Nebulized Antibiotics for Healthcare- and Ventilator-Associated Pneumonia.

Global emergence of multidrug-resistant and extensive drug-resistant gram-negative bacteria has increased the risk of treatment failure, especially for healthcare- or ventilator-associated pneumonia (HAP/VAP). Nebulization of antibiotics, by providing high intrapulmonary antibiotic concentrations, represents a promising approach to optimize the treatment of HAP/VAP due to multidrug-resistant and extensive drug-resistant gram-negative bacteria, while limiting systemic antibiotic exposure. Aminoglycosides and colistin methanesulfonate are the most common nebulized antibiotics. Although optimal nebulized drug dosing regimen is not clearly established, high antibiotic doses should be administered using vibrating-mesh nebulizer with optimized ventilator settings to ensure safe and effective intrapulmonary concentrations. When used preventively, nebulized antibiotics reduced the incidence of VAP without any effect on mortality. This approach is not yet recommended and large randomized controlled trials should be conducted to confirm its benefit and explore the impact on antibiotic selection pressure. Compared with high-dose intravenous administration, high-dose nebulized colistin methanesulfonate seems to be more effective and safer in the treatment of ventilator-associated tracheobronchitis and VAP caused by multidrug resistant and extensive-drug resistant gram-negative bacteria. Adjunctive nebulized aminoglycosides could increase the clinical cure rate and bacteriological eradication in patients suffering from HAP/VAP due to multidrug-resistant and extensive drug-resistant gram-negative bacteria. As nebulized aminoglycosides broadly diffuse in the systemic circulation of patients with extensive bronchopneumonia, monitoring of plasma trough concentrations is recommended during the period of nebulization. Large randomized controlled trials comparing high dose of nebulized colistin methanesulfonate to high dose of intravenous colistin methanesulfonate or to intravenous new ß-lactams in HAP/VAP due to multidrug-resistant and extensive drug-resistant gram-negative bacteria are urgently needed.

Inhaled antibiotics for treatment of adults with non-cystic fibrosis bronchiectasis: A systematic review and meta-analysis.

BACKGROUND: Inhaled antibiotics (IA) in non-cystic fibrosis bronchiectasis (NCFB) are recommended by some clinical practice guidelines for prevention or treatment of NCFB exacerbations. METHODS: We performed a systematic review and meta-analysis to evaluate the efficacy and safety of IA use for treatment of adults with NCFB and Pseudomonas aeruginosa chronic bronchial infection. The search was performed in the Cochrane Library, PubMed, and Web of Science databases from 2000 to 2019. Studies of IA for treatment of stable or exacerbated NCFB adults (≥18 years) with P. aeruginosa infection were considered eligible. PROSPERO Registration number: CRD42019136154. RESULTS: Twelve trials (2476 participants) were included. IA therapy increased P. aeruginosa eradication from sputum in patients with exacerbations (OR: 3.19, 95%CI: 1.70-5.99) with similar effects on stable patients (OR: 7.22, 95%CI: 2.81-18.59), and a trend to reduced emergence of new respiratory pathogens (OR: 0.58, 95%CI: 0.28-1.18). IA achieved significant reduced exacerbation rates (RR: 0.90; 95%CI: 0.82-0.98) in stable patients, with a number needed to treat (NNT) of 59, but no significant changes in FEV1, mortality, hospitalizations or quality of life were identified. In stable patients, IA use increased antimicrobial resistance (RR: 2.10, 95%CI: 1.35-3.27) at the end of therapy, with a number needed to treat of 6. CONCLUSIONS: IA therapy achieved a statistically significant eradication of P. aeruginosa from sputum, with a 10% reduction of exacerbations in stable patients. This effect has to be balanced with significant increases in antimicrobial resistance. Our meta-analysis failed to show a significant benefit in terms of patient-centered outcomes.

Neuraminidase inhibitors are effective and safe in reducing influenza complications: meta-analysis of randomized controlled trials.

