Nebulized antibiotics. An adequate option for treating ventilator-associated respiratory infection?

Ventilator-associated tracheobronchitis (VAT) is a frequent complication in critical patients. The 90% of those who develop it receive broad-spectrum antibiotic (ATB) treatment, without any strong evidence of its favorable impact. The use of nebulized ATB could be a valid treatment option, to reduce the use of systemic ATB and the pressure of selection on the local flora. Several studies suggest that an adequate nebulization technique can ensure high levels of ATB even in areas of lung consolidation, and to obtain clinical and microbiological cure. New studies are needed to properly assess the impact of treatment with nebulized ATB on the emergence of resistance.

Cystic fibrosis: Epidemiology, clinical manifestations, diagnosis and treatment. / Fibrosis quística: epidemiología, clínica, diagnóstico y tratamiento.

Cystic fibrosis is a genetic and multisystemic disease. The main comorbidity in adulthood is respiratory involvement, with the presence of bronchiectasis, chronic bronchial infection and airflow obstruction. Until a decade ago, treatments were aimed at favoring secretion drainage, reducing respiratory exacerbations, controlling chronic bronchial infection and slowing functional deterioration, but with the advent of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, the cystic fibrosis paradigm has changed. This novel treatment goes a step further in the management of this disease, it is able to improve the production of defective CFTR protein and increase its expression on the cell surface, thus achieving a better functioning of ion exchange, fluidizing respiratory secretions and reducing airflow obstruction. In addition, there are currently different lines of research aimed at correcting the genetic defect that causes cystic fibrosis.

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

BACKGROUND: Ventilator-associated lower respiratory tract infectious complications in critically ill patients cover a wide spectrum of one disease process (respiratory infection), initiating from tracheal tube and/or tracheobronchial colonization, to ventilator associated tracheobronchitis (VAT) and ventilator-associated pneumonia (VAP). VAP occurence has been associated with increased intensive care unit (ICU) morbidity (ventilator days, as well as length of ICU and hospital stay) and ICU mortality. Therefore, treatments that aim at VAP/VAT incidence reduction are a high priority. AIM: The aim of the present review is to discuss the current literature concerning two major aspects: (a) can aerosolized antibiotics (AA) administered in a pre-emptive way prevent the occurrence of ventilator-associated infections? and (b) can VAT treatment with aerosolized avert the potential evolution to VAP? RESULTS: There were identified eight studies that provided data on the use of aerosolized antibiotics for the prevention of VAT/VAP. Most of them report favorable data on reducing the colonisation rate and the progression to VAP/VAT. Another four studies dealt with the treatment of VAT/VAP. The results support the decrease in the incidence to VAP transition and/or the improvement in signs and symptoms of VAP. Moreover, there are concise reports on higher cure rates and microbiological eradication in patients treated with aerosolized antibiotics. Yet, differences in the delivery modality adopted and resistance emergence issues preclude the generalisability of the results. CONCLUSION: Aerosolized antibiotic therapy can be used to manage ventilator-associated infections, especially those with difficult to treat resistance. The limited clinical data raise the need for large randomized controlled trials to confirm the benefits of AA and to evaluate the impact on antibiotic selection pressure.

Randomized control study of nebulized colistin as an adjunctive therapy in ventilator-associated pneumonia in pediatric postoperative cardiac surgical population.

