cUTI Trial 1—RECAPTURE

Clinical efficacy demonstrated vs doripenem, including cases involving resistant Gram-negative pathogens

cUTI Phase 3 clinical trial

STUDY DESIGN1

TYPE OF TRIAL

Phase 3, multinational, multicenter, double-blind, randomized, noninferiority trial

STUDY POPULATION

1020 adults hospitalized with cUTI, which included acute pyelonephritis and complicated lower urinary tract infections.

The microbiologically modified intent-to-treat (mMITT) population, which included all patients who had at least one uropathogen isolated at baseline (≥105 CFU/mL), consisted of 810 patients; the median age was 55 years, and 69.8% were female.

COMPARATIVE AGENTS

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

Doripenem 0.5 grams IV every 8 hours

A switch to an oral antimicrobial agent was allowed after 5 days of IV dosing.

TREATMENT DURATION

10 to 14 days

PRIMARY ENDPOINTS

Symptom response rates at Day 5 and combined microbiological cure and symptom response rates at the TOC visit (21 to 25 days after randomization). A symptom response was based on the resolution of patient-reported cUTI symptoms, defined as frequency/urgency/dysuria/suprapubic pain, as well as an improvement in flank pain for individuals with acute pyelonephritis. Microbiological cure was defined as a reduction of all baseline uropathogens to less than 104 CFU/mL in the urine.

CFU, colony-forming unit.

IV, intravenous.

TOC, test of cure.

Clinical efficacy demonstrated vs doripenem1

  • AVYCAZ was noninferior to doripenem with regard to both primary endpoints

CLINICAL AND MICROBIOLOGICAL CURE RATES (mMITT)

Chat depicting Clinical and Microbiological Cure Rates comparing AVYCAZ to Doripenem. Systematic Response response at day 5 shows AVYCAZ as 70.2% and Doripenem as 66.2%. Combined microbiological cure and response at TOC Shows AVYCAZ as 71.2% and Doripenem as 64.5%. Chat depicting Clinical and Microbiological Cure Rates comparing AVYCAZ to Doripenem. Systematic Response response at day 5 shows AVYCAZ as 70.2% and Doripenem as 66.2%. Combined microbiological cure and response at TOC Shows AVYCAZ as 71.2% and Doripenem as 64.5%.

CI, confidence interval.

mMITT, microbiologically modified intent-to-treat.

Clinical efficacy demonstrated vs doripenem at TOC1

MICROBIOLOGICAL CURE AT TOC 21 TO 25 DAYS AFTER RANDOMIZATION (mMITT)

Chart depicting Microbiological Cure at TOC 21 to 25 Days After Randomization (mMITT). Microbiological cure at TOC shows AVYCAZ as 77.4% and Doripenem as 71.0%.

SYMPTOMATIC RESPONSE AT TOC 21 TO 25 DAYS AFTER RANDOMIZATION (mMITT)

Chart depicting Systematic Response at TOC 21 to 25 Days After Randomization (mMITT). Symptomatic shows AVYCAZ as 84.5% and Doripenem as 86.3%.

Per patient microbiological response at LFU showed that the treatment difference with AVYCAZ was maintained2

  • The LFU visit was performed 45 to 52 days following randomization

FAVORABLE MICROBIOLOGICAL RESPONSE RATE AT LFU VISIT (mMITT)

Chart depicting Systematic Response at TOC 21 to 25 Days After Randomization (mMITT). Symptomatic shows AVYCAZ as 84.5% and Doripenem as 86.3%.

FAVORABLE MICROBIOLOGICAL RESPONSE RATE AT LFU VISIT IN PATIENTS INFECTED BY CEFTAZIDIME-NS GRAM-NEGATIVE PATHOGENS (mMITT)

Chart depicting Favorable Microbiological Response Rate at LFU Visit (mMITT). Favorable Microbiological Response Rate at LFU shows AVYCAZ as 68.2% and Doripenem as 60.9%.

