Adjunctive inhaled amikacin in infants with Ventilator-Associated Pneumonia optimizes the complex antimicrobial therapy: pilot study
Adjunctive inhaled amikacin in infants with VAP
Keywords:
aerosol therapy, antibiotics, amikacin, ventilator-associated pneumonia, apoptosis; oxidative stressAbstract
Background and aim: VAP remains the second leading cause of death among the patients with nosocomial infections and its incidence varies significantly from 5% to 60% reaching on average 10 %. It is of crucial importance to develop novel treatment approaches and optimize the existing ones. Thus, the aim of this pilot study was to study the laboratory-microbiological effect of inhaled aminoglycosides in a complex treatment of patients with ventilator-associatedpneumonia(VAP).Methods: To study the laboratory-microbiological effect of adjunctive inhaled aminoglycosides in the treatment of VAP, twenty enrolled patients were randomly subdivided into 2 groups (n=10). Amikacin was administered via a nebulizer starting from the first day of VAP manifestation. Inhalations were performed BID for 7 days via a nebulizer integrated into the breathing circuit. We assessed: cell membrane alterations in leukocytes, Annexin V/7-AAD staining for leukocytes, ROS detection assay for leukocytes.
Results: Adjunctive administration of inhaled amikacin reduced the fluorescence intensity ratio more efficiently compared with the intravenous antimicrobial treatment with no aerosolized amikacin following both 48 h and 96 h of treatment. The amount of dead necrotic annexin V-negative, 7-AAD-positive leukocytes was significantly lower under the use of inhaled amikacin than at the beginning of treatment.
Conclusions In this pilot study, we found that administration of aerosolized amikacin combined with the systemic antimicrobial therapy improves the clinical outcome of patients with VAP, effective early microbial decrease in the sputum, reduces reactive oxygen species generation in leukocytes and the degree of leukocyte apoptosis and necrosis, decreases VAP-mediated cell membrane alterations of circulating leukocytes.
References
Кohbodi GA, Rajasurya V, Noor A. Ventilator-associated Pneumonia. 2021 Aug 22. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 29939533.
Kalil AC, Metersky ML, Klompas M, 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 Sep 1;63(5):e61-e111. doi: 10.1093/cid/ciw353. Epub 2016 Jul 14. Erratum in: Clin Infect Dis. 2017 May 1;64(9):1298. Erratum in: Clin Infect Dis. 2017 Oct 15;65(8):1435. Erratum in: Clin Infect Dis. 2017 Nov 29;65(12):2161.
Timsit JF, Esaied W, Neuville M, et al. Update on ventilator-associated pneumonia. F1000Res. 2017;6:2061. Published 2017 Nov 29. doi:10.12688/f1000research.12222.1
Metersky ML, Wang Y, Klompas M, et al. Trend in Ventilator-Associated Pneumonia Rates Between 2005 and 2013. JAMA. 2016 Dec 13;316(22):2427-2429. doi: 10.1001/jama.2016.16226.
Charles MP, Kali A, Easow JM, et al. Ventilator-associated pneumonia. Australas Med J. 2014 Aug 31;7(8):334-44. doi: 10.4066/AMJ.2014.2105.
Papazian L, Klompas M, Luyt CE. Ventilator-associated pneumonia in adults: a narrative review. Intensive Care Med. 2020;46(5):888-906. doi:10.1007/s00134-020-05980-0
Feng DY, Zhou YQ, Zhou M, et al. Risk Factors for Mortality Due to Ventilator-Associated Pneumonia in a Chinese Hospital: A Retrospective Study. Med Sci Monit. 2019;25:7660-7665. Published 2019 Oct 12. doi:10.12659/MSM.916356
Wu D, Wu C, Zhang S, Zhong Y. Risk Factors of Ventilator-Associated Pneumonia in Critically III Patients. Front Pharmacol. 2019;10:482. Published 2019 May 9. doi:10.3389/fphar.2019.00482
Melsen WG, Rovers MM, Groenwold RH, et al. Attributable mortality of ventilator-associated pneumonia: a meta-analysis of individual patient data from randomised prevention studies. Lancet Infect Dis. 2013 Aug;13(8):665-71. doi: 10.1016/S1473-3099(13)70081-1.
Kalanuria AA, Ziai W, Mirski M. Ventilator-associated pneumonia in the ICU [published correction appears in Crit Care. 2016;20:29. Zai, Wendy [corrected to Ziai, Wendy]]. Crit Care. 2014;18(2):208. Published 2014 Mar 18. doi:10.1186/cc13775
Schreiber MP, Shorr AF. Challenges and opportunities in the treatment of ventilator-associated pneumonia. Expert Rev Anti Infect Ther. 2017 Jan;15(1):23-32. doi: 10.1080/14787210.2017.1250625.
