Aerosolized Antibiotics to Manage Ventilator-Associated Infections: A Comprehensive Review

Aerosolized Antibiotics to Manage Ventilator-Associated Infections: A Comprehensive Review

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Introduction

Critically ill patients on ventilators are prone to lower respiratory tract infections, ranging from tracheal tube colonization to ventilator-associated tracheobronchitis (VAT) and ventilator-associated pneumonia (VAP). VAP is associated with increased ICU morbidity and mortality, making prevention a top priority. This review focuses on two key aspectsaspects:
(a) Can pre-emptive aerosolized antibiotics (AA) prevent ventilator-associated infections?
(b) Can aerosolized treatment for VAT prevent its progression to VAP?

Eight studies showed favorable results in reducing colonization rates and VAP/VAT progression with AA for prevention. Four studies supported the efficacy of aerosolized treatment for VAT/VAP, improving symptoms and microbiological eradication. However, variations in delivery methods and concerns about resistance emergence limit generalizability. In conclusion, aerosolized antibiotics can be used to manage ventilator-associated infections, especially those with resistant strains. Large randomized controlled trials are needed to confirm benefits, assess antibiotic selection pressure, and provide stronger clinical evidence.

Ventilator-Associated Infections: VAP and VAT

Ventilator-associated pneumonia (VAP) can occur in patients who undergo mechanical ventilation for over 48 hours. Diagnosis requires radiological evidence of pneumonia, along with symptoms such as purulent tracheal secretions, fever, inflammation signs, respiratory distress, and the presence of microorganisms. Ventilator-associated tracheobronchitis (VAT) shares similar diagnostic criteria with VAP, except for the absence of new pulmonary infiltrates. However, VAT may still include misdiagnosed VAP cases if a computed tomography scan is available. Unlike VAP, VAT typically lacks worsening oxygenation and represents a distinct entity between lower respiratory tract colonization and VAP. Patients with VAT or VAP may experience prolonged ventilator, ICU, and hospital stays. VAP is associated with more severe morbidity and higher mortality compared to VAT.

Rationale for the Use of Aerosolized Antibiotics in the Management of Ventilator Associated Infections

Early and appropriate treatment of ventilator-associated pneumonia (VAP) has consistently shown to reduce mortality, but the presence of multidrug-resistant pathogens challenges treatment efficacy. Prevention of VAP is prioritized due to its cost-effectiveness, although airway colonization, ventilator-associated tracheobronchitis (VAT), and VAP are considered a continuum, with VAP being the most severe. Approximately one-fifth of VAT cases progress to VAP within three days, allowing time for diagnosis and treatment administration, potentially preventing VAP, improving patient outcomes, and reducing healthcare costs.

Proper management of VAT is crucial for VAP prevention, avoiding prolonged mechanical ventilation, increased ICU days, difficult weaning, and higher costs. Ventilator-associated infections result from various pathophysiological mechanisms, including the risks associated with mechanical ventilation and the presence of microbial biofilm on the endotracheal tube (ET) surface. Factors such as biofilm formation, microaspiration, suppression of the cough reflex, and disturbances in mucociliary clearance contribute to infection. Positive pressure from the ventilator aids in pushing bacteria from the ET into the respiratory tract. Upper respiratory airway colonization plays a role in VAT and/or VAP with hospital-acquired microorganisms. Ventilator bundles cannot eliminate VAP entirely due to the limitations in preventing microaspiration and biofilm formation, as well as the inability of systemic antibiotics to reach the endotracheal tube and biofilms.

However, local administration of antibiotics through the endotracheal tube offers advantages by directly contacting the tubing system and potentially penetrating the biofilm. This allows for rapid delivery of antibiotics to the target organ, with concentrations exceeding the minimum inhibitory concentration of pathogens. Consequently, this approach may facilitate the eradication of multiple pathogens, including those with drug-resistant strains.

