, Volume 77, Issue 13, pp 1399–1412 | Cite as

Inhaled Antimicrobials for Ventilator-Associated Pneumonia: Practical Aspects

  • Garyphallia PoulakouEmail author
  • Dimitrios K. Matthaiou
  • David P. Nicolau
  • Georgios Siakallis
  • George Dimopoulos
Therapy in Practice


Positive experience with inhaled antibiotics in pulmonary infections of patients with cystic fibrosis has paved the way for their utilization in mechanically ventilated, critically ill patients with lower respiratory tract infections. A successful antibiotic delivery depends upon the size of the generated particle and the elimination of drug impaction in the large airways and the ventilator circuit. Generated droplet size is mainly affected by the type of the nebulizer employed. Currently, jet, ultrasonic, and vibrating mesh nebulizers are marketed; the latter can deliver optimal antibiotic particle size. Promising novel drug-device combinations are able to release drug concentrations of 25- to 300-fold the minimum inhibitory concentration of the targeted pathogens into the pulmonary alveoli. The most important practical steps of nebulization include pre-assessment and preparation of the patient (suctioning, sedation, possible bronchodilation, adjustment of necessary ventilator settings); adherence to the procedure (drug preparation, avoidance of unnecessary tubing connections, interruption of heated humidification, removal of heat-moisture exchanger); inspection of the procedure (check for residual in drug chamber, change of expiratory filter, return sedation, and ventilator settings to previous status); and surveillance of the patient for adverse events (close monitoring of the patient and particularly of peak airway pressure and bronchoconstriction). Practical aspects of nebulization are very important to ensure optimal drug delivery and safe procedure for the patient. Therefore, the development of an operational checklist is a priority for every department adopting this modality.



We would like to thank Dr I.T. Virlos for the linguistic revision of the manuscript.

Compliance with ethical standards


No funding was received for the preparation of this article.

Conflict of interest

GP, DKM, DPN, GS, and GD have no conflicts of interest directly relevant to the content of this article.


  1. 1.
    Farber JE, Ross J. The use of aerosol penicillin and streptomycin in bronchopulmonary infections. Calif Med. 1950;73:214–7.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Mearns MB, Hunt GH, Rushworth R. Bacterial flora of respiratory tract in patients with cystic fibrosis, 1950-71. Arch Dis Child. 1972;47:902–7.CrossRefGoogle Scholar
  3. 3.
    Feeley TW, Du Moulin GC, Hedley-Whyte J, Bushnell LS, Gilbert JP, Feingold DS. Aerosol polymyxin and pneumonia in seriously ill patients. N Engl J Med. 1975;293:471–5.CrossRefGoogle Scholar
  4. 4.
    Kuhn RJ. Formulation of aerosolized therapeutics. Chest. 2001;120:94S–8S.CrossRefGoogle Scholar
  5. 5.
    Mogayzel PJ Jr, Naureckas ET, Robinson KA, Mueller G, Hadjiliadis D, Hoag JB, et al. Cystic fibrosis pulmonary guidelines. Chronic medications for maintenance of lung health. Am J Respir Crit Care Med. 2013;187:680–9.CrossRefGoogle Scholar
  6. 6.
    Rouby JJ, Bouhemad B, Monsel A, Brisson H, Arbelot C, Lu Q, et al. Aerosolized antibiotics for ventilator-associated pneumonia: lessons from experimental studies. Anesthesiology. 2012;117:1364–80.CrossRefGoogle Scholar
  7. 7.
    Boucher HW, Talbot GH, Bradley JS, Edwards JE, Gilbert D, Rice LB, et al. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis. 2009;48:1–12.CrossRefGoogle Scholar
  8. 8.
    Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, et al. Management of adults with hospital-acquired and ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016;63:e61–111.CrossRefGoogle Scholar
  9. 9.
    Waters V, Smyth A. Cystic fibrosis microbiology: advances in antimicrobial therapy. J Cyst Fibros. 2015;14:551–60.CrossRefGoogle Scholar
  10. 10.