Monsel A, Torres A, Zhu Y, eta al. European Investigators Network for Nebulized Antibiotics in Ventilator-associated Pneumonia (ENAVAP). Nebulized antibiotics for ventilator-associated pneumonia: methodological framework for future multicenter randomized controlled trials. Curr Opin Infect Dis. 2021 Apr 1;34(2):156-168. doi: 10.1097/QCO.0000000000000720.
Sweeney DA, Kalil AC. Why don't we have more inhaled antibiotics to treat ventilator-associated pneumonia? Clin Microbiol Infect. 2019 Oct;25(10):1195-1199. doi: 10.1016/j.cmi.2019.04.018.
Abu-Salah T, Dhand R. Inhaled antibiotic therapy for ventilator-associated tracheobronchitis and ventilator-associated pneumonia: an update. Adv Ther. 2011 Sep;28(9):728-47. doi: 10.1007/s12325-011-0051-z.
Niederman MS. Adjunctive Nebulized Antibiotics: What Is Their Place in ICU Infections? Front Med (Lausanne). 2019 May 8;6:99. doi: 10.3389/fmed.2019.00099.
Boselli E, Breilh D, Djabarouti S, et al. Reliability of mini-bronchoalveolar lavage for the measurement of epithelial lining fluid concentrations of tobramycin in critically ill patients. Intensive Care Med. 2007 Sep;33(9):1519-23. doi: 10.1007/s00134-007-0688-x.
Tang R, Luo R, Wu B, et al. Effectiveness and safety of adjunctive inhaled antibiotics for ventilator-associated pneumonia: A systematic review and meta-analysis of randomized controlled trials. J Crit Care. 2021 Oct;65:133-139. doi: 10.1016/j.jcrc.2021.06.004.
Leache L, Aquerreta I, Aldaz A, et al. Effectiveness of adjunctive nebulized antibiotics in critically ill patients with respiratory tract infections. Eur J Clin Microbiol Infect Dis. 2020;39(2):361-368. doi:10.1007/s10096-019-03733-6
Horan TC, Andrus M, Dudeck MA. CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting. Am J Infect Control. 2008 Jun;36(5):309-32. doi: 10.1016/j.ajic.2008.03.002. Erratum in: Am J Infect Control. 2008 Nov;36(9):655. PMID: 18538699.
Foglia E, Meier MD, Elward A. Ventilator-associated pneumonia in neonatal and pediatric intensive care unit patients. Clin Microbiol Rev. 2007 Jul;20(3):409-25, table of contents. doi: 10.1128/CMR.00041-06.
Posokhov YO, Kyrychenko A, Korniyenko Y. Derivatives of 2,5-diaryl-1,3-oxazole and 2,5-diaryl-1,3,4-oxadiazole as environment-sensitive fluorescent probes for studies of biological membranes. Reviews in Fluorescence 2017 (editor C.D. Geddes), Springer Nature Switzerland AG, Chapter 9; 2018. pp. 199-230.
Posokhov Y, Kyrychenko A. Location of fluorescent probes (2-hydroxy derivatives of 2,5-diaryl-1,3-oxazole) in lipid membrane studied by fluorescence spectroscopy and molecular dynamics simulation. Biophysical Chemistry 2018; 235:9-18.
Kurad D, Jeschke G, Marsh D. Lipid membrane polarity profiles by high-field EPR. Biophys. J. 2003; 85: 1025–1033.
Ho C, Slater SJ, Stubbs CD. Hydration and order in lipid bilayers. Biochemistry 1995; 34: 6188– 6195.
Pogozhykh D, Posokhov Y, Myasoedov V, et al. Experimental Evaluation of Food-Grade Semi-Refined Carrageenan Toxicity. Int J Mol Sci. 2021 Oct 16;22(20):11178. doi: 10.3390/ijms222011178. PMID: 34681837; PMCID: PMC8539956.
Tkachenko AS, Klochkov VK, Lesovoy VN, et al. Orally administered gadolinium orthovanadate GdVO4:Eu3+ nanoparticles do not affect the hydrophobic region of cell membranes of leukocytes. Wien Med Wochenschr. 2020 May;170(7-8):189-195. doi: 10.1007/s10354-020-00735-4. Epub 2020 Feb 12. PMID: 32052227.
Stacchini A, Aliberti S, Demurtas A, et al. Flow cytometry identification of nonhemopoietic neoplasms during routine immunophenotyping. Int J Lab Hematol. 2019 Apr;41(2):208-217. doi: 10.1111/ijlh.12946. Epub 2018 Nov 27. PMID: 30480372.
