Clinical Efficacy Against cIAIs

In the ASPECT-complicated intra-abdominal infection (cIAI) non-inferiority trial...

ZERBAXA® (ceftolozane and tazobactam), in Combination With Metronidazole, Demonstrated Clinical Efficacy vs Meropenem

  • Multinational, double-blind, randomized, non-inferiority Phase 3 trial with 979 adults hospitalized with cIAI (including 34.2% of primary endpoint population with diffuse peritonitis at baseline) who received either ZERBAXA 1.5 g IV every 8 hours plus metronidazole 500 mg IV every 8 hours or meropenem 1 g IV every 8 hours for 4 to 14 daysa-c
Clinical cure rates in a Phase 3 trial of cIAIs at TOC visit (MITT population) Clinical Cure Rates With ZERBAXA® (ceftolozane and tazobactam) in Combination With Metronidazole for Treatment of cIAIs
  • In the cIAI trial, cure rates in the elderly (≥65 years of age) in the ZERBAXA plus metronidazole arm were 69% (69/100) compared with 82.4% (70/85) in the meropenem arm
Clinical cure rates in a subset of ESBL-producing E. coli and K. pneumoniae isolates
  • In 9% (53/601) of all isolates in both treatment arms that met pre-specified 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)

aThe primary efficacy endpoint was clinical response, defined as complete resolution or significant improvement in signs and symptoms of the index infection at the TOC visit, which occurred 24 to 32 days after the first dose of study drug. The primary efficacy analysis population was the MITT population, which included all patients who had at least 1 baseline intra-abdominal pathogen regardless of the susceptibility to study drug. The MITT population consisted of 806 patients; the median age was 52 years and 57.8% were male. Diagnoses included appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, perforation of the intestine, and other causes of intra-abdominal abscesses and peritonitis.

bThe 95% CI was calculated as an unstratified Wilson Score CI.

cA treatment difference (95% Cl) of -4.3 (-9.2, 0.7) was observed in the MITT population.

ASPECT=Assessment of the Safety Profile and Efficacy of Ceftolozane and Tazobactam; CI=confidence interval; ESBL=extended-spectrum beta-lactamase; MIC=minimum inhibitory concentration; MITT=microbiological intent-to-treat; TOC=test-of-cure.

Surgical Infection Society (SIS) Guidelines Now Include ZERBAXA1

The SIS suggests that ceftolozane-tazobactam plus metronidazole is an acceptable regimen for the empiric treatment of adults with cIAI (Grade 2-A). Because of the spectrum of activity of ceftolozane-tazobactam against certain ESBL-producing Enterobacteriaceae and against certain strains of P. aeruginosa, they suggest this regimen be used primarily for selected patients with cIAI strongly suspected or proven to be caused by those pathogens, for whom other agents are not suitable (Grade 2-C). Adapted and approved by the SIS.

2 - Weak Recommendation

The task force concluded that the intervention is a reasonable approach for the care of patients. Not all patients and clinicians, however, would necessarily want to follow the recommendation. A decision not to follow the recommendation is unlikely to result in a major adverse outcome. This rating was generally based on weak to moderate quality evidence. Both the magnitude of the treatment effect and its direction might be altered by future research. These recommendations are prefaced as ‘‘We suggest…’’.

A - High Quality Evidence

The evidence was primarily obtained from RCTs, meta-analyses of such trials, or methodologically sound epidemiologic studies. If the preponderance of evidence is based on studies that do not directly address the question being posed, the overall grade is downgraded to B or C. If there are conflicts in Class A data, the evidence grade is lowered to B or C, depending on the degree of conflict.

C - Weak Quality Evidence

The evidence was obtained from smaller observational studies, studies relying on retrospective or less reliable data, authoritative opinions expressed in reviews, or expert opinions of task force members.

Important Safety Information for ZERBAXA® (ceftolozane and tazobactam)
  • 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.

Reference: 1. Mazuski JE, Tessler JM, May AK, et al. The Surgical Infection Society revised guidelines on the management of intra-abdominal infection. Surg Infect. 2017; 18(1):1-76

AINF-1159189-0151 07/17

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Indications and Usage

ZERBAXA® (ceftolozane and tazobactam) 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.

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Important Safety Information for ZERBAXA® (ceftolozane and tazobactam)
  • 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.