    Poulakou G, Siakallis G, Tsiodras S, Arfaras-Melainis A, Dimopoulos G. Nebulized antibiotics in mechanically ventilated patients: roadmap and challenges. Expert Rev Anti Infect Ther. 2017;15:211–29.CrossRefGoogle Scholar
  11. 11.
    Sole-Lleonart C, Roberts JA, Chastre J, Poulakou G, Palmer LB, Blot S, et al. Global survey on nebulization of antimicrobial agents in mechanically ventilated patients: a call for international guidelines. Clin Microbiol Infect. 2016;22:359–64.CrossRefGoogle Scholar
  12. 12.
    Kollef MH, Hamilton CW, Montgomery AB. Aerosolized antibiotics: do they add to the treatment of pneumonia? Curr Opin Infect Dis. 2013;26:538–44.CrossRefGoogle Scholar
  13. 13.
    Russell CJ, Shiroishi MS, Siantz E, Wu BW, Patino CM. The use of inhaled antibiotic therapy in the treatment of ventilator-associated pneumonia and tracheobronchitis: a systematic review. BMC Pulm Med. 2016;16:40.CrossRefGoogle Scholar
  14. 14.
    Zampieri FG, Nassar AP Jr, Gusmao-Flores D, Taniguchi LU, Torres A, Ranzani OT. Nebulized antibiotics for ventilator-associated pneumonia: a systematic review and meta-analysis. Crit Care. 2015;19:150.CrossRefGoogle Scholar
  15. 15.
    Ehrmann S, Roche-Campo F, Sferrazza Papa GF, Isabey D, Brochard L, Apiou-Sbirlea G, et al. Aerosol therapy during mechanical ventilation: an international survey. Intensive Care Med. 2013;39:1048–56.CrossRefGoogle Scholar
  16. 16.
    Sole-Lleonart C, Rouby JJ, Chastre J, Poulakou G, Palmer LB, Blot S, et al. Intratracheal administration of antimicrobial agents in mechanically ventilated adults: an international survey on delivery practices and safety. Respir Care. 2016;61:1008–14.CrossRefGoogle Scholar
  17. 17.
    Palmer LB. Ventilator-associated infection: the role for inhaled antibiotics. Curr Opin Pulm Med. 2015;21:239–49.CrossRefGoogle Scholar
  18. 18.
    Wenzler E, Fraidenburg DR, Scardina T, Danziger LH. Inhaled antibiotics for gram-negative respiratory infections. Clin Microbiol Rev. 2016;29:581–632.CrossRefGoogle Scholar
  19. 19.
    Jamal J-A, Abdul-Aziz M-H, Lipman J, Roberts JA. Defining antibiotic dosing in lung infections. Clin Pulm Med. 2013;20:121–8.CrossRefGoogle Scholar
  20. 20.
    Honeybourne D, Baldwin DR. The site concentrations of antimicrobial agents in the lung. J Antimicrob Chemother. 1992;30:249–60.CrossRefGoogle Scholar
  21. 21.
    Burkhardt O, Rauch K, Kaever V, Hadem J, Kielstein JT, Welte T. Tigecycline possibly underdosed for the treatment of pneumonia: a pharmacokinetic viewpoint. Int J Antimicrob Agents. 2009;34:101–2.CrossRefGoogle Scholar
  22. 22.
    Roberts JA, Paul SK, Akova M, Bassetti M, De Waele JJ, Dimopoulos G, et al. DALI: defining antibiotic levels in intensive care unit patients: are current beta-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis. 2014;58:1072–83.CrossRefGoogle Scholar
  23. 23.
    Canton R, Morosini MI. Emergence and spread of antibiotic resistance following exposure to antibiotics. FEMS Microbiol Rev. 2011;35:977–91.CrossRefGoogle Scholar
  24. 24.
