Novel Therapeutic Strategies for Ventilator-Associated Pneumonia (VAP): Systematic Review

Ashrafi, Nima; Nikfar, Mozhdeh

doi:10.5281/zenodo.21968874

Novel Therapeutic Strategies for Ventilator-Associated Pneumonia (VAP): Systematic Review

Articles in Press

Document Type : Review Article

Authors

Nima Ashrafi ¹

Mozhdeh Nikfar ²

¹ ICU fellowship candidate , Department of anesthesiology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

² Assistant Professor of Pulmonary Diseases, Department of Internal Medicine, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

https://doi.org/10.5281/zenodo.21968874

Abstract

Introduction: Ventilator-associated pneumonia (VAP) remains a major intensive care unit complication, contributing to prolonged mechanical ventilation, antimicrobial overuse, multidrug resistance, and increased mortality. Despite advances in prevention and conventional antibiotics, treatment failure remains frequent. This study aims to review and highlight novel therapeutic strategies for improving clinical outcomes in patients with VAP.

Material and methods: This systematic review was conducted according to PRISMA guidelines. PubMed, Scopus, Web of Science, EMBASE, Google Scholar, SID, and Magiran were systematically searched using keywords including “ventilator-associated pneumonia,” “VAP,” “novel therapeutic strategies,” “bacteriophage therapy,” “immunotherapy,” “monoclonal antibodies,” “inhaled antibiotics,” and “multidrug-resistant pathogens,” combined with Boolean operators to identify eligible studies on emerging VAP treatments.

Results: Synthesis of six eligible studies (n = 6; RCTs: 33.3%, cohort designs: 33.3%) demonstrated that novel VAP strategies enhanced microbiological clearance and clinical cure against MDR/XDR pathogens. Rapid molecular diagnostics reduced time to targeted therapy, whereas resistance-guided regimens improved treatment adequacy. Overall methodology exhibited low risk of bias across key Cochrane domains (>80% domain adequacy), validating the clinical reliability of these precision-guided and adjunctive therapeutic modalities.

Conclusion: Novel therapeutic strategies, including inhaled antibiotics, bacteriophages, monoclonal antibodies, and rapid diagnostic-guided regimens, offer effective alternatives for managing multidrug-resistant VAP. Integrating these precision-driven and adjunctive modalities optimizes targeted pathogen clearance, mitigates systemic toxicity, and improves clinical management in intensive care settings. Future large-scale clinical trials remain essential to standardize protocols and validate long-term clinical efficacy.

Graphical Abstract

Keywords

Ventilator-associated pneumonia

Multidrug resistance

Bacteriophage therapy

Inhaled antibiotics

Subjects

Health

[1] Robba, C., Poole, D., McNett, M., Asehnoune, K., Bösel, J., Bruder, N., Chieregato, A., Cinotti, R., Duranteau, J., Einav, S., et al. (2020). Mechanical ventilation in patients with acute brain injury: Recommendations of the European Society of Intensive Care Medicine consensus. Intensive Care Medicine, 46(12), 2397–2410.

[2] Robba, C., Citerio, G., Taccone, F. S., Galimberti, S., Rebora, P., Vargiolu, A., Pelosi, P., & VENTIBRAIN Enlarged Steering Committee Members. (2021). VENTIBRAIN: Multicenter observational study on practice of ventilation in brain injured patients – The VENTIBRAIN study protocol. BMJ Open, 11(4), e047100.

[3] Pham, T., Heunks, L., Bellani, G., Madotto, F., Aragao, I., Beduneau, G., Goligher, E. C., Grasselli, G., & WEAN SAFE Investigators. (2023). Weaning from mechanical ventilation in intensive care units across 50 countries (WEAN SAFE): A multicenter, prospective, observational cohort study. The Lancet Respiratory Medicine, 11(5), 465–476. (Erratum published 2023, The Lancet Respiratory Medicine, 11(3), e25,

[4] Tejerina, E. E., Pelosi, P., Robba, C., Penuelas, O., Muriel, A., Barrios, D., Frutos-Vivar, F., Raymondos, K., Du, B., Thille, A. W., et al. (2021). Evolution over time of ventilatory management and outcome of patients with neurologic disease. Critical Care Medicine, 49(7), 1095–1106.

[5] Picetti, E., Pelosi, P., Taccone, F. S., Citerio, G., Mancebo, J., & Robba, C., on behalf of the ESICM NIC/ARF Sections. (2020). VENTILatOry strategies in patients with severe traumatic brain injury: The VENTILO Survey of the European Society of Intensive Care Medicine (ESICM). Critical Care, 24(1), 158.

[6] Hellyer, T. P., Ewan, V., Wilson, P., & Simpson, A. J. (2016). The Intensive Care Society recommended bundle of interventions for the prevention of ventilator-associated pneumonia. Journal of the Intensive Care Society, 17(3), 238–243.

[7] Triamvisit, S., Oprasert, W., Puttima, C., Chiangmai, M. N., Thienjindakul, N., Rodkul, L., & Jetjumnong, C. (2021). Effect of modified care bundle for prevention of ventilator-associated pneumonia in critically-ill neurosurgical patients. Acute and Critical Care, 36(4), 294–299.

[8] Russo, E., Antonini, M. V., Sica, A., Dell’Amore, C., Martino, C., Gamberini, E., Bissoni, L., Circelli, A., & Bolondi, G. (2023). Infection-related ventilator-associated complications in critically ill patients with trauma: A retrospective analysis. Antibiotics, 12(1), 176.

