Background
Methods
Search strategy
Study quality assessment
Statistical analysis
Results
Selection and characteristics of the studies
Study, year | Country | Inclusion population | No. of patients | Disease severity | Respiratory comorbidities | Administration strategy | Antibiotic given (dose) | Device for drug delivery | Main outcomes | Quality assessment/Cochrane risk of biasa | |||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
(AS/IV) | AS | IV | AS | IV | AS | IV | |||||||
Observational studies | |||||||||||||
Ghannam, 2009 [9] | USA | Gram-negative bacteria VAP | 16/16 | CPIS score: 7 ± 2.9 | CPIS score: 6 ± 1.8 | COPD: 3 | COPD: 6 | Substitution strategy | Colistin (100 mg every 8 h), tobramycin (300 mg b.i.d), gentamicin (100 mg t.i.d), and amikacin (100 mg t.i.d. or 300 mg b.i.d) | Amikacin (100 mg per 3 ml), gentamicin (40 mg per ml), and colistin (75 mg per 4 ml) | Jet nebulizer | Clinical recovery, microbiological eradication | 9 |
Kofteridis, 2010 [10] | Greece | MDR VAP due to Gram-negative bacteria | 43/43 | APACHE II score: 16.95 ± 6.59 | APACHE II score: 17.74 ± 7.61 | COPD: 12 | COPD: 7 | Adjunctive strategy | Colistin (2 million IU b.i.d) | Colistin (3 million IU t.i.d) | Not described | Clinical recovery, microbiological eradication, all-cause mortality, nephrotoxicity | 9 |
Korbila, 2010 [11] | Greece | Microbiologically documented VAP | 78/43 | APACHE II score: 17.4 ± 6 | APACHE II score: 19.2 ± 7 | Pulmonary: 17 | Pulmonary: 9 | Adjunctive strategy | Colistin (1 million IU) | Colistin (6.4 ± 2.3 million) | Ultrasonic nebulizer | Clinical recovery, mortality | 9 |
Pérez-Pedrero, 2011 [12] | Spain | VAP due to multi-resistant Acinetobacter baumannii | 36/18 | APACHE II score: 11.2 ± 4.3 | APACHE II score: 12.8 ± 5.7 | Not described | Not described | Adjunctive strategy | Colistin (1 million every 8 h, 0.5 million every 8 h, or 1 million b.i.d) | Colistin (1 million every 8 h, 0.5 million every 8 h, or 1 million b.i.d) | Not described | Clinical recovery, microbiological eradication | 8 |
Kalin, 2012 [13] | Turkey | VAP due to multi-resistant A. baumannii | 15/29 | APACHE II score: 22 | APACHE II score: 22 | COPD: 4 | COPD: 6 | Adjunctive strategy | Colistin (150 mg b.i.d) | Colistin (2.5 mg/kg b.i.d or every 6 h) | Not described | Clinical recovery, microbiological eradication, all-cause mortality, nephrotoxicity | 9 |
Arnold, 2012 [25] | USA | Pseudomonas aeruginosa and A. baumannii VAP | 19/74 | APACHE II score: 17.5 ± 5.3 | APACHE II score: 21.4 ± 5.7 | Pulmonary: 22 | Pulmonary: 6 | Adjunctive strategy | Colistin (150 mg b.i.d) or tobramycin (300 mg b.i.d) | Standard IV antibiotics | Not described | All-cause mortality | 8 |
Doshi, 2013 [14] | USA | MDR VAP due to Gram-negative bacteria | 44/51 | APACHE II score: 22.4 ± 7.1 | APACHE II score: 24 ± 6.9 | Not described | Not described | Adjunctive strategy | Colistin (75–150 mg b.i.d) | Colistin (2.5 mg/kg b.i.d) | Jet or vibrating mesh nebulizer | Clinical recovery, microbiological eradication, hospital mortality | 7 |