    Ni W, Wei C, Zhou C, Zhao J, Liang B, Cui J, et al. Tigecycline-Amikacin combination effectively suppresses the selection of resistance in clinical isolates of KPC-producing Klebsiella pneumoniae. Front Microbiol. 2016;7:1304.CrossRefGoogle Scholar
  25. 25.
    Sinel C, Jaussaud C, Auzou M, Giard JC, Cattoir V. Mutant prevention concentrations of daptomycin for Enterococcus faecium clinical isolates. Int J Antimicrob Agents. 2016;48:449–52.CrossRefGoogle Scholar
  26. 26.
    Gil-Perotin S, Ramirez P, Marti V, Sahuquillo JM, Gonzalez E, Calleja I, et al. Implications of endotracheal tube biofilm in ventilator-associated pneumonia response: a state of concept. Crit Care. 2012;16:R93.CrossRefGoogle Scholar
  27. 27.
    Bercault N, Boulain T. Mortality rate attributable to ventilator-associated nosocomial pneumonia in an adult intensive care unit: a prospective case-control study. Crit Care Med. 2001;29:2303–9.CrossRefGoogle Scholar
  28. 28.
    Luna CM, Aruj P, Niederman MS, Garzon J, Violi D, Prignoni A, et al. Appropriateness and delay to initiate therapy in ventilator-associated pneumonia. Eur Respir J. 2006;27:158–64.CrossRefGoogle Scholar
  29. 29.
    Elman M, Goldstein I, Marquette CH, Wallet F, Lenaour G, Rouby JJ, et al. Influence of lung aeration on pulmonary concentrations of nebulized and intravenous amikacin in ventilated piglets with severe bronchopneumonia. Anesthesiology. 2002;97:199–206.CrossRefGoogle Scholar
  30. 30.
    Ferrari F, Goldstein I, Nieszkowszka A, Elman M, Marquette CH, Rouby JJ, et al. Lack of lung tissue and systemic accumulation after consecutive daily aerosols of amikacin in ventilated piglets with healthy lungs. Anesthesiology. 2003;98:1016–9.CrossRefGoogle Scholar
  31. 31.
    Goldstein I, Wallet F, Nicolas-Robin A, Ferrari F, Marquette CH, Rouby JJ. Lung deposition and efficiency of nebulized amikacin during Escherichia coli pneumonia in ventilated piglets. Am J Respir Crit Care Med. 2002;166:1375–81.CrossRefGoogle Scholar
  32. 32.
    Goldstein I, Wallet F, Robert J, Becquemin MH, Marquette CH, Rouby JJ. Lung tissue concentrations of nebulized amikacin during mechanical ventilation in piglets with healthy lungs. Am J Respir Crit Care Med. 2002;165:171–5.CrossRefGoogle Scholar
  33. 33.
    Luyt CE, Brechot N, Combes A, Trouillet JL, Chastre J. Delivering antibiotics to the lungs of patients with ventilator-associated pneumonia: an update. Expert Rev Anti Infect Ther. 2013;11:511–21.CrossRefGoogle Scholar
  34. 34.
    Tonnellier M, Ferrari F, Goldstein I, Sartorius A, Marquette CH, Rouby JJ. Intravenous versus nebulized ceftazidime in ventilated piglets with and without experimental bronchopneumonia: comparative effects of helium and nitrogen. Anesthesiology. 2005;102:995–1000.CrossRefGoogle Scholar
  35. 35.
    Lu Q, Luo R, Bodin L, Yang J, Zahr N, Aubry A, et al. Efficacy of high-dose nebulized colistin in ventilator-associated pneumonia caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii. Anesthesiology. 2012;117:1335–47.CrossRefGoogle Scholar
  36. 36.
    Ari A, Areabi H, Fink JB. Evaluation of aerosol generator devices at 3 locations in humidified and non-humidified circuits during adult mechanical ventilation. Respir Care. 2010;55:837–44.PubMedGoogle Scholar
  37. 37.
    Bassetti M, Luyt CE, Nicolau DP, Pugin J. Characteristics of an ideal nebulized antibiotic for the treatment of pneumonia in the intubated patient. Ann Intensive Care. 2016;6:35.CrossRefGoogle Scholar
  38. 38.