Zampieri FG, Nassar AP Jr, Gusmao-Flores D, et al. Nebulized antibiotics for ventilator-associated pneumonia: a systematic review and meta-analysis. Crit Care. 2015;19(1):150. Published 2015 Apr 7. doi:10.1186/s13054-015-0868-y
Grishina ZV, Viryasova GM, Romanova YM, Sud'ina GF. Polymorphonuclear leukocyte apoptosis is accelerated by sulfatides or sulfatides-treated Salmonella Typhimurium bacteria. Biomed Res Int. 2015;2015:381232. doi: 10.1155/2015/381232.
Murao A, Aziz M, Wang H, et al. Release mechanisms of major DAMPs. Apoptosis. 2021 Apr;26(3-4):152-162. doi: 10.1007/s10495-021-01663-3. Epub 2021 Mar 13.
Westman J, Grinstein S, Marques PE. Phagocytosis of Necrotic Debris at Sites of Injury and Inflammation. Front Immunol. 2020 Jan 9;10:3030. doi: 10.3389/fimmu.2019.03030.
Amini Kadijani A, Javadinia F, Mirzaei A, et al. Apoptosis markers of circulating leukocytes are associated with the clinical course of inflammatory bowel disease. Gastroenterol Hepatol Bed Bench. 2018 Winter;11(Suppl 1):S53-S58.
Redza-Dutordoir M, Averill-Bates DA. Activation of apoptosis signalling pathways by reactive oxygen species. Biochim Biophys Acta. 2016 Dec;1863(12):2977-2992. doi: 10.1016/j.bbamcr.2016.09.012.
Valencia A, Morán J. Reactive oxygen species induce different cell death mechanisms in cultured neurons. Free Radic Biol Med. 2004 May 1;36(9):1112-25. doi: 10.1016/j.freeradbiomed.2004.02.013
F. Duflo, R. Debon, J. Goudable, D. Chassar, B. Allaouchiche. Alveolar and serum oxidative stress in ventilator-associated pneumonia. Br J Anaesth, 89 (2002), pp. 231-236.
Catalá Á. Lipid peroxidation modifies the assembly of biological membranes "The Lipid Whisker Model". Front Physiol. 2015;5:520. Published 2015 Jan 12. doi:10.3389/fphys.2014.00520
Reiter RJ, Tan DX, Galano A. Melatonin reduces lipid peroxidation and membrane viscosity. Front Physiol. 2014;5:377. Published 2014 Oct 6. doi:10.3389/fphys.2014.00377
Pogozhykh D, Posokhov Y, Myasoedov V, et al. Experimental Evaluation of Food-Grade Semi-Refined Carrageenan Toxicity. Int J Mol Sci. 2021 Oct 16;22(20):11178. doi: 10.3390/ijms222011178.
Tkachenko A, Onishchenko A, Posokhov Y, et al. Changes in cell membranes of white blood cells treated with a common food additive E407a. Turk J Biochem 2021; 46(5): 557–562. https://doi.org/10.1515/tjb-2020-0129
Seely AJ, Pascual JL, Christou NV. Science review: Cell membrane expression (connectivity) regulates neutrophil delivery, function and clearance. Crit Care. 2003 Aug;7(4):291-307. doi: 10.1186/cc1853.
Kantar A, Oggiano N, Giorgi PL, Fiorini R. Membrane fluidity of polymorphonuclear leukocytes from children with primary ciliary dyskinesia. Pediatr Res. 1993 Dec;34(6):725-8. doi: 10.1203/00006450-199312000-00006.
Torres A, Motos A, Battaglini D, Li Bassi G. Inhaled amikacin for severe Gram-negative pulmonary infections in the intensive care unit: current status and future prospects. Crit Care. 2018;22(1):343. Published 2018 Dec 17. doi:10.1186/s13054-018-1958-4
Liu C, Zhang YT, Peng ZY, et al. Aerosolized Amikacin as Adjunctive Therapy of Ventilator-associated Pneumonia Caused by Multidrug-resistant Gram-negative Bacteria: A Single-center Randomized Controlled Trial. Chin Med J (Engl). 2017 May 20;130(10):1196-1201. doi: 10.4103/0366-6999.205846.
Kollef MH, Ricard JD, Roux D, 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 Jun;151(6):1239-1246. doi: 10.1016/j.chest.2016.11.026.
Downloads
Published
Issue
Section
License
Copyright (c) 2023 Bohdan Levchenko, Oleksandr Nazarchuk, Dmytro Dmytriiev, Nataliia Bahniuk, Mykola Melnychenko, Kostiantyn Dmytriiev
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Transfer of Copyright and Permission to Reproduce Parts of Published Papers.
Authors retain the copyright for their published work. No formal permission will be required to reproduce parts (tables or illustrations) of published papers, provided the source is quoted appropriately and reproduction has no commercial intent. Reproductions with commercial intent will require written permission and payment of royalties.