span class="cs_fig_con">Figure 1. Of the 234 study patients ventilated > 48 hours, 39 (43%) had heavy colonization only, 34 patients (15%) developed ventilator-associated tracheobronchitis (VAT) and 34 (15%) were diagnosed with ventilator-associated pneumonia (VAP). Note that 7 patients diagnosed with VAT later progressed to VAP. Patients diagnosed with VAT or VAP experienced significantly more ventilator days (p < 0.001) and longer length of stay in the intensive care unit (ICU) (p < 0.001), when compared to patients without VAT or VAP.

Figure 2. Cumulative incident rates of patients developing heavy colonization, ventilator-associated tracheobronchitis (VAT) and pneumonia (VAP) over time using Kaplan-Meier curves. Note that incident rates increased rapidly during the first ten study days and then leveled off.

Table 1. Comparision of baseline variables for patients developing ventilator-associated tracheobronchitis (VAT) versus no VAT.

aAcute Physiology and Chronic Health Evaluation II; bClinical Pulmonary Infection Score at study entry day 1; cClinical Pulmonary Infection Score averaged during whole study days; dClinical Pulmonary Infection Score at VAT diagnosis day; eMICU―Medical intensive care unit; fSICU―Surgical intensive care unit.

not progress to VAP and the 7 VAT patients that progressed to VAP are shown in Table 2. Staphylococcus aureus was isolated in 19/34 patients (56%) of the patients diagnosed with VAT, of which 13/19 (67%) were methicilllin-resistant S. aureus (MRSA) and 6/19 (33%) were methicilllin-sensitive S. aureus (MSSA) that likely reflects increased virulence of S. aureus isolates compared to the other pathogens isolated [21] [22] . Five of the 7 (71%) patients that progressed from VAT to VAP were infected with S. aureus (4 MSSA and 1 MRSA). Klebsiella pneumoniae and Pseudomonas aeruginosa were most common Gram-negative pathogens isolated. Seventy-nine percent of VAT patients had one pathogen infection, 12% had two pathogens and 9% had three pathogens.

As shown in Figure 3, the patient was diagnosed with ventilator associated tracheobronchitis (VAT) on day 2, caused by many (++++) growth of Serratia marcescens (solid circles). Timely and appropriate cefepime was started for VAT caused by Serratia marcescens on days 1 to 8. On day 4, however, there was moderate (+++) growth of Stenotrophomonas maltophilia (open squares). No antibiotics were received for S. maltophilia until day 6, when appropriate trimethoprim/sulfamethoxazole (TMP-SMX) was prescribed up to day 12. On day 8, there was few (+++) growth of Pseudomonas aeruginosa (open triangles). Inappropriate therapy with cefepime resistance based on susceptibility testing) was given for P. aeruginosa until day 11. At the end of study period on day 12, appropriate therapy with amikacin was received for P. aeruginosa. The patient developed ventilator-associated pneumonia (VAP) on day 9 with moderate (+++) growth of S. maltophilia and P. aeruginosa.

Of the 34 VAT patients studied, 25 who received appropriate intravenous antibiotics within 24 hours were compared to 9 patients who did not receive timely appropriate antibiotics (Table 3). The two groups had similar characteristics such as age, sex, body mass index, co-morbidity, Acute Physiology and Chronic Health Evaluation II (APACHE II) score and Clinical Pulmonary Infection Score (CPIS) at VAT diagnosis. As shown in Table 4, no significant differences were observed in VAP rate (20% vs 22%, p = 1.0), ventilator days (11 vs 10 days, p = 0.9), ICU days (20 vs 15, p = 0.1), hospital days (25 vs 19, p = 0.3), or hospital mortality (24% vs 22%, p = 1).

4. Discussion

The incident rate of VAT was 15%, of which 21% later progressed to VAP. Patients developing VAT had significantly increased ventilator, ICU and hospital days which have been observed by others [23] . Seventy-four percent of VAT patients received timely and appropriate antibiotic treatment for VAT. Antibiotic treatment can

Table 2. Pathogens isolated from the 34 patients with ventilator-associated tracheobronchitis (VAT). The VAT patients were grouped into 27 patients that did not progress to VAP versus the 7 patients that progressed to VAP.

