Introduction
Materials and methods
Results
Carbapenem
Meropenem
PK parameters | Study | |||||
---|---|---|---|---|---|---|
Antibiotic drug classes and drugs | Vd, L | Cl, L/hour | T1/2, hours | Patient demographics | Study types[93] | References |
Carbapenems | ||||||
Meropenem | 21.2 ± 4.7b | 11.3 ± 4b | 1.4 ± 0.4b | N = 11 Age 63.1 years [23 to 81] Mild to severe intraabdominal sepsis | Descriptive | Lovering et al., 1995 [22] |
Meropenem | 26.6 ± 3.2c | 9.4 ± 1.2c | 2.0 | N = 15 Age 55.3 ± 14.3 years Severe sepsis | Randomized, controlled cross-over | Thalhammer et al., 1999 [27] |
Meropenem | 34.4 ± 15.9 | 11 ± 4.3 | 0.4 ± 0.12 | N = 8 Age 55 ± 8 years VAP | Descriptive | de Stoppelaar et al., 2000 [19] |
Meropenem | 19.7 ± 5 | 7.3 ± 3.1 | 3.1 ± 1.5 | N = 14 Age 73.3 ± 8.1 years Severe sepsis | Descriptive | Kitzes-Cohen et al., 2002 [21] |
Meropenem | 16.0 ± 3.7d | 8.5 ± 3.2d | 1.4 ± 0.6d | N = 9 Age 39.6 ± 15.7 years VAP | Not randomized, controlled cross-over | Jaruratanasirikul et al., 2005 [20] |
Imipenem | Imipenem 17.7 ± 4 | Imipenem 7.0 ± 2.5 | Imipenem 2 ± 0.3 | Imipenem N = 10 Age 65 ± 19 years | Randomized, parallel controlled | Novelli et al., 2005 [29] |
Meropenem | Meropenem 27.1 ± 7.7 | Meropenem 11.5 ± 3.1 | Meropenem 2.1 ± 0.5 | Meropenem N = 10 Age 67 ± 19 years Severe sepsis | ||
Meropenem | 23.8 ± 4.9 | 6.7 ± 4.2 | 3.7 ± 1.9 | N = 6 Age 65.7 ± 11.2 years Peritonitis | Descriptive | Karjagin et al., 2008 [25] |
Meropenem | 22.7 | 13.6 ± 1.3 | NR | N = 10 Age range 48 to 63 years Severe sepsis | Randomized, parallel controlled | Roberts et al., 2009 [24] |
Meropenem | Meropenem 30.1 [21.7 to 53.9]e | Meropenem 8 [5 to 10.99e | Meropenem 2.1 [1.7 to 3.4] | Meropenem N = 16 | Cross-sectional | Taccone et al., 2010 [23] |
Piperacillin | Piperacillin 26.6 [20.3 to 30.1]e | Piperacillin 8.4 [5.5 to 18.1]e | Piperacillin 2.6 [1.5 to 3.8] | Piperacillin N = 27 | ||
Ceftazidime | Ceftazidime 33.6 [25.2 to 49.7]e | Ceftazidime 3.8 [2.5 to 5.5]e | Ceftazidime 5.8 [4.1 to 7.4] | Ceftazidime N = 18 | ||
Cefepime | Cefepime 25.2 [23.1 to 30.8]e | Cefepime 5.5 [4.6 to 8.4]e | Cefepime 3.4 [2.3 to 5.3] | Cefepime N = 19 All patients: median age 63 years Severe sepsis or septic shock | ||
Imipenem | 31.4 ± 11.7 | 14.4 ± 4.5 | 1.6 ± 1.3 | N = 10 Age 44 ± 12.2 years Severe sepsis | Descriptive | McKindley et al., 1996 [34] |
Imipenem | 18.5 | 6.3 ± 0.8 | 2.0 | N = 6 Age 63.5 ± 16.7 years Severe sepsis | Not randomized, parallel, controlled | Tegeder et al., 2002 [32] |
Imipenem | 45.5 ± 47.2 | 12.1 ± 12.0 | 2.9 ± 1.7 | N = 50 Age 45.2 ± 17 years Presumed Gram-negative sepsis | Cross-sectional | Belzberg et al., 2004 [28] |
Imipenem | 12.2 ± 9.9f | 12.3 ± 4.2 | NR | N = 20 Age 60.5 years VAP | Randomized, parallel, controlled | Sakka et al., 2007 [31] |
