A phase I clinical trial assessing the safety, tolerability, and pharmacokinetics of inhaled ethanol in humans as a potential treatment for respiratory tract infections.

Background: Current treatments for respiratory infections are severely limited. Ethanol's unique properties including antimicrobial, immunomodulatory, and surfactant-like activity make it a promising candidate treatment for respiratory infections if it can be delivered safely to the airway by inhalation. Here, we explore the safety, tolerability, and pharmacokinetics of inhaled ethanol in a phase I clinical trial. Methods: The study was conducted as a single-centre, open-label clinical trial in 18 healthy adult volunteers, six with no significant medical comorbidities, four with stable asthma, four with stable cystic fibrosis, and four active smokers. A dose-escalating design was used, with participants receiving three dosing cycles of 40, 60%, and then 80% ethanol v/v in water, 2 h apart, in a single visit. Ethanol was nebulised using a standard jet nebuliser, delivered through a novel closed-circuit reservoir system, and inhaled nasally for 10 min, then orally for 30 min. Safety assessments included adverse events and vital sign monitoring, blood alcohol concentrations, clinical examination, spirometry, electrocardiogram, and blood tests. Results: No serious adverse events were recorded. The maximum blood alcohol concentration observed was 0.011% immediately following 80% ethanol dosing. Breath alcohol concentrations were high (median 0.26%) following dosing suggesting high tissue levels were achieved. Small transient increases in heart rate, blood pressure, and blood neutrophil levels were observed, with these normalising after dosing, with no other significant safety concerns. Of 18 participants, 15 completed all dosing cycles with three not completing all cycles due to tolerability. The closed-circuit reservoir system significantly reduced fugitive aerosol loss during dosing. Conclusion: These data support the safety of inhaled ethanol at concentrations up to 80%, supporting its further investigation as a treatment for respiratory infections.Clinical trial registration: identifier ACTRN12621000067875.

OPTIMA: An Open-Label, Noncomparative Pilot Trial of Inhaled Molgramostim in Pulmonary Nontuberculous Mycobacterial Infection.

Rationale: Inhaled granulocyte-macrophage colony-stimulating factor (GM-CSF) has been proposed as a potential immunomodulatory treatment for nontuberculous mycobacterial (NTM) infection.Objectives: This open-label, noncomparative pilot trial investigated the efficacy and safety of inhaled GM-CSF (molgramostim nebulizer solution) in patients with predominantly treatment-refractory pulmonary NTM infection (Mycobacterium avium complex [MAC] and M. abscessus [MABS]), either in combination with ongoing guideline-based therapy (GBT) or as monotherapy in patients who had stopped GBT because of lack of efficacy or intolerability.Methods: Thirty-two adult patients with refractory NTM infection (MAC, n = 24; MABS, n = 8) were recruited into two cohorts: those with (n = 16) and without (n = 16) ongoing GBT. Nebulized molgramostim 300 µg/d was administered over 48 weeks. Sputum cultures and smears and clinical assessments (6-min-walk distance, symptom scores, Quality of Life-Bronchiectasis Questionnaire score, and body weight) were collected every 4 weeks during treatment and 12 weeks after the end of treatment. The primary endpoint was sputum culture conversion, defined as three consecutive monthly negative cultures during the treatment period.Results: Eight patients (25%) achieved culture conversion on treatment (seven [29.2%] patients with MAC infection, one [12.5%] patient with MABS infection); in four patients, this was durable after the end of treatment. Of the 24 patients with MAC infection, an additional 4 patients had a partial response, converting from smear positive at baseline to smear negative at the end of treatment, and time to positivity in liquid culture media increased. Two of these patients sustained negative cultures from the end of treatment. Other clinical endpoints were unchanged. Serious adverse events were mainly pulmonary exacerbations or worsening NTM infection. Three deaths, not treatment related, were reported.Conclusions: In this population of patients with severe NTM disease, molgramostim was safe and well tolerated. Sputum culture conversion rates for patients with MAC infection (29.2%) were greater than reported for similar refractory MAC cohorts managed with GBT alone. Less benefit was seen for MABS infection. No serious safety concerns were identified. Further evaluation in a larger cohort is warranted.Clinical trial registered with www.clinicaltrials.gov (NCT03421743).

Impact of air pollution on respiratory microbiome: A narrative review.

BACKGROUND: Respiratory microbiome composition depends on an intricate balance between host characteristics, diet, and environmental factors. Some studies indicate a bidirectional relationship between respiratory microbiota and disease. Air pollution is consistently associated with increased respiratory morbidity and mortality in different populations and across different ages. The aim of this review was to report a summary of the evidence regarding the impact of air pollution on the upper and lower respiratory tract microbiome. METHODS: A literature search from interaction between air pollution and respiratory microbiome was performed (2010-2022). RESULTS: Sixteen studies demonstrated changes in microbiome with both environmental and household air pollution. Increasing levels of air pollutants are associated with lower relative abundance of Corynebacterium and increasing levels of pathogen colonization, such as Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae and Pseudomonas aeruginosa and Acinetobacter baumannii, altering the incidence and clinical course of respiratory infections. This ultimately leads to an excess of morbidity and mortality due to antimicrobial resistance. CONCLUSION: Changes of air pollution on the respiratory microbiome may influence respiratory infections in critical care. Use of probiotics may restore the diversity of baseline microbiome, preventing infections by resistant organisms in the critical care setting. Using protective equipment decreased the effect of air pollutants on increasing potentially pathogenic microorganisms.