Table 3. Baseline variables for the 34 patients with ventilator-associated tracheobronchitis (VAT). Comparison was made between the patients who received appropriate antibiotics within 24 hours of diagnosis and the patients who did not receive appropriate antibiotics.

aAcute Physiology and Chronic Health Evaluation II; bClinical Pulmonary Infection Score; cMICU―Medical intensive care unit; dSICU―Surgical intensive care unit.

be complicated in patients with multiple, new or MDR pathogens, as shown in Figure 3. The predominant pathogens isolated in our study were S. aureus, P. aeruginosa and K. pneumoniae, all of which have increased virulence for lung tissue and higher mortality [21] [24] - [28] .

Our analysis of 34 VAT patients with or without timely appropriate antibiotics treatment did not show statis-

Figure 3. The patient was diagnosed with ventilator associated tracheobronchitis (VAT) on day 2, caused by many (++++) growth of Serratia marcescens (solid circles). Timely and appropriate cefepime was received for Serratia on day 1 to 8. On day 4, there was moderate (+++) growth of Stenotrophomonas maltophilia (open squares). No antibiotics were received for Stenotrophomonas until day 6, when appropriate Trimethoprim/sulfamethoxazole (TMP-SMX) was used till day 12. On day 8, there was few (+++) growth of Pseudomonas aeruginosa (open triangles). Inappropriate cefepime was received for until day 11. At the end of study period on day 12, appropriate amikacin was received for Pseudomonas. The patient developed ventilator-associated pneumonia (VAP) on day 9 with moderate (+++) growth of Stenotrophomonas and Pseudomon.

Table 4. Outcomes of the patients treated with appropriate antibiotics within 24 hours of ventilator-associated thacheobronchitis. VAT diagnosis versus the patients who did not received timely appropriate antibiotics.

aVentilator-associated pneumonia; bIntensive care unit.

tically significant differences in VAP rate, ventilator days, ICU days and hospital stay (Table 4). Of note is that our study was a natural history study used daily assessment of tracheobronchial colonization, which was not reported back to treating physicians. Thus, the use of antibiotics was at the discretion of treating physicians. As shown in Figure 3, it might have been helpful to order timely and appropriate use of antibiotics, if the daily SQ-ETA results were available for treating physicians.

The finding that appropriate antibiotics treatment for VAT did not improve outcomes was disappointing. It is important to emphasize that this was a natural history study and clinicians treated patients at their discretion based on microbiological data they ordered, as they were blinded to surveillance cultures. Antibiotic administration that included prophylaxis as well as therapeutic coverage for other infections occurred throughout the course of the ICU stay. Many patients were treated with numerous antibiotics for other reasons from one day to 2 weeks. Although we evaluated appropriateness and timing of antibiotics referenced to the diagnosis of VAT, it was often impossible to map antibiotic treatment throughout the ICU stay, due to erratic patterns.

Several studies have supported treatment of VAT to prevent VAP and improve patient outcomes, but this is not a current “standard of care” [3] [5] [10] [13] [14] [29] [30] . A controlled and unblinded, multicenter clinical trial assessed the impact of antibiotic therapy for VAT for 22 study patients randomized to “early” antibiotic therapy versus 36 patients given “delayed” therapy” [20] . Early antibiotic therapy for VAT significantly decreased progression to VAP (13% vs 47%, p < 0.05), increased “ventilator free” days (22 vs 36, p < 0.001) and decreased patient mortality (18% vs 47%, p < 0.05). [20] A more recent prospective observational study by Nseir et al demonstrated that appropriate antibiotic treatment was independently associated with reduced risk of transition from VAT to VAP [31] . There were 17 of 122 VAT patients (14%) that progressed to VAP, of which 58 (48%) received appropriate antibiotic treatment, which was the only factor independently associated with reduced transition from VAT to VAP (p = 0.009). Our data showed that 21% of the VAT patients later developed VAP, which was higher than the 14% reported by Nseir and coworkers [31] . There is increasing interest in using intravenous +/− aerosolized antibiotics delivered by improved nebulizers, placed in the ventilators circuit, to treat more virulent or drug-resistant pathogen(s), such as S. aureus, P. aeruginosa, K. pneumoniae or A. baumannii. [21] [24] [26] - [28] [32] . Aerosolized antibiotic therapy can deliver higher doses of antibiotic(s) to lung parenchyma that is not absorbed systemically, and therefore reduces the risk of Clostridium difficile infection.

