Adult Patients

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 Table 12. Clinical cure rates at the TOC visit by pathogen in the MITT population are presented in Table 13.

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.

Pediatric Patients

The pediatric cIAI trial was a randomized, double-blind, multi-center, active controlled trial conducted in hospitalized patients from birth to less than 18 years (NCT03217136). Patients were randomized in a 3:1 ratio to either intravenous (IV) ZERBAXA [see Dosage and Administration (2.2)] plus metronidazole (10 mg/kg IV every 8 hours), or meropenem (20 mg/kg IV every 8 hours) plus placebo. Patients received IV study treatment for a minimum of 3 days before an optional switch to oral step-down therapy at the discretion of the investigator to complete a total of 5 to 14 days of antibacterial therapy.

The modified intent-to-treat (MITT) population consisted of 91 patients (N=70 in the ZERBAXA plus metronidazole group; N=21 in the meropenem plus placebo group) who were randomized and received at least one dose of study treatment. The median age of patients was 8.2 years and 8.5 years in the ZERBAXA plus metronidazole and meropenem plus placebo groups, respectively. In the ZERBAXA plus metronidazole group, enrollment by age group was as follows: 12 to <18 y: n=16, 6 to <12 y: n=30, 2 to <6 y: n=22, 3 months to <2 y: n=1, birth to <3 months: n=1. Patients treated with ZERBAXA plus metronidazole were predominantly male (67%) and White (87%). Patients treated with meropenem plus placebo were predominantly female (71%) and White (91%). Most patients in the MITT population had a diagnosis of complicated appendicitis at baseline (ZERBAXA plus metronidazole: 91.4%; meropenem plus placebo: 100%). The median (range) duration of IV study treatment was comparable between patients in the ZERBAXA plus metronidazole (6.3 [0.3 to 14.0] days) and meropenem plus placebo (6.0 [2.3 to 8.8] days) groups.

The primary objective of the study was to evaluate the safety and tolerability of ZERBAXA. Efficacy assessments were not powered for formal hypothesis testing of between-treatment group comparisons. At the TOC visit, which occurred 7 to 14 days after the last dose of study drug, a favorable clinical response was defined as complete resolution or marked improvement in signs and symptoms of the cIAI or return to pre-infection signs and symptoms such that no further antibiotic therapy (IV or oral) or surgical or drainage procedure was required for treatment of the cIAI. A summary of clinical response rates in the MITT and clinically evaluable (CE) populations at the TOC visit are presented in Table 14. The CE included all protocol adherent MITT patients with a clinical outcome at the visit of interest.