Introduction
Materials and methods
Study design overview
Randomization and treatment regimens
Outcomes and follow-up
Statistical analysis
Independent Data Monitoring Committee
Results
Patient disposition and characteristics
Doripenem | Imipenem | Total | |
---|---|---|---|
( N = 115) | ( N = 112) | ( N = 227) | |
Sex, n (%)
| |||
N | 115 | 112 | 227 |
Male | 72 (62.6) | 75 (67.0) | 147 (64.8) |
Female | 43 (37.4) | 37 (33.0) | 80 (35.2) |
Weight (kg)
| |||
N | 115 | 112 | 227 |
Mean (SD) | 75.6 (16.95) | 79.8 (19.07) | 77.7 (18.11) |
Median | 74.0 | 77.5 | 75.0 |
Range | (45;150) | (47; 170) | (45; 170) |
Height (cm)
| |||
N | 114 | 110 | 224 |
Mean (SD) | 169.5 (10.66) | 171.3 (9.20) | 170.3 (9.99) |
Median | 170.0 | 170.0 | 170.0 |
Range | (140; 193) | (150; 200) | (140; 200) |
Age (Years)
| |||
N | 115 | 112 | 227 |
Mean (SD) | 57.5 (16.53) | 54.6 (18.46) | 56.1 (17.53) |
Median | 58.0 | 58.0 | 58.0 |
Range | (19; 89) | (18; 88) | (18; 89) |
Race, n (%)
| |||
N | 115 | 112 | 227 |
White | 96 (83.5) | 97 (86.6) | 193 (85.0) |
Black or African American | 6 (5.2) | 6 (5.4) | 12 (5.3) |
Asian | 4 (3.5) | 1 (0.9) | 5 (2.2) |
Other | 9 (7.8) | 8 (7.1) | 17 (7.5) |
Region, n (%)
| |||
N | 115 | 112 | 227 |
Central and South America | 24 (20.9) | 24 (21.4) | 48 (21.1) |
Eastern Europe and Asia | 34 (29.6) | 33 (29.5) | 67 (29.5) |
Western Europe, North America, Australia | 57 (49.6) | 55 (49.1) | 112 (49.3) |
APACHE II score, n (%)
| |||
N | 115 | 112 | 227 |
≤15 | 48 (41.7) | 49 (43.8) | 97 (42.7) |
16 to 19 | 30 (26.1) | 34 (30.4) | 64 (28.2) |
≥20 | 37 (32.2) | 29 (25.9) | 66 (29.1) |
CPIS, n (%)
| |||
N | 115 | 112 | 227 |
Missing | 3 (2.6) | 2 (1.8) | 5 (2.2) |
<6 | 8 (7.0) | 5 (4.5) | 13 (5.7) |
6 to 7 | 64 (55.7) | 64 (57.1) | 128 (56.4) |
8 to 9 | 30 (26.1) | 34 (30.4) | 64 (28.2) |
>9 | 10 (8.7) | 7 (6.3) | 17 (7.5) |
SOFA Score
| |||
N | 57 | 58 | 115 |
Mean (SD) | 6.0 (2.70) | 5.5 (2.39) | 5.8 (2.55) |
Median | 6.0 | 5.0 | 5.0 |
Range | (0; 14) | (2; 12) | (0; 14) |
Charlson Comorbidity Index
| |||
N | 114 | 112 | 226 |
Mean (SD) | 3.0 (2.72) | 2.8 (2.45) | 2.9 (2.59) |
Median | 3.0 | 3.0 | 3.0 |
Range | (0; 14) | (0; 9) | (0; 14) |
PaO
2
/FiO
2
, n (%)
| |||
N | 115 | 112 | 227 |