    Ehrmann S, Lyazidi A, Louis B, Isabey D, Le Pennec D, Brochard L, et al. Ventilator-integrated jet nebulization systems: tidal volume control and efficiency of synchronization. Respir Care. 2014;59:1508–16.CrossRefGoogle Scholar
  39. 39.
    Miller DD, Amin MM, Palmer LB, Shah AR, Smaldone GC. Aerosol delivery and modern mechanical ventilation: in vitro/in vivo evaluation. Am J Respir Crit Care Med. 2003;168:1205–9.CrossRefGoogle Scholar
  40. 40.
    Pritchard JN. The influence of lung deposition on clinical response. J Aerosol Med. 2001;14:S19–26.CrossRefGoogle Scholar
  41. 41.
    Patton JS, Brain JD, Davies LA, Fiegel J, Gumbleton M, Kim KJ, et al. The particle has landed–characterizing the fate of inhaled pharmaceuticals. J Aerosol Med Pulm Drug Deliv. 2010;23:S71–87.CrossRefGoogle Scholar
  42. 42.
    Ferrari F, Lu Q, Girardi C, Petitjean O, Marquette CH, Wallet F, et al. Nebulized ceftazidime in experimental pneumonia caused by partially resistant Pseudomonas aeruginosa. Intensive Care Med. 2009;35:1792–800.CrossRefGoogle Scholar
  43. 43.
    Takanami C, Goto Y. Physical properties of antibiotic aerosols produced by jet and ultrasonic nebulizers. J Aerosol Med. 1990;3:45–52.CrossRefGoogle Scholar
  44. 44.
    Ari A, Atalay OT, Harwood R, Sheard MM, Aljamhan EA, Fink JB. Influence of nebulizer type, position, and bias flow on aerosol drug delivery in simulated pediatric and adult lung models during mechanical ventilation. Respir Care. 2010;55:845–51.PubMedGoogle Scholar
  45. 45.
    Laube BL, Janssens HM, de Jongh FH, Devadason SG, Dhand R, Diot P, et al. What the pulmonary specialist should know about the new inhalation therapies. Eur Respir J. 2011;37:1308–31.CrossRefGoogle Scholar
  46. 46.
    Dhand R. Aerosol delivery during mechanical ventilation: from basic techniques to new devices. J Aerosol Med Pulm Drug Deliv. 2008;21:45–60.CrossRefGoogle Scholar
  47. 47.
    Luyt CE, Clavel M, Guntupalli K, Johannigman J, Kennedy JI, Wood C, et al. Pharmacokinetics and lung delivery of PDDS-aerosolized amikacin (NKTR-061) in intubated and mechanically ventilated patients with nosocomial pneumonia. Crit Care. 2009;13:R200.CrossRefGoogle Scholar
  48. 48. Accessed 2 Aug 2016.Google Scholar
  49. 49.
    Kadrichu N BS, Corkery K, et al. In vitro efficiency of the Amikacin Inhale System, a novel integrated drug-device delivery system. ISICEM, 19–22 March 2013, Poster A384.Google Scholar
  50. 50.
    PARI eFlow rapid, Technical Data. Available from: http://wwwparide/uk-en/products/lowerairways-1/eflow-rapid-nebuliser-system-1/. Accessed 2 Aug 2016.Google Scholar
  51. 51.
    Ari A. Jet, ultrasonic, and mesh nebulizers: an evaluation of nebulizers for better clinical outcomes. Eurasian J Pulmonol. 2014;16:1–7.CrossRefGoogle Scholar
  52. 52.
    Montgomery AB, Vallance S, Abuan T, Tservistas M, Davies A. A randomized double-blind placebo-controlled dose-escalation phase 1 study of aerosolized amikacin and fosfomycin delivered via the PARI investigational eFlow(R) inline nebulizer system in mechanically ventilated patients. J Aerosol Med Pulm Drug Deliv. 2014;27:441–8.CrossRefGoogle Scholar
  53. 53.
