FDA approves ceftazidime-avibactam to treat two complicated infections

Jay Patel

Kevin ChamberlinCeftazidime-avibactam (Avycaz; Actavis) is a fixed-combination antimicrobial agent consisting of a third-generation cephalosporin, used to treat gram-negative bacterial infections, and a novel β-lactamase inhibitor. Approved February 25, it is indicated to treat adults with either complicated intra-abdominal infections (cIAI), where it is used in combination with metronidazole, or complicated urinary tract infections (cUTI), including kidney infections (pyelonephritis), in patients with few or no alternative treatment options.

Ceftazidime-avibactam is the fifth antimicrobial agent approved with priority review as a Qualified Infectious Disease Product (QIDP) under the Generating Antibiotic Incentives Now (GAIN) title of the FDA Safety and Innovation Act. This title is given to antibacterial agents used to treat serious or life-threatening infections, which often involve treatment-resistant organisms.

See also: FDA approves new antibiotic combo for two complicated infections

Efficacy

To date, there have been two published Phase II, prospective, randomized, double-blind clinical trials evaluating the efficacy of ceftazidime in combination with avibactam for infections caused, in whole or in part, by gram-negative bacilli. The trials did not have any formal hypotheses for inferential testing against active comparators.  

Trial 1 compared ceftazidime-avibactam (2 g/0.5 g) and metronidazole (0.5 g), each administered intravenously (IV) every 8 hours, to meropenem (1 g), given by IV every 8 hours, for 5 to 14 days in adults with cIAI. Among the 203 patients enrolled in the trial, the most common sites of infection were appendix and stomach/duodenum.

The primary outcome was the clinical response in the microbiologically evaluable population 2 weeks after the last dose of study medication. A favorable clinical response was observed in 91.2% of patients (62/68) treated with ceftazidime-avibactam plus metronidazole vs. 93.4% of patients (71/76) treated with meropenem.

Trial 2 compared ceftazidime-avibactam (0.5 g/0.125 g), each given by IV every 8 hours, to imipenem-cilastatin (0.5 g), given by IV every 6 hours, for a minimum of 4 days for the treatment of adults with cUTI caused by gram-negative bacteria. Step-down to oral ciprofloxacin was permitted. The dose of ceftazidime-avibactam in this trial was lower than the recommended dose. Adult patients with either acute pyelonephritis or another cUTI caused by a gram-negative pathogen were eligible for inclusion. For the 137 randomized patients, acute pyelonephritis was the primary diagnosis.

The primary outcome was a favorable microbiological response 5 to 9 days after the last dose of therapy in the microbiologically evaluable (ME) population. In the ME population, E. coli was the uropathogen in 93.5% (58/62). A favorable microbiological response was observed in 70.4% (19/27) of patients treated with ceftazidime-avibactam compared to 71.4% (25/35) treated with imipenem-cilastatin.

The aforementioned studies were not adequately powered to prove noninferiority. Further, the range of bacterial pathogens in the study populations was limited, with E. coli accounting for the majority of facultative gram-negative isolates in both studies.

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Safety

Trial 1 identified the most common treatment-emergent adverse events (TEAEs) in patients receiving ceftazidime-avibactam as nausea, vomiting, constipation, abdominal pain, anxiety, and increased liver enzymes.

In trial 2, the most common TEAEs were nausea, constipation, abdominal pain, dizziness, anxiety, and increased liver enzymes.

Ceftazidime-avibactam warnings and precautions include decreased clinical response in patients with baseline creatinine clearance of 30 to 50 mL/min, hypersensitivity reactions, Clostridium difficile-associated diarrhea, central nervous system reactions, and development of drug-resistant bacteria.

Dosing

The recommended dosage of ceftazidime-avibactam is 2.5 g (2 g ceftazidime/0.5 g avibactam) administered intravenously over 2 hours every 8 hours in patients 18 years and older. Both ceftazidime and avibactam are excreted primarily by the kidneys, requiring dosage adjustment in patients with moderate and severe renal impairment and end-stage renal disease.

Both ceftazidime and avibactam are dialyzable and should be administered after hemodialysis in applicable patients. The dosage for patients on dialysis should be based on their estimated renal function (e.g., CrCl 6-15 mL/min or CrCl ≤ 5 mL/min). There is no dose adjustment recommended for patients with hepatic impairment.

References available online

Jay Patelis a PGY-1 pharmacy resident at John Dempsey Hospital/UConn Health, University of Connecticut School of Pharmacy, Storrs, Conn. Kevin Chamberlinis associate clinical professor and assistant department head, pharmacy practice, University of Connecticut School of Pharmacy, Storrs, Conn.

References

Avycaz™ (ceftazidime-avibactam) product information. Parsippany, NJ: Actavis plc.; February 2015. Accessed: May 17, 2015.

Lucasti C, Popescu I, Ramesh MK, Lipka J, Sable C. Comparative study of the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infections in hospitalized adults: results of a randomized, double-blind, Phase II trial. J Antimicrob Chemother. 2013;68:1183-1192.

Vazquez JA, Gonzalez Patzan LD, Stricklin D, et al. Efficacy and safety of ceftazidime-avibactam versus imipenem-cilastatin in the treatment of complicated urinary tract infections, including acute pyelonephritis, in hospitalized adults: results of a prospective, investigator-blinded, randomized study. Curr Med Res Opin. 2012;28:1921-1931.

Legace-Wiens P, et al. Ceftazidime-avibactam: an evidence-based review of its pharmacology and potential use in the treatment of Gram-negative bacterial infections. Core Evid. 2014;9:13-25.