BACKGROUND: There is scarce evidence verifying the impact of neuraminidase inhibitors (NAIs) in reducing influenza complications. The aim was to evaluate the available evidence from randomized-controlled trials (RCT) regarding the efficacy and safety of NAIs in reducing influenza complications. METHODS: A systematic search of the literature was performed in the Cochrane Library, PubMed and Web of Science databases (2006-2019). Eligibility criteria were RCT that enrolled patients of any age or clinical severity with seasonal influenza (H1N1, H3N2, or B) or influenza-like syndrome and receiving NAIs comparing to placebo therapy. RESULTS: Eighteen RCTs (9004 patients) were included: nine focused on oral oseltamivir, six on inhaled zanamivir, and three on intravenous peramivir. Administration of NAIs therapy significantly decreased the time to clinical resolution (median difference: -17.7 hours; and total influenza-related complications (OR: 0.64, 95%CI: 0.51-0.82). In addition, NAIs significantly decreased acute otitis media complication (OR: 0.50, 95%CI: 0.31-0.82) and need for antibiotic treatment (OR: 0.64, 95%CI: 0.46-0.90); and showed a trend towards a reduced occurrence of pneumonia (OR: 0.44, 95%CI: 0.10-2.00), bronchitis (OR: 0.80, 95%CI: 0.43-1.48), sinusitis (OR: 0.73, 95%CI: 0.40-1.32), asthma exacerbations (OR: 0.57, 95%CI: 0.28-1.16), and hospitalizations (OR: 0.57, 95%CI: 0.24-1.38). The overall proportion of AEs tend to increase with NAIs treatment (OR: 1.16, 95%CI: 0.92-1.47). Use of NAIs was associated with a significant increase of nausea and vomiting (OR: 1.61, 95%CI: 1.04-2.50) and a decrease on diarrhea (OR: 0.81, 95%CI: 0.65-1.00). CONCLUSIONS: NAIs are effective in reducing time to clinical resolution, total influenza-related complications, otitis media, and need of antibiotic administration. Reductions on mortality, pneumonia, asthma exacerbations or hospitalization rates only did demonstrate a trend benefit in favor of NAIs. The only significant AE is the increased occurrence of nausea and vomiting.

Evaluation of the quality of evidence supporting guideline recommendations for the nutritional management of critically ill adults.

AIMS: The primary aim of this study was to evaluate the quality of evidence supporting the 2019 European Society for Clinical Nutrition and Metabolism (ESPEN) and 2016 American Society for Parenteral and Enteral Nutrition (ASPEN) recommendations for medical nutrition therapy in critically ill patients. Secondary objectives are to assess the differences between 2019 ESPEN and 2016 ASPEN recommendations and to inform relevant stakeholders of areas requiring improvement in the research. METHODS: The 2019 ESPEN and 2016 ASPEN guidelines were identified and downloaded from the official websites. The level of evidence and strength of recommendations from the guidelines were standardised to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. Level of evidence was classified as high-quality (randomised controlled trials (RCTs) without important limitations), moderate-quality (downgraded RCTs or upgraded observational studies) or low-quality (observational studies without specific strengths or important limitations, case series, case reports). In addition, good practice points (GPP; recommendations based on the clinical experience of the guideline development group) were considered. Strength of recommendation was reported as strong or weak. RESULTS: From 152 total recommendations, only five (3.3%) were supported by high-quality evidence, with 14 being strong recommendations. A total of 79 (52.0%) recommendations were GPPs. Overall, the proportion of recommendations supported by high-quality (7% [ESPEN] vs. 1.1% [ASPEN], p < 0.05) and moderate-quality evidence (33.3% [ESPEN] vs. 8.4% [ASPEN], p < 0.01) was significantly higher in ESPEN guidelines. On the other hand, ASPEN guidelines reported a greater proportion of recommendations supported by GPPs (58.9% [ASPEN] vs. 40.4% [ESPEN], p = 0.03). In enteral and parenteral nutrition, the proportion of recommendations supported by moderate-quality evidence (50% [ESPEN] vs. 15.8% [ASPEN], p < 0.01) was significantly higher in ESPEN guidelines. CONCLUSION: Published guideline recommendations for the nutritional management of critically ill adults remain largely supported by expert opinion and only a minority by high-quality evidence. An urgent unmet clinical need for high-quality clinical trials is warranted.

Quality of evidence supporting Surviving Sepsis Campaign Recommendations.

