Introduction
Methods
Study Design and Participants
Bacterial Isolates
Randomization and Blinding
Interventions
Outcomes and Assessments
Statistical Analysis
Analysis Populations
Descriptive and Inferential Analysis Methods
Characteristic | M–V (n = 32) | BAT (n = 15) | Total (N = 47) |
---|---|---|---|
Age, mean (SD), years | 63.5 (14.1) | 60.2 (13.0) | 62.5 (13.7) |
Age cohort, n (%) | |||
< 65 y | 17 (53.1) | 9 (60.0) | 26 (55.3) |
≥ 65 y | 8 (25.0) | 3 (20.0) | 11 (23.4) |
≥ 75 y | 7 (21.9) | 3 (20.0) | 10 (21.3) |
Female gender, n (%) | 18 (56.3) | 5 (33.3) | 23 (48.9) |
White race, n (%) | 28 (87.5) | 12 (80.0) | 40 (85.1) |
Region, n (%) | |||
North America | 7 (21.9) | 7 (46.7) | 14 (29.8) |
Europe | 19 (59.4) | 8 (53.3) | 27 (57.4) |
Rest of Worlda | 6 (18.8) | 0 (0) | 6 (12.8) |
BMI, mean (SD) | 27.9 (9.0) | 25.8 (7.6) | 27.2 (8.5) |
Infection type, n (%) | |||
Bacteremia | 14 (43.8) | 8 (53.3) | 22 (46.8) |
cUTI/AP | 12 (37.5) | 4 (26.7) | 16 (34.0) |
HABP/VABP | 4 (12.5) | 1 (6.7) | 5 (10.6) |
cIAI | 2 (6.3) | 2 (13.3) | 4 (8.5) |
Baseline pathogen, n (%)b | |||
Klebsiella pneumoniae | 29 (90.6) | 12 (80.0) | 41 (87.2) |
Escherichia coli | 3 (9.4) | 1 (6.7) | 4 (8.5) |
Enterobacter cloacae sp. | 1 (3.1) | 2 (13.3) | 3 (6.4) |
Proteus mirabilis | 0 (0) | 2 (13.3) | 2 (4.3) |
Serratia marcescens | 1 (3.1) | 1 (6.7) | 2 (4.3) |
Enrolled as confirmed CRE, n (%) | 23 (71.9) | 14 (93.3) | 37 (78.7) |
Enrolled as suspected CRE, n (%) | 9 (28.1) | 1 (6.7) | 10 (21.3) |
Creatinine clearance, mL/min, n (%) | |||
≥ 50 | 24 (75.0) | 9 (60.0) | 33 (70.2) |
30–49 | 4 (12.5) | 2 (13.3) | 6 (12.8) |
20–29 | 1 (3.1) | 2 (13.3) | 3 (6.4) |
< 20 | 2 (6.3) | 0 (0) | 2 (4.3) |
Missing | 1 (3.1) | 2 (13.3) | 3 (6.4) |
Charlson comorbidity index, n (%) | |||
≤ 2 | 4 (12.5) | 1 (6.7) | 5 (10.6) |
3–4 | 3 (9.4) | 2 (13.4) | 5 (10.6) |
5 | 11 (34.4) | 1 (6.7) | 12 (25.5) |
≥ 6 | 14 (43.8) | 11 (73.3) | 25 (53.2) |
Diabetes mellitus, n (%) | 12 (37.5) | 7 (46.7) | 19 (40.4) |
SIRS, n (%) | 15 (46.9) | 6 (40.0) | 21 (44.7) |
ICU admission, n (%) | 5 (15.6) | 3 (20.0) | 8 (17.0) |
Immunocompromisedc, n (%) | 11 (34.4) | 8 (53.3) | 19 (40.4) |
Prior antibiotic failured, n (%) | 9 (28.1) | 0 (0) | 9 (19.1) |
Results
Patient Disposition
M–V (n = 32) n (%) | BAT (n = 15) n (%) | Differencea (95% CI) | P value | Relative differenceb | |
---|---|---|---|---|---|
Efficacy endpoints | |||||
Clinical cure at EOT | 21 (65.6) | 5 (33.3) | 32.3 (3.3–61.3) | 0.03 | 97.0 |
Clinical cure at TOC | 19 (59.4) | 4 (26.7) | 32.7 (4.6–60.8) | 0.02 | 122.5 |
Microbiologic curec at EOT | 21 (65.6) | 6 (40.0) | 25.6 (− 4.1 to 55.4) | 0.09 | 64.0 |
Microbiologic curec at TOC | 17 (53.1) | 5 (33.3) | 19.8 (− 9.7 to 49.3) | 0.19 | 59.5 |