Expert Review on Nonsurgical Management of Parapneumonic Effusion: Advances, Controversies, and New Directions.

Parapneumonic effusion and empyema are rising in incidence worldwide, particularly in association with comorbidities in an aging population. Also driving this change is the widespread uptake of pneumococcal vaccines, leading to the emergence of nonvaccine-type pneumococci and other bacteria. Early treatment with systemic antibiotics is essential but should be guided by local microbial guidelines and antimicrobial resistance patterns due to significant geographical variation. Thoracic ultrasound has emerged as a leading imaging technique in parapneumonic effusion, enabling physicians to characterize effusions, assess the underlying parenchyma, and safely guide pleural procedures. Drainage decisions remain based on longstanding criteria including the size of the effusion and fluid gram stain and biochemistry results. Small-bore chest drains appear to be as effective as large bore and are adequate for the delivery of intrapleural enzyme therapy (IET), which is now supported by a large body of evidence. The IET dosing regimen used in the UK Multicenter Sepsis Trial -2 has the most evidence available but data surrounding alternative dosing, concurrent and once-daily instillations, and novel fibrinolytic agents are promising. Prognostic scores used in pneumonia (e.g., CURB-65) tend to underestimate mortality in parapneumonic effusion/empyema. Scores specifically based on pleural infection have been developed but require validation in prospective cohorts.

Steroid Therapy and Outcome of Parapneumonic Pleural Effusions (STOPPE): A Pilot Randomized Clinical Trial.

Rationale: Pleural effusion commonly complicates community-acquired pneumonia and is associated with intense pleural inflammation. Whether antiinflammatory treatment with corticosteroids improves outcomes is unknown. Objectives: To assess the effects of corticosteroids in an adult population with pneumonia-related pleural effusion. Methods: The STOPPE (Steroid Therapy and Outcome of Parapneumonic Pleural Effusions) trial was a pilot, multicenter, double-blinded, placebo-controlled, randomized trial involving six Australian centers. Patients with community-acquired pneumonia and pleural effusion were randomized (2:1) to intravenous dexamethasone (4 mg twice daily for 48 h) or placebo and followed for 30 days. Given the diverse effects of corticosteroids, a comprehensive range of clinical, serological, and imaging outcomes were assessed in this pilot trial (ACTRN12618000947202). Measurements and Main Results: Eighty patients were randomized (one withdrawn before treatment) and received dexamethasone (n = 51) or placebo (n = 28). This pilot trial found no preliminary evidence of benefits of dexamethasone in improving time to sustained (>12 h) normalization of vital signs (temperature, oxygen saturations, blood pressure, heart, and respiratory rates): median, 41.0 (95% confidence interval, 32.3-54.5) versus 27.8 (15.4-49.5) hours in the placebo arm (hazard ratio, 0.729 [95% confidence interval, 0.453-1.173]; P = 0.193). Similarly, no differences in C-reactive protein or leukocyte counts were observed, except for a higher leukocyte count in the dexamethasone group at Day 3. Pleural drainage procedures were performed in 49.0% of dexamethasone-treated and 42.9% of placebo-treated patients (P = 0.60). Radiographic pleural opacification decreased over time with no consistent intergroup differences. Mean duration of antibiotic therapy (22.4 [SD, 15.4] vs. 20.4 [SD, 13.8] d) and median hospitalization (6.0 [interquartile range, 5.0-10.0] vs. 5.5 [interquartile range, 5.0-8.0] d) were similar between the dexamethasone and placebo groups. Serious adverse events occurred in 25.5% of dexamethasone-treated and 21.4% of placebo-treated patients. Transient hyperglycemia more commonly affected the dexamethasone group (15.6% vs. 7.1%). Conclusions: Systemic corticosteroids showed no preliminary benefits in adults with parapneumonic effusions. Clinical trial registered with www.anzctr.org.au (ACTRN12618000947202).

Applying the lessons learned from coronavirus disease 2019 to improve pneumonia management.

PURPOSE OF REVIEW: Coronavirus disease 2019 (COVID-19) has produced an extraordinary amount of literature in a short time period. This review focuses on what the new literature has provided in terms of more general information about the management of community-acquired pneumonia (CAP). RECENT FINDINGS: Measures taken to reduce the spread of COVID-19 have caused a significant drop in influenza worldwide. Improvements in imaging, especially ultrasound, and especially in the application of rapid molecular diagnosis are likely to have significant impact on the management of CAP. Therapeutic advances are so far limited. SUMMARY: COVID-19 has taught us that we can do far more to prevent seasonal influenza and its associated mortality, morbidity and economic cost. Improvements in imaging and pathogen diagnosis are welcome, as is the potential for secondary benefits of anti-COVID-19 therapies that may have reach effect on respiratory viruses other than severe acute respiratory syndrome coronavirus 2. As community-transmission is likely to persist for many years, recognition and treatment of severe acute respiratory syndrome coronavirus 2 will need to be incorporated into CAP guidelines moving forward.

