Introduction
Methods
Literature search
Study selection
Data extraction and quality assessment
Outcome measurements
Statistical analysis
Results
Study characteristics
Study, year
|
Country
|
Number of patients (inhaled ± intravenous antibiotic/intravenous only)
|
Isolated bacteria (n)
|
Nebulizer device
|
Inhaled antibiotic given (daily dose)
|
Quality assessment
|
---|---|---|---|---|---|---|
Observational studies
| Newcastle-Ottawa Scale | |||||
Doshi, 2013 [21] | USA | 44/51 |
Acinetobacter (61), Pseudomonas (53), ESBL Enterobacteria (11) | Jet or vibrating mesh nebulizer | Colistin 150-300 mg | 7 |
Ghannam, 2009 [22] | USA | 16/16 |
Pseudomonas (22), Klebsiella (5), Stenotrophomonas (3), Serratia (2), E. coli (1), Acinetobacter (1) | Jet nebulizer | Gentamicin 300-400 mg, Amikacin 200-300 mg, Tobramycin 600-900 mg or Colistin 300 mg | 9 |
Kalin, 2012 [23] | Turkey | 29/15 |
Acinetobacter (10) | Device not described. Nebulization with oxygen flow of 8 l/min | Colistin 300 mg | 9 |
Kofteridis, 2010 [24] | Greece | 43/43 |
Acinetobacter (66), Klebsiella (12), Pseudomonas (8) | Not described | Colistin 150 mg | 9 |
Korbila, 2010 [29] | Greece | 78/43 |
Acinetobacter (92), Pseudomonas (17), Klebsiella (4) | Ultrasonic nebulizer | Colistin 150 mg | 9 |
Tumbarello, 2013 [31] | Italy | 104/104 |
Acinetobacter (128), Pseudomonas (52), Klebsiella (28) | Jet or ultrasonic nebulizer | Colistin 225 mg | 9 |
Randomized controlled trials
| Cochrane risk of bias | |||||
Hallal, 2007 [25] | USA | 5/5 |
Pseudomonas (9), Acinetobacter (3), Staphylococcus (3) | Jet nebulizer | Tobramycin 600 mg | High |
Le Conte, 2000 [26] | France | 21/17 |
Pseudomonas (16), Haemophilus (6), Enterobacter (4), E. coli (3), Klebsiella (1) | Balloon with a valve connected to the endotracheal tube | Tobramycin 2.5 mg/kg | High |
Lu, 2011 [27] | France | 20/20 |
Pseudomonas (40) | Vibrating nebulizer | Ceftazidime 120 mg/kg or Amikacin 25 mg/kg | High |
Niederman, 2012 [28] | France/Spain/USA | 47a/22 |
Pseudomonas (24), E. coli (14), Klebsiella (10), Acinetobacter (7) | Vibrating mesh nebulizer | Amikacin 800 mg | Low |
Palmer, 2014 [30] | USA | 24/18 |
Staphylococcus (18), Acinetobacter (12), Pseudomonas (9), Klebsiella (5), Enterobacter (4), Other (9)b
| Jet nebulizer | Vancomycin 360 mg and/or Gentamicin 240 mg or Amikacin 1200 mg | High |
Rattanaumpawan, 2010 [32] | Thailand | 51/49 |
Acinetobacter (65), Pseudomonas (34), Klebsiella (20), E. coli (7), Enterobacter (3), Stenotrophomonas (2) | Jet or ultrasonic nebulizer | Colistin 150 mg | High |
Study, year
|
Clinical cure criteria
|
Microbiological cure criteria
|
Adverse events assessed
|
---|---|---|---|
Observational studies
| |||
Doshi, 2013 [21] | Resolution of initial signs and symptoms of infection, including normalization of white blood cell count and temperature, by the end of therapy. | Eradication of the MDR pathogen on subsequent respiratory cultures | NA |
Ghannam, 2009 [22] | Improved clinical parameters (fever defervescence, suctioning requirements, symptoms and signs of pneumonia), ventilator parameters and laboratory findings (improved blood gases, normalization of white blood cell count), and/or receding pulmonary infiltrates on a chest radiograph at the end of therapy. | Eradication of causative organisms in patients in whom a follow-up culture was obtained at the end of therapy. | Renal dysfunction (doubling of serum creatinine in patients with pretreatment (baseline) creatinine clearance of ≥30 ml/minute or an increase in creatinine by ≥1 mg/dl at the end of therapy in patients with pretreatment creatinine clearance <30 ml/minute) |
Kalin, 2012 [23] | Resolution of symptoms and signs of VAP at the end of the therapy | Eradication of MDR A. baumannii on follow-up culture | Renal toxicity (RIFLE criteria) |
