Aminoglycosides have a narrow therapeutic index and hydrophilic concentration-dependent kill characteristics. In critically ill patients, aminoglycosides frequently result in an increased volume of distribution (Vd) that can reduce their maximum concentration (Cmax) [16,17]. In fact, IV antibiotics administered are often underdosed, resulting in insufficient lung tissue distribution in critically ill patients with VAP [18]. Furthermore, several in vitro and in vivo studies have reported that the concentration of nebulized aminoglycosides in lung interstitial space fluid and median epithelial lining fluid (ELF) is higher than that of IV aminoglycosides, with no evidence of systemic toxicity [19–23]. Niederman et al. [24] investigated 69 mechanically ventilated patients with gram-negative pneumonia who received inhaled amikacin solution (BAY 41-6551) in combination with systemic antibiotics. The findings of this randomized control trial (RCT) revealed that amikacin distributed well throughout the lung parenchyma, with extremely high tracheal and alveolar concentrations, while sustaining IV concentrations below the threshold of renal toxicity. Based on these findings, several experimental and clinical studies were conducted to evaluate the effects of aerosolized aminoglycosides in HAP/VAP.

In a meta-analysis of five RCTs that involved the administration of adjunctive aminoglycosides or alternatives via the respiratory tract in intubated patients with HAP caused by gram-negative bacteria, the administration via respiratory tract therapy showed a high success rate compared to the control (odds ratio [OR], 2.39; 95% confidence interval [CI], 1.29 to 4.44) (Table 2) [25]. However, it did not exhibit any statistically significant difference in mortality rates. A systemic review and meta-analysis of 11 studies including six RCTs reported that treatment with aerosolized aminoglycosides and colistin could be highly effective in respiratory infections, especially in those caused by resistant pathogens (OR, 1.96; 95% CI, 1.30 to 2.96), with decreased nephrotoxicity, but could compromise mechanical ventilation, especially in hypoxemic patients [26]. However, the results did not demonstrate any significant reduction in mortality rates or mechanical ventilation duration. In the study reported by Hassan et al. [27], the efficacy of nebulized (400 mg twice daily) versus IV (20 mg/kg once daily) amikacin, in adjunct with IV piperacillin-tazobactam, in HAP/VAP caused by MDR GNB strains, was evaluated in a prospective RCT involving 133 postcardiac surgery patients. The nebulized amikacin group showed better clinical cure rates and shorter ICU stays compared to the IV group. However, this study also did not demonstrate significant differences in mortality rates.

Meanwhile, other randomized trials did not present favorable results. An RCT conducted on adjunctive treatment with 300 mg amikacin/120 mg fosfomycin inhalation in 143 VAP patients with gram-negative infection (IASIS trial) did not yield effective results regarding the improvement of clinical outcomes compared to the treatment with standard IV antibiotics, despite demonstrating a reduction in the bacterial burden [28]. In this study, a well-designed formulation containing amikacin, with optimum particle size to ensure deposition in lung tissue, was administered using the highly efficient vibrating mesh nebulizers. The treatment group presented with significantly fewer positive tracheal cultures on days 3 and 7 compared to the placebo group, especially for pan-drug-resistant Acinetobacter. However, similar to the results reported by other studies, this study also showed no difference in either mortality or clinical improvement rates between the two groups at day 14. The recently concluded INHALE program, a global phase III RCT of inhaled amikacin solution (BAY 41-6551) in mechanically ventilated patients with gram-negative pneumonia, did not demonstrate the superiority of standard of care and aerosolized antibiotics compared to the placebo [29]. This program involved 725 patients with gram-negative pneumonia, who were administered with either 400 mg of aerosolized amikacin or saline placebo, both of which were administered every 12 hours for a period of 10 days, along with administration of standard of care IV antibiotics. The results did not demonstrate between-group difference in survival until days 28 to 32 (OR, 0.84; 95% CI, 0.55 to 1.28; p = 0.43). Furthermore, the inhaled amikacin group showed no significant benefits for the secondary endpoints, including pneumonia-related mortality, and duration of mechanical ventilation and ICU stay. Subgroup analyses revealed that no population group benefitted from the use of inhaled amikacin.