Our data noted time of progression from VAT to VAP was 1 to 7 days or an average of 3 days. This window allows treating physicians the opportunity to prescribe earlier targeted antibiotics to treat VAT, based on the microbiology results of surveillance cultures (e.g. SQ-ETA) and to follow the host response to treatment. Over the past two years, there has been increased interest in rapid diagnostic methods to identify bacterial pathogens and antibiotic sensitivities in sputum and blood samples, using various techniques, such as MALDI-TOF [33] [34] . These new rapid diagnostic methods may change the current management landscape and facilitate the earlier, appropriate antibiotic treatment for VAT and VAP. We currently have a universal model for treating upper and lower urinary tract infections in patients with pyuria and bacterial culture with ≥105 cfu/ml, which bacteria can be easily drained by urinating or bladder catheter [5] [13] . This treatment model could be extrapolated to the optimal management of VAT.

Our natural history study had several limitations. Small sample size was included in the analysis of antibiotics treatment for VAT. High proportion of patients was on antibiotics at study entry and received inconsistent treatment with antibiotics throughout the ICU stay. Controlled trials with pre-determined antibiotic coverage, strict duration of treatment, testing shorter vs. longer courses of therapy, and comparing standard intravenous +/- aerosolized therapy are needed. We recommend that future studies should focus on earlier diagnosis of VAT, use of randomized, double blind treatment models with assessment of the risks and benefits of intravenous versus aerosolized antibiotics delivered by improved delivery systems [32] .

5. Conclusion

In our intensive care units, 15% of ventilated patients developed VAT. About one fifth of the VAT cases progressed to VAP. VAT was a risk factor for increased ventilator days, longer length of ICU and hospital stay. Staphylococcus aureus was the most common pathogen isolated and had the highest rate of progression from VAT to VAP. Our study showed that about three quarters of patients received timely appropriate antibiotics treatment for VAT. The data collected from the natural course of the antibiotics treatment did not show significant better clinical outcomes for patients who received appropriate antibiotics for VAT. The effectiveness of antibiotics treatment for VAT needed to be carefully assessed with well-designed, larger randomized clinical studies. The time window from VAT to VAP was an average of 3 days, which allowed physicians an opportunity to identify the pathogens, and to treat VAT with targeted appropriate antibiotics in order to prevent VAP, improve patient outcomes and reduce healthcare costs.

Acknowledgements

The authors thank Joyce Pelletier, CRT, CRA, Sarah Zimmerman, MT and special thanks to the respiratory care team, microbiology team, the medical and surgical ICU nurses for their support and assistance with the study.

Abstracts of these data were presented at the 49th Infectious Disease Society of America (IDSA), Annual Meeting, Boston, October MA 2011; the American Society of Chest Physicians, Honolulu, Hawaii, October 2011; the Infectious Diseases of America (IDSA) Week, San Francisco, CA, October 5-8, 2013, and IDSA Week Philadelphia, PA in 2014.

Financial Support

This work was supported by grants from the Wise Foundation, Lahey Clinic (LCID2010-004) and Pfizer Pharmaceuticals (WS480336) to D.E.C.

Conflict of Interests

No conflict.