Kofteridis, 2010 [24] | Resolution of presenting symptoms and signs of infection by the end of colistin treatment | Eradication of the pathogen at the end of antimicrobial therapy or at discharge from ICU | Renal toxicity (serum creatinine value >2 mg/dl; reduction in the calculated creatinine clearance of 50%, compared with the value at the start of treatment; or as a decline in renal function that prompted renal replacement therapy; increase of 150% of the baseline creatinine, a reduction in the calculated creatinine clearance of 50% relative to the value at therapy initiation in patients with pre-existing renal dysfunction), bronchoconstriction, cough, apnea, or chest tightness, and arterial hypoxemia. |
Korbila, 2010 [29] | Normalization of temperature and tracheal secretions, together with a return to baseline of the white blood cell count and the C-reactive protein level, and the improvement in chest X-ray appearances, by the end of treatment. | NA | NA |
Tumbarello, 2013 [31] | Resolution of all signs and symptoms of pneumonia and improvement or lack of progression of all chest radiograph abnormalities when colistin was discontinued | Disappearance of the infecting bacterium from post-treatment respiratory samples | Acute kidney injury (a greater than twofold increase in serum creatinine or a ≥50% decrease in the glomerular filtration rate or oliguria (output <0.5 ml/kg/hour) for ≥12 hours) |
Randomized controlled trials
| |||
Hallal, 2007 [25] | Extubation within the study period, improving of MODS, resolution of fever, pulmonary infiltrates and physical signs of pneumonia. | NA | Doubling of the serum creatinine concentration or an increase of creatinine above 2 mg/dl at any timea
|
Le Conte, 2000 [26] | Extubation within 10 days | NA | Respiratory tolerance (described in results section as hypoxemia during nebulization) and evolution of serum creatinine |
Lu, 2011 [27] | Reduction of clinical and biological signs of infection, decrease in modified clinical pulmonary infection score below 6, significant lung CT re-aeration, and lower respiratory tract specimens either sterile or with nonsignificant concentrations of P. aeruginosa
| Eradication of P. aeruginosa in a lower respiratory specimens after 8 days of antimicrobial therapy | Bronchospasm, hypoxemia, obstruction of expiratory filter |
Niederman, 2012 [28] | Complete or partial resolution of signs and symptoms of pneumonia, improvement or lack of progression of abnormalities on chest X-ray, and no additional intravenous antibiotics since completion of treatment | Confirmed eradication of the original pathogen or presumed eradication in patients with complete or partial resolution of pneumonia | Septic shock, seizures and bronchospasm. |
Palmer, 2014 [30] | NA | No growth in culture and no visible organisms seen on Gram-stain of an organism identified at randomization | New resistant to antimicrobial therapy |
Rattanaumpawan, 2010 [32] | Complete resolution of all signs and symptoms of pneumonia, and improvement or lack of progression of all abnormalities on the chest radiograph | Eradication or presumed eradication after antimicrobial treatment | Renal impairment (a rise of 2 mg/dl in the serum creatinine level of patients with previously normal renal function or a doubling of the baseline serum creatinine level in patients with pre-existing renal insufficiency), bronchospasm. |
Study quality
Outcomes
Discussion
Conclusion
Key messages
-
Nebulized antibiotics may be beneficial for the treatment of VAP.
-
However, high heterogeneity and the small number of enrolled patients in the available studies preclude any optimistic conclusions regarding the benefits of nebulized antibiotics.
-
High-quality trials analyzing the value of nebulized antibiotics for VAP treatment are warranted.