Introduction
(Article introduction authored by ICU Editorial Team)
Difficult-to-treat pulmonary infections caused by multidrug-resistant (MDR) pathogens are a global concern due to increasing incidence and high morbidity/mortality. Nebulized antibiotics are increasingly used for MDR infections, offering advantages like targeted delivery and minimized systemic effects.
Despite experimental evidence, clinical studies confirming efficacy and safety are limited. Nebulized antibiotics, not first-line, gained recent interest due to MDR strains.
Mainly used in critically ill patients for ventilator-associated pneumonia (VAP), which is costly and associated with high morbidity/mortality. VAP, often caused by MDR Gram-negative bacteria, leads to prolonged mechanical ventilation and ICU/hospital stays.
Colistin and aminoglycosides are commonly prescribed nebulized antibiotics. Theoretical benefits include higher infection site concentrations and reduced systemic exposure, potentially curbing antibiotic resistance.
This review covers nebulized antibiotic use in severe respiratory infections in the ICU, addressing pharmacokinetics/pharmacodynamics, delivery methods, clinical evidence, and recommendations for usage.
Pharmacodynamic Targets to Treat Severe Infections
To effectively combat pathogens, antibiotics must achieve concentrations at the infection site surpassing the minimum inhibitory concentration (MIC).
The MIC signifies the lowest antibiotic concentration preventing visible bacterial growth and is pivotal in determining a pathogen’s susceptibility or resistance.
The pulmonary penetration ratio, particularly the antibiotic concentration in the epithelial lining fluid (ELF) compared to plasma, is crucial in assessing the efficacy of bacterial pneumonia treatment.
However, studies in critically ill patients receiving intravenous antibiotics reveal challenges in achieving optimal ELF concentrations due to limited alveolo-capillary barrier permeability and various host- and drug-related factors.
Standard antibiotic regimens often fall short of attaining the necessary Cmax/MIC or AUC/MIC ratios associated with a favorable clinical response. Inadequate ELF concentrations not only increase the risk of therapeutic failure but also elevate the potential for systemic toxicity and the emergence of antibiotic resistance.
Addressing drug-resistant Gram-negative bacteria (GNB), particularly Pseudomonas aeruginosa and Acinetobacter baumannii, presents heightened challenges.
Nebulized administration of colistin and amikacin is advocated to attain localized high antibiotic concentrations, a critical strategy against multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains.
Animal studies have demonstrated the efficacy of nebulized antibiotics, surpassing MICs, and human studies have reported favorable results, with nebulized colistin exceeding MIC breakpoints and nebulized amikacin achieving ELF concentrations well above those obtained through intravenous administration.
Despite these promising findings, understanding the pharmacokinetics of nebulized antibiotics remains incomplete due to challenges in accurately assessing lung interstitial concentrations in human studies. Techniques such as bronchoalveolar lavage have limitations, making precise evaluation challenging.
Nebulized Antibiotics: Technical Issues
Nebulizers convert liquid into inhalable droplets for respiratory treatment. Gas flow carries the aerosol into the lower respiratory tract, with particle deposition relying on impaction, sedimentation, and diffusion mechanisms.
Larger, heavier particles tend to impact in proximal airways, while sedimentation under gravity affects heavy particles. Diffusion deposits the smallest particles in the distal airways.
Particle size, influenced by nebulizer type, impacts pulmonary penetration: particles >5 μm deposit in the upper airways, 3–5 μm in proximal bronchi, and 1–3 μm in alveoli and terminal bronchioles.
Three nebulization techniques—jet, vibrating mesh, and ultrasonic—exist. Vibrating mesh and ultrasonic nebulizers are preferred over jet nebulizers due to their efficiency in particle delivery. Recent studies favor vibrating systems, minimizing liquid retention and avoiding temperature increase.
Proper nebulizer placement, removal of humidifier filters, and avoiding obtuse angles in ventilator connections enhance drug delivery. Controlled volume ventilation with a constant inspiratory flow is recommended to optimize drug delivery, requiring sedation to prevent ventilator–patient asynchrony.
