Efficacy
Complicated Urinary Tract Infections, Including Pyelonephritis
A total of 1068 adults hospitalized with cUTI (including pyelonephritis) 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 to levofloxacin (750 mg intravenously once daily) for 7 days of therapy. The primary efficacy endpoint was defined as complete resolution or marked improvement of the clinical symptoms and microbiological eradication (all uropathogens found at baseline at ≥105 were reduced to <104 CFU/mL) at the test-of-cure (TOC) visit 7 (± 2) days after the last dose of study drug. The primary efficacy analysis population was the microbiologically modified intent-to-treat (mMITT) population, which included all patients who received study medication and had at least 1 baseline uropathogen. The key secondary efficacy endpoint was the composite microbiological and clinical cure response at the TOC visit in the microbiologically evaluable (ME) population, which included protocol-adherent mMITT patients with a urine culture at the TOC visit.
The mMITT population consisted of 800 patients with cUTI, including 656 (82%) with pyelonephritis. The median age was 50.5 years and 74% were female. Concomitant bacteremia was identified in 62 (7.8%) patients at baseline; 608 (76%) patients were enrolled in Eastern Europe and 14 (1.8%) patients were enrolled in the United States.
ZERBAXA demonstrated efficacy with regard to the composite endpoint of microbiological and clinical cure at the TOC visit in both the mMITT and ME populations (table below). Composite microbiological and clinical cure rates at the TOC visit by pathogen in the mMITT population are presented in the table below.
In the mMITT population, the composite cure rate in ZERBAXA-treated patients with concurrent bacteremia at baseline was 23/29 (79.3%).
Although a statistically significant difference was observed in the ZERBAXA arm compared to the levofloxacin arm with respect to the primary endpoint, it was likely attributable to the 212/800 (26.5%) patients with baseline organisms non-susceptible to levofloxacin. Among patients infected with a levofloxacin-susceptible organism at baseline, the response rates were similar (table below).
Composite Microbiological and Clinical Cure Rates in a Phase 3 Trial of Complicated Urinary Tract Infections
Analysis Population | |||
---|---|---|---|
ZERBAXAan/N (%) | Levofloxacinbn/N (%) | Treatment Difference (95% CI)c | |
mMITT | 306/398 (76.9) | 275/402 (68.4) | 8.5 (2.3, 14.6) |
Levofloxacin resistant baseline pathogen(s) | 60/100 (60) | 44/112 (39.3) | |
No levofloxacin resistant baseline pathogen(s) | 246/298 (82.6) | 231/290 (79.7) | |
ME | 284/341 (83.3) | 266/353 (75.4) | 8.0 (2.0, 14.0) |
- (a) ZERBAXA 1.5 g intravenously every 8 hours
- (b) 750 mg intravenously once daily
- (c) The 95% confidence interval was based on the stratified Newcombe method.
Composite Microbiological and Clinical Cure Rates in a Phase 3 Trial of Complicated Urinary Tract Infections, in Subgroups Defined by Baseline Pathogen (mMITT Population)
Pathogen | ||
---|---|---|
ZERBAXA n/N (%) | Meropenem n/N (%) | |
Escherichia coli | 247/305 (81) | 228/324 (70.4) |
Klebsiella pneumoniae | 22/33 (66.7) | 12/25 (48) |
Proteus mirabilis | 11/12 (91.7) | 6/12 (50) |
Pseudomonas aeruginosa | 6/8 (75) | 7/15 (46.7) |
In a subset of the E. coli and K. pneumoniae isolates from both arms of the cUTI 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 104/687 (15%). 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.