Cite this paper

Yuxiu Lei,Jana Hudcova,Jawad Rashid,Akmal Sarwar,Wendy Gillespie,Carol Finn,Marie Goggin,Mohamed B. Omran,Edward Boroda,Donald E. Craven,1 1, (2016) Natural History, Outcomes and Antibiotic Treatment for Ventilator-Associated Tracheobronchitis in Critical Ill Patients. Modern Research in Inflammation,05,1-11. doi: 10.4236/mri.2016.51001

References

  1. 1. ATS Board of Directors and the IDSA Guideline Committee (2005) Guidelines for the Management of Adults with Hospital-Acquired, Ventilator-Associated, and Healthcare-Associated Pneumonia. American Journal of Respiratory and Critical Care Medicine, 171, 388-416. http://dx.doi.org/10.1164/rccm.200405-644ST

  2. 2. Chastre, J. and Fagon, J.Y. (2002) Ventilator-Associated Pneumonia. American Journal of Respiratory and Critical Care Medicine, 165, 867-903. http://dx.doi.org/10.1164/ajrccm.165.7.2105078

  3. 3. Craven, D.E., Chroneou, A., Zias, N. and Hjalmarson, K.I. (2009) Ventilator-Associated Tracheobronchitis: The Impact of Targeted Antibiotic Therapy on Patient Outcomes. Chest, 135, 521-528. http://dx.doi.org/10.1378/chest.08-1617

  4. 4. Craven, D.E., Hudcova, J. and Lei, Y. (2011) Diagnosis of Ventilator-Associated Respiratory Infections (VARI): Microbiologic Clues for Tracheobronchitis (VAT) and Pneumonia (VAP). Clinics in Chest Medicine, 32, 547-357. http://dx.doi.org/10.1016/j.ccm.2011.06.001

  5. 5. Craven, D.E., Hudcova, J. and Rashid, J. (2015) Antibiotic Therapy for Ventilator-Associated Tracheobronchitis: A Standard of Care to Reduce Pneumonia, Morbidity and Costs? Current Opinion in Pulmonary Medicine, 21, 250-259. http://dx.doi.org/10.1097/MCP.0000000000000158

  6. 6. Craven, D.E., Lei, Y., Ruthazer, R., Sarwar, A. and Hudcova, J. (2013) Incidence and Outcomes of Ventilator-Associated Tracheobronchitis and Pneumonia. American Journal of Medicine, 126, 542-549.
    http://dx.doi.org/10.1016/j.amjmed.2012.12.012

  7. 7. Dallas, J., Skrupky, L., Abebe, N., Boyle, W.A. and Kollef, M.H. (2011) Ventilator-Associated Tracheobronchitis in a Mixed Surgical and Medical ICU Population. Chest, 139, 513-518.
    http://dx.doi.org/10.1378/chest.10-1336

  8. 8. Karvouniaris, M., Makris, D., Manoulakas, E., Zygoulis, P., Mantzarlis, K., Triantaris, A., Chatzi, M. and Zakynthinos, E. (2013) Ventilator-Associated Tracheobronchitis Increases the Length of Intensive Care Unit Stay. Infection Control & Hospital Epidemiology, 34, 800-808. http://dx.doi.org/10.1086/671274

  9. 9. Niederman, M.S. (2005) The Clinical Diagnosis of Ventilator-Associated Pneumonia. Respiratory Care, 50, 788-796. http://dx.doi.org/10.1201/b14114-9

  10. 10. Nseir, S., Ader, F. and Marquette, C.H. (2009) Nosocomial Tracheobronchitis. Current Opinion in Infectious Diseases, 22, 148-153. http://dx.doi.org/10.1097/QCO.0b013e3283229fdb

  11. 11. Palmer, L.B. (2009) Ventilator-Associated Infection. Current Opinion in Pulmonary Medicine, 15, 230-235. http://dx.doi.org/10.1097/MCP.0b013e3283292650

  12. 12. Torres, A. and Carlet, J. (2001) Ventilator-Associated Pneumonia. European Task Force on Ventilator-Associated Pneumonia. European Respiratory Society, 17, 1034-1045.
    http://dx.doi.org/10.1183/09031936.01.17510340

  13. 13. Craven, D.E., Hudcova, J., Craven, K.A., Scopa, C. and Lei, Y. (2014) Antibiotic Treatment of Ventilator-Associated Tracheobronchitis: To Treat or Not to Treat? Current Opinion in Critical Care, 20, 532-541. http://dx.doi.org/10.1097/MCC.0000000000000130