[9] Jovanovic, B., Milan, Z., Markovic-Denic, L., Djuric, O., Radinovic, K., Doklestic, K., Velickovic, J., Ivancevic, N., Gregoric, P., Pandurovic, M., et al. (2015). Risk factors for ventilator-associated pneumonia in patients with severe traumatic brain injury in a Serbian trauma centre. International Journal of Infectious Diseases, 38, 46–51.

[10] Bronchard, R., Albaladejo, P., Brezac, G., Geffroy, A., Seince, P.-F., Morris, W., Branger, C., & Marty, J. (2004). Early onset pneumonia risk factors and consequences in head trauma patients. Anesthesiology, 100(2), 234–239.

[11] Esnault, P., Nguyen, C., Bordes, J., D’Aranda, E., Montcriol, A., Contargyris, C., Cotte, J., Goutorbe, P., Joubert, C., Dagain, A., et al. (2017). Early-onset ventilator-associated pneumonia in patients with severe traumatic brain injury: Incidence, risk factors, and consequences in cerebral oxygenation and outcome. Neurocritical Care, 27(2), 187–198.

[12] Zygun, D. A., Zuege, D. J., Boiteau, P. J. E., Laupland, K. B., Henderson, E. A., Kortbeek, J. B., & Doig, C. J. (2006). Ventilator-associated pneumonia in severe traumatic brain injury. Neurocritical Care, 5(2), 108–114.

[13] Rodríguez, A., Berrueta, J., Páez, C., Huertas, R., Marotta, M., Claverias, L., Gómez, J., Trefler, S., Gómez Bertomeu, F. F., Guerrero-Torres, M. D., et al. (2025). Ten-year evaluation of ventilator-associated pneumonia (VAP) according to initial empiric treatment: A retrospective analysis using real-world data. Biomedicines, 13(2), 360.

[14] Craven, D. E., Hudcova, J., & Lei, Y. (2011). Diagnosis of ventilator-associated respiratory infections (VARI): Microbiologic clues for tracheobronchitis (VAT) and pneumonia (VAP). Clinics in Chest Medicine, 32(3), 547–557.

[15] Keane, S., Sole Valle Coccia, M., Nseir, S., & Martin-Loeches, I. (2018). How can we distinguish ventilator-associated tracheobronchitis from pneumonia? Clinics in Chest Medicine, 39(4), 785–796.

[16] Magill, S. S., Klompas, M., Balk, R., Burns, S. M., Diekema, D., Fridkin, S., Greene, L., Guh, A., Gutterman, D., Hammer, B., et al. (2013). Developing a new, national approach to surveillance for ventilator-associated events: Executive summary. Clinical Infectious Diseases, 57(12), 1742–1746.

[17] Mrozek, S., Constantin, J.-M., & Geeraerts, T. (2015). Brain–lung crosstalk: Implications for neurocritical care patients. World Journal of Critical Care Medicine, 4(3), 163–178.

[18] Li, C., Chen, W., Lin, F., Li, W., Wang, P., Liao, G., & Zhang, L. (2023). Functional two-way crosstalk between brain and lung: The brain–lung axis. Cellular and Molecular Neurobiology, 43(3), 991–1003.

[19] Battaglini, D., Parodi, L., Cinotti, R., Sahnoun, K., Taccone, F. S., Orengo, G., Zona, G., Uccelli, A., Ferro, G., Robba, M., et al. (2023). Ventilator-associated pneumonia in neurocritically ill patients: Insights from the ENIO international prospective observational study. Respiratory Research, 24(1), 146.

[20] Lou, M., Chen, X., Wang, K., Xue, Y., Cui, D., & Xue, F. (2013). Increased intracranial pressure is associated with the development of acute lung injury following severe traumatic brain injury. Clinical Neurology and Neurosurgery, 115(7), 904–908.

[21] Robba, C., Camporota, L., & Citerio, G. (2023). Acute respiratory distress syndrome complicating traumatic brain injury: Can opposite strategies converge? Intensive Care Medicine, 49(5), 583–586.

[22] Ziaka, M., & Exadaktylos, A. (2024). Pathophysiology of acute lung injury in patients with acute brain injury: The triple-hit hypothesis. Critical Care, 28(1), 71.

[23] Mascia, L., D’Albo, R., Cavalli, I., Giaccari, L., Della Giovampaola, M., & Donati, B. (2025). Organ crosstalk: Brain–lung interaction. Frontiers in Medicine, 12, 1655813.

[24] Huang, S., Zhou, Y., Ji, H., Zhang, T., Liu, S., Ma, L., Deng, D., Ding, Y., & Han, L. (2025). Decoding mechanisms and protein markers in lung–brain axis. Respiratory Research, 26(1), 190.

[25] Abelson, J. L., Khan, S., & Giardino, N. (2010). HPA axis, respiration and the airways in stress – A review in search of intersections. Biological Psychology, 84(1), 57–65.

[26] Kim, I. D., Lee, H., Kim, S. W., Lee, H. K., Choi, J., Han, P. L., & Lee, J. K. (2018). Alarmin HMGB1 induces systemic and brain inflammatory exacerbation in post-stroke infection rat model. Cell Death & Disease, 9(4), 426.

[27] Prass, K., Meisel, C., Höflich, C., Braun, J., Halle, E., Wolf, T., Ruscher, K., Victorov, I. V., Priller, J., Dirnagl, U., et al. (2003). Stroke-induced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by poststroke T helper cell type 1-like immunostimulant. Journal of Experimental Medicine, 198(5), 725–736.