Bronchoscopic Improvement of Tracheobronchitis Due to Methicillin-Resistant Staphylococcus aureus After Aerosolized Vancomycin: A Case Series

Abstract

Background:

Ventilator-associated tracheobronchitis (VAT) is an important risk factor for ventilator-associated pneumonia (VAP). The efficacy of aerosolized vancomycin (AV) in treating VAT has not been clearly demonstrated.

Methods:

Four mechanically ventilated patients with methicillin-resistant Staphylococcus aureus (MRSA) pneumonia were treated with an additional AV. AV (250 mg twice per day) was administered through a vibrating mesh device for 5 days. All patients were receiving intravenous vancomycin and had severe tracheobronchitis, based on bronchoscopic findings before or soon after additional AV treatment.

Results:

After several days of AV treatment, follow-up bronchoscopies showed dramatic improvement of tracheobronchitis. All patients achieved microbiological eradication of MRSA. Finally, two of four patients survived through to hospital discharge.

Conclusion:

This case series study suggests a potential role of AV in the treatment of MRSA tracheobronchitis, which were accompanied by VAP. Clinical trial addressing the efficacy of AV in MRSA VAT and/or VAP should be needed.

Introduction

Ventilator-associated pneumonia (VAP) is problematic due to its poor prognosis. Microaspirations from the oral cavity or the gastrointestinal tract, as well as inhalation of bacteria in the endotracheal tube, have been considered the essential pathogenesis of VAP.⁽¹⁾ Beyond VAP, ventilator-associated tracheobronchitis (VAT) is also seen in patients with mechanical ventilation (MV), which is associated with longer intensive care unit (ICU) stay and prolonged MV. ⁽²⁾ Although the relationship between VAT and VAP has not been fully understood, VAT may be considered an important risk factor for VAP. Craven et al.⁽³⁾ reported that approximately one-third of patients with tracheobronchitis developed pneumonia. Furthermore, in one randomized control trial, targeted antibiotic therapies for VAT decreased the development of VAP, and ICU mortality.⁽⁴⁾

In general, systemic antibiotics are the mainstay in the treatment of VAT/VAP. However, unexpected and variable lung penetration of systemic antibiotics might result in a prolonged course of treatment, with subsequent systemic toxicities and antibiotic resistance. As such, aerosolized antibiotics (AAs) have been long proposed as an alternative option.^(5–7) According to developments in nebulizing devices (e.g., ultrasonic or vibrating mesh), the effect of AA treatments has recently been highlighted.^(8,9) Although AAs for VAT/VAP have been mostly used as off-label drugs, several AAs in ICU may provide effective treatment options, including adjunctive inhaled aminoglycosides or polymixins, which are recommended in patients with nosocomial pneumonia.⁽¹⁰⁾

However, aerosolized vancomycin (AV) in this field has been rarely studied and the efficacy of AV in treating VAT has not been clearly demonstrated. We aimed to demonstrate the efficacy of additional AV in mechanically ventilated patients with tracheobronchitis who were also diagnosed with methicillin-resistant Staphylococcus aureus (MRSA) pneumonia.

Materials and Methods

We selected four patients with tracheobronchitis between January 2014 and July 2017. The diagnosis of tracheobronchitis was made when severe mucosal inflammation of the trachea and/or the bronchus was seen using bronchoscopy before or soon after AV treatment. AV (250 mg) was continuously administered for approximately 30 minutes, every 12 hours, with a vibrating mesh device (Aeroneb^® Pro, Aerogen, Ireland), which was placed proximal to the ventilator Y-connector and linked to an aerosol generator. Aerosol treatment lasted for 5 days. The same device was used each day for each patient. Protocols for AV treatment are detailed in Table 1.

Table 1.