≤250 | 67 (58.3) | 61 (54.5) | 128 (56.4) |
>250 | 48 (41.7) | 51 (45.5) | 99 (43.6) |
Bacteremia, n (%)
| |||
N | 115 | 112 | 227 |
No | 109 (94.8) | 107 (95.5) | 216 (95.2) |
Yes | 6 (5.2) | 5 (4.5) | 11 (4.8) |
Creatinine clearance, n (%)
| |||
N | 115 | 112 | 227 |
Supra normal (≥150 ml/min) | 23 (20.0) | 34 (30.4) | 57 (25.1) |
Normal (≥80 to <150 ml/min) | 46 (40.0) | 44 (39.3) | 90 (39.6) |
Mild renal failure (>50 to <80 ml/min) | 33 (28.7) | 26 (23.2) | 59 (26.0) |
Moderate renal failure (>30 to ≤50 ml/min) | 7 (6.1) | 4 (3.6) | 11 (4.8) |
Severe renal failure (≤30 ml/min) | 6 (5.2) | 4 (3.6) | 10 (4.4) |
Failed antibiotic treatment for VAP, n (%)
| |||
N | 69 | 78 | 147 |
No | 59 (85.5) | 67 (85.9) | 126 (85.7) |
Yes | 10 (14.5) | 11 (14.1) | 21 (14.3) |
Prior antibacterial therapy usage (hours), n (%)
| |||
N | 115 | 112 | 227 |
<24 | 28 (24.3) | 35 (31.3) | 63 (27.8) |
≥24 to <48 | 10 (8.7) | 10 (8.9) | 20 (8.8) |
≥48 to ≤72 | 9 (7.8) | 5 (4.5) | 14 (6.2) |
>72 | 68 (59.1) | 62 (55.4) | 130 (57.3) |
Adjunctive therapy, n (%)
| |||
N | 115 | 112 | 227 |
No | 75 (65.2) | 79 (70.5) | 154 (67.8) |
Yes | |||
≤72 Hrs | 32 (27.8) | 25 (22.3) | 57 (25.1) |
>72 Hrs | 8 (7.0) | 8 (7.1) | 16 (7.0) |
Adjunctive aminoglycoside, n (%)
| |||
N | 40 | 33 | 73 |
No | 19 (47.5) | 20 (60.6) | 39 (53.4) |
Yes | |||
≤72 Hrs | 20 (50.0) | 12 (36.4) | 32 (43.8) |
>72 Hrs | 1 (2.5) | 1 (3.0) | 2 (2.7) |
Adjunctive vancomycin/linezolid, n (%)
| |||
N | 40 | 33 | 73 |
No | 14 (35.0) | 9 (27.3) | 23 (31.5) |
Yes | |||
≤72 hrs | 20 (50.0) | 18 (54.5) | 38 (52.1) |
>72 hrs | 6 (15.0) | 6 (18.2) | 12 (16.4) |
Doripenem | Imipenem | Total | |
---|---|---|---|
( N = 79) | ( N = 88) | ( N = 167) | |
Sex, n (%)
| |||
N | 79 | 88 | 167 |
Male | 48 (60.8) | 61 (69.3) | 109 (65.3) |
Female | 31 (39.2) | 27 (30.7) | 58 (34.7) |
Weight (kg)
| |||
N | 79 | 88 | 167 |
Mean (SD) | 75.5 (17.85) | 78.7 (15.66) | 77.2 (16.75) |
Median | 75.0 | 78.0 | 76.0 |
Range | (45; 150) | (47; 143) | (45; 150) |
Height (cm)
| |||
N | 79 | 87 | 166 |
Mean (SD) | 170.8 (9.76) | 171.7 (8.73) | 171.3 (9.22) |
Median | 170.0 | 170.0 | 170.0 |
Range | (148; 193) | (150; 190) | (148; 193) |
Age (years)
| |||
N | 79 | 88 | 167 |
