Is there literature describing the efficacy or safety of inhaled vancomycin to treat MRSA ventilator-associated tracheobronchitis?

Background

Patients who require mechanical ventilation are at risk for a number of potential complications related to their endotracheal tube, including localized inflammation or damage, unintentional movement or displacement of the tube, and development of infection in the lungs or sinuses.1 One of the infectious complications that can develop in intubated, mechanically ventilated patients is ventilator-associated tracheobronchitis (VAT), which is a lower respiratory infection that is not associated with visible pulmonary infiltrates on a radiograph.2 Consensus has not been reached as to how VAT should be diagnosed; however, the diagnosis is often made with the absence of radiographic findings combined with various clinical and microbiologic findings. Clinical signs that may help to diagnose VAT include fever without another obvious cause, increased or new sputum production, cough, wheezing, bronchospasm, an elevated or depressed white blood cell count, and a purulent endotracheal aspirate (ETA) or bronchoalveolar lavage (BAL).1,3-5 Microbiologic findings include a positive culture of a pathogenic organism from an ETA or BAL. Reports for incidence of VAT have varied between 0 and 16.5% due to the lack of a standardized definition for VAT and the fact that its clinical features overlap with those of ventilator-associated pneumonia (VAP).6 Multidrug-resistant organisms, such as methicillin-resistant Staphylococcus aureus (MRSA), are commonly isolated from samples of patients with VAT.4 In fact, MRSA is the most commonly reported gram-positive pathogen identified in patients with VAT.7

The clinical significance of VAT is unclear. Historically, it was believed to be a condition that did not require antimicrobial treatment; however, more recent literature suggests that VAT may be a precursor or risk factor for development of VAP.1,8 Existing studies have shown conflicting results when investigating whether treatment of VAT reduces development of VAP, as well as other complications including mortality. Some of these studies have shown significant reductions in progression to VAP, days requiring mechanical ventilation, and mortality in the intensive care unit in patients with VAT treated with systemic antibiotics, while others have shown no difference in these outcomes in patients that were and were not treated with antibiotics.9 All but one of the studies assessing the utility of antibiotic treatment for VAT were observational in nature, so it is difficult to determine the true effect of antibiotics in the treatment of VAT. The existing studies also only evaluated intravenous antibiotics. Since systemic antibiotics may reduce complications related to VAT, but their widespread use could lead to development of antibiotic resistance and other associated adverse effects, administration of aerosolized antibiotics via inhalation for the treatment of VAT has been proposed.2 Administration of antibiotics via inhalation allows for concentrated, localized treatment of VAT while minimizing systemic adverse effects and the potential for development of antibiotic resistance. Therefore, the purpose of this FAQ is to review literature assessing the efficacy and/or safety of inhaled vancomycin when used to treat VAT with MRSA, the most common gram-positive organism that is isolated from patients with VAT.

Guideline Recommendations

Organizational guidelines provide minimal guidance on management of VAT, which is likely due to the uncertainties previously described. The 2016 guidelines on hospital-acquired and VAP management from the Infectious Diseases Society of America (IDSA) and the American Thoracic Society recommend against provision of antibiotic treatment in patients with VAT.10 These recommendations are specific to intravenous antibiotics, since the panel excluded 2 studies that assessed inhaled antibiotics. Based on the results of 1 randomized, open-label trial and 4 observational studies, the authors stated that the existing evidence indicates that antibiotic treatment may decrease the length of time that a patient requires mechanical ventilation, but findings are variable as to whether antibiotic therapy improves other clinical outcomes such as duration of hospital stay or mortality. Similarly, the 2014 guidelines from the Society for Healthcare Epidemiology of America (SHEA) and IDSA on prevention of VAP in acute care hospitals recommend against provision of systemic antibiotics in pediatric patients with VAT due to a lack of data on potential risks and how this strategy might impact development of VAP.11 No recommendations on treatment of VAT are provided for adults in the SHEA/IDSA guidelines.

Evidence Summary

Literature assessing the efficacy or safety of inhaled vancomycin for treatment of VAT caused by MRSA is extremely limited. To date, there have only been 2 randomized controlled trials published assessing the efficacy of inhaled antibiotics, including vancomycin, in patients with VAT (Table 1).12,13 Collectively, the 2 trials only assess use of aerosolized vancomycin for the treatment of MRSA in 9 patients, compared to 9 control patients who received an aerosolized placebo. Neither study individualized the results to describe outcomes by the antibiotic received or the organism targeted, so the true benefit of inhaled vancomycin for treatment of VAT caused by MRSA is unable to be determined. However, in general the studies showed that administration of aerosolized antibiotics, including vancomycin, may help to eradicate pulmonary pathogens while limiting the development of antimicrobial resistance. One of the studies also suggested that administration of aerosolized antibiotics may help to prevent development of VAP, and may reduce pulmonary symptoms related to infection in patients with VAT.13 However, the variation in outcomes tested, small total sample sizes, low number of patients with MRSA who were treated with inhaled vancomycin, and concomitant administration of systemic antibiotics to participants in these studies make it difficult to definitively conclude whether or not inhaled vancomycin is an appropriate treatment for VAT.