Tumbarello, 2013 [15] | Italy | Patients with VAP caused by Acinetobacter, Pseudomonas, or Klebsiella | 104/104 | CPIS: 7.8 ± 1.2 | CPIS: 7.9 ± 1.3 | COPD: 21 | COPD: 28 | Adjunctive strategy | Colistin (1 million IU t.i.d) | Colistin (0.1 IU/kg every 8 to 12 h) | Jet or ultrasonic nebulizer | Clinical recovery, microbiological eradication, all-cause mortality, nephrotoxicity | 9 |
Migiyama, 2017 [16] | Japan | ARDS patients with VAP caused by P. aeruginosa | 22/22 | APACHE II score: 26.2 ± 6.6 | APACHE II score: 24.5 ± 7.0 | Pulmonary: 6 | Pulmonary: 5 | Adjunctive strategy | Tobramycin (240 mg) | Tobramycin | Ultrasonic nebulizer | Clinical recovery, ICU mortality | 9 |
Le Conte, 2000 [17] | France | Intubated and mechanically ventilated patients with nosocomial pneumonia | 21/17 | N/A | N/A | Not described | Not described | Adjunctive strategy | Tobramycin (6 mg/kg/day) | Betalactam and tobramycin | Pneumatic nebulizer | Clinical recovery, mortality | High |
Hallal, 2007 [18] | USA | VAP caused by Pseudomonas or Acinetobacter | 5/5 | APACHE II score: 17 ± 1.26 | APACHE II score: 15 ± 3.3 | Not described | Not described | Substitution strategy | Tobramycin (300 mg b.i.d) | Betalactam and tobramycin | Jet nebulizer | Clinical recovery, nephrotoxicity | High |
Rattanaumpawan, 2010 [19] | Thailand | Gram-negative bacteria VAP | 51/49 | APACHE II score: 19.1 ± 5.8 | APACHE II score: 18.5 ± 4.7 | Not described | Not described | Adjunctive strategy | Colistin (75 mg b.i.d) | Standard intravenous antibiotics | Jet or ultrasonic nebulizer | Clinical recovery, microbiological eradication, 28-day mortality, nephrotoxicity | High |
Lu, 2011 [20] | France | VAP caused by Pseudomonas | 20/20 | CPIS score: 8 (7–8) | CPIS score: 9 (8–9) | COPD: 3 | COPD: 4 | Substitution strategy | Amikacin (25 mg/kg/day) | Amikacin (15 mg/kg/day) and ceftazidime (90 mg/kg/3 h) | Vibrating nebulizer | Clinical recovery, microbiological eradication, 28-day mortality | High |
Niederman, 2012 [21] | France/Spain/USA | Mechanically ventilated patients with Gram-negative pneumonia | 46/22 | CPIS score: 6.8 (1.2) | CPIS score: 7 (1.2) | Not described | Not described | Adjunctive strategy | Amikacin (400 mg b.i.d or 400 mg/day) | Standard intravenous antibiotics | Vibrating mesh nebulizer | Clinical recovery, microbiological eradication, all-cause mortality, nephrotoxicity | Low |
Palmer, 2014 [22] | USA | Patients with high risk for MDR organisms in the respiratory tract | 24/18 | APACHE II score: 20.96 ± 5.8 | APACHE II score: 14.4 ± 5.5 | COPD: 3 | COPD: 2 | Adjunctive strategy | Vancomycin (120 mg t.i.d), gentamicin sulfate (80 mg t.i.d), or amikacin (400 mg t.i.d) | Standard IV antibiotics | Jet nebulizer | Microbiological eradication, all-cause mortality | High |
Abdellatif, 2016 [23] | Tunisia | Gram-negative bacteria VAP | 73/76 | SOFA score: 7.03 ± 3.8 | SOFA score: 6.5 ± 4.1 | Pulmonary: 32 | Pulmonary: 29 | Adjunctive strategy | Colistin (4 million IU t.i.d) | Imipenem (1 g t.i.d) | Ultrasonic vibrating plate nebulizer | Clinical recovery, 28-day mortality | Low |
