Clinical efficacy demonstrated vs meropenem in critically
ill patients
HABP/VABP Phase 3 trial
STUDY DESIGN1
TYPE OF TRIAL
Phase 3, multinational, multicenter, double-blind, randomized, noninferiority trial
STUDY POPULATION
870 adults hospitalized with HABP/VABP; the ITT population included all randomized patients who received study drug. The micro-ITT population included all patients with at least one Gram-negative pathogen.
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. Overall 43.6% of patients were ventilated at enrollment, including 33.3% with VABP and 10.2% with ventilated HABP. Bacteremia at baseline was present in 4.8% of patients.
COMPARATIVE AGENTS
AVYCAZ 2.5 g (ceftazidime 2 grams and avibactam 0.5 grams) IV every 8 hours
Meropenem 1 gram intravenously every 8 hours
Study medication dosages were adjusted per renal function.
The protocol allowed for administration of prior and concomitant systemic antibacterial therapy.
TREATMENT DURATION
7 to 14 days
PRIMARY ENDPOINTS
The primary efficacy endpoint was 28-day all-cause mortality evaluated in the ITT population (28 to 32 days after randomization).
APACHE II, Acute Physiology and Chronic Health Evaluation II.
ITT, intent-to-treat.
IV, intravenous.
micro-ITT, microbiological intent-to-treat.
28-day all-cause mortality and clinical cure rates vs meropenem1
- AVYCAZ was noninferior to meropenem with regard to the primary endpoint (28-day all-cause mortality in the ITT population)
28-DAY ALL-CAUSE MORTALITY RATES (ITT)
28-DAY ALL-CAUSE MORTALITY RATES (micro-ITT)
- 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
CLINICAL CURE RATES VS MEROPENEM AT TOC (ITT)*†‡
*A quantitative estimate of treatment effect has not been established for the clinical cure endpoint.
†Clinical cure was defined as resolution or significant improvement in signs and symptoms associated with pneumonia and cessation of antibacterial treatment for HABP/VABP.
‡The TOC visit occurred 21 to 25 days from randomization.
CI, confidence interval.
TOC, test of cure.
Clinical efficacy demonstrated in patients with bacteremia1
>10% of AVYCAZ patients in the micro-ITT population were bacteremic at baseline (21/187)
BACTEREMIA SUBSET POPULATION: SURVIVAL THROUGH THE DAY-28 FOLLOW-UP VISIT (micro-ITT)
BACTEREMIA SUBSET POPULATION: CLINICAL CURE RATES AT TOC (micro-ITT)
- Of the 382 patients in the micro-ITT population, 36 patients were bacteremic at baseline
Clinical efficacy in patients who received potentially effective prior or concomitant antibacterial therapy1
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%]).
Clinical efficacy vs ceftazidime-NS Gram-negative pathogens, including K. pneumoniae and P. aeruginosa1
- At baseline, 28.3% (108/382) 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 isolates1
- Among the inclusion criteria for the study was a need for mechanical ventilation or, for already ventilated patients, acute changes made in the ventilator support system to enhance oxygenation, as determined by, for example, arterial blood gas or worsening PaO2/FiO22
- The micro-ITT population included a greater baseline proportion of patients who were ventilated (68.6%), had VABP (54.2%), had late VABP (40.3%), and were bacteremic (9.4%) than the ITT population2
CEFTAZIDIME-NS SUBSET POPULATION: 28-DAY ALL-CAUSE MORTALITY (micro-ITT)1
CEFTAZIDIME-NS SUBSET POPULATION: CLINICAL CURE RATES AT TOC (micro-ITT)1
NS, nonsusceptible.
IDSA treatment guidance for antimicrobial-resistant Gram-negative bacterial infections recommends AVYCAZ as a preferred antibiotic when facing the challenge of Pseudomonas aeruginosa with difficult-to-treat resistance (DTR-P. aeruginosa).*3
This recommendation includes infections such as HABP/VABP.3
*DTR is defined as P. aeruginosa exhibiting nonsusceptibility to all of the following: piperacillin-tazobactam, ceftazidime, cefepime, aztreonam, meropenem, imipenem-cilastatin, ciprofloxacin, and levofloxacin.3
IDSA, Infectious Diseases Society of America.
Clinical efficacy vs a broad range of key Gram-negative pathogens in HABP/VABP1
28-DAY ALL-CAUSE MORTALITY BY BASELINE PATHOGEN (micro-ITT)
CLINICAL CURE RATES AT TOC BY BASELINE PATHOGEN (micro-ITT)1
HABP/VABP Pediatric Study
An open-label single-dose pharmacokinetic (PK) and safety trial was conducted in pediatric patients with HABP/VABP and enrolled four patients aged 11.6 months to 9.4 years.