INTRODUCTION: The Surviving Sepsis Campaign (SSC) guidelines, released in 2017, are a combination of expert opinion and evidence-based medicine, adopted by many institutions as a standard of practice. The aim was to analyse the quality of evidence supporting recommendations on the management of sepsis. METHODS: The strength and quality of evidence (high, moderate, low-very low and best practice statements) of each recommendation were extracted. Randomised controlled trials were required to qualify as high-quality evidence. RESULTS: A total of 96 recommendations were formulated, and 87 were included. Among thirty-one (43%) strong recommendations, only 15.2% were supported by high-quality evidence. Overall, thirty-seven (42.5%) recommendations were based on low-quality evidence, followed by 28 (32.2%) based on moderate-quality, 15 (17.2%) were best practice statements and only seven (8.0%) were supported by high-quality evidence. Randomised controlled trials supported 21.4%, 9.5% and 8.6% recommendations on mechanical ventilation, resuscitation, and management/adjuvant therapy, respectively. In contrast, none high-quality evidence recommendation supported antimicrobial/source control (82.4% were low-very low evidence or best practice statements), and nutrition. CONCLUSIONS: In the SSC guidelines most recommendations were informed by indirect evidence and non-systematic observations. While awaiting trials results, Delphi-like approaches or multi-criteria decision analyses should guide recommendations.

Alternative Regimens of Neuraminidase Inhibitors for Therapy of Hospitalized Adults with Influenza: A Systematic Review of Randomized Controlled Trials.

INTRODUCTION: Influenza in hospitalized intensive care unit (ICU) patients with respiratory failure is associated with 25% mortality, despite timely oseltamivir treatment. A systematic review of randomized controlled trials (RCTs) was conducted to evaluate the efficacy and safety of alternative neuraminidase inhibitor (NAI) regimens compared to standard of care in patients hospitalized for H1N1, H3N2, or B influenza. METHODS: The Cochrane collaboration searching methods were followed in Cochrane Library, PubMed, and Web of Science databases (2009-2019). Eligibility criteria were RCTs comparing different regimens of NAIs in hospitalized patients (at least 1 year old) for clinically diagnosed influenza (H1N1, H3N2, or B). Pre-defined endpoints were time to clinical resolution (TTCR), overall mortality, hospital discharge, viral clearance, drug-related adverse events (AEs), and serious adverse events. RESULTS: Seven trials (1579 patients) were included. Two trials compared two regimens of oral oseltamivir therapy, and one trial compared two regimens of intravenous zanamivir therapy vs oral oseltamivir therapy. Four trials focused on intravenous peramivir therapy: two trials compared two different regimens and two trials compared two different regimens vs oral oseltamivir therapy. Overall, the different regimens were well tolerated, with no significant differences in AEs; nonetheless non-significant differences were reported among different regimens regarding TTCR, mortality, and viral clearance. CONCLUSION: Higher compared to standard doses of NAIs or systemic peramivir therapy compared to oral oseltamivir therapy did not demonstrate benefit.

Nebulization of antimicrobial agents in mechanically ventilated adults in 2017: an international cross-sectional survey.

2017 ESCMID practice guidelines reported safety concerns and weak evidence of benefit supporting use of aerosolized antibiotics in mechanically ventilated patients. Our primary goal was to assess current patterns of aerosolized antibiotic prescription in mechanically ventilated patients. A sequential global survey was performed prior to the release of the ESCMID guidelines, from the 1st of February to the 30th of April 2017, using an electronic platform. Responses were analyzed comparing geographical regions. A total of 410 units responded, with 261 (177 from Europe) being eligible for the full survey. 26.8% of units reported not using aerosolized antibiotics. The two major indications amongst prescribing units were ventilator-associated pneumonia and ventilator-associated tracheobronchitis (74.3% and 49.4%, respectively). 63.6% of units indicated prescription solely in response to multi-drug resistant organisms. In comparison with a survey undertaken in 2014, there was a significant reduction in use of aerosolized antibiotics for prophylaxis (50.6% vs 7.7%, p < 0.05) and colonization (52.9% vs 25.3%, p < 0.05). The large majority of units (91.7%) reported only prescribing in patients with positive pulmonary cultures. Asia appeared to be an outlier, with 53.3% of units reporting empirical use. The most commonly used device was the jet nebulizer. The most commonly prescribed drugs were colistin methanesulfonate (57.6%), colistin base (41.9%) and amikacin (31.4%), although there was considerable heterogeneity across geographical areas. A significant gap exists between ESCMID clinical practice recommendations and the use of aerosolized antibiotics in clinical practice. Our findings indicate an urgent need for high-quality education to bring practice into line with evidence-based guidelines.