Methods for Delivery of Antibiotics in the Tracheal Tree

Jet nebulizers utilize compressed gas from a wall system or ventilator to create aerosols. They are cost-effective and can be synchronized with each breath, but they have disadvantages such as long treatment time, high residual drug volume, and potential denaturation of medication due to turbulent flow. Ultrasonic nebulizers generate aerosols through high-frequency vibrations, offering flexibility in droplet size. They are more efficient than jet nebulizers but can overheat the drug solution. Vibrating mesh nebulizers are the most efficient for drug delivery, with a short treatment time and minimal drug inactivation.

However, they are costly. It is crucial to consider nebulizer type, ventilator settings, and medication properties to ensure effective delivery to mechanically ventilated patients. Particle deposition in the lungs varies based on lung pathophysiology, breathing pattern, and disease severity. Larger particles deposit in the upper respiratory tract, while smaller particles may be exhaled. Spontaneous mechanical ventilation modes hinder drug delivery, so volume assist-controlled modes are preferred. Adding humidity promotes mucociliary clearance, and using heliox gas improves aerosol penetration. The choice of antibiotic for aerosolization should meet specific criteria to ensure efficacy and safety, avoiding preservatives found in IV formulations.

Aerosolized or Instilled Antibiotics for the Prevention of Ventilator Associated Infections

Recent studies have shown that nebulized antibiotics are ineffective in treating ventilator-associated pneumonia (VAP) or reducing mortality rates, as demonstrated by Phase 2 and 3 trials (IASIS, INHALE). However, prophylactic administration of antibiotics in the tracheobronchial tree could be effective in preventing VAP in ICU patients. Antibiotics administered via intratracheal instillation target the prevention of tube biofilm formation and can also penetrate existing biofilms, reducing microbial growth. In contrast, aerosolized antibiotics primarily settle on the tracheal epithelium to kill existing microbes or inhibit their growth, aiming to reduce bacterial colonization and prevent VAP. Experimental and clinical studies have explored the use of tracheal antibiotics for VAP prevention, focusing on specific antibiotics that are available for nebulization and known to be effective against respiratory infections caused by multidrug-resistant bacteria.

Polymyxin and amikacin are often the only available antimicrobial agents for treating Pseudomonas aeruginosa and Acinetobacter baumannii, the most common pathogens causing VAP in Europe and Asia. Nebulized administration of these drugs has been proposed to achieve high local concentrations that surpass the minimum inhibitory concentration of the pathogens. This approach may be useful in managing colonization and preventing VAP. Initial clinical studies evaluated the use of colistin-polymyxin instilled into the trachea or sprayed into the pharynx to prevent pneumonia caused by Gram-negative bacteria. One study demonstrated a significant reduction in Gram-negative bronchopneumonia incidence with intratracheal colistin instillation, although digestive selective decontamination was also administered alongside tracheal instillation. Mortality rates were not significantly affected, and no infections from colistin-resistant microorganisms were observed.

Another study evaluated the efficacy of aerosolized polymyxin B in preventing P. aeruginosa pneumonia and reported a higher mortality rate for acquired pneumonia compared to studies without polymyxin usage. Some patients developed pneumonia caused by polymyxin-resistant organisms or infrequently pathogenic bacteria. Although these results were not replicated, they raised doubts about the effectiveness of intratracheal instillation of drugs for VAP prevention. A study by Klastersky et al. investigated the effects of endotracheal gentamicin in a randomized double-blind trial. The incidence of tracheal secretion colonization by Gram-negative bacteria was significantly reduced in the gentamicin-treated group, leading to fewer bacteriologically confirmed respiratory tract infections. However, the bacteria isolated from the gentamicin group showed slightly higher resistance to gentamicin compared to the control group, indicating the need for careful consideration to prevent the emergence of resistance.

In a randomized controlled trial, prophylactic nebulized colistin was administered to ICU patients at high risk of VAP caused by multidrug-resistant Gram-negative bacilli. Although the incidence of VAP was lower in the intervention group, the difference was not statistically significant at the 30-day follow-up. However, the intervention group had a lower VAP incidence density rate, fewer VAP episodes from Gram-negative bacteria or multidrug-resistant bacteria, and lower ICU mortality among patients who developed VAP. The control of airway inflammation during VAP episodes may explain the observed survival benefit. Neurosurgical patients, in particular, had a lower incidence of VAP caused by Gram-negative bacteria in the prophylactic colistin group. Notably, the development of colistin-resistant bacteria or multidrug resistance did not differ between the two groups during the study period.