Existing Evidence on the Efficacy of Inhaled Antibiotics
Ceftazidime
In an animal study involving ventilated piglets with P. aeruginosa pneumonia, nebulized ceftazidime demonstrated more effective bacterial killing compared to intravenous administration, highlighting its potential in treating lung infections with reduced susceptibility to ceftazidime [38].
A prospective randomized study with 40 patients experiencing ventilator-associated pneumonia (VAP) caused by P. aeruginosa compared dual therapy with intravenous ceftazidime and amikacin to exclusively nebulized therapy.
After 8 days of antibiotic administration, there were no statistically significant differences in the cure rate, duration of mechanical ventilation, ICU length of stay, or mortality between the two treatment arms.
However, in the nebulized therapy group, Pseudomonas regrowth or persistence exclusively occurred with susceptible strains, while in the intravenous group, half of the strains had become intermediate or resistant to one or both drugs.
Fosfomycin
In a prospective, randomized study in pigs [40] with severe pneumonia due to P. aeruginosa resistant to amikacin and fosfomycin but susceptible to meropenem, intravenous meropenem was compared to different combinations of nebulized antibiotics.
The pigs were randomized to receive either nebulized saline solution four times a day (QID), nebulized amikacin QID, nebulized fosfomycin QID, intravenous meropenem three times a day (TID), nebulized amikacin and fosfomycin QID, or nebulized amikacin and fosfomycin QID with intravenous meropenem TID.
This study demonstrated that the efficacy of the nebulized antibiotics was greatest in tracheal secretions but that intravenous meropenem was needed to reduce the bacterial loads of P. aeruginosa in lung tissue.
Amikacin and Tobramycin
Several studies have examined the efficacy and safety of nebulized aminoglycosides, yielding conflicting results.
A retrospective study in ventilated surgical ICU patients with Gram-negative bacteria (GNB) VAP showed that nebulized aminoglycosides (tobramycin or amikacin) alongside systemic therapy resulted in clinical resolution and quicker weaning from mechanical ventilation [41].
Another retrospective study compared clinical outcomes in P. aeruginosa and A. baumannii VAP patients treated with intravenous antibiotics plus nebulized antibiotics (colistin or tobramycin) to those receiving intravenous antibiotics alone, revealing significantly lower 30-day mortality in the nebulized group [46].
Nebulized antibiotics, mainly tobramycin, achieved clinical and microbiological success in approximately 70% of patients with VAP caused by P. aeruginosa and/or A. baumannii, and even in cases where systemic antibiotics failed, the addition of nebulized antibiotics resulted in clinical success in 85% of instances [46].
However, large randomized controlled trials, including IASIS, INHALE, and VAPORISE, showed no survival benefit with nebulized aminoglycosides combined with intravenous antibiotics in treating VAP, possibly due to heterogeneous populations, pathogen variations, sub-optimal nebulized doses, and non-optimal ventilator settings.
Colistin
Numerous studies, including randomized controlled trials (RCTs), have explored the use of nebulized colistin for treating multidrug-resistant (MDR) ventilator-associated pneumonia (VAP) and ventilator-associated tracheobronchitis (VAT).
Varied study designs, including nebulized colistin alone or in combination with intravenous administration, have been employed with varying daily doses and treatment durations. In an RCT involving 100 patients with MDR VAP, those receiving nebulized colistin alongside systemic antibiotics showed significantly improved microbiological outcomes compared to a control group, but no significant difference in favorable clinical outcomes.
Another RCT compared the efficacy of nebulized and intravenous colistin alone or in combination with intravenous beta-lactam antibiotics in MDR Gram-negative bacteria (GNB) VAP patients, finding no statistically significant benefit in clinical efficacy but improved PaO2/FiO2 ratio, bacterial eradication time, and earlier weaning from mechanical ventilation in the nebulized colistin group.