    Rello J, Rouby JJ, Sole-Lleonart C, Chastre J, Blot S, Luyt CE, et al. Key conceptional considerations on nebulization of antimicrobial agents to mechanically ventilated patients: a consensus statement from the European Society of Clinical Microbiology and Infectious Diseases. Clin Microbiol Infect. 2017;S1198–743X:30187–8.Google Scholar
  54. 54.
    Le J, Ashley ED, Neuhauser MM, Brown J, Gentry C, Klepser ME, et al. Consensus summary of aerosolized antimicrobial agents: application of guideline criteria. Insights from the Society of Infectious Diseases Pharmacists. Pharmacotherapy. 2010;30:562–84.CrossRefGoogle Scholar
  55. 55.
    Eschenbacher WL, Boushey HA, Sheppard D. Alteration in osmolarity of inhaled aerosols cause bronchoconstriction and cough, but absence of a permeant anion causes cough alone. Am Rev Respir Dis. 1984;129:211–5.PubMedGoogle Scholar
  56. 56.
    Byron PR. Physicochemical effects on lung disposition of pharmaceutical aerosols. Aerosol Sci Tech. 1993;18:223–9.CrossRefGoogle Scholar
  57. 57.
    Montgomery ABPW, Nardella P, et al. Sputum concentrations and systemic pharmacokinetics of aerosolized tobramycin (Tobi) in diseased lungs. Respir Drug Deliv. 2000;1:19–24.Google Scholar
  58. 58.
    Abdellatif S, Trifi A, Daly F, Mahjoub K, Nasri R, Ben Lakhal S. Efficacy and toxicity of aerosolised colistin in ventilator-associated pneumonia: a prospective, randomised trial. Ann Intensive Care. 2016;6:26.CrossRefGoogle Scholar
  59. 59.
    Arnold HM, Sawyer AM, Kollef MH. Use of adjunctive aerosolized antimicrobial therapy in the treatment of Pseudomonas aeruginosa and Acinetobacter baumannii ventilator-associated pneumonia. Respir Care. 2012;57:1226–33.CrossRefGoogle Scholar
  60. 60.
    Falagas ME, Siempos II, Rafailidis PI, Korbila IP, Ioannidou E, Michalopoulos A. Inhaled colistin as monotherapy for multidrug-resistant gram (−) nosocomial pneumonia: a case series. Respir Med. 2009;103:707–13.CrossRefGoogle Scholar
  61. 61.
    Ghannam DE, Rodriguez GH, Raad II, Safdar A. Inhaled aminoglycosides in cancer patients with ventilator-associated Gram-negative bacterial pneumonia: safety and feasibility in the era of escalating drug resistance. Eur J Clin Microbiol Infect Dis. 2009;28:253–9.CrossRefGoogle Scholar
  62. 62.
    Kalin G, Alp E, Coskun R, Demiraslan H, Gundogan K, Doganay M. Use of high-dose IV and aerosolized colistin for the treatment of multidrug-resistant Acinetobacter baumannii ventilator-associated pneumonia: do we really need this treatment? J Infect Chemother. 2012;18:872–7.CrossRefGoogle Scholar
  63. 63.
    Kofteridis DP, Alexopoulou C, Valachis A, Maraki S, Dimopoulou D, Georgopoulos D, et al. Aerosolized plus intravenous colistin versus intravenous colistin alone for the treatment of ventilator-associated pneumonia: a matched case-control study. Clin Infect Dis. 2010;51:1238–44.CrossRefGoogle Scholar
  64. 64.
    Kollef MH, Ricard JD, Roux D, Francois B, Ischaki E, Rozgonyi Z, et al. A randomized trial of the amikacin fosfomycin inhalation system for the adjunctive therapy of gram-negative ventilator-associated pneumonia: IASIS trial. Chest. 2017;151:1239–46.CrossRefGoogle Scholar
  65. 65.
