ZERBAXA®

(ceftolozane and tazobactam) for injection (1.5 g), for intravenous use

Efficacy

Clinical efficacy against cUTIs

In the ASPECT-complicated urinary tract infection (cUTI) non-inferiority trial ZERBAXA demonstrated clinical efficacy vs levofloxacin

  • Multinational, double-blind, randomized, noninferiority phase 3 trial with 1,068 adults hospitalized with cUTI (82% of primary end point population diagnosed with pyelonephritis) who received either ZERBAXA 1.5 g IV every 8 hours or levofloxacin 750 mg IV once daily for 7 days.
    • The primary efficacy end point was composite microbiological and clinical cure response, defined as complete resolution or marked improvement of clinical symptoms and microbiological eradication (all uropathogens found at baseline at ≥105 were reduced to <104 colony-forming units/mL) at the TOC visit 7 (±2) days after the last dose of study drug. The primary efficacy analysis population was the mMITT population, which included all patients who received study medication and had at least 1 baseline uropathogen. The mMITT population consisted of 800 patients (74% female; median age of 50.5 years) with cUTI, including 656 (82%) with pyelonephritis.
    • The 95% CI was based on the stratified Newcombe method.
    • A treatment difference (95% Cl) of 8.5 (2.3, 14.6) was observed in the mMITT population.
  • Although a statistically significant difference was observed in the ZERBAXA arm compared to the levofloxacin arm with respect to the primary end point, 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.

Composite microbiological and clinical cure rates in a phase 3 trial of cUTIs at TOC visit (mMITT population)

Composite Microbiological and Clinical Cure Rates in a Phase 3 Trial of cUTIs at TOC Visit (mMITT Population)

The composite cure rate in patients with concurrent bacteremia receiving ZERBAXA was 79.3% (23/29) in the mMITT population.

Clinical cure rates in a subset of ESBL-producing E. coli and K. pneumoniae isolates

  • In 15% (104/687) of all isolates in both treatment arms that met prespecified criteria for beta-lactam susceptibility, genotypic testing identified certain ESBL groups (eg, TEM, SHV, CTX-M, OXA).
  • Cure rates in this subset were similar to those of the overall trial results. In vitro susceptibility testing showed that some of the isolates were susceptible to ZERBAXA (MIC ≤2 mcg/mL) while some others were not susceptible (MIC >2 mcg/mL).

Definitions

ASPECT = Assessment of the Safety Profile and Efficacy of Ceftolozane and Tazobactam 

CI = confidence interval 

ESBL = extended-spectrum beta-lactamase 

MIC = minimum inhibitory concentration 

mMITT = microbiologically modified intent-to-treat 

TOC = test-of-cure

Indications

ZERBAXA is indicated in adult patients for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis, caused by the following Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa.

ZERBAXA used in combination with metronidazole is indicated in adult patients for the treatment of complicated intra-abdominal infections (cIAI) caused by the following Gram-negative and Gram-positive microorganisms: Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Bacteroides fragilis, Streptococcus anginosus, Streptococcus constellatus, and Streptococcus salivarius.

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZERBAXA and other antibacterial drugs, ZERBAXA should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Selected Safety Information

  • Patients with renal impairment: Decreased efficacy of ZERBAXA has been observed in patients with baseline creatinine clearance (CrCl) of 30 to ≤50 mL/min. In a clinical trial, patients with cIAIs with CrCl >50 mL/min had a clinical cure rate of 85.2% when treated with ZERBAXA plus metronidazole vs 87.9% when treated with meropenem. In the same trial, patients with CrCl 30 to ≤50 mL/min had a clinical cure rate of 47.8% when treated with ZERBAXA plus metronidazole vs 69.2% when treated with meropenem. A similar trend was also seen in the cUTI trial. Monitor CrCl at least daily in patients with changing renal function and adjust the dose of ZERBAXA accordingly.
  • Hypersensitivity: ZERBAXA is contraindicated in patients with known serious hypersensitivity to ceftolozane/tazobactam, piperacillin/tazobactam, or other members of the beta-lactam class. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials. Before initiating therapy with ZERBAXA, make careful inquiry about previous hypersensitivity reactions to cephalosporins, penicillins, or other beta-lactams. If an anaphylactic reaction to ZERBAXA occurs, discontinue use and institute appropriate therapy.
  • Clostridium difficile–associated diarrhea (CDAD), ranging from mild diarrhea to fatal colitis, has been reported with nearly all systemic antibacterial agents, including ZERBAXA. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents. If CDAD is confirmed, antibacterial use not directed against C. difficile should be discontinued, if possible.
  • Development of drug-resistant bacteria: Prescribing ZERBAXA in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
  • Adverse reactions: The most common adverse reactions occurring in ≥5% of patients were headache (5.8%) in the cUTI trial, and nausea (7.9%), diarrhea (6.2%), and pyrexia (5.6%) in the cIAI trial.

Before prescribing ZERBAXA, please read the accompanying Prescribing Information.

AINF-1159589-017904/18