Background: Ventilator-associated pneumonia (VAP) with multidrug-resistant (MDR) gram negative organisms is a common problem in intensive care unit (ICU). Aerosolized antibiotics enhance the efficacy of systemic antibiotics when added as adjuvants. Aim: The primary objective of the study was to compare the clinical and bacteriological outcome of patients with VAP who were administered intravenous (IV) antibiotics alone with those patients who were treated with adjunctive nebulized colistin (NC) along with IV antibiotics. The secondary objective was to study the occurrence of any adverse events during colistin nebulization. Settings and Design: The study was a prospective, randomized, double-blinded controlled study conducted at a tertiary-care teaching institution. Materials and Methods: Ninety-eight children from surgical ICU aged less than 12 years who were diagnosed with VAP due to gram negative bacteria following cardiac surgery were chosen and divided randomly into two groups. The experimental group (NC group) was treated with systemic antibiotics along with NC, whereas the control group (NS group) was administered systemic antibiotics with nebulized normal saline (NS). Clinical and bacteriological outcomes were noted. Statistical analysis was done using SPSS Version 20.0 software. The patient characteristics were compared using independent Student's t test and Chi-square test. Results: There was a statistically significant reduction in the duration of mechanical ventilation, postoperative ICU and hospital stay (P < 0.05) in the NC group compared with the NS group. Conclusion: Aerosolized colistin may be considered as an adjunct to systemic IV antibiotics in pediatric patients with VAP due to gram negative bacteria susceptible to colistin.

Inhaled Colistimethate Sodium in the Management of Patients with Bronchiectasis Infected by Pseudomonas aeruginosa: A Narrative Review of Current Evidence.

International guidelines on the treatment of bronchiectasis indicate that the use of inhaled antibiotics is effective, especially in symptomatic chronic bronchial infection (CBI) due to Pseudomonas aeruginosa (PA). To date, however, no such treatment has been approved by regulatory agencies. Of the inhaled antibiotics on the market, colistimethate sodium (colistin) is one of the most used in many countries, either in its nebulized presentation or as dry powder. Among the characteristics of this antibiotic, it is worth noting that its main target is the lipopolysaccharide in the outer membrane of the cell wall of gram-negative bacteria and that it has a low rate of resistance to PA (<1%). Most observational studies have shown that the use of colistin in patients with bronchiectasis and CBI due to PA results in a decrease in both the number and severity of exacerbations, an improvement in quality of life, a decrease in sputum volume and purulence, and a high rate of PA eradication, although there are no clear differences with respect to other inhaled antibiotics. However, the lack of randomized clinical trials (RCT) with positive results for its main variable (exacerbations) in an intention-to-treat analysis has prevented its approval by regulatory agencies as a formal indication for use in bronchiectasis. The PROMIS program, made up of two RCT with identical methodology, is currently underway. The first of these RCT (already concluded) has demonstrated a clearly positive effect on the group randomized to colistin in its main variable (number of annual exacerbations), while the results of the second are still pending. This review presents exhaustive information on the pharmacological and microbiological characteristics of colistin, the results of the studies carried out to date, and the future challenges associated with this treatment.

The effect of nebulized antibiotics in children with tracheostomy.

INTRODUCTION: Children with tracheostomy have an increased risk of bacterial colonization and infection of the lower respiratory tracts. This study aimed to investigate the effects of nebulized antibiotics on the bacterial load, the need for oral antibiotics, the number of hospitalizations, and the length of stay in the intensive care unit in tracheotomised children with persistent colonization. METHODS: Children with tracheostomy and persistent bacterial colonization who were started on nebulized antibiotic therapy after a lower respiratory tract infection were included in the study. Nebulized gentamicin or colistin were used according to the results of the tracheal aspirate cultures. Demographic and clinic characteristics were recorded from one year prior until one year after initiation of nebulized antibiotic treatment. RESULTS: Nebulized antibiotic treatment was initiated in 22 patients. Nebulized gentamicin was administered to 14 patients (63.6%) and colistin to 8 patients (36.4%). The median duration of treatment was 3 months (range 2-5 months). Following nebulized antibiotic treatment, median number of hospitalizations decreased from 2 (range 1.0-3.5) to 1 (range 0.0-1.5) (p = 0.04). The median length of stay in the intensive care unit reduced significantly from 89.5 days (range 43.0-82.5) to 25 days (range 7.75-62.75) after starting nebulized antibiotics (p = 0.028). Following nebulized antibiotic treatment median bacterial colony count also decreased (from 105 CFU/ml (range 105-106) to 6 × 104 CFU/ml (range 104-105); p = 0.003). There were no significant side effects during nebulized antibiotic therapy. CONCLUSIONS: The use of nebulized antibiotics reduced the number of hospitalizations, length of stay in the intensive care unit, and bacterial load in tracheotomised children with persistent airway colonization without significant side effects. The use of nebulized antibiotics showed a statistically significant decrease in the measures studied. Use of nebulized antibiotics may help to decrease the health care burden of these children, families and health care system. Further studies are needed to determine the indications and optimal duration of long-term nebulized antibiotic treatment in children with tracheostomy.

