Assessment of Aerosolized Colistin Efficacy for Nosocomial Pneumonia

The aim of the study was the assessment of aerosolized colistin (AC) efficacy as adjunctive therapy to systemic antibiotic therapy for nosocomial pneumonia (NP).

Materials and methods. This observation study included 90 NP patients under critical care. The primary criterion of therapy efficacy was NP resolution. As the secondary criteria of therapy efficacy, eradication of germs from sputum, the time to patients’ spontaneous breathing, the time in critical care unit, and mortality were evaluated. Patients were split into 2 groups: Gr.1 (n=48) — systemic antibiotics combined with AC; Gr. 2 (n=42) — systemic antibiotics cross over due to sensitivity. The groups were comparable in main characteristics. Aerosolized colistin was dosed 2 mln. U 3 times/day (Xellia Pharmaceuticals ApS, Denmark) in Gr. 1. The regimen of systemic antibiotic therapy was not changed upon AC prescription. Statistical analysis was carried out using Statistica 7.0 (M, σ, Newman—Keuls test; P<0.05).

Results. This study has demonstrated efficacy of aerosolized colistin 2 mln. U 3 times/day as adjuvant therapy to systemic antibiotic therapy for NP caused by multidrug-resistant gram-negative germs: the NP resolution rate was 75% (versus 52% in Gr. 2, P=0.0295); eradication of pathogens by therapy day 7 was achieved in 80% in Gr. 1 and 60% Gr. 2 (n=12) (P>0.05); in Gr. 1, spontaneous breathing took place earlier than in Gr. 2 — 7.6±1.6 days in Gr. 1 versus 11.7±3.4 days in Gr. 2 (P=0.0000); in Gr. 1, the critical care unit duration was shorter than in Gr. 2 — 12.0±3.4 days in Gr. 1 versus 16.3±3.4 days in Gr. 2 (P=0.0000).

Conclusions. Aerosolized colistin 2 mln. U 3 times a day is an effective adjuvant therapy combined with systemic antibiotic therapy for nosocomial pneumonia caused by multidrug-resistant gram-negative germs. This modified treatment assisted faster pneumonia resolution, earlier spontaneous breathing of patients, and shorter time in the intensive care unit. Addition of aerosolized colistin to systemic antibiotics should be regarded as a possible algorithm of treatment in a case of inefficient first-line antibiotic therapy.

1. Gelfand B.R. (ed.). Nosocomial pneumonia in adults. Russian national guidelines. Moscow: Meditsinskoe Informatsionnoe Agentstvo; 2016: 176. [InRuss.]

2. Bekaert M., Timsit J.F., Vansteelandt S., Depuydt P., Vesin A., Garrouste-Orgeas M., Decruyenaere J., Clec'h C., Azoulay E., Benoit D.; Outcomerea Study Group. Attributable mortality of ventilator-associated pneumonia: a reappraisal using causal analysis. Am. J. Respir. Crit. Care Med. 2011; 184:1133-1139.DOI: 10.1164/rccm.201105-0867OC. PMID: 21852541

3. Shabanov A.K., Khubutiya M.Sh., Bulava G.V., Beloborodova N.V., Kuzovlev A.N., Grebenchikov O.A., Kosolapov D.A., Shpitonkov M.I. Time course of changes in the level of procalcitonin in the development of nosocomial pneumonia in victims with severe concomitant injury in an intensive care unit. Obshchaya Reanimatologiya = General Reanimatology. 2013; 9 (5): 11-18. DOI: 10.15360/1813-9779-2013-5-11. [In Russ., In Engl.]

4. Moroz V.V., Smelaya T.V., Golubev A.M., Salnikova L.E. Genetics and medicine of critical conditions: from theory to practice. Obshchaya Re-animatologiya = General Reanimatology. 2012; 8 (4): 5-12. DOI: 10.15360/1813-9779-2012-4-5. [In Russ., In Engl.]

