Avycaz (ceftazidime-avibactam) - 2 Indications

Scroll down for more information on each indication:

• for complicated intra-abdominal and urinary tract infections in adults 18 years of age and older; approved February 2015; expanded March of 2018 to include patients 3 months to less than 18 years of age
• for hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia in adults 18 years of age and older; approved February 2018

General Information

Avycaz (ceftazidime-avibactam) is a combination of a cephalosporin and a beta-lactamase inhibitor.

Avycaz is specifically indicated for the following:

• Complicated Intra-abdominal Infections (cIAI), used in combination with metronidazole, in adult and pediatric patients 3 months and 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, in adult and pediatric patients 3 months and 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) in patients 18 years and older caused by the following susceptible Gram-negative microorganisms: Klebsiella pneumoniae, Enterobacter cloacae, Escherichia coli, Serratia marcescens, Proteus mirabilis, Pseudomonas aeruginosa, and Haemophilus influenzae.

Avycaz is supplied as a solution for intravenous infusion. The recommended dosage of Avycaz is 2.5 grams (2 grams ceftazidime and 0.5 grams avibactam) administered every 8 hours by intravenous (IV) infusion over 2 hours. For treatment of cIAI, metronidazole should be given concurrently.

Mechanism of Action

The ceftazidime component of Avycaz is a cephalosporin antibacterial drug with in vitro activity against certain gram-negative and gram-positive bacteria. The bactericidal action of ceftazidime is mediated through binding to essential penicillin-binding proteins (PBPs). The avibactam component of Avycaz is a non-betalactam beta-lactamase inhibitor that inactivates some beta-lactamases and protects ceftazidime from degradation by certain beta-lactamases. Avibactam does not decrease the activity of ceftazidime against ceftazidimesusceptible organisms. 

Side Effects

Adverse effects associated with the use of Avycaz in adult cIAI, cUTI and HABP/VABP patients may include, but are not limited to, the following:

• cIAI (≥ 5%, when used with metronidazole):
  • diarrhea
  • nausea
  • vomiting
• cUTI
  • diarrhea
  • nausea
• HABP/VABP
  • diarrhea
  • vomiting

Adverse effects associated with the use of Avycaz in pediatric cIAI and cUTI patients may inlcude, but are not limited to, the following:

• vomiting
• diarrhea
• rash
• infusion site phlebitis

Indication 1 - for complicated intra-abdominal and urinary tract infections in patients 3 months of age and older

Approved February of 2015; March of 2018

Clinical Trial Results

The FDA approval of Avycaz was supported in part by the previous findings of the efficacy and safety of ceftazidime for the treatment of cIAI and cUTI. The contribution of avibactam to Avycaz was primarily established in vitro and in animal models of infection. Avycaz was studied in two phase II randomized, blinded, active-controlled, multicenter trials, one each in cIAI and cUTI, including pyelonephritis. These trials were not designed with any formal hypotheses for inferential testing against the active comparators. 

The FDA approval of Avycaz for use in pediatric patients was based on results from two active-controlled clinical studies evaluating Avycaz in children or infants with cIAI or cUTI, as well as a single-dose pharmacokinetic study. In the cIAI study, the safety and efficacy of Avycaz (in combination with metronidazole) was compared with meropenem. In the cUTI study, Avycaz was compared with cefepime. Across the trials, 128 pediatric patients 3 months to less than 18 years of age were treated with Avycaz. In the pediatric cIAI study, the clinical cure rate at the test-of-cure (TOC) visit in the intent-to-treat (ITT) population was 91.8% (56/61) in the Avycaz plus metronidazole group and 95.5% (21/22) in the meropenem group. Clinical cure rates for the predominant pathogens, Escherichia coli and Pseudomonas aeruginosa, were 90.5% and 85.7%, respectively for patients treated with Avycaz plus metronidazole, and 92.3% and 88.9%, respectively, for patients treated with meropenem. In the pediatric cUTI study, the combined favorable clinical and microbiological response rate at TOC in the microbiological-ITT population was 72.2% (39/54) in the Avycaz group and 60.9% (14/23) in the cefepime group. The microbiologic response rate for E.coli, the most common uropathogen identified in the study, was 79.6% for patients treated with Avycaz and 59.1% for patients treated with cefepime.

Indication 2 - for hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia in adults 18 years of age and older

approved February 2018

Clinical Trial Results

A total of 870 hospitalized adult patients with HABP or VABP were randomized and received trial medications in a pivotal Phase 3, multinational, double-blind trial (REPROVE) comparing Avycaz 2.5 g (ceftazidime 2 grams and avibactam 0.5 grams) intravenously every 8 hours to meropenem 1 gram intravenously every 8 hours, for 7 to 14 days of therapy. Study medication dosages were adjusted per renal function. The protocol allowed for administration of prior and concomitant systemic antibacterial therapy for patients with proven or suspected Gram-positive or drug resistant infections.

Clinical efficacy was evaluated in the intent-to treat (ITT) population, which included all randomized patients who received study drug. Overall, 379 (43.6%) patients were ventilated at enrollment, including 290 (33.3%) patients with VABP and 89 (10.2%) with ventilated-HABP. Bacteremia at baseline was present in 4.8% of patients.

The primary efficacy endpoint of the study was 28-day all-cause mortality (28 to 32 days after randomization) in the ITT population. The study successfully demonstrated that Avycaz was non-inferior to meropenem with respect to the primary endpoint based on a 10% non-inferiority margin; the 28-day all-cause mortality rate was 9.6% (42/436) in patients treated with Avycaz compared with 8.3% (36/434) in meropenem treated patients. 

At baseline, 108/382 (28.3%) of patients in the microbiological intent-to-treat (micro-ITT) population, which included all patients with positive culture results indicating the presence of at least one Gram-negative pathogen, had Gram-negative isolates that were not susceptible to ceftazidime, including 53 patients with K. pneumoniae and 28 patients with P. aeruginosa isolates. The 28-day all-cause mortality in patients with ceftazidime non-susceptible Gram-negative isolates was 8.2% in the Avycaz arm and 8.5% in the meropenem arm.