Comparative lung distribution of radiolabeled tobramycin between nebulized and intravenous administration in a mechanically-ventilated ovine model, an observational study.

BACKGROUND: Ventilator-associated pneumonia is common and is treated using nebulized antibiotics. Although adequate pulmonary biodistribution is important for antibiotic effect, there is a lack of data for both intravenous (IV) and nebulized antibiotic administration during mechanical ventilation. OBJECTIVE: To describe the comparative pulmonary regional distribution of IV and nebulized technetium-99m-labeled tobramycin (99mTc-tobramycin) 400 mg in a mechanically-ventilated ovine model. METHODS: The study was performed in a mechanically-ventilated ovine model. 99mTc-tobramycin 400 mg was obtained using a radiolabeling process. Computed tomography (CT) was performed. Ten sheep were given 99mTc-tobramycin 400 mg via either an IV (five sheep) or nebulized (five sheep) route. Planar images (dorsal, ventral, left lateral and right lateral) were obtained using a gamma camera. Blood samples were obtained every 15 min for 1 h (4 time points) and lung, liver, both kidney, and urine samples were obtained post-mortem. RESULTS: Ten sheep were anesthetized and mechanically ventilated. Whole-lung deposition of nebulized 99mTc-tobramycin 400 mg was significantly lower than with IV (8.8% vs. 57.1%, P<0.001). For both administration routes, there was significantly lower deposition in upper lung zones compared with the rest of the lungs. Dorsal deposition was significantly higher with nebulized 99mTc-tobramycin 400 mg compared with IV (68.9% vs. 58.9%, P=0.003). Lung concentrations of 99mTc-tobramycin were higher with IV compared with nebulized administration. There were significantly higher concentrations of 99mTc-tobramycin in blood, liver and urine with IV administration compared with nebulized. CONCLUSIONS: Nebulization resulted in lower whole and regional lung deposition of 99mTc-tobramycin compared with IV administration and appeared to be associated with low blood and extra-pulmonary organ concentrations.

Uninterrupted Continuous and Intermittent Nebulizer Therapy in a COVID-19 Patient Using Sequential Vibratory Mesh Nebulizers: A Case Report.

Interruptions in continuous nebulized pulmonary vasodilators, such as epoprostenol, can potentially result in clinical deterioration in respiratory status. Coadministration of other intermittent nebulized therapies may require opening the ventilator circuit to facilitate administration. However, in patients with SARS-CoV2 infection, it is preferred to avoid opening the circuit whenever feasible to prevent aerosolization of the virus and exposure of health care workers. In this study, we describe a unique method of administering continuous epoprostenol nebulization and intermittent nebulized antibiotics, mucolytics, and bronchodilators, using Aerogen vibrating mesh nebulizers without interruptions in epoprostenol or opening the ventilator circuit. This technique set up consisted of stacking two Aerogen nebulizer cups, each with its own controller. This approach was successful in allowing concomitant delivery of intermittent and continuous nebulized therapy without interruptions. To our knowledge, this method has not been previously described in the literature and may be helpful to bedside clinicians facing a similar clinical scenario.

Effectiveness of treatment with nebulized colistin in patients with COPD.

