Background
Methods
Search Strategy
Study selection
Recorded data
Results
Populations enrolled
First author | Year of publication | Tested molecule | Comparator | Statistical design | Blinded | Causative pathogen | Patients with VAP (ITT or mITT, %) | Number of ITT patients | Patient with positive respiratory samples (% of ITT/primary endpoint population) | Mean age ± SDa
| Mean Apache II score ± SDa
| Duration of study therapy, (days) | Cure rate (%) | Mortality rate (%) |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Jaccard | 1998 | Piperacillin/tazobactam | Imipenem/cilastatin | NM | Yes | All pathogens | NM | 154 | 81/81 | 59.7 ± 16.9 | 14.9 ± 6.8 | 7–14 | 77 | 8.4l
|
Brun-Buisson | 1998 | Piperacillin/tazobactam + amikacin | Ceftazidim + amikacin | Equivalence | No | All pathogens | 100 | 204 | 62/100 | 55.5 ± 16 | 37.4 ± 1.4f
| 15–21 | 42 | 20i
|
Fagon | 2000 | Quinupristin/dalfopristin | Vancomycin | Equivalence | No | Only Gram-positive pathogens | 70 | 304 | 73/100 | 57 ± 18 | 15 ± 6.9 | 5–14 | 44 | 23k
|
Torres | 2000 | Ciprofloxacin | Imipenem/cilastatin | NM | No | All pathogens | NM | 149 | 68/100 | 61 ± 16 | 13.8 ± 8 | NM | 68 | 16k
|
Alvarez-Lerma | 2001 | Piperacillin/tazobactam + amikacin | Ceftazidim + amikacin | Equivalence | No | All pathogens | 85 | 124 | 56/64 | 59 ± 19 | 16.7 ± 6.5 | NM | 48 | 35k
|
Nicolau | 2001 | Continuous ceftazidime | Intermittent ceftazidime | NM | No | All pathogens | 91 | 35 | 68/80 | 51 ± 18 | 14.5 ± 5.5 | NM | 37 | NM |
Rubinstein | 2001 | Linezolid | Vancomycin | Equivalence | Yes | All pathogens | 63 | 396 | 42//NM | 62 ± 18 | 15.5 ± 6.8 | 7 | 52 | 21k
|
Wunderlink | 2003 | Linezolid | Vancomycin | Equivalence | Yes | All pathogens | 35 | 623 | 71//100 | 62.5 ± 19.1 | 14.1 ± 6 | 7–21 | 53 | 20j
|
Zanetti | 2003 | Cefepim | Imipenem/cilastatin | Non inferiority | Yes | All pathogens | NM | 209 | NM/71 | 54 ± 18 | 15 ± 6.5 | NM | 39 | 22i
|
Shorr | 2005 | Levofloxacin | Imipenem/cilastatin | Non inferiority | No | All pathogens | 100 | 222 | >50/>50 | 53 ± 21 | 15 ± 14 | NM | 61 g
| NM |
Joshi | 2006 | Piperacillin/tazobactam + tobramycin | Imipenem/cilastatin + tobramycin | Equivalence | Yes | All pathogens | 69 | 437 | 92//100 | 52.3 ± 20 | 13.5 | >5 | 53 | NM |
Schmidt | 2006 | Piperacillin/tazobactam | Imipenem/cilastatin | NM | Yes | All pathogens | NM | 221 | 100/100 | 67 ± 13.7 | 13.4 ± 4.2 | 5–21 | 68 g
| 13k
|
Betrosian | 2008 | Ampicillin-sulbactam | Colistin | NM | No |
Acinetobacter baumanii
| 100 | 28 | 100/100 | 70 ± 7 | 14 ± 3.5 | 8–10 | 68 | 28h
|
Chastre | 2008 | Doripenem | Imipenem/cilastatin | Non inferiority | No | All pathogens | 100 | 531 | 78/82 | 50,5 ± 19 | RS 59 < 15 | 7–14 | 58 | 10h
|
Giamarallos-Bourboulls | 2008 | ATB + clarithromycin | ATB + placebo | NM | yes | All pathogens | 100 | 200 | 100/100 | 58.4 ± 18.4 | 17 ± 6 | NM | 75 | 25i
|
Heyland | 2008 | Meropenem + ciprofloxacin | Meropenem | Superiority | no | All pathogens | 100 | 740 | 82/82 | 59 ± 17.8 | 20 ± 6.3 | NM | NM | 19h
