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cUTI Trial 2—REPRISE

STUDY DESIGN1

Type of Trial

Multinational, multicenter, randomized, open-label trial

Study Population

305 adults hospitalized with cUTI, including acute pyelonephritis and complicated lower urinary tract infections, due to ceftazidime-nonsusceptible Gram-negative pathogens.

The mMITT population consisted of 281 cUTI patients with at least one baseline ceftazidime-NS uropathogen (defined as MIC greater or equal to 8 mg/L for Enterobacteriaceae and greater or equal to 16 mg/L for P. aeruginosa). The median age was 65 years and 54.8% were male.

Comparative Agents

AVYCAZ® 2.5 g (ceftazidime 2 grams and avibactam 0.5 grams) IV every 8 hours

Best available IV therapy (BAT)—meropenem, imipenem, doripenem, and colistin—for 5 to 21 days of total therapy. The majority (96.1%) of patients in the BAT arm received monotherapy with a carbapenem antibiotic.

There was no optional switch to oral therapy.

Treatment Duration

5 to 21 days

CLINICAL EFFICACY
ASSESSMENT

Evaluation of both the clinical cure (defined as resolution or significant improvement of baseline cUTI signs and symptoms) and microbiological cure (all baseline uropathogens were reduced to less than 104 CFU/mL) rates at the follow-up visit (21 to 25 calendar days from randomization) in the mMITT population.

mMITT, microbiologically modified intent-to-treat.

NS, nonsusceptible.

MIC, minimum inhibitory concentration.

IV, intravenous.

CFU, colony-forming unit.

In a trial vs carbapenems and colistin...

Clinical efficacy demonstrated in cUTI caused by ceftazidime-NS Gram-negative pathogens1

  • AVYCAZ demonstrated a higher cure rate with regard to the combined clinical and microbiological cure vs best available therapy (BAT)* at the Day 21 to 25 visit1

COMBINED CLINICAL AND MICROBIOLOGICAL CURE RATES AT THE DAY 21 TO 25 VISIT (mMITT)1

A chart of clinical cure rates in the Overall analysis population and Ceftazidime-NS Gram-negative pathogens

* Best available therapy (BAT) options were meropenem, imipenem, doripenem, and colistin; the majority of patients received carbapenem monotherapy.1

NS, nonsusceptible.

mMITT, microbiologically modified intent-to-treat.

CI, confidence interval.

  • Clinical cure at the Day 21 to 25 visit was 88.2% (127/144) for AVYCAZ and 88.3% (121/137) for BAT, a treatment difference of -0.1 (95% CI: -7.9, 7.7)1
  • Microbiological cure at the Day 21 to 25 visit was 71.5% (103/144) for AVYCAZ and 56.9% (78/137) for BAT, a treatment difference of 14.6 (95% CI: 3.4, 25.5)1

Subset population

Clinical efficacy demonstrated in cUTI involving ESBLs and AmpC, including KPC-producing CRE1

  • In a subset of Gram-negative uropathogens, genotypic testing identified certain ESBL groups and AmpC in 97.2% (273/281) of patients in the mMITT population, all of which were expected to be inhibited by avibactam1:

KPC-2

KPC-3

TEM-1

SHV-12

CTX-M-15

CTX-M-27

OXA-48

AmpC

CLINICAL AND MICROBIOLOGICAL CURE RATES IN THIS SUBSET WERE SIMILAR TO THE OVERALL RESULTS1

ESBLs, extended-spectrum β-lactamases.

KPC, Klebsiella pneumoniae carbapenemase.

CRE, carbapenem-resistant Enterobacteriaceae.

mMITT, microbiologically modified intent-to-treat.

Clinical efficacy in cUTI across baseline ceftazidime-NS Gram-negative pathogens1

MICROBIOLOGICAL RESPONSE RATES BY BASELINE CEFTAZIDIME-NS PATHOGEN AT THE DAY 21 TO 25 VISIT (mMITT)1

chart showing REPRISE Microbiological response rates by baseline ceftazidime-NS pathogen at day 21-25 visit

NS, nonsusceptible.

mMITT, microbiologically modified intent-to-treat.

BAT, best available therapy.

INDICATIONS AND USAGE

Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP)

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

Complicated Intra-Abdominal Infections (cIAI)

AVYCAZ, in combination with metronidazole, is indicated for the treatment of complicated intra-abdominal infections (cIAI) caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, Klebsiella oxytoca, Citrobacter freundii complex, and Pseudomonas aeruginosa in patients 18 years or older.

Complicated Urinary Tract Infections (cUTI), including Pyelonephritis

AVYCAZ is indicated for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Citrobacter freundii complex, Proteus mirabilis, and Pseudomonas aeruginosa in patients 18 years or older.

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of AVYCAZ and other antibacterial drugs, AVYCAZ should be used to treat only indicated infections that are proven or strongly suspected to be caused by susceptible bacteria.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

AVYCAZ is contraindicated in patients with known serious hypersensitivity to the components of AVYCAZ (ceftazidime and avibactam), avibactam-containing products, or other members of the cephalosporin class.

WARNINGS AND PRECAUTIONS

  • In a Phase 3 cIAI trial, clinical cure rates were lower in a subgroup of patients with baseline creatinine clearance (CrCl) of 30 to less than or equal to 50 mL/min compared to those with CrCl greater than 50 mL/min. The reduction in clinical cure rates was more marked in patients treated with AVYCAZ plus metronidazole compared to meropenem-treated patients. Within this subgroup, patients treated with AVYCAZ received a 33% lower daily dose than is currently recommended for patients with CrCl of 30 to less than or equal to 50 mL/min. Clinical cure rate in patients with normal renal function/mild renal impairment (CrCl greater than 50 mL/min) was 85% (322/379) with AVYCAZ plus metronidazole vs 86% (321/373) with meropenem, and clinical cure rate in patients with moderate renal impairment (CrCl 30 to less than or equal to 50 mL/min) was 45% (14/31) with AVYCAZ plus metronidazole vs 74% (26/35) with meropenem. The decreased clinical response was not observed for patients with moderate renal impairment at baseline (CrCl 30 to less than or equal to 50 mL/min) in the Phase 3 cUTI trials or the Phase 3 HABP/VABP trial. Monitor CrCl at least daily in patients with changing renal function and adjust the dosage of AVYCAZ accordingly.
  • Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. Before therapy with AVYCAZ is instituted, careful inquiry about previous hypersensitivity reactions to other cephalosporins, penicillins, or carbapenems should be made. Exercise caution if this product is to be given to a penicillin or other beta-lactam-allergic patient because cross sensitivity among beta-lactam antibacterial drugs has been established. Discontinue the drug if an allergic reaction to AVYCAZ occurs.
  • Clostridium difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial drugs, including AVYCAZ, and may range in severity from mild diarrhea to fatal colitis. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial drugs. If CDAD is suspected or confirmed, antibacterials not directed against C. difficile should be discontinued, if possible.
  • Seizures, nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported in patients treated with ceftazidime, particularly in the setting of renal impairment. Adjust dosing based on CrCl.
  • Prescribing AVYCAZ 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 in cIAI patients (≥ 5% when used with metronidazole) were diarrhea (8%), nausea (7%), and vomiting (5%). The most common adverse reactions in cUTI patients (3%) were diarrhea and nausea. The most common adverse reactions in HABP/VABP patients (≥ 5%) were diarrhea (15%) and vomiting (6%).