    Korbila IP, Michalopoulos A, Rafailidis PI, Nikita D, Samonis G, Falagas ME. Inhaled colistin as adjunctive therapy to intravenous colistin for the treatment of microbiologically documented ventilator-associated pneumonia: a comparative cohort study. Clin Microbiol Infect. 2010;16:1230–6.CrossRefGoogle Scholar
  66. 66.
    Kuo SC, Lee YT, Yang SP, Chen CP, Chen TL, Hsieh SL, et al. Eradication of multidrug-resistant Acinetobacter baumannii from the respiratory tract with inhaled colistin methanesulfonate: a matched case-control study. Clin Microbiol Infect. 2012;18:870–6.CrossRefGoogle Scholar
  67. 67.
    Lin CC, Liu TC, Kuo CF, Liu CP, Lee CM. Aerosolized colistin for the treatment of multidrug-resistant Acinetobacter baumannii pneumonia: experience in a tertiary care hospital in northern Taiwan. J Microbiol Immunol Infect. 2010;43:323–31.CrossRefGoogle Scholar
  68. 68.
    Lu Q, Yang J, Liu Z, Gutierrez C, Aymard G, Rouby JJ, et al. Nebulized ceftazidime and amikacin in ventilator-associated pneumonia caused by Pseudomonas aeruginosa. Am J Respir Crit Care Med. 2011;184:106–15.CrossRefGoogle Scholar
  69. 69.
    Michalopoulos A, Fotakis D, Virtzili S, Vletsas C, Raftopoulou S, Mastora Z, et al. Aerosolized colistin as adjunctive treatment of ventilator-associated pneumonia due to multidrug-resistant Gram-negative bacteria: a prospective study. Respir Med. 2008;102:407–12.CrossRefGoogle Scholar
  70. 70.
    Michalopoulos A, Kasiakou SK, Mastora Z, Rellos K, Kapaskelis AM, Falagas ME. Aerosolized colistin for the treatment of nosocomial pneumonia due to multidrug-resistant Gram-negative bacteria in patients without cystic fibrosis. Crit Care. 2005;9:R53–9.CrossRefGoogle Scholar
  71. 71.
    Niederman MS, Chastre J, Corkery K, Fink JB, Luyt CE, Garcia MS. BAY41-6551 achieves bactericidal tracheal aspirate amikacin concentrations in mechanically ventilated patients with Gram-negative pneumonia. Intensive Care Med. 2012;38:263–71.CrossRefGoogle Scholar
  72. 72.
    Pereira GH, Muller PR, Levin AS. Salvage treatment of pneumonia and initial treatment of tracheobronchitis caused by multidrug-resistant Gram-negative bacilli with inhaled polymyxin B. Diagn Microbiol Infect Dis. 2007;58:235–40.CrossRefGoogle Scholar
  73. 73.
    Rattanaumpawan P, Lorsutthitham J, Ungprasert P, Angkasekwinai N, Thamlikitkul V. Randomized controlled trial of nebulized colistimethate sodium as adjunctive therapy of ventilator-associated pneumonia caused by Gram-negative bacteria. J Antimicrob Chemother. 2010;65:2645–9.CrossRefGoogle Scholar
  74. 74.
    Zah Bogovic TBR, Tomasevic B, et al. Inhalation plus intravenous colistin versus intravenous colistin alone for treatment of ventilator associated pneumonia. Signa Vitae. 2014;9:29–33.Google Scholar
  75. 75.
    Boisson M, Jacobs M, Gregoire N, Gobin P, Marchand S, Couet W, et al. Comparison of intrapulmonary and systemic pharmacokinetics of colistin methanesulfonate (CMS) and colistin after aerosol delivery and intravenous administration of CMS in critically ill patients. Antimicrob Agents Chemother. 2014;58:7331–9.CrossRefGoogle Scholar
  76. 76.
    Rodvold KA, George JM, Yoo L. Penetration of anti-infective agents into pulmonary epithelial lining fluid: focus on antibacterial agents. Clin Pharmacokinet. 2011;50:637–64.CrossRefGoogle Scholar
  77. 77.