Mean (SD) | 54.9 (16.10) | 53.4 (18.94) | 54.1 (17.62) |
Median | 56.0 | 57.0 | 57.0 |
Range | (19; 89) | (18; 88) | (18; 89) |
Race, n (%)
| |||
N | 79 | 88 | 167 |
White | 65 (82.3) | 75 (85.2) | 140 (83.8) |
Black or African American | 5 (6.3) | 6 (6.8) | 11 (6.6) |
Asian | 1 (1.3) | 1 (1.1) | 2 (1.2) |
Other | 8 (10.1) | 6 (6.8) | 14 (8.4) |
Region, n (%)
| |||
N | 79 | 88 | 167 |
Central and South America | 20 (25.3) | 19 (21.6) | 39 (23.4) |
Eastern Europe and Asia | 24 (30.4) | 27 (30.7) | 51 (30.5) |
Western Europe, North America, Australia | 35 (44.3) | 42 (47.7) | 77 (46.1) |
APACHE II score group, n (%)
| |||
N | 79 | 88 | 167 |
≤15 | 34 (43.0) | 42 (47.7) | 76 (45.5) |
16 to 19 | 24 (30.4) | 21 (23.9) | 45 (26.9) |
≥20 | 21 (26.6) | 25 (28.4) | 46 (27.5) |
CPIS, n (%)
| |||
N | 79 | 88 | 167 |
Missing | 2 (2.5) | 1 (1.1) | 3 (1.8) |
<6 | 4 (5.1) | 2 (2.3) | 6 (3.6) |
6 to 7 | 43 (54.4) | 50 (56.8) | 93 (55.7) |
8 to 9 | 23 (29.1) | 29 (33.0) | 52 (31.1) |
>9 | 7 (8.9) | 6 (6.8) | 13 (7.8) |
SOFA score
| |||
N | 41 | 46 | 87 |
Mean (SD) | 5.7 (2.53) | 5.2 (2.24) | 5.4 (2.38) |
Median | 6.0 | 5.0 | 5.0 |
Range | (0; 11) | (2; 12) | (0; 12) |
Charlson Comorbidity Index
| |||
N | 79 | 88 | 167 |
Mean (SD) | 2.4 (2.08) | 2.8 (2.48) | 2.6 (2.30) |
Median | 3.0 | 2.0 | 3.0 |
Range | (0; 9) | (0; 9) | (0; 9) |
PaO
2
/FiO
2
, n (%)
| |||
N | 79 | 88 | 167 |
≤250 | 50 (63.3) | 51 (58.0) | 101 (60.5) |
>250 | 29 (36.7) | 37 (42.0) | 66 (39.5) |
Bacteremia, n (%)
| |||
N | 79 | 88 | 167 |
No | 73 (92.4) | 84 (95.5) | 157 (94.0) |
Yes | 6 (7.6) | 4 (4.5) | 10 (6.0) |
Creatinine Clearance, n (%)
| |||
N | 79 | 88 | 167 |
Supra normal (≥150 ml/min) | 18 (22.8) | 28 (31.8) | 46 (27.5) |
Normal (≥80 to <150 ml/min) | 31 (39.2) | 37 (42.0) | 68 (40.7) |
Mild renal failure (>50 to <80 ml/min) | 23 (29.1) | 18 (20.5) | 41 (24.6) |
Moderate renal failure (>30 to ≤50 ml/min) | 5 (6.3) | 2 (2.3) | 7 (4.2) |
Severe renal failure (≤30 ml/min) | 2 (2.5) | 3 (3.4) | 5 (3.0) |
Failed antibiotic treatment, n (%)
| |||
N | 55 | 68 | 123 |
No | 45 (81.8) | 58 (85.3) | 103 (83.7) |
Yes | 10 (18.2) | 10 (14.7) | 20 (16.3) |
Prior antibacterial therapy usage (hours), n (%)
| |||
N | 79 | 88 | 167 |
<24 | 19 (24.1) | 29 (33.0) | 48 (28.7) |