LFU, late follow-up.

NS, nonsusceptible.

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

  • At baseline, 75 patients in the AVYCAZ arm and 84 patients in the doripenem arm of the mMITT population had
    Gram-negative isolates that were not susceptible to ceftazidime

CEFTAZIDIME-NS SUBSET POPULATION: MICROBIOLOGICAL AND CLINICAL CURE RATES AT TOC (mMITT)

Chart depicting Ceftazidime-NS Subset Population: Microbiological and Clinical Cure Rates at TOC (mMITT). Microbiological cure shows AVYCAZ as 62.7% and Doripenem 60.7%. Clinical Cures shows AVYCAZ as 89.3% and Doripenem as 89.3%.

NS, nonsusceptible.

Clinical efficacy in cUTI involving ESBLs and AmpC1

  • In a subset of Gram-negative pathogens from the Phase 3 cUTI trial, genotypic testing identified certain ESBL groups and AmpC in 21.7% (176/810) of patients in the mMITT population, all of which were expected to be inhibited by avibactam:
Chart representing Microbiological and Clinical Cure Rates in This Subset were Similar to the Overall Results including TEM-1, SHV-12, CTX-M-5, CTX-M-27- OXA-48, and AmpC.

ESBLs, extended-spectrum β-lactamases.

Clinical efficacy vs a broad range of key Gram-negative pathogens in cUTI1

MICROBIOLOGICAL CURE RATE BY BASELINE PATHOGEN AT TOC (mMITT)

Chart depicting Clinical Efficacy vs a Broad Range if Key Gram-Negative Pathogens in cUTI comparing AVYCAZ and Doripenem.
Phase 3 adult HABP/VABP,
cUTI, and cIAI data >
Pediatric cIAI and
cUTI data >
INFORM: Susceptibility data >

INDICATIONS AND USAGE

Complicated Intra-Abdominal Infections (cIAI)

AVYCAZ® (ceftazidime and avibactam), in combination with metronidazole, is indicated for the treatment of complicated intra-abdominal infections (cIAI) in adult and pediatric patients (at least 31 weeks gestational age) caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, Klebsiella oxytoca, Citrobacter freundii complex, and Pseudomonas aeruginosa.

Complicated Urinary Tract Infections (cUTI), including Pyelonephritis

AVYCAZ (ceftazidime and avibactam) is indicated for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis in adult and pediatric patients (at least 31 weeks gestational age) caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Citrobacter freundii complex, Proteus mirabilis, and Pseudomonas aeruginosa.

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) in adult and pediatric patients (at least 31 weeks gestational age) caused by the following susceptible Gram-negative microorganisms: Klebsiella pneumoniae, Enterobacter cloacae, Escherichia coli, Serratia marcescens, Proteus mirabilis, Pseudomonas aeruginosa, and Haemophilus influenzae.

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of AVYCAZ and other antibacterial drugs, AVYCAZ should be used only to treat or prevent 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 in adult patients, 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 adult and pediatric 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.
  • Clostridioides 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 or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

ADVERSE REACTIONS

Adult cIAI, cUTI, and HABP/VABP Patients

The most common adverse reactions in adult patients with cIAI (≥5% when used with metronidazole) were diarrhea (8%), nausea (7%), and vomiting (5%). The most common adverse reactions in adult patients with cUTI (3%) were diarrhea and nausea. The most common adverse reactions in adult patients with HABP/VABP (≥5%) were diarrhea (15%) and vomiting (6%).

Pediatric Patients

The most common adverse reactions (>3%) in pediatric patients aged 3 months and older were vomiting, diarrhea, rash, and infusion site phlebitis.

The most common adverse reactions (>3%) in pediatric patients less than 3 months of age were vomiting and increased transaminases.

References: 1. AVYCAZ® (ceftazidime and avibactam) [prescribing information]. North Chicago, IL: AbbVie, Inc. 2. Data on file. Allergan, Inc.

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