OBJECTIVES: To analyze whether the introduction of nebulized colistin in patients with chronic obstructive pulmonary disease (COPD) and infection with Pseudomonas aeruginosa (PA) is associated with a decrease of the number and duration of severe exacerbations. MATERIALS AND METHODS: Thirty six patients with COPD and infection with PA treated with nebulized colistin attending a day hospital during a 5-year (January 2010-December 2014) period were prospectively included. Repeated-measures t-tests were used to assess whether the introduction of colistin was associated with changes in the number of exacerbations or the length of the hospitalizations, comparing for each patient the year prior to the introduction of colistin with the year after. RESULTS: After the introduction of colistin, the number of admissions decreased from 2.0 to 0.9 per individual year (P=0.0007), and hospitalizations were shorter (23.3 vs 10.9 days, P=0.00005). These results persisted when patients with and without bronchiectasis or with and without persistence of Pseudomonas were separately analyzed. No pre-post differences were detected in the number of exacerbations not requiring admission. CONCLUSION: Nebulized colistin seems associated with a strong decrease in the number and duration of hospitalizations due to exacerbation in patients with COPD and infection with PA. Clinical trials with a larger number of patients are needed in order to confirm these results.

Global survey on nebulization of antimicrobial agents in mechanically ventilated patients: a call for international guidelines.

Nebulized antimicrobial agents are increasingly administered for treatment of respiratory infections in mechanically ventilated (MV) patients. A structured online questionnaire assessing the indications, dosages and recent patterns of use for nebulized antimicrobial agents in MV patients was developed. The questionnaire was distributed worldwide and completed by 192 intensive care units. The most common indications for using nebulized antimicrobial agent were ventilator-associated tracheobronchitis (VAT; 58/87), ventilator-associated pneumonia (VAP; 56/87) and management of multidrug-resistant, Gram-negative (67/87) bacilli in the respiratory tract. The most common prescribed nebulized agents were colistin methanesulfonate and sulfate (36/87, 41.3% and 24/87, 27.5%), tobramycin (32/87, 36.7%) and amikacin (23/87, 26.4%). Colistin methanesulfonate, amikacin and tobramycin daily doses for VAP were significantly higher than for VAT (p < 0.05). Combination of parenteral and nebulized antibiotics occurred in 50 (86%) of 58 prescriptions for VAP and 36 (64.2%) of 56 of prescriptions for VAT. The use of nebulized antimicrobial agents in MV patients is common. There is marked heterogeneity in clinical practice, with significantly different in use between patients with VAP and VAT. Randomized controlled clinical trials and international guidance on indications, dosing and antibiotic combinations to improve clinical outcomes are urgently required.

Lung function comparison between two decades in cystic fibrosis children: A single centre study.

OBJECTIVES: The purpose of this study was to compare two cohorts of cystic fibrosis (CF) patients born and treated in two different decades, diagnosed through a CF neonatal screening program. METHODOLOGY: We compared pulmonary function decline from 10 to 15 years of age in patients with cystic fibrosis born between 1979 and 1984 (Cohort 1) and between 1991 and 1996 (Cohort 2). Forced expiratory volume in 1 sec (FEV1%) and forced expiratory flow from 25% to 75% (FEF 25-75%) were analyzed by a linear mixed model approach. The differences between the two cohorts were estimated and the overall cohort effect was tested. RESULTS: Ninety-two patients (51 males, 41 females) fulfilled the selection criteria. Pancreatic insufficiency and CF related diabetes were present in 91% and 20% of patients, respectively. The mean absolute decrement of FEV1% was 9.2 (standard deviation [SD] 11.2) in Cohort 1 and 0.6 (SD 10.4) in Cohort 2 (P < 0.001). The mean decrement of FEF 25-75% was 16.3 (SD 19.5) in Cohort 1 and 1.3 (SD 16.8) in Cohort 2 (P < 0.001) and the Pseudomonas aeruginosa (Pa) colonization was 28% and 15% respectively (P = 0.1). CONCLUSIONS: Our results show that pulmonary function has clearly ameliorated over a decade in young CF patients, in a period during which several significant therapeutic changes have been introduced, such as dornase alfa, tobramycin and hypertonic saline. To our knowledge this is the first study showing a cohort effect in patients diagnosed after neonatal screening.

[Inhaled colistin in elderly patients with non-cystic fibrosis bronchiectasis and chronic Pseudomonas aeruginosa bronchial infection]. / Tratamiento inhalado con colistina a largo plazo en pacientes ancianos con infección crónica por Pseudomonas aeruginosa y bronquiectasias.