Imipenem | 27.2 ± 6.5 | 13.3 ± 5.2 | 1.4 ± 0.2 | N = 6 Age 53.3 ± 19.9 years Severe sepsis | Not randomized, parallel, controlled | Dahyot et al., 2008 [33] |
Imipenem | 16.7 ± 5.3g | 8.7 ± 5.3g | 1.5 ± 0.7g | N = 9 Age 63.3 ± 14.9 years VAP | Not randomized, controlled, cross-over | Jaruratanasirikul and Sudsai, 2009 [30] |
Penicillins | ||||||
Piperacillin | 25.0 ± 17.2 | 23.8 ± 17.2 | 1.5 ± 2.1 | N = 11 Age 43.6 ± 15.9 years Surgical patients | Descriptive | Shikuma et al., 1990 [36] |
Piperacillin | 19.5 ± 3.4b | 8.4 ± 1.4b | 1.8 ± 0.3b | N = 10 Age 37.7 ± 2.8 years Burn patients | Descriptive | Bourget et al., 1996 [38] |
Piperacillin | 40.7 ± 8.7 | 8.2 ± 2 | 4.1 ± 1.3 | N = 6 Age 64 ± 7 years Septic shock | Not randomized, parallel, controlled | Joukhadar et al., 2001 [44] |
Piperacillin | 34.6 ± 6.8c | 11.8 ± 4.3c | 2.4 ± 1.2c | N = 7 Age range 45 to 76 years Severe sepsis | Not randomized, controlled, cross-over | Langgartner et al., 2007 [39] |
Piperacillin | 11.7f | 17.2 | 0.4 | N = 13 Age 37.5 ± 19.4 years Severe sepsis | Randomized, parallel, controlled | Roberts et al., 2009 [45] |
Cephalosporins | ||||||
Cefpirome | 23.6 ± 8.0 | 8.0 ± 3.0 | 2.2 ± 0.5 | N = 9 Age 31 years [19 to 53] Severe sepsis | Not randomized, parallel, controlled | Jacolot et al., 1999 [47] |
Cefpirome | 26.4 ± 7.9 | 8.8 ± 3.4 | 3.1 ± 1.2 | N = 12 Age 41.2 ± 19 years Severe sepsis | Descriptive | Lipman et al., 2001 [48] |
Cefpirome | 25.9 ± 7.1 | 4.5 ± 0.7 | 3.3 ± 0.5 | N = 12 Age 67.2 ± 8.1 years Severe sepsis or septic shock | Not randomized, parallel, controlled | Joukhadar et al., 2002 [52] |
Cefpirome | 21.9 ± 4.5 | 4.8 ± 1.6 | 3.1 ± 0.9 | N = 11 Age 66 ± 8 years Severe sepsis | Not randomized, parallel, controlled | Sauermann et al., 2005 [51] |
Cefepime | 32.6 ± 17.5 | 7.5 ± 3.1 | 3.5 ± 1.1 | N = 7 Age 73.7 ± 4.9 years Severe sepsis | Descriptive | Kieft et al., 1993 [53] |
Cefepime | 21.8 ± 5.1 | 7.6 ± 2.0 | 3 ± 1.2 | N = 13 Age 55 years Severe sepsis | Descriptive | Lipman et al., 1999 [56] |
Cefepime | 36.1 ± 11.8 | 8.8 ± 2.4 | 2.8 ± 0.6 | N = 12 Age 41 ± 13 years Burn patients | Descriptive | Bonapace et al., 1999 [57] |
Cefepime | 26.0b | 9.1 ± 1.5b | 2.5 ± 0.6b | N = 6 Age 39.8 ± 11.3 years Burn patients | Descriptive | Sampol et al., 2000 [61] |
Cefepime | Cefepime 19.6 | Cefepime 7.1 ± 3.6 | Cefepime 2.9 ± 3.2 | Cefepime N = 13 Age 48.2 ± 21.2 years | Cross-sectional | Conil et al., 2007 [54] |
Ceftazidime | Ceftazidime 28.8 | Ceftazidime 7.5 ± 3.8 | Ceftazidime 3.1 ± 2.1 | Ceftazidime N = 17 Age 62.9 ± 22.4 years Burn patients | ||
Cefepime | 28.7 ± 13.3d | 9.1 ± 5.6d | 4.3 ± 4.2 | N = 21 Age 55.1 years (median) Nosocomial pneumonia | Cross-sectional | Chapuis et al., 2010 [55] |
