Adult Patients

The efficacy of AVYCAZ in patients with cUTI was evaluated in two randomized, actively controlled clinical trials (Trial 1 and Trial 2) as described below.

cUTI Trial 1 

A total of 1020 adults hospitalized with cUTI 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 doripenem 0.5 grams intravenously every 8 hours for 10 to 14 days of total therapy. A switch to an oral antimicrobial agent was allowed after 5 days of intravenous dosing. Complicated urinary tract infections included acute pyelonephritis and complicated lower urinary tract infections.

The mMITT population, which included all patients who had at least one uropathogen isolated at baseline (greater or equal to 105 CFU/mL), consisted of 810 patients; the median age was 55 years and 69.8% were female. The majority of patients (75.4%) were from Eastern Europe; less than 1% of patients were from the United States. The majority of patients were White (83%) or Asian (7.8%); other racial subgroups were each represented at less than 1%. The most common diagnosis was acute pyelonephritis, occurring in 72% of patients. Bacteremia was present at baseline in 8.8% of patients. 

Clinical efficacy was determined by comparing the response rate of AVYCAZ to doripenem at both primary endpoints; symptom response rates at Day 5 and combined microbiological cure and symptom response rates at the TOC visit (21 to 25 days after randomization). A symptom response was based on the resolution of patient-reported cUTI symptoms, defined as frequency/urgency/dysuria/suprapubic pain, as well as an improvement in flank pain for individuals with acute pyelonephritis. Microbiological cure was defined as a reduction of all baseline uropathogens to less than 104 CFU/mL in the urine. 

AVYCAZ was non-inferior to doripenem with regard to both primary endpoints as presented in Table 18. 

Microbiological cure rates by pathogen are presented in Table 19. Microbiological cure in individuals with bacteremia at baseline was achieved in 31/38 (81.6%) patients in the AVYCAZ arm and 24/33 (72.7%) patients in the doripenem arm at the TOC visit in the mMITT population. The most common pathogen isolated from blood was Escherichia coli, for which 31/32 (96.9%) patients in the AVYCAZ arm were microbiological cures, compared with 28/28 (100%) patients in the doripenem arm. 

At baseline, 159 patients in the mMITT population had Gram-negative isolates that were not susceptible to ceftazidime, including 75 patients in the AVYCAZ arm and 84 in the doripenem arm. Microbiological and clinical cure rates at TOC were 47/75 (62.7%) and 67/75 (89.3%), respectively, in patients who received AVYCAZ, compared to 51/84 (60.7%) and 75/84 (89.3%) in patients who received doripenem. 

In a subset of Gram-negative pathogens from both arms of the Phase 3 cUTI trial that met phenotypic screening criteria for the presence of a beta-lactamase, genotypic testing identified certain ESBL groups (e.g., TEM-1, SHV-12, CTX-M-15, CTX-M-27, OXA-48) and AmpC that were expected to be inhibited by avibactam in isolates from 176 (21.7%) of the 810 patients in the mMITT population. Microbiological and clinical cure rates in this subset were similar to the overall trial results.

cUTI Trial 2

In a multinational, multi-center, open-label study of adults hospitalized with ceftazidime non-susceptible (CAZ-NS) Gram-negative infections, 305 patients with cUTI were randomized and received AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) intravenously every 8 hours or the best available intravenous therapy (BAT) for 5 to 21 days of treatment. There was no optional switch to oral therapy. The majority (96.1%) of patients in the BAT arm received monotherapy with a carbapenem antibacterial drug. Complicated urinary tract infections included acute pyelonephritis and complicated lower urinary tract infections. 

The mMITT population consisted of 281 cUTI patients with at least one baseline CAZ-NS uropathogen (defined as MIC greater or equal to 8 mg/L for Enterobacteriaceae and greater or equal to 16 mg/L for P. aeruginosa). The median age was 65 years and 54.8% were male. The majority of cUTI patients (82.2%) were from Eastern Europe; 2.8% were from the United States. The majority of patients (95%) were White. The most common diagnosis was cUTI without pyelonephritis, occurring in 54.8% of patients. Bacteremia at baseline was present in 3.6% of patients.

Clinical efficacy was based on evaluation of both the clinical cure (defined as resolution or significant improvement of baseline cUTI signs and symptoms) and microbiological cure (all baseline uropathogens were reduced to less than 104 CFU/mL) rates at the follow-up visit (21 to 25 calendar days from randomization) in the mMITT population.

The clinical and microbiological response rates at the follow-up visit in the mMITT population are presented in Table 20. The microbiological response rates at the follow-up visit by baseline CAZ-NS uropathogen in the mMITT population are presented in Table 21.

Among Gram-negative uropathogens from both arms of Trial 2, genotypic testing identified certain ESBL groups (e.g., TEM-1, SHV-12, CTX-M-15, CTX-M-27, KPC-2, KPC-3, OXA-48) and AmpC beta-lactamases expected to be inhibited by avibactam in isolates from 273/281 (97.2%) patients in the mMITT population. Clinical and microbiological cure rates in this subset were similar to the overall results. 

Pediatric Patients

The cUTI pediatric trial was a randomized, single-blind, multi-center, active-controlled study conducted in hospitalized patients aged 3 months to less than 18 years. Patients were randomized in a 3:1 ratio to receive either AVYCAZ [see Dosage and Administration (2.2)] or cefepime (dosed per local standard of care, and not to exceed 2000 mg per infusion). Patients received IV treatment for a minimum of 72 hours before an optional switch to oral therapy at the discretion of the investigator to complete a total of 7 to 14 days of antibacterial therapy. 

A study population of 95 patients with cUTI received study medication (AVYCAZ, n=67, cefepime n=28); 81% were female, and the median age was 4.2 years in the AVYCAZ group (range 3.5 months to 18 years). The pediatric age groups who received AVYCAZ were as follows: 12 to <18 years, (n=13), 6 to < 12 years, (n=17), 2 to < 6 years (n=11), 1 to < 2 years (n=12), and 3 months to < 1 year of age (n=14). Most patients had a diagnosis of acute pyelonephritis (83%). The micro-ITT population consisted of 77 patients with at least one Gram-negative uropathogen at baseline (greater or equal to 105 CFU/mL). The predominant baseline pathogen was E. coli (92.2%). 

The primary objective of the study was to evaluate the safety and tolerability of AVYCAZ and it was not powered for a statistical analysis of efficacy. At the TOC visit, which occurred 8 to 15 days after the last dose of study drug, a favorable clinical response was defined as a resolution of all acute signs and symptoms of cUTI or improvement to such an extent that no further antimicrobial therapy was required. A favorable microbiological response at the TOC was defined as eradication of baseline uropathogen(s) from the urine culture. 

A summary of clinical, microbiological and combined response at TOC by treatment group for the micro-ITT population is provided in Table 22. 

The microbiologic response rate for E.coli, the most common uropathogen identified in the study, was 79.6% for patients treated with AVYCAZ and 59.1% for patients treated with cefepime.