A meta-analysis reported a 70% success rate with nebulized colistin monotherapy for respiratory tract infections caused by MDR or colistin-only susceptible GNB.
While some meta-analyses showed better clinical and microbiological responses with lower infection-related mortality for combined intravenous and nebulized colistin compared to intravenous therapy alone, conflicting results and limitations exist, warranting further studies to determine the equivalence or superiority of nebulized colistin over intravenous treatment.
Vancomycin
In a non-comparative study, 21 critically ill ventilated patients with MRSA VAP were treated with a 7-day course of endotracheal vancomycin, intravenous linezolid plus rifampicin, nasal mupirocin, and decontamination.
The treatment achieved a clinical cure rate of over 95%, effectively eradicating MRSA.
In an RCT for VAT, nebulized vancomycin and/or gentamicin significantly reduced VAP development, respiratory infection symptoms, facilitated weaning, and lowered bacterial resistance compared to placebo, with no significant mortality difference.
Another RCT for high-risk VAP patients showed nebulized vancomycin and/or aminoglycoside, alongside systemic treatment, led to higher pathogen eradication and clinical improvement, with no significant differences in mortality or ventilation duration.
In a non-comparative study of 20 mechanically ventilated patients with MRSA pneumonia, nebulized vancomycin alongside intravenous treatment resulted in a 65% clinical cure/improvement rate and 70% microbiological eradication, surpassing systemic vancomycin results.
Adverse Effects of Nebulized Antibiotics
Nebulized administration of antibiotics, such as aminoglycosides or colistin, is assumed to reduce nephrotoxicity due to lower systemic passage.
Some studies have reported a lower incidence of renal failure with nebulized antibiotics compared to intravenous administration, particularly with colistin or amikacin.
However, not all studies have observed this potential benefit, especially when evaluating nebulized colistin in addition to intravenous colistin.
While the inhalation route doesn’t fully protect against systemic drug passage and renal impairment, a systematic review in critically ill adults receiving mechanical ventilation showed no increased nephrotoxicity risk when adding nebulized antibiotics to intravenous therapy.
Pulmonary adverse effects during nebulized antibiotic administration include cough, bronchospasm, wheezing, desaturation, and hypoxemia, especially in patients with severe hypoxemia. Colistin is often associated with these effects, more so than other antibiotics.
Complications are less common in mechanically ventilated patients compared to those with spontaneous ventilation.
Prolonged nebulization can lead to obstruction of the ventilation circuit and intubation tube. Nebulization may cause airway irritation and inflammation, leading to bronchospasm.
Sedation may be necessary to prevent ventilator–patient asynchrony, potentially affecting the duration of mechanical ventilation.
Conclusions
The 2016 Infectious Diseases Society of America and the American Thoracic Society guidelines recommend adding nebulized antibiotics to systemic treatment for ventilator-associated pneumonia (VAP) caused by multidrug-resistant Gram-negative bacteria (MDR GNB) susceptible to aminoglycosides or polymyxins, particularly as a last-resort treatment for non-responsive cases (weak recommendation, low-quality evidence).
However, the 2017 European Society of Clinical Microbiology and Infectious Diseases advises against nebulized antibiotics for respiratory infections in mechanically ventilated adults due to potential toxicity and insufficient strong evidence of efficacy.
Nebulized antibiotic therapy could be considered in frail, possibly immunocompromised patients with VAP caused by MDR bacteria and a high risk of therapeutic failure, aiming to achieve high drug concentrations at the infection site.
However, for patients with VAP caused by susceptible pathogens, the clinical benefit of nebulized antibiotics is challenging to establish given the simplicity and proven effectiveness of intravenous antibiotic therapy.
Source: Gorham, J.; Taccone, F.S.; Hites, M. How to Use Nebulized Antibiotics in Severe Respiratory Infections. Antibiotics 2023, 12, 267. https://doi.org/10.3390/antibiotics12020267