≥24 to <48 | 8 (10.1) | 8 (9.1) | 16 (9.6) |
≥48 to ≤72 | 6 (7.6) | 3 (3.4) | 9 (5.4) |
>72 | 46 (58.2) | 48 (54.5) | 94 (56.3) |
Adjunctive therapy, n (%)
| |||
N | 79 | 88 | 167 |
No | 49 (62.0) | 68 (77.3) | 117 (70.1) |
Yes | |||
≤72 Hrs | 23 (29.1) | 15 (17.0) | 38 (22.8) |
>72 Hrs | 7 (8.9) | 5 (5.7) | 12 (7.2) |
Adjunctive aminoglycoside, n (%)
| |||
N | 30 | 20 | 50 |
No | 15 (50.0) | 11 (55.0) | 26 (52.0) |
Yes | |||
≤72 hrs | 14 (46.7) | 8 (40.0) | 22 (44.0) |
>72 hrs | 1 (3.3) | 1 (5.0) | 2 (4.0) |
Adjunctive vancomycin/linezolid, n (%)
| |||
N | 30 | 20 | 50 |
No | 9 (30.0) | 6 (30.0) | 15 (30.0) |
Yes | |||
≤72 hrs | 16 (53.3) | 11 (55.0) | 27 (54.0) |
>72 hrs | 5 (16.7) | 3 (15.0) | 8 (16.0) |
Clinical and microbiologic response
Doripenem | Imipenem | Total | |
---|---|---|---|
( N = 79) | ( N = 88) | ( N = 167) | |
n (%) | n (%) | n (%) | |
Specific Gram-negative Pathogens
| 65 (82.3) | 62 (70.5) | 127 (76.0) |
Pseudomonas aeruginosa | 17 (21.5) | 10 (11.4) | 27 (16.2) |
Monomicrobial* | 8 ( 10.1) | 6 (6.8) | 14 (8.4) |
Polymicrobial** | 9 (11.4) | 4 (4.5) | 13 (7.8) |
Acinetobacter spp. | 15 (19.0) | 10 (11.4) | 25 (15.0) |
Monomicrobial* | 3 (3.8) | 4 (4.5) | 7 (4.2) |
Polymicrobial** | 12 (15.2) | 6 (6.8) | 18 (10.8) |
Enterobacteriaceae
| 43 (54.4) | 49 (55.7) | 92 (55.1) |
Monomicrobial* | 14 (17.7) | 14 (15.9) | 28 (16.8) |
Citrobacter koseri
| 1 (1.3) | 0 | 1 (0.6) |
Enterobacter aerogenes
| 0 | 1 (1.1) | 1 (0.6) |
Enterobacter cloacae
| 4 (5.1) | 3 (3.4) | 7 (4.2) |
Escherichia coli
| 1 (1.3) | 2 (2.3) | 3 (1.8) |
Klebsiella pneumoniae
| 5 (6.3) | 4 (4.5) | 9 (5.4) |
Pantoea agglomerans
| 1 (1.3) | 0 | 1 (0.6) |
Proteus mirabilis
| 1 (1.3) | 2 (2.3) | 3 (1.8) |
Serratia marcescens
| 1 (1.3) | 2 (2.3) | 3 (1.8) |
Polymicrobial** | 29 (36.7) | 35 (39.8) | 64 (38.3) |
Citrobacter freundii
| 0 | 3 (3.4) | 3 (1.8) |
Enterobacter aerogenes
| 0 | 2 (2.3) | 2 (1.2) |
Enterobacter asburiae
| 1 (1.3) | 0 | 1 (0.6) |
Enterobacter cloacae
| 4 (5.1) | 2 (2.3) | 6 (3.6) |
Enterobacter spp. (Not Speciated) | 1 (1.3) | 0 | 1 (0.6) |
Escherichia coli
| 5 (6.3) | 12 (13.6) | 17 (10.2) |
Klebsiella oxytoca
| 1 (1.3) | 1 (1.1) | 2 (1.2) |
Klebsiella pneumoniae
