Ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa complicated urinary tract infections or complicated intra-abdominal infections (REPRISE): a randomised, pathogen-directed, phase 3 study.
BACKGROUND
Carbapenems are frequently the last line of defence in serious infections due to multidrug-resistant Gram-negative bacteria, but their use is threatened by the growing prevalence of carbapenemase-producing pathogens. Ceftazidime-avibactam is a potential new agent for use in such infections. We aimed to assess the efficacy, safety, and tolerability of ceftazidime-avibactam compared with best available therapy in patients with complicated urinary tract infection or complicated intra-abdominal infection due to ceftazidime-resistant Gram-negative pathogens.


METHODS
REPRISE was a pathogen-directed, international, randomised, open-label, phase 3 trial that recruited patients from hospitals across 16 countries worldwide. Eligible patients were aged 18-90 years with complicated urinary tract infection or complicated intra-abdominal infection caused by ceftazidime-resistant Enterobacteriaceae or Pseudomonas aeruginosa. Patients were randomised (1:1) to 5-21 days of treatment with either ceftazidime-avibactam (a combination of 2000 mg ceftazidime plus 500 mg avibactam, administered via a 2-h intravenous infusion every 8 h) or best available therapy. The primary endpoint was clinical response at the test-of-cure visit, 7-10 days after last infusion of study therapy, analysed in all patients who had at least one ceftazidime-resistant Gram-negative pathogen, as confirmed by the central laboratory, and who received at least one dose of study drug. Safety endpoints were assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01644643.


RESULTS
Between Jan 7, 2013, and Aug 29, 2014, 333 patients were randomly assigned, 165 to ceftazidime-avibactam and 168 to best available therapy. Of these, 154 assigned to ceftazidime-avibactam (144 with complicated urinary tract infection and ten with complicated intra-abdominal infection) and 148 assigned to best available therapy (137 with complicated urinary tract infection and 11 with complicated intra-abdominal infection) were analysed for the primary outcome. 163 (97%) of 168 patients in the best available therapy group received a carbapenem, 161 (96%) as monotherapy. The overall proportions of patients with a clinical cure at the test-of-cure visit were similar with ceftazidime-avibactam (140 [91%; 95% CI 85·6-94·7] of 154 patients) and best available therapy (135 [91%; 85·9-95·0] of 148 patients). 51 (31%) of 164 patients in the ceftazidime-avibactam group and 66 (39%) of 168 in the best available therapy group had an adverse event, most of which were mild or moderate in intensity. Gastrointestinal disorders were the most frequently reported treatment-emergent adverse events with both ceftazidime-avibactam (21 [13%] of 164 patients) and best available therapy (30 [18%] of 168 patients). No new safety concerns were identified for ceftazidime-avibactam.


CONCLUSIONS
These results provide evidence of the efficacy of ceftazidime-avibactam as a potential alternative to carbapenems in patients with ceftazidime-resistant Enterobacteriaceae and P aeruginosa.


BACKGROUND
AstraZeneca.
Division of Epidemiology and the National Center for Antibiotic Resistance and Infection Control, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. Electronic address: yehudac@tlvmc.gov.il.
Yehuda
Y
Carmeli
AstraZeneca, Infection GMed, Global Medicines Development, Alderley Park, UK.
Jon
J
Armstrong
AstraZeneca, Infection GMed, Global Medicines Development, Alderley Park, UK; Statistical Services Unit, University of Sheffield, Sheffield, UK.
Peter J
PJ
Laud
AstraZeneca, Infection GMed, Global Medicines Development, Alderley Park, UK.
Paul
P
Newell
AstraZeneca, Infection GMed, Global Medicines Development, Waltham, MA, USA.
Greg
G
Stone
AstraZeneca, Infection GMed, Global Medicines Development, Alderley Park, UK.
Angela
A
Wardman
AstraZeneca, Infection GMed, Global Medicines Development, Wilmington, DE, USA.
Leanne B
LB
Gasink
D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D053961:Azabicyclo Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D015780:Carbapenems / Q000627:therapeutic use; D002442:Ceftazidime / Q000008:administration & dosage* / Q000009:adverse effects; D004338:Drug Combinations; D024901:Drug Resistance, Multiple, Bacterial; D004755:Enterobacteriaceae / Q000187:drug effects*; D005260:Female; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006801:Humans; D059413:Intraabdominal Infections / Q000188:drug therapy* / Q000382:microbiology; D008297:Male; D008875:Middle Aged; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D014552:Urinary Tract Infections / Q000188:drug therapy* / Q000382:microbiology; D065093:beta-Lactamase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*
D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D015780:Carbapenems; D004338:Drug Combinations; C000595613:avibactam, ceftazidime drug combination; D065093:beta-Lactamase Inhibitors; D002442:Ceftazidime