5. Chuchalin A.G. (ed.). Respiratory medicine. Manual. Moscow: GEOTAR-Media; 2007: 757. [In Russ.]

6. Valencia M., Torres A. Ventilator-associated pneumonia. Curr. Opin. Crit. Care. 2009; 15 (1): 30-35. DOI: 10.1097/MCC.0b013e3283220e78. PMID: 19186407

7. Ketsko Y.L., Lunina A.V., Petrovskaya E.V., Lyamin A.V. Evaluation of the efficiency of antibiotic therapy in patients with viral and bacterial pneumonia in 2009/2011. Obshchaya Reanimatologiya = General Reanima-tology. 2015; 11 (4): 33-40. DOI: 10.15360/1813-9779-2015-4-33-40. [In Russ., In Engl.]

8. Karpov O.E., Gusarov V.G., Lashenkova N.N., Petrova N.V., Dementienko M.V., Shilkin D.N., Nesterova E.E., Zamyatin M.N. Register of microorganisms as a tool for automated antibiotics consumption planning and monitoring of antibiotic resistance in intensive care units and specilized hospital departments. Obshchaya Reanimatologiya = General Reanima-tology. 2016; 12 (6): 39-48. DOI: 10.15360/1813-9779-2016-6-39-48. [In Russ., In Engl.]

9. Spellberg В. The future of antibiotics. Crit. Care. 2014; 18 (3): 228. DOI: 10.1186/cc13948. PMID: 25043962

10. Zilberberg M., Shorr A. Prevalence of multidrug-resistant Pseudomonas aeruginosa and carbapenem-resistant Enterobacteriaceae among specimens from hospitalized patients with pneumonia and bloodstream infections in the United States from 2000 to 2009. J. Hosp. Med.2013; 8 (10): 559-563. DOI: 10.1002/jhm.2080. PMID: 24022878

11. Sievert D., Ricks P., EdwardsJ., Schneider A., Patel J., Srinivasan A., Kallen A., Limbago B., Fridkin S.; National Healthcare Safety Network (NHSN) Team and Participating NHSN Facilities. Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009-2010. Infect. Control Hosp. Epidemiol. 2013; 34 (1): 1-14. DOI: 10.1086/668770. PMID: 23221186

12. Kuzovlev A.N., Moroz V.V., Golubev A.M.Inhaled antibiotics in treatment of nosocomial pneumonia. Anesteziologiya i Reanimatologiya. 2015; 60 (4): 55-61. PMID: 26596034. [In Russ.]

13. Kuzovlev A.N., Moroz V.V., Golubev A.M.,Polovnikov S.G.Inhaled antibiotics in the treatment of nosocomial pneumonia. Obshchaya Reanima-tologiya = General Reanimatology. 2013; 9 (6): 61-70. DOI: 10.15360/1813-9779-2013-6-61. [In Russ., In Engl.]

14. Kuzovlev A.N., Moroz V.V., Golubev A.M., Polovnikov S.G. Inhaled tobramycin in the treatment of ventilator-associated pneumonia. Klinich-eskaya Farmakologiya i Terapiya. 2014; 23 (4): 52-58. [In Russ.]

15. Ehrmann S., Roche-Campo F., Sferrazza Papa G.F., Isabey D., Brochard L. , Apiou-Sbirlea G.; REVA research network. Aerosol therapy during mechanical ventilation: an international survey. Intensive Care Med. 2013; 39(6):1048-1056. DOI: 10.1007/s00134-013-2872-5. PMID: 23525741

16. Palmer L.B. Aerosolized antibiotics in the intensive care unit. Clin. Chest Med. 2011; 32 (3): 559-574. DOI: 10.1016/j.ccm.2011.05.012. PMID: 21867823

17. Tolker-Nielsen T., Heiby N. Extracellular DNA and F-actin as targets in antibiofilm cystic fibrosis therapy. Future Microbiol. 2009; 4 (6): 645-647. DOI: 10.2217/fmb.09.38. PMID: 19659420