BACKGROUND: Bronchiectasis is a frequent cause of admission for elderly patients and chronic respiratory diseases. Although some guidelines recommend long-term treatment with inhaled antibiotics in non-cystic fibrosis bronchiectasis with chronic Pseudomonas aeruginosa (P. aeruginosa) infection, there is limited evidence supporting these prolonged antibiotic treatments in this population. The aim of this study was to assess the effectiveness of inhaled colistin in elderly patients with bronchiectasis and chronic bronchial P. aeruginosa infection in reducing hospital readmissions. MATERIAL AND METHODS: A prospective, controlled and open label study was conducted on patients with bronchiectasis diagnosed by computed tomography and persistence of P. aeruginosa in sputum after appropriate antimicrobial therapy. All patients received education, and physiotherapy training. The intervention group also received nebulized colistin 1 million IU twice a day for one year. Data were collected on the demographics, clinical and functional characteristics, admissions in previous year, and sputum microbiology. Patients were followed up every two months for one year, with readmissions, microbiological results, functional tests, and deaths being evaluated. RESULTS: The study included 39 patients, of whom 20 received nebulized colistin and 19 conventional therapy. There were no differences between the two groups in baseline clinical and functional characteristics or previous hospital stay. The mean age was 77.7+/-5, Charlson index 2.85, and FEV1% 41.3+/-15. Five patients (25%) stopped the nebulized treatment because of adverse effects. P. aeruginosa was eradicated in 45% of the colistin treated patients, and in only one of the control group (statistically significant), but at the end of the study year, there were no differences in the number of hospital admissions (control group 1.6+/-1.7 and 2.7+/-3 colistin group), or days of stay (19+/-31 and 23+/-20). There were no differences in lung function or clinical symptoms between the two groups No significant changes were observed in P. aeruginosa A antibiotic sensitivity or in sputum flora. CONCLUSIONS: More patients in the treatment group achieved Pseudomonas eradication, but benefits in clinical symptoms, lung function or use of healthcare resources in our elderly patients, could not be demonstrated. Adverse effects were common. Further studies are needed in order to identify factors associated with response, or subgroups of patients with bronchiectasis and chronic infection with P. aeruginosa, who benefit from (expensive) long term treatments with inhaled antibiotics.

Nebulized therapy. SEPAR year.

Inhaled drugs are deposited directly in the respiratory tract. They therefore achieve higher concentrations with faster onset of action and fewer side effects than when used systemically. Nebulized drugs are mainly recommended for patients that require high doses of bronchodilators, when they need to inhale drugs that only exist in this form (antibiotics or dornase alfa) or when they are unable to use other inhalation devices. Technological development in recent years has led to new devices that optimize pulmonary deposits and reduce the time needed for treatment. In this review we focus solely on drugs currently used, or under investigation, for nebulization in adult patients; basically bronchodilators, inhaled steroids, antibiotics, antifungals, mucolytics and others such as anticoagulants, prostanoids and lidocaine.

Novel drug-delivery systems for patients with chronic rhinosinusitis.

Chronic rhinosinusitis, one of the most common chronic medical complaints in the United States, seems to be increasing in incidence and prevalence, and has a significant impact on quality of life. Topical forms of medical therapy represent an attractive alternative for drug delivery to the nasal cavity and paranasal sinuses. Topical drug delivery has the advantage of directly acting on the site of inflammation, producing a higher concentration at the target site while avoiding systemic side effects. Although considerable research has been undertaken into improving nasal formulations in order to enhance absorption, little attention has so far been directed to upgrading the delivery devices. The aim of this review is to present current knowledge on the novel drug-delivery devices in use in the management of chronic rhinosinusitis patients, and to present the current available knowledge on topical drug penetration into the sinuses using various delivery devices. Additionally, methods used to enhance fluid sinus deposition are presented and the published clinical studies on the results of nebulized antibiotics in the treatment of chronic rhinosinusitis patients are discussed.