Table 1. Randomized controlled trials assessing inhaled vancomycin for treatment of VAT12,13
Study design Subjects

 		InterventionsResultsConclusions
Palmer et al 201412

DB, SC RCT		N=42 adult patients requiring intubation and mechanical ventilation who were at high risk for development of MDROs in the respiratory tract and expected to survive for ≥14 days

Patients with these characteristics were then observed and were eligible for inclusion if they displayed prespecified signs of pulmonary infection

To be considered high risk for MDROs, patients were required to have 3 out of 4 of the following risk factors:

·      >5 days in the hospital

·      Use of systemic antibiotics within ≤90 days

·      High frequency of resistance in the hospital

·      Immunosuppression

 		Aerosolized antibiotics (AA; n=24 total; n=16 with MDRO)

Placebo (n=18 total; n=11 with MDRO)

Antibiotic choice based on gram stain of sputum culture:

·      Gram positive: vancomycin 120 mg in 2 mL NS every 8 hours

·      Gram negative: gentamicin 80 mg or amikacin 400 mg in 2 mL NS every 8 hours

·      Both gram positive and gram negative: Both vancomycin and an aminoglycoside

Antibiotics were nebulized via an AeroTech II nebulizer for 14 days or until extubation

Systemic antibiotics were also given before and during the treatment period with AA		·     Of the total patient population, 6 patients in each group had MRSA isolates

·     When considering the full cohort, 96% of organisms present at randomization were eradicated with AA vs 9% with placebo (p<0.0001)

·     Of the patients with MDRO, 88% achieved eradication of the MDRO with AA vs 9% with placebo (p<0.0001)

·     New microbial resistance to systemic antibiotics (not seen at initial randomization) developed in 13% of patients in the AA group vs 55% of patients in the placebo group (p=0.03)		·    The authors concluded that AA eradicated MDRO in tracheal secretions and reduced development of antimicrobial resistance
Palmer et al 200813

DB, SC RCT		N=43 critically ill adults requiring mechanical ventilation for ≥3 days and expected to survive for ≥14 days

Patients with these characteristics were then observed and were eligible for inclusion if they displayed prespecified signs of pulmonary infection

VAT was defined by production of  ≥2 mL of sputum over 4 hours in patients who did not meet CDC-NNIS criteria for VAP		AA (n=19)

Placebo (n=24)

Patients were either given vancomycin or gentamicin (same dosing and administration as described in the Palmer 2014 study) based on gram positive or gram negative sputum cultures, respectively

Systemic antibiotics were permitted and determined by the attending physician when indicated		·     3 patients in each group had bacterial isolates for MRSA

·     After controlling for age, patients who received AA were significantly less likely to demonstrate VAP (as defined by CDC-NNIS) than those treated with placebo (adjusted OR, 0.29; 95% CI, 0.13 to 0.66; p=0.006)

·     On the last day of treatment, CPIS was significantly reduced in patients treated with AA (-1.42 ± SD 2.36; p=0.021), but not placebo (-0.04 ± SD 3.14; p=1)

·   MDRO developed in 33% of patients with placebo vs 0% with AA (p=0.0056) by the end of treatment		·    The authors concluded that AA effectively resolved signs of infection in patients with VAT while reducing development of bacterial resistance
Abbreviations: AA=aerosolized antibiotics; CDC-NNIS=Centers for Disease Control and Prevention National Nosocomial Infection Survey; CI=confidence interval; CPIS=clinical pulmonary infection score; DB=double-blind; MDRO=multidrug-resistant organism; MRSA=methicillin-resistant staphylococcus aureus; NS=normal saline; OR=odds ratio; RCT=randomized controlled trial; SC=single center; SD=standard deviation; VAP=ventilator-associated pneumonia.

