Why Nebulized Antibiotics Should Not Be Routinely Used in Ventilator-Associated Pneumonia

Intuitively, the benefit of nebulized antibiotics for ventilator-associated pneumonia (VAP) always seemed obvious to me: Directly delivering antibiotics to the site of infection should allow for high local concentrations while concomitantly minimizing systemic toxicity. Thus, over the years, I have prescribed multiple times nebulized antibiotics for VAP caused by difficult-to-treat organisms. However, intuition can be unreliable in medicine. In this post, I will explore the role of nebulized antibiotics by addressing the following questions:

1) Why are the benefits of nebulized antibiotics less obvious than they seem?

2) Why is there no robust evidence for nebulized antibiotics?

3) What are the controversies around the implementation of nebulized antibiotics?

1) Why the benefits of nebulized antibiotics are less obvious than they seem

Many advantages are often cited for nebulized antibiotics (1-3). While these seem logical, lets take a closer look at the main ones:

A. In VAP, nebulized antibiotics reach higher concentrations in the lung parenchyma.

As nebulization delivers antibiotics directly to the lungs, it is often promoted as a way to achieve higher local concentrations compared to parenteral administration (4). However, some caveats:

• First, most reported concentrations are measured in the epithelial lining fluid, which may overestimate the clinically more relevant interstitial concentrations by up to 100-fold (4,5).

• Moreover, direct deposition of nebulized antibiotics in severely injured lungs is limited and delayed (4,6,7), though indirect penetration into consolidations occurs, possibly via aerated bronchioles and intraparenchymal pseudocysts (8).

• Additionally, VAP increases alveolar-capillary barrier permeability, leading to greater penetratin of parenteral administered aminoglycosides into lung consolidations (8).

• Finally, in VAP with bacteremia, nebulized antibiotics alone are insufficient, as they do not reach adequate plasma concentrations. This is especially the case for polymyxins (7).

B. Nebulized antibiotics have fewer side effects than parenteral antibiotics.

Nebulized antibiotics are often considered less toxic due to limited systemic penetration (1-3). However, this does not apply to aminoglycosides(8). Because VAP increases alveolar-capillary permeability, nebulized aminoglycosides diffuse into the systemic compartment, potentially achieving plasma concentrations similar to intravenous administration (8). By contrast, nebulized polymyxins have limited systemic diffusion (9). As a consequence, nephrotoxicity is less frequent than with parenteral administration (1). However, bronchospasm and bronchial irritation are more common due to inhalation of solutions with high osmolality or certain preservatives (1,9,10).

Beyond drug-related side effects, the nebulization process itself has its own repercussions. To optimize drug delivery in the distal alveoli, the ventilator must be set to a low flow, low frequency mandatory mode (4). However, this often requires significant sedation to avoid patient-ventilator dyssynchrony (10). As a result, patients may end up deeply sedated for 60 minutes per nebulization, up to three times a day (1), potentially delaying extubation. Moreover, in severely injured lungs, the optimal ventilator settings for nebulization may be unachievable due to lung derecruitment and hypercapnia (11).

2) Why there is no robust evidence for nebulized antibiotics

Nebulized antibiotics are widely used in critically ill patients. For example, an international survey of 410 intensive care units found that 75% reported administering nebulized antibiotics for VAP, most commonly polymyxins and aminoglycosides (12). However, despite their frequent use, a recent review of systematic reviews concluded that the evidence supporting nebulized antibiotics is weak and biased (5). Moreover, the different randomized controlled trials are very heterogenous, mainly in the following areas (5):

I. Substitution or adjunctive strategy?

The literature supports co-administering nebulized antibiotics with a backbone of parenteral antibiotics from a different class (1). However, the limited studies on nebulized antibiotics disagree on whether they should be given together with (substitution) or without (adjunctive) their respective intravenous form (1).

• For aminoglycosides, a substitution strategy is not logical, as nebulized antibiotics penetrate the systemic circulation due to a leaky alveolar-capillary barrier and may reach plasma concentrations similar to parenteral administration (8). Concomitant nebulized and parenteral administration will only increase toxicity (8). As previously noted, nebulized polymyxins poorly diffuse into the blood (7). However, parenteral administration is associated with increased toxicity (7).