Kollef, 2017 [24] | USA | Gram-negative bacteria VAP | 71/72 | APACHE II score: 18.5 ± 5.6 | APACHE II score: 18.4 ± 5.9 | Not described | Not described | Adjunctive strategy | Amikacin (300 mg) and fosfomycin (120 mg) | Meropenem or imipenem | Vibrating plate electronic nebulizer | Clinical recovery, 28-day mortality | Low |
Pairwise meta-analysis
Publication bias
Sensitivity analyses
Bayesian network meta-analysis
Outcome | Subgroup | Relative risk (95% confidence interval) and rank probabilities | |||||
---|---|---|---|---|---|---|---|
Tobramycin vs control; tobramycin (rank probability) | Colistin vs control; colistin (rank probability) | Amikacin vs control; amikacin (rank probability) | Tobramycin vs colistin | Tobramycin vs amikacin | Colistin vs amikacin | ||
Clinical recovery | Geography | ||||||
USA | 2.37 (1.7–5.62); tobramycin 97.3% | 1.3 (0.68–2.7); colistin 2.2% | 0.68 (0.27–1.7); amikacin 0.2% | 1.83 (1.2–4.67) | 3.4 (2.2–8.89) | 2 (0.65–6.3) | |
Europe | 1.52 (0.52–6.6); tobramycin 65.4% | 1.2 (0.86–1.5); colistin 28.7% | 0.98 (0.67–1.5); amikacin 4.6% | 1.3 (0.42–5.7) | 1.6 (0.5–7.1) | 1.3 (0.72–1.9) | |
Asia | 1.6 (0.74–3.3); tobramycin 82.3% | 0.95 (0.48–1.9); colistin 5.6% | – | 1.6 (0.60–4.5) | – | – | |
Type of inhaled drug delivery system | |||||||
Jet nebulizer | 2.1 (1.5–5.34); tobramycin 98.6% | 1.1 (0.71–1.8); colistin 1.2% | – | 2.53 (1.2–6.7) | – | – | |
Ultrasonic nebulizer | 1.5 (0.85–3); tobramycin 78.8% | 1.2 (0.95–1.6); colistin 20.5% | – | 1.3 (0.67–2.6) | – | – | |
Vibrating nebulizer | – | 1.3 (0.93–2); colistin 91.9% | 0.95 (0.72–1.2); amikacin 4.2% | – | – | 1.4 (0.91–2.3) | |
VAP with or without MDR | |||||||
VAP with MDR | – | 1.2 (0.70–1.7); colistin 66.4% | 0.97 (0.40–2.5); amikacin 24.8% | – | – | 1.2 (0.40–3.1) | |
VAP without MDR | 1.7 (1.1–3.2); tobramycin 88.5% | 1.2 (0.83–1.7); colistin 9% | 0.68 (0.27–1.6); amikacin 2.1% | 1.5 (0.8–2.9) | 2.6 (0.94–7.8) | 1.8 (0.68–4.8) | |
Type of studies | |||||||
Randomized controlled trials | 2.2 (0.95–8); tobramycin 92.9% | 1.1 (0.71–1.8); colistin 5.6% | 0.94 (0.65–1.3); amikacin 0.8% | 2.5 (0.93–9.9) | 2.4 (0.96–8.7) | 1.2 (0.69–2.1) | |
High risk of bias | 2.2 (0.91–7.7); tobramycin 87.5% | 0.94 (0.43–2); colistin 5.6% | 0.98 (0.47–2.1); amikacin 5.7% | 2.4 (0.74–10) | 2.3 (0.73–9.5) | 0.96 (0.33–2.8) | |
Low risk of bias | – | 1.4 (0.73–2.8); colistin 82.1% | 0.92 (0.59–1.3); amikacin 7.7% | – | – | 1.5 (0.72–3.5) | |
Observational studies | 1.6 (0.78–3.3); tobramycin 75.9% | 1.2 (0.88–1.6); colistin 22.9% | – | 1.3 (0.63–2.9) | – | – | |
NOS = 9 | 1.6 (0.48–5.1); tobramycin 70.8% | 0.96 (0.51–1.81); colistin 23.7% | – | 1.3 (0.40–5.5) | – | – | |
NOS < 9 | – | 1.2 (0.84–1.9); colistin 87.6% | – | – | – | – | |
Administration strategy | |||||||