  14. 14. Nseir, S., Di Pompeo, C., Pronnier, P., Beague, S., Onimus, T., Saulnier, F., Grandbastien, B., Mathieu, D., Delvallez-Roussel, M. and Durocher, A. (2002) Nosocomial Tracheobronchitis in Mechanically Ventilated Patients: Incidence, Aetiology and Outcome. European Respiratory Society, 20, 1483-1489. http://dx.doi.org/10.1183/09031936.02.00012902

  15. 15. Fagon, J.Y. (2006) Diagnosis and Treatment of Ventilator-Associated Pneumonia: Fiberoptic Bronchoscopy with Bronchoalveolar Lavage Is Essential. Seminars in Respiratory and Critical Care Medicine, 27, 34-44. http://dx.doi.org/10.1055/s-2006-933672

  16. 16. Rea-Neto, A., Youssef, N.C., Tuche, F., Brunkhorst, F., Ranieri, V.M., Reinhart, K. and Sakr, Y. (2008) Diagnosis of Ventilator-Associated Pneumonia: A Systematic Review of the Literature. Critical Care, 12, R56. http://dx.doi.org/10.1186/cc6877

  17. 17. Shorr, A.F., Sherner, J.H., Jackson, W.L. and Kollef, M.H. (2005) Invasive Approaches to the Diagnosis of Ventilator-Associated Pneumonia: A Meta-Analysis. Critical Care Medicine, 33, 46-53.
    http://dx.doi.org/10.1097/01.CCM.0000149852.32599.31

  18. 18. Wunderink, R.G. (2000) Radiologic Diagnosis of Ventilator-Associated Pneumonia. Chest, 117, 188S-190S. http://dx.doi.org/10.1378/chest.117.4_suppl_2.188S

  19. 19. Nseir, S., Di Pompeo, C., Soubrier, S., Delour, P., Onimus, T., Saulnier, F. and Durocher, A. (2004) Outcomes of Ventilated COPD Patients with Nosocomial Tracheobronchitis: A Case-Control Study. Infection, 32, 210-216. http://dx.doi.org/10.1007/s15010-004-3167-0

  20. 20. Nseir, S., Favory, R., Jozefowicz, E., Decamps, F., Dewavrin, F., Brunin, G., Di Pompeo, C., Mathieu, D. and Durocher, A. (2008) Antimicrobial Treatment for Ventilator-Associated Tracheobronchitis: A Randomized, Controlled, Multicenter Study. Critical Care, 12, R62. http://dx.doi.org/10.1186/cc6890

  21. 21. Lowy, F.D. (1998) Staphylococcus aureus Infections. The New England Journal of Medicine, 339, 520-532. http://dx.doi.org/10.1056/NEJM199808203390806

  22. 22. Stulik, L., Malafa, S., Hudcova, J., Rouha, H., Henics, B.Z., Craven, D.E., Sonnevend, A.M. and Nagy, E. (2014) Alpha-Hemolysin Activity of Methicillin-Susceptible Staphylococcus aureus Predicts Ventilator-Associated Pneumonia. American Journal of Respiratory and Critical Care Medicine, 190, 1139-1148. http://dx.doi.org/10.1164/rccm.201406-1012OC

  23. 23. Nseir, S., Di Pompeo, C., Soubrier, S., Lenci, H., Delour, P., Onimus, T., Saulnier, F., Mathieu, D. and Durocher, A. (2005) Effect of Ventilator-Associated Tracheobronchitis on Outcome in Patients without Chronic Respiratory Failure: A Case-Control Study. Critical Care, 9, R238.
    http://dx.doi.org/10.1186/cc3508

  24. 24. Crouch Brewer, S., Wunderink, R.G., Jones, C.B. and Leeper Jr., K.V. (1996) Ventilator-Associated Pneumonia Due to Pseudomonas aeruginosa. Chest, 109, 1019-1029.
    http://dx.doi.org/10.1378/chest.109.4.1019

  25. 25. Nseir, S., Deplanque, X., Di Pompeo, C., Diarra, M., Roussel-Delvallez, M. and Durocher, A. (2008) Risk Factors for Relapse of Ventilator-Associated Pneumonia Related to Nonfermenting Gram Negative Bacilli: A Case-Control Study. Journal of Infection, 56, 319-325. http://dx.doi.org/10.1016/j.jinf.2008.02.012