Protocols for Aerosolized Vancomycin Treatment

Drug	Vancomycin HCl 500 mg mixed with isotonic saline 10 mL
Nebulizing device	Vibrating mesh
Frequency	250 mg/5 mL nebulizing for 30 minutes every 12 hours
Duration	5 days
Premedication	Salbutamol 2.5 mg inhalation for 15 minutes
Mechanical ventilator setting	Constant inspiratory flow
	Tidal volume 6–8 mL/kg (predicted body weight)
	I: E ratio 1:1.5–1:2.5
	Plateau pressure <30 cm H₂O
	Remove any humidification system and optimize alveolar recruitment
	Proper sedation

These four patients all underwent bronchoscopies to obtain microbiologic samples or bronchial toileting. Serial bronchoscopies were also performed to follow affected lesions. Based on quantitative or semiqualitative culture results, MRSA eradication was assessed at the end of AV treatment. Follow-up cultures were done at day 3, the end of AV treatment, and the end of intravenous treatment.

As this was a study of case series, informed consent was waived for this electronic health record review and this study was approved by the Institutional Review Board (IRB) and Ethics Committee in our institution (IRB No.: B-1708-417-107) in compliance with the Declaration of Helsinki.

Results

Baseline characteristics of the four patients are summarized in Table 2. All patients showed tracheobronchitis improvement in their serial bronchoscopies and achieved MRSA eradication through hospitalization. There were no treatment-related adverse events. Patient 1 underwent bronchoscopy due to bronchial toileting on the second day of AV treatment. Severe ulcerative lesions were observed with purulent secretion at the carina and in the left main bronchus. One day after the end of AV treatment, a follow-up bronchoscopy showed improved status with remnant ulcerative mucosa. Pneumonia was resolved and he survived through to hospital discharge (Fig. 1–A, B).

FIG. 1.

Improvement of tracheobronchitis as seen on serial bronchoscopies. (A, B) A severe ulcerative lesion with purulent secretion at the carina and the left main bronchus was observed on day 2 of AV treatment. One day after the end of AV treatment, an improved status with remnant ulcerative mucosa was noted. (C, D) Improvement of severe mucosal inflammation in the right bronchus intermedius 5 days after the end of AV treatment. (E, F) Severe inflammatory mucosal change with thick secretion in the right main bronchus was observed 6 days before AV treatment. The affected lesion had resolved by 4 days after the end of AV treatment. (G, H) Easy touch bleeding and edematous mucosa at the carina were noted before AV treatment. The affected lesion was partly resolved on day 4 of AV treatment. AV, aerosolized vancomycin. Color images available online at www.liebertpub.com/jamp

Table 2.

Baseline Characteristics, Microbiologic Response, and Final Outcomes of Four Patients

	Patient 1	Patient 2	Patient 3	Patient 4
Years	2014	2014	2015	2016
Age, years	47	81	67	74
Gender	Male	Female	Male	Female
Type of pneumonia	VAP	HAP	VAP	VAP
MRSA cultured sample	ETA	BAL	BAL	BAL
MRSA bacteremia	No	Yes	Yes	No
Other isolates	None	None	Acinetobacter baumannii, Klebsiella pneumoniae	None
CPIS	6	5	5	5
APACHE II	35	32	24	19
MV days before treatment	22	5	18	5
Systemic vancomycin before treatment	8	2	9	1
MRSA eradication	Yes	Yes	Yes	Yes
Outcome	Survived	Death	Death	Survived

APACHE, acute physiology and chronic health evaluation; BAL, bronchoalveolar lavage; CPIS, clinical pulmonary infection score; ETA, endotracheal aspirates; HAP, hospital acquired pneumonia; MRSA, methicillin-resistant Staphylococcus aureus; MV, mechanical ventilation; VAP, ventilator-associated pneumonia.

Patient 2 showed localized consolidations in the right lung field on chest radiograph and underwent bronchoscopy to obtain a bronchoalveolar lavage (BAL) specimen 3 days before AV treatment. Diffuse erythematous hyperemic mucosal inflammation was observed in the right-sided bronchus. Five days after the end of AV treatment, a follow-up bronchoscopy showed an improved status and she was successfully weaned from MV and discharged from ICU. She showed recurrent dynamic airway obstruction on serial bronchoscopies in ICU. However, it occurred episodically even after ICU discharge. She and her family members consented to a “do-not-resuscitate”order and she died from sudden respiratory failure in the general ward (Fig. 1–C, D).