|
Freire | 2010 | Tigecyclin | Imipenem/cilastatin | Non inferiority | yes | All pathogens | 26.8 | 945 | 65/62 | 57.4 ± 18.6 | RS 396 > 15 | 7–14 | 52 | 13k
|
Jung | 2010 | Vancomycin + rifampicin | Vancomycin | Superiority | no | Methicillin-resistant Staphylococcus aureus | 73 | 83 | 100/100 | 69 (28-98)b
| 24 (15–38)b
| 14 | 42 | 30h
|
Rattanaum-pawan | 2010 | ATB + nebulized colistimetate | ATB + placebo | Superiority | no | Only Gram-negative pathogens | 100 | 102 | 100/100 | 68 ± 16.5 | 18.7 ± 5 | NS | 52 | 42h
|
Lu | 2011 | Nebulized ceftazidime + amikacin | IV ceftazidim + amikacin | NM | No |
Pseudomonas aeruginosa
| 100 | 40 | 100/100 | 59 ± 16 | 33 ± 13f
| 8 | 72 | 18h
|
Rubinstein | 2011 | Telavancin | Vancomycin | Non inferiority | Yes | Only Gram-positive pathogens | 28 | 1503 | 60/73 | 62 ± 18 | 15.5 ± 6.2 | 7–21 | 59 | 19h
|
Aydemir | 2012 | Colistin | Colistin + rifampicin | NM | No |
Acinetobacter baumanii
| 100 | 43 | 100/100 | 61 ± 20 | 19.1 ± 6 | NS | 46 | 67k
|
Kollef | 2012 | Doripenem | Imipenem | Non inferiority | Yes | All pathogens | 100 | 227 | 74/100 | 54.7 ± 17.6 | RSe
| 7–10 | 52 | 18h
|
Wunderlink | 2012 | Linezolid | Vancomycin | Non inferiority | Yes |
Staphylococcus aureus
| 63 | 448 | 100/100 | 61 ± 18 | 17 ± 6 | 7–14 | 50 | 16j
|
Ramirez | 2013 | Tigecyclin Low dose/Tigecyclin High dose | Imipenem/cilastatin | Non inferiority | Yes | All pathogens | 39 | 105 | 63/71 | 62 ± 15 | 13.8 | NS | 59 | 16k
|
Awad | 2014 | Ceftobiprol medocaril | Ceftazidim + vancomycin | Non inferiority | Yes | All pathogens | 27 | 781 | 69/NM | RSc
| RSd
| 7–14 | 51 | 17i
|
Kollef | 2016 | Imipenem or meropenem + Nebulized amikacin and fosfomycin | Imipenem or meropenem + placebo | NM | Yes | Only Gram-negative pathogens | 100 | 143 | 100/100 | 62 ± 11 | 18.4 ± 5.9 | 10 | 23 | 20 |
Clinical trial design
Primary endpoint
Definition of clinical cure and timing of the assessment
Mortality
Improvement in methodological quality over time
Features of currently unpublished RCTs reported on ClinicalTrials.gov. comparing antimicrobial treatment strategies in HAP/VAP
ClinicalTrial.gov identifier | Investigational agent | Comparator | Name of the study | Condition | Primary outcome | Definition of clinical cure | Primary endpoint assessment timing | Analyzed populations | Current status of the study |
---|---|---|---|---|---|---|---|---|---|
NCT02714595 | S-649266 | Best available therapy | CREDIBLE | Severe infections due to carbapenem-resistant GNB including HCAP, HAP and VAP | Clinical cure | 1) Resolution or improvement of baseline signs of pneumonia | Day 7 after EOT | Not reported | Recruiting |
2) Improvement of chest radiography | |||||||||
3) No additional antibacterial therapy required for current infection treatment | |||||||||
NCT02070757 | Ceftolozane/ | Meropenem | ASPECT-NP | VAP or ventilated HAP | All-cause mortality | Not detailed | Day 28 | ITT | Recruiting |