    Rodriguez-Rojas A, Macia MD, Couce A, Gomez C, Castaneda-Garcia A, Oliver A, et al. Assessing the emergence of resistance: the absence of biological cost in vivo may compromise fosfomycin treatments for P. aeruginosa infections. PLoS One. 2010;5:e10193.CrossRefGoogle Scholar
  78. 78.
    Souli M, Galani I, Boukovalas S, Gourgoulis MG, Chryssouli Z, Kanellakopoulou K, et al. In vitro interactions of antimicrobial combinations with fosfomycin against KPC-2-producing Klebsiella pneumoniae and protection of resistance development. Antimicrob Agents Chemother. 2011;55:2395–7.CrossRefGoogle Scholar
  79. 79.
    Walsh CC, Landersdorfer CB, McIntosh MP, Peleg AY, Hirsch EB, Kirkpatrick CM, et al. Clinically relevant concentrations of fosfomycin combined with polymyxin B, tobramycin or ciprofloxacin enhance bacterial killing of Pseudomonas aeruginosa, but do not suppress the emergence of fosfomycin resistance. J Antimicrob Chemother. 2016;71:2218–29.CrossRefGoogle Scholar
  80. 80.
    Montgomery AB, Rhomberg PR, Abuan T, Walters KA, Flamm RK. Amikacin-fosfomycin at a five-to-two ratio: characterization of mutation rates in microbial strains causing ventilator-associated pneumonia and interactions with commonly used antibiotics. Antimicrob Agents Chemother. 2014;58:3708–13.CrossRefGoogle Scholar
  81. 81.
    Montgomery AB, Rhomberg PR, Abuan T, Walters KA, Flamm RK. Potentiation effects of amikacin and fosfomycin against selected amikacin-nonsusceptible Gram-negative respiratory tract pathogens. Antimicrob Agents Chemother. 2014;58:3714–9.CrossRefGoogle Scholar
  82. 82.
    Trapnell BC, McColley SA, Kissner DG, Rolfe MW, Rosen JM, McKevitt M, et al. Fosfomycin/tobramycin for inhalation in patients with cystic fibrosis with pseudomonas airway infection. Am J Respir Crit Care Med. 2012;185:171–8.CrossRefGoogle Scholar
  83. 83.
    Hurley MN, Ariff AH, Bertenshaw C, Bhatt J, Smyth AR. Results of antibiotic susceptibility testing do not influence clinical outcome in children with cystic fibrosis. J Cyst Fibros. 2012;11:288–92.CrossRefGoogle Scholar
  84. 84.
  85. 85.
    Palmer LB, Smaldone GC. Reduction of bacterial resistance with inhaled antibiotics in the intensive care unit. Am J Respir Crit Care Med. 2014;189:1225–33.CrossRefGoogle Scholar
  86. 86.
    Palmer LB, Smaldone GC, Chen JJ, Baram D, Duan T, Monteforte M, et al. Aerosolized antibiotics and ventilator-associated tracheobronchitis in the intensive care unit. Crit Care Med. 2008;36:2008–13.CrossRefGoogle Scholar
  87. 87.
    Le Conte P, Potel G, Peltier P, Horeau D, Caillon J, Juvin ME, et al. Lung distribution and pharmacokinetics of aerosolized tobramycin. Am Rev Respir Dis. 1993;147:1279–82.CrossRefGoogle Scholar
  88. 88.
    Laghi F, Goyal A. Auto-PEEP in respiratory failure. Min Anestesiol. 2012;78:201–21.Google Scholar
  89. 89.
    Determann RM, Royakkers A, Wolthuis EK, Vlaar AP, Choi G, Paulus F, et al. Ventilation with lower tidal volumes as compared with conventional tidal volumes for patients without acute lung injury: a preventive randomized controlled trial. Crit Care. 2010;14:R1.CrossRefGoogle Scholar
  90. 90.
