Efficacy
Complicated Intra-abdominal Infections
A total of 979 adults hospitalized with cIAI were randomized and received study medications in a multinational, double-blind study comparing ZERBAXA 1.5 g (ceftolozane 1 g and tazobactam 0.5 g) intravenously every 8 hours plus metronidazole (500 mg intravenously every 8 hours) to meropenem (1 g intravenously every 8 hours) for 4 to 14 days of therapy. Complicated intra-abdominal infections included appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, perforation of the intestine, and other causes of intra-abdominal abscesses and peritonitis. The majority of patients (75%) were from Eastern Europe; 6.3% were from the United States.
The primary efficacy endpoint was clinical response, defined as complete resolution or significant improvement in signs and symptoms of the index infection at the test-of-cure (TOC) visit which occurred 24 to 32 days after the first dose of study drug. The primary efficacy analysis population was the microbiological intent-to-treat (MITT) population, which included all patients who had at least 1 baseline intra-abdominal pathogen regardless of the susceptibility to study drug. The key secondary efficacy endpoint was clinical response at the TOC visit in the microbiologically evaluable (ME) population, which included all protocol-adherent MITT patients.
The MITT population consisted of 806 patients; the median age was 52 years and 57.8% were male. The most common diagnosis was appendiceal perforation or peri-appendiceal abscess, occurring in 47% of patients. Diffuse peritonitis at baseline was present in 34.2% of patients.
ZERBAXA plus metronidazole was non-inferior to meropenem with regard to clinical cure rates at the TOC visit in the MITT population. Clinical cure rates at the TOC visit are displayed by patient population in the table below. Clinical cure rates at the TOC visit by pathogen in the MITT population are presented in the table below.
Clinical Cure Rates in a Phase 3 Trial of Complicated Intra-Abdominal Infections
Analysis Population | ZERBAXA plus metronidazolea n/N (%) | Meropenemb n/N (%) | Treatment Difference (95% CI)c |
---|---|---|---|
MITT | 323/389 (83) | 364/417 (87.3) | -4.3 (-9.2, 0.7) |
ME | 259/275 (94.2) | 304/321 (94.7) | -0.5 (-4.5, 3.2) |
- (a) ZERBAXA 1.5 g intravenously every 8 hours + metronidazole 500 mg intravenously every 8 hours
- (b) 1 gram intravenously every 8 hours
- (c) The 95% confidence interval (CI) was calculated as an unstratified Wilson Score CI.
Clinical Cure Rates by Pathogen in a Phase 3 Trial of Complicated Intra-abdominal Infections (MITT Population)
Organism Group Pathogen | ZERBAXA plus metronidazolea n/N (%) | Meropenem n/N (%) |
---|---|---|
Aerobic Gram-negative | ||
Escherichia coli | 216/255 (84.7) | 238/270 (88.1) |
Klebsiella pneumoniae | 31/41 (75.6) | 27/35 (77.1) |
Pseudomonas aeruginosa | 30/38 (79) | 30/34 (88.2) |
Enterobacter cloacae | 21/26 (80.8) | 24/25 (96) |
Klebsiella oxytoca | 14/16 (87.5) | 24/25 (96) |
Proteus mirabilis | 11/12 (91.7) | 9/10 (90) |
Aerobic Gram-positive | ||
Streptococcus anginosus | 26/36 (72.2) | 24/27 (88.9) |
Streptococcus constellatus | 18/24 (75) | 20/25 (80) |
Streptococcus salivarius | 9/11 (81.8) | 9/11 (81.8) |
Anaerobic Gram-negative | ||
Bacteroides fragilis | 42/47 (89.4) | 59/64 (92.2) |
Bacteroides ovatus | 38/45 (84.4) | 44/46 (95.7) |
Bacteroides thetaiotaomicron | 21/25 (84) | 40/46 (87) |
Bacteroides vulgatus | 12/15 (80) | 24/26 (92.3) |
In a subset of the E. coli and K. pneumoniae isolates from both arms of the cIAI Phase 3 trial that met pre-specified criteria for beta-lactam susceptibility, genotypic testing identified certain ESBL groups (e.g., TEM, SHV, CTX-M, OXA) in 53/601 (9%). Cure rates in this subset were similar to the overall trial results. In vitro susceptibility testing showed that some of these isolates were susceptible to ZERBAXA (MIC ≤ 2 mcg/mL), while some others were not susceptible (MIC >2 mcg/mL). Isolates of a specific genotype were seen in patients who were deemed to be either successes or failures.