Clinical efficacy of ZERBAXA® (ceftolozane and tazobactam) against cIAIs

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cIAI in adult patients
cIAI in pediatric patients

Complicated intra-abdominal infections (cIAIs) in 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 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 in adult patients

Analysis population	MITT	ME
ZERBAXA plus metronidazole^a n/N (%)	323/389 (83)	259/275 (94.2)
Meropenem^b n/N (%)	364/417 (87.3)	304/321 (94.7)
Treatment difference (95% CI)^c	-4.3 (-9.2, 0.7)	-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 in adult patients (MITT population)

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.

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cIAI in adult patients
cIAI in pediatric patients

Complicated intra-abdominal infections (cIAIs) in 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 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 the table below. The CE included all protocol adherent MITT patients with a clinical outcome at the visit of interest.

Clinical response rates in a pediatric study of complicated intra-abdominal infections

Analysis population	ZERBAXA plus metronidazole n/N (%)	Meropenem n/N (%)	Treatment difference (95% CI)^d
MITT Population	56/70 (80.0)	21/21 (100.0)	-19.1 (-30.2, -2.9)
CE Population	52/58 (89.7)	19/19 (100.0)	-10.7 (-21.5, 6.8)

^dThe Miettinen & Nurminen method stratified by age group with Cochran-Mantel-Haenszel weights was used.

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cIAI in adult patients
cIAI in pediatric patients

Indications and Usage

ZERBAXA is indicated for the treatment of adult patients (18 years and older) with hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP), caused by the following susceptible Gram-negative microorganisms: Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Serratia marcescens.

ZERBAXA is indicated for the treatment of adult and pediatric patients (birth to less than 18 years old) with complicated urinary tract infections (cUTI), including pyelonephritis, caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa.

ZERBAXA used in combination with metronidazole is indicated for the treatment of adult and pediatric patients (birth to less than 18 years old) with complicated intra-abdominal infections (cIAI) caused by the following susceptible 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 or prevent 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.

Important Safety Information

Patients with renal impairment: Decreased efficacy of ZERBAXA has been observed in patients with baseline CrCl of 30 to ≤50 mL/min. In a clinical trial of adult patients, 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. Dose adjustment is required for adult patients with CrCl 50 mL/min or less. All doses of ZERBAXA are administered over 1 hour. 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 the components of ZERBAXA (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.
Clostridioides 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 or a prophylactic indication is unlikely to provide benefit to the patient and risks the development of drug-resistant bacteria.
Adverse reactions in adult patients with HABP/VABP: The most common adverse reactions occurring in ≥5% of adult patients receiving ZERBAXA in the HABP/VABP trial were hepatic transaminase increased (11.9%), renal impairment/renal failure (8.9%), and diarrhea (6.4%).
Adverse reactions in adult patients with cIAI or cUTI: The most common adverse reactions occurring in ≥5% of adult patients receiving ZERBAXA in the cUTI and cIAI trials were headache (5.8%) in the cUTI trial, and nausea (7.9%), diarrhea (6.2%), and pyrexia (5.6%) in the cIAI trial.
Adverse reactions in pediatric patients with cIAI or cUTI: The most common adverse reactions occurring in ≥7% of pediatric patients receiving ZERBAXA in the cIAI trial were diarrhea (17%), thrombocytosis (16%), pyrexia (13%), abdominal pain (11%), vomiting (10%), increased aspartate aminotransferase (7%), and anemia (7%). The most common adverse reactions occurring in ≥7% of pediatric patients receiving ZERBAXA in the cUTI trial were thrombocytosis (9%), leukopenia (8%), diarrhea (7%), and pyrexia (7%).
Pediatric Use: There is insufficient information to recommend dosage adjustment for pediatric patients younger than 18 years of age with cIAI and cUTI with eGFR 50 mL/min/1.73m ² or less. ZERBAXA is not recommended in pediatric patients who have an eGFR 50 mL/min/1.73m ² or less. Pediatric patients born at term or pre-term may not have an eGFR of 50 mL/min/1.73m ² or greater at birth or within the first few months of life.

Before prescribing ZERBAXA, please read the accompanying Prescribing Information.

Indications and Usage Indications and Usage

Usage

ZERBAXA is indicated for the treatment of adult patients (18 years and older) with hospital-

Important Safety Information Important Safety Information

Patients with renal impairment: Decreased efficacy of ZERBAXA has been observed in patients with baseline CrCl of 30 to ≤50 mL/min. In a clinical trial of adult patients, 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. Dose adjustment is required for adult patients with CrCl 50 mL/min or less. All doses of ZERBAXA are administered over 1 hour. 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 the components of ZERBAXA (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.
Clostridioides 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 or a prophylactic indication is unlikely to provide benefit to the patient and risks the development of drug-resistant bacteria.
Adverse reactions in adult patients with HABP/VABP: The most common adverse reactions occurring in ≥5% of adult patients receiving ZERBAXA in the HABP/VABP trial were hepatic transaminase increased (11.9%), renal impairment/renal failure (8.9%), and diarrhea (6.4%).
Adverse reactions in adult patients with cIAI or cUTI: The most common adverse reactions occurring in ≥5% of adult patients receiving ZERBAXA in the cUTI and cIAI trials were headache (5.8%) in the cUTI trial, and nausea (7.9%), diarrhea (6.2%), and pyrexia (5.6%) in the cIAI trial.
Adverse reactions in pediatric patients with cIAI or cUTI: The most common adverse reactions occurring in ≥7% of pediatric patients receiving ZERBAXA in the cIAI trial were diarrhea (17%), thrombocytosis (16%), pyrexia (13%), abdominal pain (11%), vomiting (10%), increased aspartate aminotransferase (7%), and anemia (7%). The most common adverse reactions occurring in ≥7% of pediatric patients receiving ZERBAXA in the cUTI trial were thrombocytosis (9%), leukopenia (8%), diarrhea (7%), and pyrexia (7%).
Pediatric Use: There is insufficient information to recommend dosage adjustment for pediatric patients younger than 18 years of age with cIAI and cUTI with eGFR 50 mL/min/1.73m ² or less. ZERBAXA is not recommended in pediatric patients who have an eGFR 50 mL/min/1.73m ² or less. Pediatric patients born at term or pre-term may not have an eGFR of 50 mL/min/1.73m ² or greater at birth or within the first few months of life.