (20/200), meropenem 6.2% (12/195) [difference 3.8%; 95% CI: -1.6 % to 9.5%]). In the subset of patients who received more than 24 hours of potentially effective antibacterial therapy prior to randomization or more than 72 hours of concomitant potentially effective antibacterial therapy following randomization, results were similar to the overall ITT population (AVYCAZ 9.7% (25/258), meropenem 10.5% (28/266) [difference -0.08%; 95% CI: (-6.1% to 4.4%)]).

All-cause mortality rates by pathogen are presented in Table 24. Of the 382 patients in the micro-ITT population, 36 patients were bacteremic at baseline; 20/21 (95.2%) in the AVYCAZ arm and 13/15 (86.7%) in the meropenem arm survived through the day-28 follow-up visit; 13/21 (61.9%) patients in the AVYCAZ arm and 9/15 (60%) of patients in the meropenem arm had a clinical cure at the TOC visit.

The 28-day all-cause mortality rates by pathogen in the micro-ITT population are presented in Table 24. The clinical cure rates at TOC by pathogen in the micro-ITT population are presented in Table 25.

At baseline, 108/382 (28.3%) of patients in the micro-ITT population had Gram-negative isolates that were not susceptible to ceftazidime, including 53 patients with K. pneumoniae and 28 patients with P. aeruginosa isolates. The 28-day all-cause mortality in patients with ceftazidime non-susceptible Gram-negative isolates was 8.2% (4/49) in the AVYCAZ arm and 8.5% (5/59) in the meropenem arm. Clinical cure rates at TOC were 37/49 (75.5%) in patients who received AVYCAZ and 42/59 (71.2%) in patients who received meropenem.