  26. 26. Planquette, B., Timsit, J.F., Misset, B.Y., Schwebel, C., Azoulay, E., Adrie, C., Vesin, A., Jamali, S., Zahar, J.R., Allaouchiche, B., Souweine, B., Darmon, M., Dumenil, A.S., Goldgran-Toledano, D., Mourvillier, B.H. and Bedos, J.P. (2013) Pseudomonas aeruginosa ventilator-associated pneumonia. Predictive factors of Treatment Failure. American Journal of Respiratory and Critical Care Medicine, 188, 69-76. http://dx.doi.org/10.1164/rccm.201210-1897OC

  27. 27. Sawa, T. (2014) The Molecular Mechanism of Acute Lung Injury Caused by Pseudomonas aeruginosa: From Bacterial Pathogenesis to Host Response. Journal of Intensive Care, 2, 10.
    http://dx.doi.org/10.1186/2052-0492-2-10

  28. 28. Van Delden, C. and Iglewski, B.H. (1998) Cell-to-Cell Signaling and Pseudomonas aeruginosa Infections. Emerging Infectious Diseases, 4, 551-560. http://dx.doi.org/10.3201/eid0404.980405

  29. 29. Agrafiotis, M., Siempos, I.I. and Falagas, M.E. (2010) Frequency, Prevention, Outcome and Treatment of Ventilator-Associated Tracheobronchitis: Systematic Review and Meta-Analysis. Respiratory Medicine, 104, 325-336. http://dx.doi.org/10.1016/j.rmed.2009.09.001

  30. 30. Palmer, L.B., Smaldone, G.C., Chen, J.J., Baram, D., Duan, T., Monteforte, M., Varela, M., Tempone, A.K., O’Riordan, T., Daroowalla, F. and Richman, P. (2008) Aerosolized Antibiotics and Ventilator-Associated Tracheobronchitis in the Intensive Care Unit. Critical Care Medicine, 36, 2008-2013.
    http://dx.doi.org/10.1097/CCM.0b013e31817c0f9e

  31. 31. Nseir, S., Martin-Loeches, I., Makris, D., Jaillette, E., Karvouniaris, M., Valles, J., Zakynthinos, E. and Artigas, A. (2014) Impact of Appropriate Antimicrobial Treatment on Transition from Ventilator-Associated Tracheobronchitis to Ventilator-Associated Pneumonia. Critical Care, 18, R129.
    http://dx.doi.org/10.1186/cc13940

  32. 32. Montgomery, A.B., Vallance, S., Abuan, T., Tservistas, M. and Davies, A. (2014) A Randomized Double-Blind Placebo-Controlled Dose-Escalation Phase 1 Study of Aerosolized Amikacin and Fosfomycin Delivered via the PARI Investigational eFlow Inline Nebulizer System in Mechanically Ventilated Patients. Journal of Aerosol Medicine and Pulmonary Drug Delivery, 27, 441-448.

  33. 33. Burnham, C.A., Frobel, R.A., Herrera, M.L. and Wickes, B.L. (2014) Rapid Ertapenem Susceptibility Testing and Klebsiella pneumoniae Carbapenemase Phenotype Detection in Klebsiella pneumoniae Isolates by Use of Automated Microscopy of Immobilized Live Bacterial Cells. Journal of Clinical Microbiology, 52, 982-986. http://dx.doi.org/10.1128/JCM.03255-13

  34. 34. Laffler, T.G., Cummins, L.L., McClain, C.M., Quinn, C.D., Toro, M.A., Carolan, H.E., Toleno, D.M., Rounds, M.A., Eshoo, M.W., Stratton, C.W., Sampath, R., Blyn, L.B., Ecker, D.J. and Tang, Y.W. (2013) Enhanced Diagnostic Yields of Bacteremia and Candidemia in Blood Specimens by PCR-Electrospray Ionization Mass Spectrometry. Journal of Clinical Microbiology, 51, 3535-3541.
    http://dx.doi.org/10.1128/JCM.00876-13

NOTES

*Corresponding author.

Journal Menu >>