| 14 (17.7) | 16 (18.2) | 30 (18.0) |
Proteus mirabilis
| 3 (3.8) | 3 (3.4) | 6 (3.6) |
Proteus vulgaris
| 1 (1.3) | 1 (1.1) | 2 (1.2) |
Providencia spp. (Not Speciated) | 0 | 1 (1.1) | 1 (0.6) |
Serratia marcescens
| 3 (3.8) | 3 (3.4) | 6 (3.6) |
Pneumonia with MRS
| 7 (8.9) | 4 (4.5) | 11 (6.6) |
Pseudomonas aeruginosa | 2 (2.5) | 1 (1.1) | 3 (1.8) |
Polymicrobial** | 2 (2.5) | 1 (1.1) | 3 (1.8) |
Acinetobacter spp. | 2 (2.5) | 1 (1.1) | 3 (1.8) |
Polymicrobial** | 2 (2.5) | 1 (1.1) | 3 (1.8) |
Enterobacteriaceae
| 4 (5.1) | 2 (2.3) | 6 (3.6) |
Polymicrobial** | 4 (5.1) | 2 (2.3) | 6 (3.6) |
Doripenem | Imipenem | Total | |
---|---|---|---|
( N = 17) | ( N = 10) | ( N = 27) | |
Sex, n (%)
| |||
N | 17 | 10 | 27 |
Male | 13 (76.5) | 7 (70.0) | 20 (74.1) |
Female | 4 (23.5) | 3 (30.0) | 7 (25.9) |
Weight (kg)
| |||
N | 17 | 10 | 27 |
Mean (SD) | 74.0 (17.85) | 68.3 (12.12) | 71.9 (15.96) |
Median | 75.0 | 64.0 | 72.7 |
Range | (45; 110) | (52; 90) | (45; 110) |
Height (cm)
| |||
N | 17 | 10 | 27 |
Mean (SD) | 172.0 (10.11) | 170.8 (7.74) | 171.6 (9.17) |
Median | 170.0 | 171.0 | 170.0 |
Range | (156; 190) | (159; 180) | (156; 190) |
Age (Years)
| |||
N | 17 | 10 | 27 |
Mean (SD) | 57.5 (15.58) | 50.9 (20.32) | 55.1 (17.40) |
Median | 57.0 | 53.5 | 57.0 |
Range | (33; 89) | (25; 77) | (25; 89) |
Race, n (%)
| |||
N | 17 | 10 | 27 |
White | 16 (94.1) | 7 (70.0) | 23 (85.2) |
Black or African American | 1 (5.9) | 2 (20.0) | 3 (11.1) |
Asian | 0 | 1 (10.0) | 1 (3.7) |
Region, n (%)
| |||
N | 17 | 10 | 27 |
Central and South America | 5 (29.4) | 3 (30.0) | 8 (29.6) |
Eastern Europe and Asia | 5 (29.4) | 4 (40.0) | 9 (33.3) |
Western Europe, North America, Australia | 7 (41.2) | 3 (30.0) | 10 (37.0) |
APACHE II score group, n (%)
| |||
N | 17 | 10 | 27 |
≤15 | 6 (35.3) | 3 (30.0) | 9 (33.3) |
16 to 19 | 5 (29.4) | 3 (30.0) | 8 (29.6) |
≥20 | 6 (35.3) | 4 (40.0) | 10 (37.0) |
CPIS, n (%)
| |||
N | 17 | 10 | 27 |
<6 | 0 | 1 (10.0) | 1 (3.7) |
6 to 7 | 10 (58.8) | 8 (80.0) | 18 (66.7) |
8 to 9 | 5 (29.4) | 1 (10.0) | 6 (22.2) |
>9 | 2 (11.8) | 0 | 2 (7.4) |
SOFA score
| |||
N | 10 | 4 | 14 |
Mean (SD) | 5.4 (3.10) | 4.0 (1.41) | 5.0 (2.75) |
Median | 4.0 | 4.5 | 4.0 |
Range | (1; 10) | (2; 5) | (1; 10) |