Patient 3 showed diffuse opacities in the right lung on chest radiograph and underwent bronchoscopy to obtain a BAL specimen. Severe inflammatory mucosal change with thick secretions in the right bronchus intermedius was observed. The affected lesion had resolved 4 days after the end of AV treatment. At the time of entry, he also had Acinetobacter (multidrug resistant) and Klebsiella isolates from BAL fluid, which subsequently cleared up after course of intravenous colistin. However, 15 days after the end of AV treatment, recurrent VAP due to multidrug-resistant Acinetobacter baumannii occurred during prolonged MV. Subsequently, he died from massive pulmonary hemorrhage (Fig. 1–E, F).

Patient 4 presented with a small localized infiltration on the right lung and severe mucosal inflammation with bleeding at the carina before treatment. The affected lesion was resolved on day 3 of AV treatment. She continuously improved and survived through to hospital discharge (Fig. 1–G, H).

Discussion

To our knowledge, studies that report AV treatment in MRSA tracheobronchitis are rare and we are the first to describe the dramatic improvements of tracheobronchial inflammation in four mechanically ventilated patients with MRSA pneumonia after AV treatment. Although systemic vancomycin had been administrated, the treatment period before AV treatment was relatively short. In addition, AV treatment was not accompanied with any treatment-related adverse events. Although a microbiological eradication of MRSA and clinical improvement of MRSA pneumonia were achieved in all patients, two of four patients were not finally discharged from the hospital. Some were in an advanced disease state, with MRSA bacteremia and coinfection with gram negative bacilli. However, concurrent causes of death were not directly related to MRSA infection.

The most important aspect of this case series was the visual confirmation of the efficacy of AV in MRSA tracheobronchitis. In general, nosocomial tracheobronchitis (particularly VAT) has been diagnosed clinically. Although there is no clear definition of VAT, Craven et al.⁽¹¹⁾ have proposed diagnostic criteria for tracheobronchitis, considering clinical signs and symptoms, radiologic findings, and microbiology data. However, objective assessment using clinical evaluation for the improvement of tracheobronchitis has been difficult. We consider that these bronchoscopy findings were apt examples of tracheobronchitis.

It is encouraging that MRSA was eradicated in all patients. In mechanically ventilated patients, the endotracheal tube promotes biofilm formation, and persistent colonization and infection commonly develop in airways.^(12,13) In a study by Stulik et al.,⁽¹⁴⁾ systemic vancomycin failed to reduce the MRSA or methicillin-sensitive Staphylococcus aureus burden in the airways among 48 mechanically ventilated patients who were confirmed as S. aureus positive through endotracheal aspirates samples. Subsequently, 38% of patients developed pneumonia despite a minimum 2-day duration of antibiotic treatment.

Systemic vancomycin may have had a limited role in MRSA eradication and improvement of tracheobronchitis because vancomycin poorly penetrates the lung parenchyma, particularly in critically ill patients.^(15,16) Moreover, it is not clear whether systemic treatment led to favorable drug concentration in airway epithelial lining fluid. However, there is also no clear evidence for the role of AV against an MRSA biofilm formation and final clinical outcomes including pneumonia. Further study should be advocated to assess the appropriateness of drug delivery through aerosol route, if we can measure the drug concentration from the airway to alveoli of lung, and the mechanism and role of AV treatment in an MRSA biofilm formation should be identified.

Clinical outcomes in nosocomial pneumonia due to MRSA are still known to be poor.⁽¹⁷⁾ Particularly in mechanically ventilated patients, the role of treating MRSA tracheobronchitis is still unclear in terms of the development of VAP. However, as mentioned earlier, evidence has emerged in favor of VAT treatment. We consider VAT treatment has a significant clinical effect, and the present case series suggests a potential role of AV in the treatment of MRSA tracheobronchitis and accompanied pneumonia.

In summary, this case series study suggests a potential role of AV in the treatment of MRSA tracheobronchitis, which were accompanied by VAP. Clinical trial addressing the efficacy of AV in MRSA VAT and/or VAP should be needed.

Footnotes

Acknowledgments

The authors thank all members of the medical intensive care unit in Seoul National University Bundang Hospital. This research was supported by Grant No. 11-2012-022 from the Seoul University Bundang Hospital Research Fund.