The effectiveness of aerosolized antibiotics is affected not only by the drug, but also by the types of nebulizers. In general, vibrating mesh nebulizers deliver antibiotics more efficiently than jet or ultrasonic nebulizers [30–32]. This is because jet nebulizers remain a large amount of medication in its chamber at the end of nebulization, and ultrasonic nebulizers can overheat the antibiotic solution and thus, degrade heat-sensitive drugs. In addition, in terms of application of the nebulizers, inspiratory synchronization of nebulizers is better reduces drug loss than continuous nebulization [33,34]. Therefore, to optimize the delivery of antibiotics by nebulization in mechanically ventilated patients, vibrating mesh nebulizers and inspiratory synchronization should be employed. However, there exists a practical difficulty when vibrating mesh nebulizers are not available.

Colistin, a formerly ‘abandoned’ antibiotic, is gradually gaining popularity because of its potential to overcome VAP caused by MDR pathogens. Owing to physicochemical characteristics, such as high molecular weight, hydrophobicity, and cationic nature of the decapetide, it exhibits low lung tissue penetration when administered through the IV route [9]. Moreover, IV colistin is also associated with incidences of increased nephrotoxicity and neurotoxicity [35]. In studies conducted on animals, colistin administered via inhalation demonstrated higher concentrations in the lung tissue or ELF compared with IV administration [36,37]. Furthermore, several small retrospective studies that evaluated the effects of inhaled colistin in mechanically ventilated patients with MDR pneumonia, reported high rates of clinical response and pathogen eradication [38–40]. These encouraging findings have increased expectations that aerosolized colistin may contribute to the treatment of VAP that does not exhibit responses to conventional treatment methods.

In a pharmacokinetics study conducted on nebulized colistin, a single dose of 80 mg of colistimethate sodium (CMS) (equivalent to 30 mg of colistin base activity [CBA]) led to the achievement of high colistin concentrations in the ELF for up to 4 hours (median 6.7 and 3.9 μg/mL at 1 and 4 hours, respectively), and concentrations were higher than the minimum inhibitory concentration (MIC) breakpoint (2 μg/mL) for A. baumannii and Klebsiella pneumoniae as indicated by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) [41]. However, the median concentration at 4 hours was below the MIC breakpoint (4 μg/mL) for P. aeruginosa. In another study, Boisson et al. [42] showed that following administration of a dose with 2 million international units (MIU) of inhaled CMS (equivalent to 60 mg of CBA), the concentrations of colistin in the ELF were even higher (9.53 to 1,137 mg/L) than those in the plasma (0.15 to 0.73 mg/L), which indicated low systemic exposure and toxicity.

Several clinical studies that have evaluated the benefits of aerosolized colistin in patients with pneumonia have reported mixed results, with randomized trials not demonstrating any significant improvements in clinical cure rates. A randomized trial compared aerosolized colistin with saline in addition to IV antibiotics among 100 patients with VAP caused by MDR P. aeruginosa and/or A. baumannii [43]. Although aerosolized colistin increased microbial eradication (60.9% vs. 38.2%, p = 0.03), no difference was observed in the clinical outcomes (51% vs. 53.1%, p = 0.84). In another randomized single-blind trial involving 149 patients with gram-negative VAP, aerosolized colistin plus IV imipenem administration resulted in a more favorable improvement in respiratory failure (PaO₂/FiO₂ ratio 349 vs. 316 at day 14, p = 0.012), shortened time to microbial eradication (9.89 days vs. 11.26 days, p = 0.023) and earlier weaning from ventilator compared to IV colistin plus IV imipenem administration [44]. However, no difference was observed in the clinical cure rates (67.1% vs. 72%, p = 0.59), the length of stay, and the 28-day mortality between the two groups. Moreover, the study findings showed that the efficacy of aerosolized colistin was not inferior to that of IV colistin administered in the treatment of VAP caused by MDR bacilli, with lower nephrotoxicity.