Tazobactam | |||||||||
NCT01808092 | Ceftazidime/ | Meropenem | REPROVE | HAP/VAP | Clinical cure | 1) Patient alive | Day 21 to day 25 after randomization | Co-primary: | Completed-has results |
Avibactam | 2) Resolution or improvement of all signs of pneumonia | - clinically ITT | |||||||
- clinically evaluable | |||||||||
NCT02452047 | Imipenem | Imipenem + cilastatin | RESTORE-IMI 1 | Severe infections due to Imipenem-resistant bacteria including HAP/VAP | Favorable clinical success | Not specified | Up to day 28 | Not reported | Recruiting |
+ Cilastatin/ | +Colistimethate sodium | ||||||||
Relebactam | |||||||||
NCT02493764 | Imipenem | Piperacillin/tazobactam | RESTORE-IMI 2 | HAP/VAP | All-cause mortality | Not specified | Day 28 | Not reported | Recruiting |
+Cilastatin/ | |||||||||
Relebactam | |||||||||
NCT01970371 | Plazomicin (+meropenem or tigecyclin) | Colistin | CARE | Infections due to Carbapenem-resistant Enterobacteriaceae including HAP and VAP | All-cause mortality | Not specified | Day 28 | Not reported | Completed |
+Meropenem or Tigecyclin | |||||||||
NCT02168946 | Meropenem | Best available therapy | Not reported | Infections due to Carbapenem-resistant Enterobacteriaceae including HAP and VAP | Clinical cure | Resolution or improvement of the baseline signs and symptoms and no further antimicrobial warranted | Days 12–23 | Microbiological ITT | Recruiting |
Vaborbactam | |||||||||
NCT02019420 | Tedizolid phosphate | Linezolid | MK-1986-002 | Gram-positive HAP/VAP | All-cause mortality | Not specified | Day 28 | Microbiological ITT | Recruiting |
NCT02440828 | Standard treatment + inhaled tobramycin | Standard treatment + Placebo | VAPORISE | VAP | Clinical response | 1) Improvement of hypoxemia, | After 72 hours of treatment | Not reported | Recruiting |
2) Resolution of signs of sepsis | |||||||||
3) No worseming of chest radiography | |||||||||
NCT02478710 | Standard treatment + inhaled tobramycin or inhaled vancomycin | Standard treatment + Placebo | AAINTVAP | VAP | Persistance/recurrence of pneumonia | Not specified | After 8 days of treatment/day 9 to day 21 | Not reported | Recruiting |
NCT02728518 | Standard treatment + nebulized amikacin | Standard treatment + intravenous amikacin | Not reported | GNB-related VAP | Clinical cure | Not specified | Not reported | Not reported | Completed |
NCT02574130 | Standard treatment + nebulized amikacin | Standard treatment + placebo | Not reported | GNB-related VAP | Clinical cure | No worsening on chest radiography + improvement of leukocytosis and/or fever and/or tracheal secretion | 10 days after treatment | Not reported | Recruiting |
NCT01799993 | Standard treatment + amikacin inhalation solution (BAY41-6551) | Standard treatment + placebo | INHALE-1 and 2 | GNB-related mechanically ventilated pneumonia | Clinical success | Not specified | 28–32 days after treatment initiation | Modified ITT | Recruiting |
and | |||||||||
NCT00805168 |