Aerosolized Antibiotics as a Monotherapy for Ventilator-Associated Tracheobronchitis

Aerosolized antibiotics (AA) have been studied as a potential treatment for ventilator-associated tracheobronchitis (VAT). Some studies suggest that AA can improve outcomes by resolving symptoms, reducing systemic antibiotic use, and decreasing bacterial resistance. Palmer et al.discovered that AA may have beneficial outcomes in resolving symptoms of ventilator-associated pneumonia (VAP) and reducing systemic antibiotic usage in critically ill VAT patients. It can also help decrease bacterial resistance, facilitate weaning, and reduce tracheal secretions in patients with multidrug resistant Gram-negative bacteria (MDR-GNB) VAT, potentially lowering the risk of subsequent VAP. Only one patient in their study developed VAP. In a more recent study, Palmer et al. found that AA eradicated the original resistant organism and MDR bacteria compared to a placebo, with fewer resistant organisms observed.

The intervention significantly reduced the severity of illness, tracheal secretions volume, and duration of ventilation in the treatment group. Another ongoing study, the AMIKINHAL study, is evaluating the effectiveness of inhaled amikacin in preventing VAP among 850 patients on mechanical ventilation. Results will be available in 2023. However, the available data on AA for VAT are limited, and systematic reviews have not provided clear conclusions. There are variations in study methods, antibiotic delivery, and outcome definitions. More research, including randomized controlled trials, is needed to determine the effectiveness of aerosolized antibiotics and their role in preventing ventilator-associated pneumonia (VAP) in critically ill patients. The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines recommend against the additional use of aerosolized antibiotics for VAT due to the low quality of available data.

Adverse Effects of the Aerosolized Antibiotic Therapies

The emergence of multidrug-resistant (MDR) bacteria is a concern when using aerosolized antibiotics to prevent infections. However, studies have shown that resistance emergence is not common with aerosolized antibiotics. In a study, the use of nebulized colistin resulted in a reduced risk of MDR pathogen-related ventilator-associated pneumonia (VAP). Another study found that aerosolized antibiotics did not contribute to the emergence of new drug resistance. Despite these findings, concerns about antibiotic resistance and the optimal administration criteria for inhaled antibiotics remain. Scientific societies, such as the American Thoracic Society and the Centers for Disease Control and Prevention, do not recommend the use of aerosolized antibiotics for VAP prevention. Adverse effects, such as airway irritation and inflammation, can occur with aerosolized antibiotics, particularly colistin. Close monitoring and precautions are necessary during administration to minimize potential complications.

Conclusion

Antibiotic aerosolized therapy shows promise in managing ventilator-associated infections, particularly those caused by multidrug-resistant Gram-negative bacteria. However, the available clinical data are limited, and there are still unanswered questions that require further research. This is particularly important due to the significant variations in clinical practices regarding the use of aerosolized antibiotics among patients. To validate the benefits of aerosolized antibiotics and assess their impact on antibiotic selection pressure, large-scale randomized controlled trials are needed. Research should also investigate the potential of early (pre-emptive) treatment of ventilator-associated tracheobronchitis to prevent its progression to ventilator-associated pneumonia, utilizing appropriate nebulized antibiotics, especially in high-risk individuals. Additionally, future studies should focus on optimizing aerosolized treatment by refining delivery device technology, determining optimal antibiotic dosing, and developing specific treatment protocols.

 

Source:  Myrianthefs, P.; Zakynthinos, G.E.; Tsolaki, V.; Makris, D. Aerosolized Antibiotics to Manage Ventilator-Associated Infections: A Comprehensive Review. Antibiotics 2023, 12, 801. https://doi.org/10.3390/antibiotics12050801.

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