Steroids and COVID-19: We Need a Precision Approach, Not One Size Fits All.

COVID-19 is a new infectious disease causing severe respiratory failure and death for which optimal treatment is currently unclear. Many therapies have been proven to be ineffective; however, promising findings related to corticosteroid therapy have been published. Analysis of published data including in this issue suggests that therapy with corticosteroids in the range of 6 mg of dexamethasone (or equivalent) per day likely has a positive effect in patients requiring mechanical ventilation but there remains considerable doubt in patients over the age of 70, in patients with diabetes and patients with milder disease. Clinicians must consider the individual potential risks and benefits of corticosteroid in patients with COVID-19 rather than routinely using them until more data is available.

Steroids and COVID-19: We Need a Precision Approach, Not One Size Fits All.

COVID-19 is a new infectious disease causing severe respiratory failure and death for which optimal treatment is currently unclear. Many therapies have been proven to be ineffective; however, promising findings related to corticosteroid therapy have been published. Analysis of published data including in this issue suggests that therapy with corticosteroids in the range of 6 mg of dexamethasone (or equivalent) per day likely has a positive effect in patients requiring mechanical ventilation but there remains considerable doubt in patients over the age of 70, in patients with diabetes and patients with milder disease. Clinicians must consider the individual potential risks and benefits of corticosteroid in patients with COVID-19 rather than routinely using them until more data is available.

Antibiotic Stewardship in the Intensive Care Unit. An Official American Thoracic Society Workshop Report in Collaboration with the AACN, CHEST, CDC, and SCCM.

Intensive care units (ICUs) are an appropriate focus of antibiotic stewardship program efforts because a large proportion of any hospital's use of parenteral antibiotics, especially broad-spectrum, occurs in the ICU. Given the importance of antibiotic stewardship for critically ill patients and the importance of critical care practitioners as the front line for antibiotic stewardship, a workshop was convened to specifically address barriers to antibiotic stewardship in the ICU and discuss tactics to overcome these. The working definition of antibiotic stewardship is "the right drug at the right time and the right dose for the right bug for the right duration." A major emphasis was that antibiotic stewardship should be a core competency of critical care clinicians. Fear of pathogens that are not covered by empirical antibiotics is a major driver of excessively broad-spectrum therapy in critically ill patients. Better diagnostics and outcome data can address this fear and expand efforts to narrow or shorten therapy. Greater awareness of the substantial adverse effects of antibiotics should be emphasized and is an important counterargument to broad-spectrum therapy in individual low-risk patients. Optimal antibiotic stewardship should not focus solely on reducing antibiotic use or ensuring compliance with guidelines. Instead, it should enhance care both for individual patients (by improving and individualizing their choice of antibiotic) and for the ICU population as a whole. Opportunities for antibiotic stewardship in common ICU infections, including community- and hospital-acquired pneumonia and sepsis, are discussed. Intensivists can partner with antibiotic stewardship programs to address barriers and improve patient care.

Update in adult community-acquired pneumonia: key points from the new American Thoracic Society/Infectious Diseases Society of America 2019 guideline.

PURPOSE OF REVIEW: The American Thoracic Society and Infectious Diseases Society of America recently released their joint guideline for the diagnosis and treatment of adults with community-acquired pneumonia (CAP). The co-chairs of the guideline committee provide a summary of the guideline process, key recommendations from the new guideline and future directions for CAP research. RECENT FINDINGS: The guideline committee included 14 experts from the two societies. Sixteen questions for the guideline were selected using the PICO format. The GRADE approach was utilized to review the available evidence and generate recommendations. The recommendations included expanded microbiological testing for patients suspected of drug-resistant infections, empiric first-line therapy recommendations for outpatients and inpatients including use of beta-lactam monotherapy for uncomplicated outpatients, elimination of healthcare-associated pneumonia as a treatment category, and not recommending corticosteroids as routine adjunct therapy. SUMMARY: CAP is a major cause of morbidity and mortality. Effective antibiotic therapy is available and remains largely empirical. New diagnostic tests and treatment options are emerging and will lead to guideline updates in the future.

Invasive Pneumococcal and Meningococcal Disease.

This review focuses on current knowledge of the epidemiology, prevention, and treatment of invasive pneumococcal (IPD) and meningococcal disease (IMD). IPD decreased significantly with the introduction of effective conjugate vaccines but is on the rise again. Effective antibiotic therapy of IPD includes the combination of a beta-lactam and a macrolide with additional considerations in meningitis. Steroids are mandatory in pneumococcal meningitis but not indicated in pneumococcal pneumonia except in the setting of refractory shock. There is increasing concern about the cardiovascular complications of IPD. IMD continues to be a significant health problem with major concerns about rising antibiotic resistance.