• Even guidelines disagree on the optimal strategy. Whereas the 2017 ESCMID position paper recommended that further randomized trials should focus on a substitution strategy (while acknowledging the aforementioned caveats) (11), the 2016 American guidelines recommended an adjunctive strategy for VAP caused by Gram-negative bacilli susceptible only to aminoglycosides or polymyxins (13).

II. Which dose to nebulize?

Another source of heterogeneity is the dosing of the nebulized antibiotics: studies differ considerably in both the dose and diluent volume of the nebulized antibiotic, which makes meta-analyses nearly impossible (5). Below is an overview of the dosing controversy for the two most important classes of nebulized antibiotics:

Aminoglycosides: In two of the few recent randomized trials, amikacin was dosed at 600-800 mg/day, based on high epithelial lining fluid concentrations achieved in an observational study of 28 mechanically ventilated patients (14). Unfortunately - as previously noted - epithelial lining fluid concentrations substantially overestimate the clinically relevant concentration in the lung interstitium, likely leading to under-dosing of the nebulized antibiotics in these studies and, consequently, negative trial results (14). In contrast, animal studies suggest that much higher doses of nebulized amikacin (up to 45 mg/kg/day) may have greater bactericidal activity (8). Some authors also recommend such high doses in humans (15).

Polymyxins: The use of nebulized colistin methanesulfonate (CMS) has been studied in over 20 articles in the past 20 years, most of which are retrospective (7). Until 2015, CMS doses of up to 6 million IU/day were applied (7). Since then, higher doses (9-15 million IU/day) have been used, based on animal data indicating increased efficacy at these levels (7). However, the optimal dose of polymyxins in clinical practice remains unclear and unfortunately, therapeutic drug monitoring may be unhelpful (7).

III. Which infections to include?

A further criticism of recent randomized controlled trials is that they included too few infections caused by multidrug-resistant bacteria (14). Because of favorable outcomes in the placebo group, the added benefit of nebulized antibiotics could not be demonstrated (14).

3) What are the controversies around the implementation of nebulized antibiotics?

In addition to unclear benefits and lack of robust evidence for effectiveness, the practical implementation of nebulized antibiotics faces several uncertainties. Key controversies include:

A. The type of nebulizer to use

The three most common modalities for nebulizing antibiotics are jet nebulizers, vibrating mesh nebulizers and ultrasonic nebulizers (9). Although ultrasonic nebulizers demonstrate high experimental efficiency for drug delivery, their use is limited by hygienic concerns, higher costs and the potential for heat generated during nebulization to modify the antibiotic (9). Worldwide, jet nebulizers are the most widely used for antibiotic nebulization (2), although they are considered less efficient at depositing aerosolized drugs in the lung parenchyma (2,9). However, a recent pharmacokinetic study has cast doubt on this assumption by demonstrating similar epithelial lining fluid concentrations of polymyxins when delivered via jet or vibrating mesh nebulizers (2). Notably, pharmacokinetic data for polymyxins are currently limited to fewer than 100 patients (2).

B. Stop of heat and moist exchanger

Similarly, most authors recommend stopping heat and moist exchangers (HMEs) before nebulization, as they increase aerosol particle diameter and reduce drug delivery to the lung parenchyma (1,2,4,7,9,14). However, recent studies have not demonstrated improved drug delivery when HMEs are switched off (16). Moreover, this practice leads to a rapid decline in gas humidity, which may aggravate airway injury (17).

Furthermore, as discussed above:

C. Determining the optimal dose of nebulized antibiotics

D. The need for sedation to tolerate low-flow ventilator settings

E. Whether to use nebulized antibiotics as an adjunctive or substitution strategy

My view: Nearly a decade after the European Society of Clinical Microbiology and Infectious Diseases recommended avoiding nebulized antibiotics in invasively mechanically ventilated adults (11), I feel this conclusion remains valid. The benefits of nebulized antibiotics remain uncertain, the supporting evidence is weak to non-existent and their implementation is controversial. Hopefully, future research will shed new light on this promising therapy.