Similarly, in the meta-analysis conducted by Valachis et al. [45], adjunctive therapy with aerosolized colistin showed significant improvements in clinical outcome (OR, 1.57; 95% CI, 1.14 to 2.15; p = 0.006), microbial eradication (OR, 1.61; 95% CI, 1.11 to 2.35; p = 0.01), and infection-related mortality (OR, 0.58; 95% CI, 0.34 to 0.96; p = 0.04), compared to IV administration only. However, adjunctive therapy with aerosolized colistin did not improve the overall mortality (OR, 0.74; 95% CI, 0.54 to 1.01; p = 0.06).

Despite the above-mentioned limitations, the clinical and microbiological findings of these studies seem to be encouraging. Thus, further investigation is warranted to consider an approach based on inhaled colistin for the treatment of respiratory infections caused by MDR P. aeruginosa and A. baumannii.

The use of aerosolized antibiotics for the purpose of prophylaxis for VAP has not been well established, and there are many concerns regarding antibiotic resistance. In the meta-analysis conducted by Falagas et al. [46], the authors reviewed eight comparative trials (five RCTs and three non-RCTs) that evaluated the prophylactic effects of several antibiotics administered via the respiratory tract. Among these, analysis of the five RCTs showed a low prevalence of ICU-acquired pneumonia among patients who received antibiotic prophylaxis (OR, 0.49; 95% CI, 0.32 to 0.76), whereas no difference in mortality was observed between the compared groups (OR, 0.86; 95% CI, 0.55 to 1.32). However, analysis of the data for evidence regarding antibiotic resistance was not conducted for this study.

Karvouniaris et al. [47] conducted an RCT involving 168 subjects to ascertain whether prophylactic aerosolized colistin would reduce the prevalence rates of VAP caused by gram-negative pathogens. The results did not demonstrate a significant difference in VAP incidence between the colistin group and saline group (16.7% vs. 29.8%, p = 0.07). Additionally, there was no significant difference in the incidence of ventilator-associated tracheobronchitis and colonization rates. Evidence of increased colistin or multidrug resistance was also not reported in the study. Recently, a systematic review and meta-analysis conducted by Povoa et al. [48] presented an evaluation of the role of aerosolized antibiotics in the prevention of VAP in mechanically ventilated patients. Six comparative trials involving 1,158 patients were included in the analysis and it was concluded that the prophylactic use of aerosolized antibiotics reduced the occurrence of VAP (OR, 0.46; 95% CI, 0.22 to 0.97), without any significant change in ICU mortality or incidence of VAP caused by MDR pathogens. However, the current guidelines of both United States and Europe do not recommend the use of aerosolized antibiotics for prophylactic treatment [3,49].

As per the recent HAP/VAP guidelines (2016) of the Infectious Diseases Society of America (IDSA) and American Thoracic Society (ATS), adjunctive therapy with aerosolized antibiotics is recommended along with the administration of systemic antibiotics rather than systemic antibiotics alone for patients with gram-negative VAP (not HAP) ‘only’ susceptible to aminoglycosides or colistin [3]. They also suggested that this therapy could be provided as a last resort for patients who do not exhibit responses to IV antibiotics alone, whether the irrespective of the drug resistance status of the infecting organism. In 2017, the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) recommended that the use of aerosolized antibiotics should be avoided in clinical practice because of insufficient evidence regarding their efficacy and high potential for underestimating risks of developing side effects [50]. Currently, there are no recommendations available for using aerosolized antibiotics as routine adjunctive therapy in HAP/VAP patients.

Currently, there is no insurance coverage for inhaled antibiotic therapy in the Republic of Korea, and aerosolized formulations of antibiotics are not commercialized. Nevertheless, there have been several retrospective studies conducted in Korea regarding the nephrotoxicity caused by aerosolized colistin use and the effects of inhaled colistin monotherapy and, more recently, a comparative study on the use of loading dose (LD) with inhaled or IV colistin has been reported.

