Nebulized Amikacin and Fosfomycin for Severe Pseudomonas aeruginosa Pneumonia: An Experimental Study.

OBJECTIVES: Latest trials failed to confirm merits of nebulized amikacin for critically ill patients with nosocomial pneumonia. We studied various nebulized and IV antibiotic regimens in a porcine model of severe Pseudomonas aeruginosa pneumonia, resistant to amikacin, fosfomycin, and susceptible to meropenem. DESIGN: Prospective randomized animal study. SETTING: Animal Research, University of Barcelona, Spain. SUBJECTS: Thirty female pigs. INTERVENTIONS: The animals were randomized to receive nebulized saline solution (CONTROL); nebulized amikacin every 6 hours; nebulized fosfomycin every 6 hours; IV meropenem alone every 8 hours; nebulized amikacin and fosfomycin every 6 hours; amikacin and fosfomycin every 6 hours, with IV meropenem every 8 hours. Nebulization was performed through a vibrating mesh nebulizer. The primary outcome was lung tissue bacterial concentration. Secondary outcomes were tracheal secretions P. aeruginosa concentration, clinical variables, lung histology, and development of meropenem resistance. MEASUREMENTS AND MAIN RESULTS: We included five animals into each group. Lung P. aeruginosa burden varied among groups (p < 0.001). In particular, IV meropenem and amikacin and fosfomycin + IV meropenem groups presented lower P. aeruginosa concentrations versus amikacin and fosfomycin, amikacin, CONTROL, and fosfomycin groups (p < 0.05), without significant difference between these two groups undergoing IV meropenem treatment. The sole use of nebulized antibiotics resulted in dense P. aeruginosa accumulation at the edges of the interlobular septa. Amikacin, amikacin and fosfomycin, and amikacin and fosfomycin + IV meropenem effectively reduced P. aeruginosa in tracheal secretions (p < 0.001). Pathognomonic clinical variables of respiratory infection did not differ among groups. Resistance to meropenem increased in IV meropenem group versus amikacin and fosfomycin + meropenem (p = 0.004). CONCLUSIONS: Our findings corroborate that amikacin and fosfomycin alone efficiently reduced P. aeruginosa in tracheal secretions, with negligible effects in pulmonary tissue. Combination of amikacin and fosfomycin with IV meropenem does not increase antipseudomonal pulmonary tissue activity, but it does reduce development of meropenem-resistant P. aeruginosa, in comparison with the sole use of IV meropenem. Our findings imply potential merits for preemptive use of nebulized antibiotics in order to reduce resistance to IV meropenem.

Characteristics and influence on quality of life of new-onset pain in critical COVID-19 survivors.

BACKGROUND: Pain is a clinical feature of COVID-19, however, data about persistent pain after hospital discharge, especially among ICU survivors is scarce. The aim of this study was to explore the incidence and characteristics of new-onset pain and its impact on Health-Related Quality of Life (HRQoL), and to quantify the presence of mood disorders in critically ill COVID-19 survivors. METHODS: This is a preliminary report of PAIN-COVID trial (NCT04394169) presenting a descriptive analysis in critically ill COVID-19 survivors, following in person interview 1 month after hospital discharge. Pain was assessed using the Brief Pain Inventory, the Douleur Neuropathique 4 questionnaire and the Pain Catastrophizing Scale. HRQoL was evaluated with the EQ 5D/5L, and mood disorders with the Hospital Anxiety and Depression Scale (HADS). RESULTS: From 27 May to 19 July 2020, 203 patients were consecutively screened for eligibility, and 65 were included in this analysis. Of these, 50.8% patients reported new-onset pain; 38.5% clinically significant pain (numerical rating score ≥3 for average pain intensity); 16.9% neuropathic pain; 4.6% pain catastrophizing thoughts, 44.6% pain in ≥2 body sites and 7.7% widespread pain. Patients with new-onset pain had a worse EQ-VAS and EQ index value (p < 0.001). Pain intensity was negatively correlated to both the former (Spearman ρ: -0.546, p < 0.001) and the latter (Spearman ρ: -0.387, p = 0.001). HADS anxiety and depression values equal or above eight were obtained in 10.8% and 7.7% of patients, respectively. CONCLUSION: New-onset pain in critically ill COVID-19 survivors is frequent, and it is associated with a lower HRQoL. Trial registration No.: NCT04394169. Registered 19 May 2020. https://clinicaltrials.gov/ct2/show/NCT04394169. SIGNIFICANCE: A substantial proportion of severe COVID-19 survivors may develop clinically significant persistent pain, post-intensive care syndrome and chronic ICU-related pain. Given the number of infections worldwide and the unprecedented size of the population of critical illness survivors, providing information about the incidence of new-onset pain, its characteristics, and its influence on the patients' quality of life might help establish and improve pain management strategies.

Rationale and study design of an early care, therapeutic education, and psychological intervention program for the management of post-intensive care syndrome and chronic pain after COVID-19 infection (PAIN-COVID): study protocol for a randomized controlled trial.

BACKGROUND: Critically ill patients with COVID-19 are an especially susceptible population to develop post-intensive care syndrome (PICS) due to acute respiratory distress syndrome (ARDS). Patients can suffer acute severe pain and may have long-term mental, cognitive, and functional health deterioration after discharge. However, few controlled trials are evaluating interventions for the prevention and treatment of PICS. The study hypothesis is that a specific care program based on early therapeutic education and psychological intervention improves the quality of life of patients at risk of developing PICS and chronic pain after COVID-19. The primary objective is to determine whether the program is superior to standard-of-care on health-related quality of life at 6 months after hospital discharge. The secondary objectives are to determine whether the intervention is superior to standard-of-care on health-related quality of life, incidence of chronic pain and degree of functional limitation, incidence of anxiety, depression, and post-traumatic stress syndrome at 3 and 6 months after hospital discharge. METHODS: The PAINCOVID trial is a unicentric randomized, controlled, patient-blinded superiority trial with two parallel groups. The primary endpoint is the health-related quality of life at 6 months after hospital discharge, and randomization will be performed with a 1:1 allocation ratio. This paper details the methodology and statistical analysis plan of the trial and was submitted before outcome data were available. The estimated sample size is 84 patients, 42 for each arm. Assuming a lost to follow-up rate of 20%, a sample size of 102 patients is necessary (51 for each arm). DISCUSSION: This is the first randomized clinical trial assessing the effectiveness of an early care therapeutic education, and psychological intervention program for the management of PICS and chronic pain after COVID-19. The intervention will serve as proof of the need to implement early care programs at an early stage, having an incalculable impact given the current scenario of the pandemic. TRIAL REGISTRATION: This study is being conducted in accordance with the tenets of the Helsinki Declaration and has been approved by the authors' institutional review board Comité Ético de Investigación Clínica del Hospital Clínic de Barcelona (approval number: HCB/2020/0549) and was registered on May 9, 2020, at clinicaltrials.gov ( NCT04394169 ).