18. Dhand R. The role of aerosolized antimicrobials in the treatment of ventilator-associated pneumonia. Respir. Care. 2007; 52 (7): 866-884. PMID: 17594731

19. Gurjar M. Colistin for lung infection: an update. J. Intensive Care. 2015; 3 (1): 3. DOI: 10.1186/s40560-015-0072-9. PMID: 25705428

20. Rello J., Sole-Lleonart C., Rouby J., Chastre J., Blot S., Poulakou G., Luyt C., Riera J., Palmer L., Pereira J., Felton T., Dhanani J., Bassetti M., Welte T., Roberts J. Use of nebulized antimicrobials for the treatment of respiratory infections in invasively mechanically ventilated adults: a position paper from the European Society of Clinical Microbiology and Infectious Diseases. Clin. Microbiol. Infect. 2017; pii: S1198-743X(17)30219-7. DOI: 10.1016/j.cmi.2017.04.011. PMID: 28412382

21. Kalil A., Metersky M., Klompas M., Muscedere J., Sweeney D., Palmer L., Napolitano L., O’Grady N., Bartlett J., CarratalaJ., El Solh A., Ewig S., Fey P., File T., Restrepo M., Roberts J., Waterer G., Cruse P., Knight S., Brozek J. Executive Summary: 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 (5): 575-582. DOI: 10.1093/cid/ciw504. PMID: 27521441

22. Doshi N., Cook C., Mount K., Stawicki S., Frazee E., Personett H., Schramm G., Arnold H., Murphy C. Adjunctive aerosolized colistin for multi-drug resistant gram-negative pneumonia in the critically ill: a retrospective study. BMC Anesthesiol. 2013; 13 (1): 45. DOI: 10.1186/1471-2253-13-45. PMID: 24274315

23. Tumbarello M., De Pascale G., Trecarichi E., De Martino S., Bello G., Mav-iglia R., Spanu T., Antonelli M. Effect of aerosolized colistin as adjunctive treatment on the outcomes of microbiologically documented ventilator-associated pneumonia caused by colistin-only susceptible gram-negative bacteria. Chest. 2013; 144 (6): 1768-1775. DOI: 10.1378/chest.13-1018. PMID: 23989805

24. Korbila I., Michalopoulos A., Rafailidis P.I., Nikita D., Samonis G., Falagas M. E. Inhaled colistin as adjunctive therapy to intravenous colistin for thetreatment of microbiologically documented ventilator-associated pneumonia: a comparative cohort study. Clin. Microbiol. Infect. 2010; 16 (8): 1230-1236. DOI: 10.1111/j.1469-0691.2009.03040.x. PMID: 19732088

25. Liu D., Zhang J., Liu H., Zhu Y., Qu J. Intravenous combined with aerosolised polymyxin versus intravenous polymyxin alone in the treatment of pneumonia caused by multidrug-resistant pathogens: a systematic review and meta-analysis. Int. J. Antimicrob. Agents. 2015; 46 (6): 603-609. DOI: 10.1016/j.ijantimicag.2015.09.011. PMID: 26607337

26. 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 (12): 2645-2649. DOI: 10.1093/jac/dkq360. PMID: 20876621

27. Valachis A., Samonis G., Kofteridis D. The role of aerosolized colistin in the treatment of ventilator-associated pneumonia: a systematic review and metaanalysis. Crit. Care Med. 2015; 43 (3): 527-533. DOI: 10.1097/CCM.0000000000000771. PMID: 25493971

28. Florescu D., Qiu F., McCartan M., Mindru C., Fey P., Kalil A. What is the efficacy and safety of colistin for the treatment of ventilator-associated pneumonia? A systematic review and meta-regression. Clin. Infect. Dis. 2012; 54 (5): 670-680. DOI: 10.1093/cid/cir934. PMID: 22322268

