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cIAI Pediatric Trial—ANDI

cIAI pediatric trial vs meropenem

STUDY DESIGN1

Type of Trial

Multicenter, single-blind, randomized, actively-controlled trial

Study Population

83 hospitalized pediatric patients aged 3 months to less than 18 years of age with cIAI

The median age in the AVYCAZ group was 11.0 years.

The intent-to-treat (ITT) included 83 patients who were randomized to receive treatment (AVYCAZ plus metronidazole, n=61; meropenem, n=22).

The microbiological intent-to treat (micro-ITT) population, which included all patients who had at least one baseline intra-abdominal pathogen, consisted of 69 patients (AVYCAZ plus metronidazole, n=50; meropenem, n=19).

Comparative Agents

AVYCAZ® 62.5 mg/kg (ceftazidime 50 mg/kg and avibactam 12.5 mg/kg) IV every 8 hours for 2 hours in patients 2 years to <18 years with a maximum dose of ceftazidime 2 grams and avibactam 0.5 grams + metronidazole (10 mg/kg IV over 20-30 min every 8 hours)

AVYCAZ® 62.5 mg/kg (ceftazidime 50 mg/kg and avibactam 12.5 mg/kg) IV every 8 hours for 2 hours in patients 6 months to <2 years + metronidazole (10 mg/kg IV over 20-30 min every 8 hours)

AVYCAZ® 50 mg/kg (ceftazidime 40 mg/kg and avibactam 10 mg/kg) IV every 8 hours for 2 hours in patients 3 months to <6 months of age + metronidazole (10 mg/kg IV over 20-30 min every 8 hours)

Meropenem (20 mg/kg IV every 8 hours)

Patients received IV treatment for a minimum of 72 hours before an optional switch to oral therapy at the discretion of the investigator

Treatment Duration

7 to 15 days (IV drug and oral switch treatment)

CLINICAL EFFICACY ASSESSMENT

The primary objective of the study was to evaluate the safety and tolerability of AVYCAZ, and it was not powered for a statistical analysis of efficacy.

Favorable clinical response at TOC was defined as resolution of all acute signs and symptoms of cIAI or improvement to such an extent that no further antimicrobial therapy was required. TOC assessment was performed 8 to 15 days after the last dose of any study drug (IV or oral).

cIAI, complicated intra-abdominal infection.

IV, intravenous.

TOC, test of cure.

Clinical response in pediatric cIAI demonstrated vs meropenem1

CLINICAL CURE RATES AT TOC (ITT and micro-ITT)

chart depicting clinical cure rates at TOC

The primary objective of the study was to evaluate the safety and tolerability of AVYCAZ, and it was not powered for a statistical analysis of efficacy.

Clinical cure rates at the TOC visit by baseline pathogen (micro-ITT)

E. coli (79.7%) and P. aeruginosa (33.3%) were the predominant baseline pathogens

  • Clinical cure rates in patients infected with E. coli were 90.5% in those treated with AVYCAZ plus metronidazole and 92.3% in those treated with meropenem
  • Clinical cure rates in patients infected with P. aeruginosa were 85.7% in those treated with AVYCAZ plus metronidazole and 88.9% in those treated with meropenem

TOC, test of cure.

ITT, intent-to-treat.

micro-ITT, microbiological intent-to-treat.

The use of AVYCAZ in pediatric patients 3 months of age and older in the treatment of cIAI is also supported by evidence from adequate and well-controlled studies of AVYCAZ in adults with cIAI along with additional pharmacokinetic and safety data from pediatric trials. Safety and effectiveness in pediatric patients less than 18 years of age with HABP/VABP have not been established.

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 3 months or older 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 is indicated for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis in adult and pediatric patients 3 months or older 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 is indicated for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) in patients 18 years or older 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 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 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.
  • 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

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 cIAI and cUTI Patients:

The most common adverse reactions in pediatric patients with cIAI and cUTI (>3%) were vomiting, diarrhea, rash, and infusion site phlebitis.