In one retrospective study, therapy with adjunctive aerosolized colistin resulted in a high negative bacterial conversion rate (84.6%) and was relatively safe in terms of nephrotoxicity [51]. A daily dose of 300 mg of CBA was administered to 25 patients with VAP caused by MDR gram-negative bacteria in the ICU. Min et al. [52], in a retrospective study, compared the incidence of nephrotoxicity following administration of IV versus aerosolized colistin in a cohort of 464 patients. The results showed that the aerosolized colistin group exhibited a significantly lower incidence of nephrotoxicity compared to the IV group (7.84% vs. 20.26%, p < 0.001).

In another retrospective study that was conducted to investigate the efficacy of nebulized colistin monotherapy, 219 patients with VAP due to carbapenem-resistant A. baumannii were treated with either IV (n = 93) or aerosolized colistin (n = 126) and were evaluated through propensity score matching [53]. The findings showed that the aerosolized colistin group was not inferior to the IV group in terms of clinical failure (adjusted OR [aOR], 0.48; 95% CI, 0.19 to 1.19, p = 0.11) or ICU mortality rates (aOR, 0.36; 95% CI, 0.12 to 1.09; p = 0.070), while a significantly lower incidence of acute kidney injury was observed in the aerosolized colistin group (18% vs. 49%, p = 0.004). Recently, Choe et al. [54] reviewed the retrospective progress in 191 critically ill patients with HAP/VAP caused by carbapenem-resistant gram-negative bacteria. The patients were divided into the following three groups: LD IV group (IV colistin with LD), non-LD IV group (IV colistin without LD), and additional aerosolized (AS)-LD group (AS colistin and IV colistin with LD). No difference was observed in the clinical outcomes of the three groups. However, the microbial eradication rate was markedly higher in the AS-LD group than that in the LD IV and non-LD IV groups (60%, 33%, and 31%, respectively; p = 0.010). Additionally, patients in the AS-LD group demonstrated a significantly lower all-cause mortality rate at 30 days than the patients treated with IV colistin alone (aOR, 0.338; 95% CI, 0.132 to 0.864; p = 0.024). However, no change in nephrotoxicity was observed in the LD or AS-LD groups (p = 0.100).

However, all such studies are single-center and retrospective, and since these studies did not report the use of a standardized dose or inhalation method, the limitations are evident.

Additionally, because of the pharmacokinetic/pharmacodynamics (PK/PD) data of colistin for Koreans were still insufficient, the dose standardization should be prioritized and conduction of a well-designed RCT is warranted to standardize an appropriate antibiotic inhalation protocol.

Through inhalation, the concentration of drugs that enter the systemic blood circulation can be significantly reduced, thereby preventing the occurrence of serious side effects, the most important of which is nephrotoxicity.

In an RCT of HAP/VAP among postcardiac surgery patients conducted by Hassan et al. [27], nebulized amikacin therapy demonstrated reduced nephrotoxicity associated with lower deterioration in kidney function compared to systemic amikacin therapy. However, caution should be exercised in patients with impaired baseline kidney function. Although aerosolized aminoglycosides are generally safe for usage under normal circumstances, systemic absorption may be substantial in patients with renal dysfunction, and thus drug monitoring is recommended for aminoglycoside use [55,56].

In the study conducted by Min et al. [52], although aerosolized colistin was not associated with any significant risk factors for nephrotoxicity, the duration of colistin use and underlying renal function might affect the development of nephrotoxicity. Therefore, the authors recommended a short-term use of aerosolized colistin and evaluation of underlying renal function before treatment to reduce nephrotoxicity. Another retrospective study reported that although aerosolized colistin was considered to be safe for usage, and the incidence of acute kidney injury was high when it was administered with other nephrotoxic drugs, especially aminoglycosides [51].