Nebulization of Antiinfective Agents in Invasively Mechanically Ventilated Adults: A Systematic Review and Meta-analysis.

BACKGROUND: Nebulization of antiinfective agents is a common but unstandardized practice in critically ill patients. METHODS: A systematic review of 1,435 studies was performed in adults receiving invasive mechanical ventilation. Two different administration strategies (adjunctive and substitute) were considered clinically relevant. Inclusion was restricted to studies using jet, ultrasonic, and vibrating-mesh nebulizers. Studies involving children, colonized-but-not-infected adults, and cystic fibrosis patients were excluded. RESULTS: Five of the 11 studies included had a small sample size (fewer than 50 patients), and only 6 were randomized. Diversity of case-mix, dosage, and devices are sources of bias. Only a few patients had severe hypoxemia. Aminoglycosides and colistin were the most common antibiotics, being safe regarding nephrotoxicity and neurotoxicity, but increased respiratory complications in 9% (95% CI, 0.01 to 0.18; I = 52%), particularly when administered to hypoxemic patients. For tracheobronchitis, a significant decrease in emergence of resistance was evidenced (risk ratio, 0.18; 95% CI, 0.05 to 0.64; I = 0%). Similar findings were observed in pneumonia by susceptible pathogens, without improvement in mortality or ventilation duration. In pneumonia caused by resistant pathogens, higher clinical resolution (odds ratio, 1.96; 95% CI, 1.30 to 2.96; I = 0%) was evidenced. These findings were not consistently evidenced in the assessment of efficacy against pneumonia caused by susceptible pathogens. CONCLUSIONS: Performance of randomized trials evaluating the impact of nebulized antibiotics with more homogeneous populations, standardized drug delivery, predetermined clinical efficacy, and safety outcomes is urgently required. Infections by resistant pathogens might potentially have higher benefit from nebulized antiinfective agents. Nebulization, without concomitant systemic administration of the drug, may reduce nephrotoxicity but may also be associated with higher risk of respiratory complications.

Intratracheal Administration of Antimicrobial Agents in Mechanically Ventilated Adults: An International Survey on Delivery Practices and Safety.

BACKGROUND: Intratracheal antibiotic administration is increasingly used for treating respiratory infections. Limited information is available on delivery devices, techniques, and safety. METHODS: An online survey on intratracheal administration of anti-infective agents in mechanically ventilated adults was answered by health-care workers from 192 ICUs to assess the most commonly used devices, current delivery practices, and safety issues. We investigated whether ICU usage experience (≥3 y) impacted its performance. RESULTS: Intratracheal antibiotic administration was a current practice in 87 ICUs (45.3%), with 40 (46%) having experience with the technique (≥3 y). Sixty-six (78.6%) of 84 health-care workers reported avoiding intratracheal antibiotic administration due to an absence of evidence-based guidelines (78.6%). Jet nebulizers were the most commonly used devices for delivery, in 24 less experienced ICUs (27.6%) and in 18 (20.7%) experienced ICUs. Direct tracheal instillation (6; 6.9%) was still considered for drug prescription in 12 ICUs (6.9%). More experience resulted in neither greater adherence to measures improving the drug's delivery efficiency (93 measures in the experienced group; 27.9%) nor a greater adoption of measures to increase safety. Indeed, the expiratory filter was changed after each nebulization in only 2 experienced ICUs (6.9%), whereas 15 (51.7%) changed it daily instead. CONCLUSIONS: Intratracheal antibiotic administration is a common therapeutic modality in ICUs, but inadequate practices were widely encountered, independent of the level of experience with the technique. This suggests a need to develop standardization to reduce variability and improve safety and efficacy.