Ceftazidime | 24.5 | 7.5 | 2.1 | N = 16 Age range 18 to 70 years Pseudomonas infection | Descriptive | Rondanelli et al., 1986 [64] |
Ceftazidime | 49.3 ± 18.2e | 15.5 ± 2.5e | 1.8 ± 0.5e | N = 5 Age 52.3 years [21 to 69] VAP | Not randomized, controlled, cross-over | Langer et al., 1991 [76] |
Ceftazidime | 29.5 ± 8.7 | 4.2 ± 1.9 | 6.1 ± 2.5 | N = 12 Age 60 ± 13 years VAP | Not randomized, controlled, cross-over | Bressolle et al., 1992 [77] |
Ceftazidime | 18.9 ± 9c | 5.1c | 3.5 ± 1.6c | N = 12 Age 57 ± 12 years Suspected Gram-negative sepsis | Not randomized, controlled, cross-over | Benko et al., 1996 [67] |
Ceftazidime | 15.0 ± 4.3 | 5.2 ± 2.2 | 1.3 ± 1.2 | N = 10 Age 48 ± 15.1 years Severe sepsis | Descriptive | Young et al., 1997 [65] |
Ceftazidime | 56.9 ± 25.9 | 9.1 ± 4.8 | 4.8 ± 1.9 | N = 15 Age 59.3 ± 14.6 years Severe sepsis | Descriptive | Gómez et al., 1999 [66] |
Ceftazidime | 22.9 [11.8 to 28.1] | 2.8 [0.2 to 7.8] | 7.7 [2 to 44.7] | N = 21 Age range 27 to 73 years Melioidosis | Not randomized, parallel, controlled | Angus et al., 2000 [71] |
Ceftazidime | 25.6 ± 11.2c | 11.0 ± 5.3c | 1.7 ± 0.7c | N = 14 Age 36.1 ± 12.8 years Gram-negative nosocomial pneumonia | Not randomized, parallel, controlled | Hanes et al., 2000 [70] |
Ceftazidime | 19.6 [14 to 28]c, e | 5.1 [2.3 to 8.9]c | 4.2 [1.3 to 12.3]c | N = 6 Age 64 years [42 to 87] Surgical peritonitis | Not randomized, parallel, controlled | Buijk et al., 2002 [74] |
Antibiotics | PD targets | Percentage of patients achieving targets | References |
---|---|---|---|
Meropenem, 1 g tid or 3 g/day CI | 40% f T > MIC, with f assumed to be 98%. CFR according to Mystic database | PTA for MIC = 2 mg/L: bolus 100%, CI 100% | Roberts et al., 2009 [24] |
PTA for MIC = 8 mg/L: bolus 70%, CI 100% | |||
CFR for EC: bolus 100%, CI 100% | |||
CFR for PA: bolus 40.6%, CI 100% | |||
Ceftazidime, 2 g | 70% T > 4 × EUCAST breakpoint of PA | 28% | Taccone et al., 2010 [23] |
Cefepime, 2 g | 70% T > 4 × EUCAST breakpoint of PA | 16% | |
Meropenem, 1 g | 40% T > 4 × EUCAST breakpoint of PA | 75% | |
Piperacillin/tazobactam, 4.5 g | 50% T > 4 × EUCAST breakpoint of PA | 44% | |
Imipenem 1 g tid or 2 g/day CI | 40% f T > MIC, with f assumed to be 80% | MIC = 2 mg/L bolus dosing 88%, CI 100% | Sakka et al., 2007 [31] |
MIC = 4 mg/L bolus 75%, CI 86% | |||
Piperacillin/tazobactam 4.5 g qid or 13.5 g CI | 50% f T > MIC. CFR according to Mystic database | PTA for MIC = 0.25 mg/L bolus 79.2%, CI 100% | Roberts et al., 2009 [46] |
PTA for MIC = 1 mg/L bolus 60%, CI 100% | |||
CFR for 18 g/day: bolus 53.4%, CI 92.5% | |||
CFR for 13.5 g/day: bolus 40%, CI 92.4% | |||
Cefpirome 2 g bid | 60% T > MIC | PTA for MIC = 4 mg/L: bolus 60%, CI (4 g/day) 100% | Lipman et al., 2001 [48] |
PTA for MIC = 16 mg/L: bolus 10%, CI (4 g/day) 50% | |||
