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Table 1 Characteristics of included studies

From: Prolonged versus intermittent β-lactam antibiotics intravenous infusion strategy in sepsis or septic shock patients: a systematic review with meta-analysis and trial sequential analysis of randomized trials

No. First author, year Country Design Double blinding Number of study participants, total (P vs I) Age, P vs I, median APACHEII, P vs I, median Sepsis definition or type of infection Organism Antibiotics Prolonged infusion Intermittent infusion
1 Angus, 2000 Thailand RCT NR 21 (10 vs 11) 43 vs 48 21 vs 15 Septic melioidosis Only Gram-negative β-Lactam (unknown in detail) 12 mg/kg loading dose, followed by 4 mg/kg/h by constant rate infusion 40 mg/kg every 8 h, intermittent bolus injection
2 Nicolau, 2001 USA RCT No 35 (17 vs 18) 46 vs 56 (mean) 13.9 vs 15.5 (mean) Nosocomial pneumonia Mostly Gram-negative β-Lactam (ceftazidime) plus tobramycin Ceftazidime, 3 g/day, continuously; tobramycin, 7 mg/kg/day Ceftazidime: 2 g, over 30 min, every 8 h; tobramycin, 7 mg/kg/day
3 Georges, 2005 France RCT No 50 (26 vs 24) 50 vs 46 (mean) a45 vs 44 (aSAPS II, median) Nosocomial pneumonia or bacteremia Mostly Gram-negative β-Lactam (cefepime) plus amikacin Cefepime, 4 g/day, continuously; amikacin, 20 mg/kg loading dose, followed by 15 mg/kg/day Cefepime, 2 g, over 30 min, twice daily; amikacin: 20 mg/kg loading dose, followed by 15 mg/kg/day
4 Rafati, 2006 Iran RCT NR 40 (20 vs 20) 50.1 vs 48.0 (mean) 16.4 vs 14.2 (mean) Septic patients with SIRS (Sepsis-2) Only Gram-negative β-Lactam (piperacillin) plus amikacin Piperacillin, 2 g loading dose, followed by 8 g/day, continuously; amikacin, 15 mg/kg/day Piperacillin, 3 g, over 30 min, every 6 h; amikacin, 15 mg/kg/day
5 Lau, 2006 USA RCT No 258 (128 vs 130) 51.5 vs 48.0 7 vs 7 Complicated intra-abdominal infections Gram-negative and Gram-positive β-Lactam (piperacillin–tazobactam) 2.25 g loading dose, followed by 13.5 g/day, continuously 3.375 g, over 30 min, every 6 h
6 Roberts, 2007 Australia RCT No 57 (29 vs 28) 41 vs 56 20 vs 17 Sepsis (SIRS criteria) Mixed β-Lactam (ceftriaxone) Continuous infusion, 2 g/day Intermittent bolus, 2 g every 24 h
7 Roberts and Kirkpatrick, 2009 Australia RCT No 10 (5 vs 5) 57 vs 55 a5 vs 3 (aSOFA, median) Sepsis (SIRS criteria) Only Gram-negative β-Lactam (meropenem) Continuous infusion, 3 g/day Intermittent bolus, 1 g every 8 h
8 Chytra, 2012 Czech Republic RCT No 214 (106 vs 108) 44.9 vs 47.2 (mean) 21.4 vs 22.1 (mean) Sepsis (Sepsis-2) Mostly Gram-negative β-Lactam (meropenem) Continuous infusion, loading dose 2 g; 4 g every 24 h 30 min; 2 g every 8 h
9 Dulhunty, 2013 Australia, Hong Kong RCT Yes 60 (30 vs 30) 54 vs 60 (mean) 21 vs 23 (mean) Severe sepsis (Sepsis-2) Mixed β-Lactam (piperacillin–tazobactam, ticarcillin–clavulanate, or meropenem) Continuous infusion, clinician chosen from piperacillin–tazobactam, ticarcillin–clavulanate, or meropenem Intermittent bolus, clinician chosen from piperacillin–tazobactam, ticarcillin–clavulanate, or meropenem
10 Dulhunty, 2015 Australia, New Zealand, Hong Kong RCT Yes 432 (212 vs 220) 64 vs 65 21 vs 20 Severe sepsis (Sepsis-2) Mixed β-Lactam (piperacillin–tazobactam, ticarcillin–clavulanate, or meropenem) Continuous infusion clinician chosen from piperacillin–tazobactam, ticarcillin–clavulanate, or meropenem Intermittent bolus clinician chosen from piperacillin–tazobactam, ticarcillin–clavulanate, or meropenem
11 Laterre, 2015 Belgium RCT NR 28 (14 vs 14) 68 vs 65 17 vs 16 Pulmonary or abdominal infection in ICU Mostly Gram-negative β-Lactam (temocillin) Loading dose (2 g) administered over 30 min in 50 mL of water for injection followed by infusion (6 g in 48 mL of water for injection infused at a rate of 2 mL/h) 2 g of temocillin (in 50 mL of water for injection) every 8 h injected over a 30 min period
12 Abdul, 2016 Malaysia RCT No 140 (70 vs 70) 54vs 56 21 vs 21 Severe sepsis (Sepsis-2) Mostly Gram-negative β-Lactam (cefepime, meropenem or piperacillin/tazobactam) aContinuous infusion bIntermittent bolus
13 Zhao, 2017 China RCT No 50 (25 vs 25) 68 vs 67 19.4 vs 19.7 Severe sepsis and septic shock (Sepsis-2) Only Gram-negative β-Lactam (meropenem) Loading dose of 0.5 g of meropenem followed by a continuous infusion of 3 g/day Initial dose of 1.5 g followed by 1 g for every 8 h
  1. P prolonged, I intermittent, RCT randomized control trial, NR not reported, SAPS II Simplified Acute Physiology Score II, SOFA Sequential Organ Failure Assessment, SIRS systemic inflammatory response syndrome, ICU intensive care unit
  2. aContinuous infusion: Cefepime: day 1—2 g intravenous (IV) loading dose (infused over 30 min) followed by 2 g IV (infused over 480 min) every 8 h; day 2 onwards—2 g IV (infused over 480 min) every 8 h. Meropenem: day 1—1 g IV loading dose (infused over 30 min) followed by 1 g IV (infused over 480 min) every 8 h; day 2 onwards—1 g IV (infused over 480 min) every 8 h. Piperacillin/tazobactam: day 1—4 g/0.5 g IV loading dose (infused over 30 min) followed by 4 g/0.5 g IV (infused over 360 min) every 6 h; day 2 onwards—4 g/0.5 g IV (infused over 360 min) every 6 h
  3. bIntermittent bolus: cefepime—2 g intravenous (IV) (infused over 30 min) every 8 h; meropenem—1 g IV (infused over 30 min) every 8 h; piperacillin/tazobactam—4 g/0.5 g IV (infused over 30 min) every 6 h