Charlson Comorbidity Index
| |||
N | 17 | 10 | 27 |
Mean (SD) | 3.0 (2.26) | 2.5 (1.96) | 2.8 (2.13) |
Median | 3.0 | 3.0 | 3.0 |
Range | (0; 9) | (0; 5) | (0; 9) |
PaO
2
/FiO
2
, n (%)
| |||
N | 17 | 10 | 27 |
≤250 | 10 (58.8) | 5 (50.0) | 15 (55.6) |
>250 | 7 (41.2) | 5 (50.0) | 12 (44.4) |
Bacteremia, n (%)
| |||
N | 17 | 10 | 27 |
No | 16 (94.1) | 10 (100) | 26 (96.3) |
Yes | 1 (5.9) | 0 | 1 (3.7) |
Creatinine clearance, n (%)
| |||
N | 17 | 10 | 27 |
Supra normal(≥150 ml/min) | 5 (29.4) | 4 (40.0) | 9 (33.3) |
Normal (≥80 to <150 ml/min) | 5 (29.4) | 2 (20.0) | 7 (25.9) |
Mild renal failure (>50 to <80 ml/min) | 4 (23.5) | 3 (30.0) | 7 (25.9) |
Moderate renal failure (>30 to ≤50 ml/min) | 2 (11.8) | 1 (10.0) | 3 (11.1) |
Severe renal failure (≤30 ml/min) | 1 (5.9) | 0 | 1 (3.7) |
Failed antibiotic treatment, n (%)
| |||
N | 11 | 8 | 19 |
No | 8 (72.7) | 6 (75.0) | 14 (73.7) |
Yes | 3 (27.3) | 2 (25.0) | 5 (26.3) |
Prior antibacterial therapy usage (hours), n (%)
| |||
N | 17 | 10 | 27 |
<24 | 4 (23.5) | 0 | 4 (14.8) |
≥24 to <48 | 2 (11.8) | 1 (10.0) | 3 (11.1) |
≥48 to ≤72 | 1 (5.9) | 0 | 1 (3.7) |
>72 | 10 (58.8) | 9 (90.0) | 19 (70.4) |
Adjunctive therapy, n (%)
| |||
N | 17 | 10 | 27 |
No | 7 (41.2) | 6 (60.0) | 13 (48.1) |
Yes | |||
≤72 hrs | 8 (47.1) | 3 (30.0) | 11 (40.7) |
>72 hrs | 2 (11.8) | 1 (10.0) | 3 (11.1) |
Adjunctive aminoglycoside, n (%)
| |||
N | 10 | 4 | 14 |
No | 4 (40.0) | 2 (50.0) | 6 (42.9) |
Yes | |||
≤72 hrs | 5 (50.0) | 2 (50.0) | 7 (50.0) |
>72 hrs | 1 (10.0) | 0 | 1 (7.1) |
Adjunctive vancomycin/linezolid, n (%)
| |||
N | 10 | 4 | 14 |
No | 5 (50.0) | 1 (25.0) | 6 (42.9) |
Yes | |||
≤72 hrs | 4 (40.0) | 2 (50.0) | 6 (42.9) |
>72 hrs | 1 (10.0) | 1 (25.0) | 2 (14.3) |
Safety
Pharmacokinetics
Discussion
Conclusions
Key messages
-
A fixed 7-day course of doripenem was found to have non-significant higher rates of clinical failure and mortality compared to a fixed 10-day course of imipenem-cilastatin for the treatment of VAP.
-
VAP due to NLFGNB should be treated with antibiotic courses that are longer than seven days.
-
The use of prolonged infusion antibiotic therapy for VAP needs additional study to determine its relative efficacy compared to standard therapy.