Cefpirome 2 g tid | 60% T > MIC plasma and tissue | PTA for MIC = 4 mg/L: plasma 100%, tissue 100% | Sauermann et al., 2005 [51] |
PTA for MIC = 16 mg/L: plasma 87.5%, tissue 75% | |||
Cefpirome 2 g bid | 65% f T > MIC, with f assumed to be 90%. CFR according to EUCAST database | CFR for EC: bolus 99.9%, CI (4 g/day) 100% | Roos et al., 2007 [50] |
CFR for PA: bolus 56.1%, CI (4 g/day) 84.4% | |||
Cefepime 2 g | 60% T > MIC MIC = 8 mg/L (NCCLS break point of PA) | PTA with 1 g bid 45% PTA with 2 g bid 68% | Bonapace et al., 1999 [57] |
PTA for MIC = 4 mg/L: 1 g bid 68%, 2 g bid 89% | |||
Cefepime 2 g | 65% f T > MIC, with f assumed to be 90%. CFR according to Queensland Health Pathology Service | CFR for EC: 2 g bid 78.9%, CI (4 g/day) 96.9% | Roos et al., 2006 [60] |
CFR for PA: 2 g bid 54%, CI (4 g/day) 91.7% | |||
Ceftazidime 1 g every 4 hours | 100% T > 4 × MIC (isolated pathogens; if negative cultures 100% T > 16 mg/L) | Ceftazidime 47.8% PTA with 1 g every 3 hours 88.2% | Conil et al., 2007 [54] |
Cefepime 2 g tid | Cefepime 20% PTA with 1 g every 4 hours 88.2% | ||
Cefepime 2 g tid | 50% f T > MIC, with f assumed to be 85% | PTA for MIC = 8 mg/L 91.8% | Nicasio et al., 2009 [59] |
PTA for MIC = 32 mg/L 50.3% | |||
Cefepime 2 g (each 12 to 36 hours) | 50% T > MIC MIC = 8 mg/L | First dose 67%; steady-state 44% | Chapuis et al., 2010 [55] |
Ceftazidime 2 g tid | 100% T > 5 × MIC MIC = 8 mg/L (PA break point) | 10% | Young et al., 1997 [65] |
PTA for CI (6 g/day) 60% | |||
Ceftazidime 2 g tid or 6 g/day CI | 100% T > 5 × MIC MIC = 8 mg/L (PA break point) | Bolus 20% | Lipman et al., 1999 [68] |
CI 100% | |||
Ceftazidime 1.5 g tid or 4.5 g/day CI | T > 4 × MIC plasma and peritoneum (isolated pathogens) | Plasma: bolus dosing 100%, CI 100% | Buijk et al., 2002 [74] |
Peritoneum: bolus 88%, CI 100% | |||
Ceftazidime 2 to 6 g/day CI | 100% T > 5 × MIC MIC = 8 mg/L (PA break point) Target concentration 40 ± 10 mg/L | 35.9% | Aubert et al., 2010 [72] |
Percentage of time on target (mean)
| |||
Meropenem 2 g tid or 3 g CI | T > MIC (isolated susceptible pathogens) | Bolus T = 100%; CI T = 100% | Thalhammer et al., 1999 [27] |
Meropenem 1 g tid | T > MIC (isolated pathogens) | T = 90.8% | de Stoppelaar et al, 2000 [19] |
T > 4 × MIC T = 52% | |||
Meropenem 1 g bid or 1 g tid | T > MIC (isolated pathogens) | T = 80.9% (Cr Cl > 50 mL/minute; 1 g tid) | Kitzes-Cohen et al, 2002 [21] |
T = 91.7% (Cr Cl < 50 mL/minute; 1 g bid) | |||
Imipenem 1 g tid | T > MIC (isolated sensitive [MIC ≤ 2 mg/L] pathogens) | T = 100%; T > 4 × MIC T = 87.5% | Novelli et al., 2005 [29] |
Meropenem 1 g tid | T > MIC (isolated sensitive [MIC ≤ 2 mg/L] pathogens) | T = 100%; T > 4 × MIC T = 87.5% | |