29. Kofteridis D., Alexopoulou C., Valachis A., Maraki S., Dimopoulou D., Georgopoulos D., Samonis G. 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 (11): 1238-1244. DOI: 10.1086/657242. PMID: 20973727

30. Demirdal T., Sari U., Nemli S. Is inhaled colistin beneficial in ventilator associated pneumonia or nosocomial pneumonia caused by Acinetobacter baumannii? Ann. Clin. Microbiol. Antimicrob. 2016; 15: 11. DOI: 10.1186/s12941-016-0123-7. PMID: 26911714

31. Czosnowski Q.A., Wood G.C., Magnotti L.J., Croce M.A., Swanson J.M., Boucher B.A., Fabian T.C.Adjunctive aerosolized antibiotics for treatment of ventilator-associated pneumonia. Pharmacotherapy. 2009; 29 (9): 1054-1060. DOI: 10.1592/phco.29.9.1054. PMID: 19698010

32. Arnold H., Sawyer A., Kollef M. Use of Adjunctive aerosolized antimicrobial therapy in the treatment of Pseudomonas aeruginosa and Acineto-bacter baumannii ventilator-associated pneumonia. Respir. Care. 2012; 57 (8): 1226-1233. DOI: 10.4187/respcare.01556. PMID: 22349038

33. Niederman M.S., ChastreJ., Corkery K., Fink J.B., Luyt C.E., Garcna M.S. Bay41-6551 achieves bactericidal tracheal aspirate amikacin concentrations in mechanically ventilated patients with Gram-negative pneumonia. Intensive Care Med. 2012; 38 (2): 263-271. DOI: 10.1007/s00134-011-2420-0. PMID: 22147112

34. Le Conte P., Potel G., Clementi E., Legras A., Villers D., Bironneau E., Cous-son J., Baron D. Administration of tobramycin aerosols in patients with nosocomial pneumonia: a preliminary study. Presse. Med. 2000; 29 (2): 76-78. PMID: 10682031

35. Lu Q., Yang J., Liu Z., Gutierrez C., Aymard G., Rouby JJ.; Nebulized Antibiotics Study Group. Nebulized ceftazidime and amikacin in ventilator-associated pneumonia caused by Pseudomonas aeruginosa. Am. J. Respir. Crit. Care Med. 2011; 184 (1): 106-115. DOI: 10.1164/rccm.201011-1894OC. PMID: 21474643

36. Lu Q., Luo R., Bodin L., Yang J., Zahr N., Aubry A., Golmard J.L., Rouby J. J.; Nebulized Antibiotics Study Group. Efficacy of high-dose nebulized colistin in ventilator-associated pneumonia caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii. Anesthesiology. 2012; 117 (6): 1335-1347. DOI: 10.1097/ALN.0b013e31827515de. PMID: 23132092

37. Ghannam D.E., Rodriguez G.H., Raad I.I., 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 (3): 253-259. DOI: 10.1007/s10096-008-0620-5. PMID: 18752007

38. Le J., Ashley E.D., Neuhauser M.M., Brown J., Gentry C., Klepser M.E., Marr A.M., Schiller D., Schwiesow J.N., Tice S., VandenBussche H.L., Wood G.C.; Society of Infectious Diseases Pharmacists Aerosolized Antimicrobials Task Force. Consensus summary of aerosolized antimicrobial agents: application of guideline criteria. Insights from the Society of Infectious Diseases Pharmacists. Pharmacotherapy. 2010; 30 (6): 562-584. DOI: 10.1592/phco.30.6.562. PMID: 20500046

39. Riethmuller J., Herrmann G., Graepler-Mainka U., Hellwig D., Heuer H., Heyder S., Koster H., Kinder B., Kroger K., Paul K., Poplawska K., Melichar V., Smaczny C., Mellies U. Sequential inhalational tobramycin-colistin-combination in CF-patients with chronic P. Aeruginosa colonization — an observational study. Cell Physiol. Biochem. 2016; 39 (3): 1141-1151. DOI: 10.1159/000447821. PMID: 27576543