Adjunctive strategy | 1.6 (0.94–2.70); tobramycin 81.4% | 1.2 (1.0–1.4); colistin 16.8% | 0.93 (0.64–1.3); amikacin 1.4% | 1.3 (0.76–2.3) | 1.7 (0.92–3.2) | 1.3 (0.87–2) | |
Substitution strategy | 1.57 (0.46–5.34); tobramycin 98.9% | – | 0.96 (0.76–1.21); amikacin 0.7% | – | 1.64 (0.47–5.69) | – | |
Mortality | Geography | ||||||
USA | – | 1.4 (0.76–2.6); colistin 3.6% | 0.66 (0.30–1.4); amikacin 83.9% | – | – | 2.1 (0.79–5.8) | |
Europe | 0.31 (0.039–1.6); tobramycin 85.7% | 1.2 (0.40–4.1); colistin 0.1% | 0.87 (0.57–1.3); amikacin 7.8% | 0.36 (0.044–5.0) | 0.25 (0.022–1.8) | 0.72 (0.20–2.3) | |
Asia | 0.33 (0.074–1.4); tobramycin 86.9% | 0.92 (0.26–3.3); colistin 10.6% | – | 0.36 (0.051–2.4) | – | – | |
Type of inhaled drug delivery system | |||||||
Jet nebulizer | – | 0.88 (0.63–1.2); colistin 81.6% | – | – | – | – | |
Ultrasonic nebulizer | 0.33 (0.11–0.87); tobramycin 97.2% | 0.92 (0.64–1.4); colistin 1.7% | – | 0.36 (0.11–1.0) | – | – | |
Vibrating nebulizer | – | 1.3 (0.70–2.4); colistin 20% | 1.3 (0.68–2.6); amikacin 14.8% | – | – | 1.0 (0.40–2.4) | |
VAP with or without MDR | |||||||
VAP with MDR | – | 0.81 (0.55–1.2); colistin 70.9% | 1.3 (0.39–6.3); amikacin 22.3% | – | – | 0.61 (0.12–2.1) | |
VAP without MDR | 0.34 (0.13–0.78); tobramycin 71.7% | 0.91 (0.54–1.5); colistin 7.4% | 0.7 (0.3–1.7); amikacin 26.7% | 0.37 (0.12–1) | 0.48 (0.13–1.6) | 1.3 (0.47–3.5) | |
Type of studies | |||||||
Randomized controlled trials | 0.31 (0.039–1.6); tobramycin 80.9% | 0.95 (0.45–2); colistin 6.6% | 0.83 (0.41–1.8); amikacin 11.3% | 0.32 (0.036–2) | 1.1 (0.38–3.1) | 0.37 (0.042–2.3) | |
High risk of bias | 0.31 (0.039–1.8); tobramycin 73.5% | 0.92 (0.32–2.7); colistin 8% | 1.1 (0.11–10); amikacin 16.3% | 0.33 (0.033–2.7) | 0.28 (0.013–5.2) | 0.86 (0.073–10) | |
Low risk of bias | – | 0.81 (0.43–1.6); colistin 31.4% | 1 (0.25–3.9); amikacin 50.3% | – | – | 1.2 (0.27–5.5) | |
Observational studies | 0.34 (0.11–0.9); tobramycin 95.7% | 0.83 (0.58–1.1); colistin 3.9% | – | 0.41 (0.12–1.2) | – | – | |
NOS = 9 | 0.34 (0.094–0.96); tobramycin 95.1% | 0.86 (0.54–1.3); colistin 4.2% | – | 0.39 (0.1–1.2) | – | – | |
NOS < 9 | – | 0.67 (0.35–1.3); colistin 90.2% | – | – | – | – | |
Administration strategy | |||||||
Adjunctive strategy | 0.34 (0.14–0.72); tobramycin 95% | 0.85 (0.66–1.1); colistin 0.83% | 0.8 (0.44–1.5); amikacin 4.1% | 0.4 (0.16–0.88) | 0.42 (0.14–1.1) | 1.1 (0.54–2) | |
Substitution strategy | – | – | 0.99 (0.088–9.5); amikacin 48.7% | – | – | – |
Discussion
Conclusions
Key messages
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Aerosolized antibiotics appear to be beneficial for the treatment of VAP.
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The current evidence from network meta-analysis indicates that aerosolized tobramycin is associated with the best outcome on clinical recovery and mortality.
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The current evidence from network meta-analysis indicates that aerosolized colistin is associated with improved clinical recovery and microbiological eradication.