In addition to the 2 randomized controlled trials previously described, a case series describing 4 mechanically ventilated patients who received aerosolized vancomycin for treatment of MRSA tracheobronchitis was published in 2018.14 The patients, who ranged in age between 47 and 81 years, were mechanically ventilated for at least 5 days prior to treatment, were determined to have tracheobronchitis based on severe mucosal inflammation of the trachea or bronchus visualized during bronchoscopy, and also had a diagnosis of MRSA pneumonia. Systemic vancomycin was given to all patients at least once prior to administration of aerosolized vancomycin. Tracheobronchitis was treated in all patients with vancomycin 500 mg mixed with 10 mL of isotonic saline and aerosolized via a vibrating mesh nebulizer at a dose of 250 mg over 30 minutes given every 12 hours. Aerosolized vancomycin was administered for a total of 5 days. Repeat bronchoscopies showed improvements in all patients, and MRSA eradication was maintained after treatment throughout hospitalization. Two of the 4 patients died; one died from respiratory failure and the other from massive pulmonary hemorrhage after developing recurrent VAP with multidrug-resistant Acinetobacter baumannii. The authors stated that the causes of death were not directly related to MRSA infection, and concluded that aerosolized may have a potential role in the treatment of MRSA tracheobronchitis in patients who also have pneumonia.

Conclusion

Ventilator-associated tracheobronchitis is an important infectious complication related to endotracheal intubation and mechanical ventilation. There is a lack of consensus as to how VAT should be diagnosed or defined, and limited existing evidence is conflicting as to the clinical implications related to treatment of VAT with antibiotics. Based on the results of 2 small RCTs and a case series, administration of vancomycin via inhalation may help to eradicate MRSA in patients with VAT and potentially reduce other infectious complications. However, the dose, administration technique, and outcomes assessed were variable among studies. Based on these factors, it is unclear whether administration of inhaled vancomycin is an appropriate strategy for treatment of VAT, and whether VAT even warrants treatment with antibiotics. Larger RCTs should be performed to better elucidate the diagnosis and true clinical significance of VAT, and to determine whether antibiotic treatment (either systemic or aerosolized) is warranted.

References

  1. Hyzy R.Complications of the endotracheal tube following initial placement: Prevention and management in adult intensive care patients. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed February 19, 2020.
  2. Koulenti D, Arvaniti K, Judd M, et al. Ventilator-associated tracheobronchitis: To treat or not to treat? Antibiotics (Basel). 2020;9(2):E51. doi: 3390/antibiotics9020051.
  3. Keane S, Vallecoccia MS, Nseir S, Martin-Loeches I. How can we distinguish ventilator-associated tracheobronchitis from pneumonia? Clin Chest Med. 2018;39(4):785-796.
  4. Martin-Loeches I, Povoa P, Rodriguez A, et al. Incidence and prognosis of ventilator-associated tracheobronchitis (TAVeM): a multicenter, prospective, observational study. Lancet Respir Med. 2015;3(11):859-868.
  5. Nseir S, Favory R, Jozefowicz E, et al. Antimicrobial treatment for ventilator-associated tracheobronchitis: a randomized, controlled, multicenter study. Crit Care. 2008;12(3):R62.
  6. Keane S, Vallecoccia MS, Nseir S, Martin-Loeches I. How can we distinguish ventilator-associated tracheobronchitis from pneumonia? Clin Chest Med. 2018;39(4):785-796.
  7. Craven DE, Hudcova J, Rashid J. Antibiotic therapy for ventilator-associated tracheobronchitis: a standard of care to reduce pneumonia, morbidity and costs? Curr Opin Pulm Med. 2015;21(3):250-259.
  8. Salluh JIF, Souza-Dantas VC, Martin-Loeches I, et al. Ventilator-associated tracheobronchitis: an update. Rev Bras Ter Intensiva. 2019;31(4):541-547.
  9. Alves AE, Pereira JM. Antibiotic therapy in ventilator-associated tracheobronchitis: a literature review. Rev Bras Ter Intensiva. 2018;30(1):80-85.
  10. 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 American and the American Thoracic Society. Clin Infect Dis. 2016;63(5):e61-e111.
  11. Klompas M, Branson R, Eichenwald EC, et al. Strategies to prevent ventilator-associated pneumonia in acute care hospitals: 2014 update. Infect Control Hosp Epidemiol. 2014;35(8):915-936.
  12. Palmer LB, Smaldone GC. Reduction of bacterial resistance with inhaled antibiotics in the intensive care unit. Am J Respir Crit Care Med. 2014;189(10):1225-1233.
  13. Palmer LB, Smaldone GC, Chen JJ, et al. Aerosolized antibiotics and ventilator-associated tracheobronchitis in the intensive care unit. Crit Care Med. 2008;36(7):2008-2013.
  14. Cho JY, Kim Y, Lee SH, et al. Bronchoscopic improvement of tracheobronchitis due to methicillin-resistant staphylococcus aureus after aerosolized vancomycin: A case series. J Aerosol Med Pulm Drug Deliv. 2018;31(6):372-372.

Prepared by:
Jessica Elste, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

March 2020

The information presented is current as of February 17, 2020. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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