Meropenem 1 g tid (bolus or 3-hour infusion) or 2 g tid (3-hour infusion) | T > MIC | For MIC = 1 mg/L: 1 g tid bolus T = 74.7%, 1 g tid 3 hours T = 93.6%, 2 g tid 3 hours T = 98.6%s | Jaruratanasirikul et al., 2005 [20] |
For MIC = 16 mg/L: 1 g tid bolus T = 28.3%, 1 g tid 3 hours T = 37.8%, 2 g tid 3 hours T = 57.9% | |||
Meropenem 1 g tid | T > MIC | For MIC = 4 mg/L: plasma T = 87%, peritoneum T = 87% | Karjagin et al., 2008 [25] |
For MIC = 16 mg/L: plasma T = 55%, peritoneum T = 43% | |||
Imipenem 500 mg qid (30 minutes or 2-hour infusion) or 1 g qid (2-hour infusion) | T > MIC | For MIC = 1 mg/L: 500 mg qid 30 minutes T = 64.7%, 500 mg qid 2 hours T = 76.5%, 1 g qid 2 hours T = 93.4% | Jaruratanasirikul and Sudsai, 2009 [30] |
For MIC = 4 mg/L: 500 mg qid 30 minutes T = 20.3%, 500 mg qid 2 hours T = 17.7%, 1 g qid 2 hours T = 60.3% | |||
Piperacillin 3 g qid or 8 g/day CI | T > MIC | For MIC = 16 mg/L: bolus dosing T = 62%, CI T = 100% | Rafati et al., 2006 [40] |
For MIC = 32 mg/L: bolus T = 39%, CI T = 65% | |||
Cefepime 2 g bid | T > MIC MIC = 7 mg/L (MIC90 of PA) | T = 80% | Kieft et al., 1993 [53] |
Ceftazidime 2 g tid or 3 g/day CI | T > MIC MIC = 4 mg/L (MIC of one isolated PA) | Bolus T = 92%; CI T = 100% | Benko et al., 1996 [67] |
Ceftazidime 2 g tid or 60 mg/kg/day CI | T > MIC (isolated pathogens) | Bolus T = 92.9%; CI T = 100% | Hanes et al., 2000 [70] |
Antibiotics | Samples | Patient demographics | Concentration ratiosb | References |
---|---|---|---|---|
Muscle and subcutaneous tissue | ||||
Meropenem | Microdialysis in subcutaneous tissue | N = 10 severe sepsis, 5 continuous infusion | Bolus 0.44 Continuous infusion 0.57 (day 2) | Roberts et al., 2009 [24] |
Imipenem | Microdialysis in muscle and subcutaneous tissue | N = 11 (6 patients) Severe sepsis | Patients | Tegeder et al., 2002 [32] |
• Muscle 0.1 | ||||
• Subcutaneous 0.14 | ||||
Volunteers | ||||
• Muscle 0.5 | ||||
• Subcutaneous 0.43 | ||||
Imipenem | Microdialysis in muscle | N = 12 (6 patients) Severe sepsis | Patients 1 Volunteers 0.97 | Dahyot et al., 2008 [33] |
Piperacillin | Microdialysis in muscle and subcutaneous tissue | N = 12 (6 patients) Septic shock | Patients | Joukhadar et al., 2001 [44] |
• Muscle 0.19 | ||||
• Subcutaneous 0.1 | ||||
Volunteers | ||||
• Muscle 0.55 | ||||
• Subcutaneous 0.31 | ||||
Piperacillin | Microdialysis in subcutaneous tissue | N = 13 Severe sepsis | Bolus 0.21 Continuous infusion 0.2 | Roberts et al., 2009 [45] |
Cefpirome | Microdialysis in muscle | N = 18 (12 patients) Severe sepsis or septic shock | Patients 0.63 Volunteers 0.83 | Joukhadar et al., 2002 [52] |
Cefpirome | Microdialysis in subcutaneous tissue | N = 18 (11 patients) Severe sepsis | Patients 0.43 Volunteers 0.79 | Sauermann et al., 2005 [51] |
Burned skin | ||||