Author Disclosure Statement

The authors declare there are no conflicts of interest.

Reviewed by:

Lucy Pamer

References

Koerner

: Contribution of endotracheal tubes to the pathogenesis of ventilator-associated pneumonia. J Hosp Infect. 1997; 35:83–89.

Nseir

, Di Pompeo

, Pronnier

, Beague

, Onimus

, Saulnier

, Grandbastien

, Mathieu

, Delvallez-Roussel

, and Durocher

: Nosocomial tracheobronchitis in mechanically ventilated patients: Incidence, aetiology and outcome. Eur Respir J. 2002; 20:1483–1489.

Craven

, Lei

, Ruthazer

, Sarwar

, and Hudcova

: Incidence and outcomes of ventilator-associated tracheobronchitis and pneumonia. Am J Med. 2013; 126:542–549.

Nseir

, Favory

, Jozefowicz

, Decamps

, Dewavrin

, Brunin

, Di Pompeo

, Mathieu

, and Durocher

: Antimicrobial treatment for ventilator-associated tracheobronchitis: A randomized, controlled, multicenter study. Crit Care. 2008; 12:R62.

Klastersky

, Geuning

, Mouawad

, and Daneau

: Endotracheal gentamicin in bronchial infections in patients with tracheostomy. Chest. 1972; 61:117–120.

Feeley

, Du Moulin

, Hedley-Whyte

, Bushnell

, Gilbert

, and Feingold

: Aerosol polymyxin and pneumonia in seriously ill patients. N Engl J Med. 1975; 293:471–475.

Klick

, Du Moulin

, Hedley-Whyte

, Teres

, Bushnell

, and Feingold

: Prevention of gram-negative bacillary pneumonia using polymyxin aerosol as prophylaxis. II. Effect on the incidence of pneumonia in seriously ill patients. J Clin Invest. 1975; 55:514–519.

Dhand

: The role of aerosolized antimicrobials in the treatment of ventilator-associated pneumonia. Respir Care. 2007; 52:866–884.

Dhand

: Aerosol delivery during mechanical ventilation: From basic techniques to new devices. J Aerosol Med Pulm Drug Deliv. 2008; 21:45–60.

10.

Kalil

, Metersky

, Klompas

, Muscedere

, Sweeney

, Palmer

, Napolitano

, O'Grady

, Bartlett

, Carratalà

, El Solh

, Ewig

, Fey

, File

Jr , Restrepo

, Roberts

, Waterer

, Cruse

, Knight

, and Brozek

: 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; 63:575–582.

11.

Craven

, Chroneou

, Zias

, and Hjalmarson

: Ventilator-associated tracheobronchitis: The impact of targeted antibiotic therapy on patient outcomes. Chest. 2009; 135:521–528.

12.

Jackson

, Keyser

, and Wozniak

: The role of biofilms in airway disease. Semin Respir Crit Care Med. 2003; 24:663–670.

13.

Prince

: Biofilms, antimicrobial resistance, and airway infection. N Engl J Med. 2002; 347:1110–1111.

14.

Stulik

, Hudcova

, Craven

, Nagy

, and Nagy

: Low efficacy of antibiotics against Staphylococcus aureus airway colonization in ventilated patients. Clin infect Dis. 2017; 64:1081–1088.

15.

Lamer

, De Beco

, Soler

, Calvat

, Fagon

, Dombret

, Farinotti

, Chastre

, and Gibert

: Analysis of vancomycin entry into pulmonary lining fluid by bronchoalveolar lavage in critically ill patients. Antimicrob Agents Chemother. 1993; 37:281–286.

16.

Cruciani

, Gatti

, Lazzarini

, Furlan

, Broccali

, Malena

, Franchini

, and Concia

: Penetration of vancomycin into human lung tissue. J Antimicrob Chemother. 1996; 38:865–869.

17.

Wang

, Zou

, Xie

, Wang

, Zheng

, He

, Dong

, Xing

, and Dong

: Linezolid versus vancomycin for the treatment of suspected methicillin-resistant Staphylococcus aureus nosocomial pneumonia: A systematic review employing meta-analysis. Eur J Clin Pharmacol. 2015; 71:107–115.