Day-28 mortality | 5 (15.6) | 5 (33.3) | − 17.7 (− 44.7 to 9.3) | 0.20 | − 53.2 |
M–V (n = 23) n (%) | BAT (n = 15) n (%) | Differencea (95% CI) | P value | Relative differenceb | |
---|---|---|---|---|---|
Sensitivity analysis of clinical cure at TOC and all-cause mortality at day 28 across all infection types (mCRE-MITT) excluding prior antibiotic failured | |||||
Clinical cure at TOC | 16 (69.6) | 4 (26.7) | 42.9 (13.7–72.1) | 0.004 | 160.7 |
Day-28 all-cause mortality | 1 (4.3) | 5 (33.3) | − 29.0 (− 54.3 to -3.7) | 0.02 | − 87.1 |
M–V (n = 32) n (%) | BAT (n = 15) n (%) | Differencea (95% CI) | P value | Relative Differenceb | |
---|---|---|---|---|---|
Exploratory analysis of risk–benefit profile of meropenem–vaborbactam compared to best available therapy | |||||
Day-28 all-cause mortality or nephrotoxicitye | 8 (25.0) | 6 (40.0) | − 15.0 (− 44.0 to 14.0) | 0.31 | − 37.5 |
Clinical failure or nephrotoxicityf | 10 (31.3) | 12 (80.0) | − 48.7 (− 74.6 to − 22.9) | < 0.001 | − 60.9 |
Day-28 all-cause mortality or renal AEsg | 6 (18.8) | 9 (60.0) | − 41.2 (− 69.5 to − 13.0) | 0.004 | − 68.7 |
Clinical failure or renal AEsh | 9 (28.1) | 12 (80.0) | − 51.9 (− 77.4 to − 26.3) | < 0.001 | − 64.9 |
Efficacy
Safety and Tolerability
Adverse events | M–V (n = 50) n (%) | BAT (n = 25) n (%) | Total (N = 75) n (%) |
---|---|---|---|
TEAEs | |||
Anya | 42 (84.0) | 23 (92.0) | 65 (86.7) |
Diarrhea | 6 (12.0) | 4 (16.0) | 10 (13.3) |
Anemia | 5 (10.0) | 3 (12.0) | 8 (10.7) |
Hypokalemia | 5 (10.0) | 2 (8.0) | 7 (9.3) |
Hypotension | 4 (8.0) | 3 (12.0) | 7 (9.3) |
Sepsis | 2 (4.0) | 5 (20.0) | 7 (9.3) |
Septic shock | 1 (2.0) | 4 (16.0) | 5 (6.7) |
Renal failure acute | 1 (2.0) | 4 (16.0) | 4 (5.3) |
Drug-related | 12 (24.0) | 11 (44.0) | 23 (30.7) |
TEAEs by maximum severity | |||
Mild | 11 (22.0) | 4 (16.0) | 15 (20.0) |
Moderate | 11 (22.0) | 5 (20.0) | 16 (21.3) |
Severe | 7 (14.0) | 7 (28.0) | 14 (18.7) |
Life-threatening | 3 (6.0) | 1 (4.0) | 4 (5.3) |
Death | 10 (20.0) | 6 (24.0) | 16 (21.3) |
SAEs | |||
All | 17 (34.0) | 11 (44.0) | 28 (37.3) |
Drug-related | 0 (0) | 2 (8.0) | 2 (2.7) |
Study drug discontinuations due to TEAEs | 5 (10.0) | 3 (12.0) | 8 (10.7) |
Study discontinuations due to TEAEs | 8 (16.0) | 5 (20.0) | 13 (17.3) |
Renal-related safety endpoints | |||
Renal-related TEAEs (Preferred Term) | 2 (4.0) | 6 (24.0) | 8 (10.7) |
Renal failure acute | 1 (2.0) | 3 (12.0) | 4 (5.3) |
Renal impairment | 1 (2.0) | 2 (8.0) | 3 (4.0) |
Renal failure | 0 (0) | 1 (4.0) | 1 (1.3) |
Any post-baseline RIFLE Criteriab | 1 (2.1) | 2 (8.3) | 3 (4.2) |
Maximum post-baseline creatinine increase | |||
≥ 0.5 mg/dL | 7 (14.0) | 6 (24.0) | 13 (17.3) |