References:

 1. Karaiskos I, Gkoufa A, Polyzou E, et al. High-Dose Nebulized Colistin Methanesulfonate and the Role in Hospital-Acquired Pneumonia Caused by Gram-Negative Bacteria with Difficult-to-Treat Resistance: A Review. Microorganisms. 2023 May 31;11(6):1459.

 2. Kyriakoudi A, Pontikis K, Valsami G, et al. Pharmacokinetic Characteristics of Nebulized Colistimethate Sodium Using Two Different Types of Nebulizers in Critically Ill Patients with Ventilator-Associated Respiratory Infections. Antibiotics (Basel). 2022 Nov 1;11(11):1528.

 3. Szychowiak P, Desgrouas M, Ehrmann S. Inhaled antibiotics in critical care: State of the art and future perspectives. Infect Dis Now. 2022 Sep;52(6):327-333.

 4. Monsel A, Torres A, Zhu Y, et al. Nebulized antibiotics for ventilator-associated pneumonia: methodological framework for future multicenter randomized controlled trials. Curr Opin Infect Dis. 2021 Apr 1;34(2):156-168.

5. Karvouniaris M, Koulenti D, Bougioukas KI, et al. Nebulized Antibiotics for Preventing and Treating Gram-Negative Respiratory Infections in Critically Ill Patients: An Overview of Reviews. Antibiotics (Basel). 2025 Apr 2;14(4):370.

 6. Ansari Z, Battikha J, Singh C, et al. Alveolar distribution of nebulized solution in health and lung injury assessed by confocal microscopy. Physiol Rep. 2024 Oct;12(20):e70018.

 7. Zhu Y, Monsel A, Roberts JA, et al. Nebulized Colistin in Ventilator-Associated Pneumonia and Tracheobronchitis: Historical Background, Pharmacokinetics and Perspectives. Microorganisms. 2021 May 27;9(6):1154. 8. Rouby JJ, Xia J, Dhanani J, et al. Nebulized aminoglycosides for ventilator-associated pneumonia: Methodological considerations and lessons from experimental studies. J Intensive Med. 2024 Oct 16;5(1):12-22.

9. Rello J, Rouby JJ, Sole-Lleonart C, et al. Key considerations on nebulization of antimicrobial agents to mechanically ventilated patients. Clin Microbiol Infect. 2017 Sep;23(9):640-646.

 10. Candel FJ, Salavert M, Estella A, et al. Ten Issues to Update in Nosocomial or Hospital-Acquired Pneumonia: An Expert Review. J Clin Med. 2023 Oct 14;12(20):6526.

 11. Rello J, Solé-Lleonart C, Rouby JJ, et al. Use of nebulized antimicrobials for the treatment of respiratory infections in invasively mechanically ventilated adults: a position paper from the European Society of Clinical Microbiology and Infectious Diseases. Clin Microbiol Infect. 2017 Sep;23(9):629-639.

 12. Alves J, Alp E, Koulenti D, et al. Nebulization of antimicrobial agents in mechanically ventilated adults in 2017: an international cross-sectional survey. Eur J Clin Microbiol Infect Dis. 2018 Apr;37(4):785-794.

 13. Kalil AC, Metersky ML, Klompas M, et al. Executive Summary: 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 Sep 1;63(5):575-82.

 14. Rouby JJ, Monsel A, Leone M, et al. The IASIS, INHALE and VAPORISE trials. Reasons for a triple failure: Study design, aminoglycosides dosing and technique of nebulisation. Anaesth Crit Care Pain Med. 2020 Apr;39(2):179-183.

 15. Rouby JJ, Sole-Lleonart C, Rello J, et al. Ventilator-associated pneumonia caused by multidrug-resistant Gram-negative bacteria: understanding nebulization of aminoglycosides and colistin. Intensive Care Med. 2020 Apr;46(4):766-770.

16. Li J. Reassessing the Role of Heated Humidification During Nebulization: Implications for Clinical Practice. Respir Care. 2024 Sep 26;69(10):1351-1352.

 17. Lellouche F, Bouchard PA. Consequences of Pausing Heated Humidification During Invasive Ventilation. Respir Care. 2024 Sep 26;69(10):1239-1244.