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

Abstract

Objectives:

The aim of this prospective phase II, randomized, investigator-blinded study (NCT00690378) was to compare the efficacy and safety of ceftazidime–avibactam and imipenem–cilastatin in hospitalized adults with serious complicated urinary tract infection (cUTI) due to Gram-negative pathogens.

Patients and methods:

Patients aged between 18 and 90 years with cUTI were enrolled and stratified by infection type (acute pyelonephritis or other cUTI) and randomized 1:1 to receive intravenous ceftazidime 500 mg plus avibactam 125 mg every 8 hours or imipenem–cilastatin 500 mg every 6 hours. Patients meeting pre-specified improvement criteria after 4 days could be switched to oral ciprofloxacin. Patients were treated for a total of 7–14 days. The primary efficacy objective was a favorable microbiological response at the test-of-cure (TOC) visit 5–9 days post-therapy in microbiologically evaluable (ME) patients.

Results:

Overall, 135 patients received study therapy (safety population); 62 were included in the ME population (ceftazidime–avibactam, n = 27; imipenem–cilastatin, n = 35). The predominant uropathogen was Escherichia coli. Favorable microbiological response was achieved in 70.4% of ME patients receiving ceftazidime–avibactam and 71.4% receiving imipenem–cilastatin at the TOC visit (observed difference −1.1% [95% CI: −27.2%, 25.0%]). Among ME patients with ceftazidime-resistant uropathogens, response was observed in 6/7 (85.7%) receiving ceftazidime–avibactam. Adverse events were observed in 67.6% and 76.1% of patients receiving ceftazidime–avibactam and imipenem–cilastatin, respectively. Limitations of the study include the small number of patients in the ME population.

Conclusion:

The results suggest that the efficacy and safety of ceftazidime–avibactam may be similar to that of imipenem–cilastatin.

Trial registration: ClinicalTrials.gov identifier: NCT00690378.

Keywords::

• Ceftazidime-resistant
• Microbiological response
• uropathogens

Transparency

Declaration of funding

This study was led by Novexel and ceftazidime-avibactam is now being developed by AstraZeneca and Forest-Cerexa. The design and conduct of the study, as well as analysis of the study data and opinions, conclusions, and interpretation of the data, are the responsibility of the authors.

Declaration of financial/other relationships

J.A.V., L.D.G.P. and D.S. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article. D.D.D. received a study grant from Novexel & Trident Clinical Research for the conduct of the study. Z.K. received a study grant from Novexel. At the time this study was conducted, J.L. and C.S. were employees of Novexel/AstraZeneca.

CMRO peer reviewers on this manuscript have received honoraria for their review work, but have no other relevant financial relationships to disclose.

Author contributions

C.S. designed the study, J.A.V. was International Co-ordinating Investigator and is guarantor for the study data, and all authors were involved in all diverse phases of the study (including enrolment of patients) and writing and editing the manuscript.

Acknowledgements

Medical writing support was provided by Liz Anfield, Prime Medica Ltd, Knutsford, Cheshire, and was funded by AstraZeneca. She prepared a preliminary outline and subsequent revisions of the manuscript based on extensive critical input from all the authors.

Study investigators (in addition to authors): Guatamala: Magdalena Gonzalez, Gilberto Recinos, Rodolfo Sanchez, Luis Juarez. India: Shriniwas Ambike, Jaydeep Date, Bharat Kalambe, Guntupalli Malakondaiah, Anthony Rozario. Jordan: Ibrahim BaniHani, Mamum Ezzibdeh, Ghazi Al-Edwan. Lebanon: Ghenwa El-Dakdouki, Ahmad Fawaz, Ahmad Moussa, Zouayr Tabbarah, Walid Alame. US: Salah Bibi, Ravi Kamepalli, Stanley Link, Carol Tanner-St James.

A preliminary report of these results was presented at the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), Milan, Italy, May 2011 (Poster Presentation [P1533]).