Cefepime | Biopsy of burned area | N = 6 Burn patients | Day 3 1.52 (point concentration 3 to 5 hours after dose) | Sampol et al., 2000 [61] |
Peritoneum | ||||
Meropenem | Microdialysis in peritoneum | N = 6 Surgical peritonitis | 0.74 | Karjagin et al., 2008 [25] |
Ceftazidime | Peritoneal drainage | N = 18 Surgical peritonitis | Day 2 • Continuous infusion 0.56 | Buijk et al., 2002 [74] |
• Bolus 0.35 | ||||
Imipenem | ELF (bronchoscopy) | N = 8 Pneumonia | 0.20 (point concentration ratio 2 hours after dose) | Muller-Serieys et al., 1987 [35] |
Imipenem | Bronchial secretions (tracheal aspirate) | N = 10 Trauma patients with VAP | NR | McKindley et al., 1996 [34] |
Piperacillin | ELF (bronchoscopy) | N = 10 VAP | 0.57 (point concentration ratio 5 hours after dose) | Boselli et al., 2004 [41] |
Piperacillin | ELF (bronchoscopy) | N = 40 VAP | 0.44 (point concentration ratio 4 hours after dose) | Boselli et al., 2008 [43] |
Piperacillin | Bronchial secretions (tracheal aspirate) | N = 8 VAP | 0.36 | Jehl et al., 1994 [42] |
Cefepime | ELF (bronchoscopy) | N = 20 VAP | 1.04 (point concentration ratio) | Boselli et al., 2003 [63] |
Cefepime or ceftazidime | Bronchial secretions (tracheal aspirate) | N = 5 cefepime VAP | Cefepime < 0.02 | Klekner et al., 2006 [62] |
N = 4 ceftazidime VAP | Ceftazidime < 0.05 | |||
Ceftazidime | Bronchial secretions (tracheal aspirate) | N = 5 Pneumonia | 0.12 | Langer et al., 1991 [76] |
Ceftazidime | Bronchial secretions (tracheal aspirate) | N = 12 Nosocomial pneumonia | 0.76 | Bressolle et al., 1992 [77] |
Ceftazidime | ELF (bronchoscopy) | N = 15 VAP | 0.21 (point concentration ratio at steady state) | Boselli et al., 2004 [69] |
Imipenem
Penicillins
Piperacillin
Cephalosporins
Cefpirome
Cefepime
Ceftazidime
Discussion
Conclusions
Key messages
-
Among ICU patients, the PK of β-lactam antibiotics are markedly unpredictable.
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A large volume of distribution is commonly observed in ICU patients and contributes to a lower antibiotic concentration, but also to a greater exposure time.
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An increased glomerular filtration rate is usually associated with a short half-life of β-lactam antibiotics, whilst renal failure is associated with a greater exposure and increased risk of accumulation.
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Continuous infusion of β-lactam antibiotics commonly increases the time that the antibiotic concentration exceeds its MIC and may therefore increase efficacy.
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Therapeutic drug monitoring of β-lactam antibiotic concentration may help to improve its efficacy and prevent toxicity, but currently is unavailable in most clinical settings.