In summary, aerosolized antibiotics are generally safe in terms of systemic side effects, especially nephrotoxicity. However, the duration of drug administration and underlying renal conditions may affect drug toxicity. Additionally, caution should be exercised when other nephrotoxic drugs are used concurrently, and drug monitoring should be conducted.

Nebulization can lead to the development of direct mucosal toxicity. Particularly, long-term exposure to high concentrations of inhaled antibiotics can cause bronchial toxicity and alveolar damage. Though transient benign cough is common, bronchospasm is a more serious but rare side effect that is reportedly occurs during antibiotic nebulization [23,43,57,58]. In an RCT involving 74 patients with bronchiectasis, along with identification of P. aeruginosa in sputum, patients who were administered with aerosolized tobramycin reported increased cough, wheezing, dyspnea, and non-cardiac chest pain as local side effects, compared to placebo patients, but the symptoms did not pose limitations to the treatment [58]. In another RCT involving 100 patients with gram-negative VAP, all patients received systemic antibiotics and were randomized to receive an additional therapy with nebulized colistin or sterile normal saline for the entire duration of the systemic antibiotic therapy. Bronchospasm was observed in 7.8% of the colistin group and 2.0% of the control group, but there was no statistical significance reported (p = 0.36) [43]. The occurrence of bronchospasm can be diminished by conducting pretreatment with a short-acting bronchodilator. In general, preventive treatment with bronchodilators is not necessary for all patients, although the occurrence of bronchospasm results in aerosol interruption, which necessitates the conduction of bronchodilator nebulization. In this regard, European Respiratory Society guidelines for bronchiectasis state that prior treatment with a bronchodilator is advisable [59].

In conclusion, therapy with aerosolized antibiotics often causes local side effects including mild respiratory symptoms, although the occurrence of serious side effects such as bronchospasm is rare. Therefore, in patients with a high probability of bronchospasm, preventive treatment with bronchodilator may be considered.

In addition to the potential toxicity associated with systemic absorption and local side effects, complications related to nebulization also should be considered. Filtering devices are used during mechanical ventilation to avoid dysfunction of flow and pressure transducers and to contain airborne microorganisms [60,61]. Residual nebulization particles may cause ventilator dysfunction and circuit obstructions. These particles are usually larger than mist and can cause obstruction of the filters, which may lead to increased resistance, and thus, this resistance may serve as auto-positive end-expiratory pressure, leading to increased airway pressure [62,63]. In a randomized phase II trial conducted on VAP caused by P. aeruginosa, nebulization with amikacin or ceftazidime resulted in the obstruction of the exhalation filter in three out of 20 patients [57]. One of these patients experienced cardiac arrest due to the obstruction but recovered completely after cardiopulmonary resuscitation.

Additionally, nebulization is a potential hazard due to the generation of aerosols and droplets that cause infection transmission. In particular, in the current coronavirus disease 2019 (COVID-19) pandemic, concerns about the risk of virus transmission to healthcare workers when using aerosolized antibiotics should be fully considered. According to an in vitro study, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains viable and infectious in aerosols for 3 hours post-nebulization, and is stably maintained on plastic surface for up to 72 hours [64]. In the same context, Global Initiative for Asthma (GINA) guidelines (updated 2021) recommended avoiding aerosol generating procedures, including nebulization, where possible, to reduce the risk of spreading the virus during the COVID-19 pandemic [65]. Nevertheless, if nebulization therapy is required, as a way to reduce transmission of infection to the ambient environment, the use of HEPA filters on the exhaled limb of the ventilator and/or a disposable nebulizer is recommended [66,67]. In addition, maximum protection of the healthcare workers is required for more than 3 hours post-nebulization, and the risk of contamination of the ambient environment by nebulized aerosols should also be considered.

In brief, aerosolized antibiotic usage may cause complications such as exhalation filter obstruction and, therefore, it is necessary to regularly monitor the saturation level of the filter, in addition to frequent changes in cases where optimal ventilation is critical. Furthermore, it should be borne in mind that nebulization can pose a potential hazard due to the generation of aerosols and droplets that cause infection transmission.