    Parrilla FJ, Moran I, Roche-Campo F, Mancebo J. Ventilatory strategies in obstructive lung disease. Semin Respir Crit Care Med. 2014;35:431–40.CrossRefGoogle Scholar
  91. 91.
    Soltaninejad F, Kheiri S, Habibian R, Amra A, Asgari-Savadjani S. Evaluation effects of nebulized gentamicin in exacerbation of chronic obstructive lung disease. J Res Med Sci. 2016;21:56.CrossRefGoogle Scholar
  92. 92.
    Mojoli F, Iotti GA, Imberti R, Braschi A. The importance of protecting the mechanical ventilator during colistin methanesulfonate nebulization. Intensive Care Med. 2013;39:535–6.CrossRefGoogle Scholar
  93. 93.
    Cunningham S, Prasad A, Collyer L, Carr S, Lynn IB, Wallis C. Bronchoconstriction following nebulised colistin in cystic fibrosis. Arch Dis Child. 2001;84:432–3.CrossRefGoogle Scholar
  94. 94.
    Dodd ME, Abbott J, Maddison J, Moorcroft AJ, Webb AK. Effect of tonicity of nebulised colistin on chest tightness and pulmonary function in adults with cystic fibrosis. Thorax. 1997;52:656–8.CrossRefGoogle Scholar
  95. 95.
    Hodson ME, Gallagher CG, Govan JR. A randomised clinical trial of nebulised tobramycin or colistin in cystic fibrosis. Eur Respir J. 2002;20:658–64.CrossRefGoogle Scholar
  96. 96.
    Konstan MW, Flume PA, Kappler M, Chiron R, Higgins M, Brockhaus F, et al. Safety, efficacy and convenience of tobramycin inhalation powder in cystic fibrosis patients: the EAGER trial. J Cyst Fibros. 2011;10:54–61.CrossRefGoogle Scholar
  97. 97.
    Maddison J, Dodd M, Webb AK. Nebulized colistin causes chest tightness in adults with cystic fibrosis. Respir Med. 1994;88:145–7.CrossRefGoogle Scholar
  98. 98.
    Schuster A, Haliburn C, Doring G, Goldman MH, Freedom Study G. Safety, efficacy and convenience of colistimethate sodium dry powder for inhalation (Colobreathe DPI) in patients with cystic fibrosis: a randomised study. Thorax. 2013;68:344–50.CrossRefGoogle Scholar
  99. 99.
    Dominguez-Ortega J, Manteiga E, Abad-Schilling C, Juretzcke MA, Sanchez-Rubio J, Kindelan C. Induced tolerance to nebulized colistin after severe reaction to the drug. J Investig Allergol Clin Immunol. 2007;17:59–61.PubMedGoogle Scholar
  100. 100.
    Food And Drug Administration. Information for Healthcare Professionals: Colistimethate; an alert. Posted in 2007. Accessed 30 Aug 2016.Google Scholar
  101. 101.
    McCoy KS. Compounded colistimethate as possible cause of fatal acute respiratory distress syndrome. N Engl J Med. 2007;357:2310–1.CrossRefGoogle Scholar
  102. 102.
    Leong KW, Ong S, Chee HL, Lee W, Kwa AL. Hypersensitivity pneumonitis due to high-dose colistin aerosol therapy. Int J Infect Dis. 2010;14:e1018–9.CrossRefGoogle Scholar
  103. 103.
    Ratjen F, Rietschel E, Kasel D, Schwiertz R, Starke K, Beier H, et al. Pharmacokinetics of inhaled colistin in patients with cystic fibrosis. J Antimicrob Chemother. 2006;57:306–11.CrossRefGoogle Scholar

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© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Fourth Department of Internal Medicine and Infectious Diseases UnitAthens National and Kapodistrian University, Medical School, Attikon University General Hospital of AthensAthensGreece
  2. 2.Department of Critical Care, University Hospital Attikon, Faculty of MedicineNational and Kapodistrian University of AthensAthensGreece
  3. 3.Center for Anti-Infective Research and Development, Hartford HospitalHartfordUSA

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