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Pharmacokinetic Characteristics of Nebulized Colistimethate Sodium Using Two Different Types of Nebulizers in Critically Ill Patients with Ventilator-Associated Respiratory Infections.

ABSTRACT: Background: Rising antimicrobial resistance has led to a revived interest in inhaled colistin treatment in the critically ill patient with ventilator-associated respiratory infection (VARI). Nebulization via vibrating mesh nebulizers (VMNs) is considered the current standard-of-care, yet the use of generic jet nebulizers (JNs) is more widespread. Few data exist on the intrapulmonary pharmacokinetics of colistin when administered through VMNs, while there is a complete paucity regarding the use of JNs. Methods: In this study, 18 VARI patients who received 2 million international units of inhaled colistimethate sodium (CMS) through a VMN were pharmacokinetically compared with six VARI patients who received the same drug dose through a JN, in the absence of systemic CMS administration. Results: Surprisingly, VMN and JN led to comparable formed colistin exposures in the epithelial lining fluid (ELF) (median (IQR) AUC_0-24: 86.2 (46.0-185.9) mg/L∙h with VMN and 91.5 (78.1-110.3) mg/L∙h with JN). The maximum ELF concentration was 10.4 (4.7-22.6) mg/L and 7.4 (6.2-10.3) mg/L, respectively. Conclusions: Based on our results, JN might be considered a viable alternative to the theoretically superior VMN. Therapeutic drug monitoring in the ELF can be advised due to the observed low exposure, high variability, and appreciable systemic absorption.

SUBMITTER: Kyriakoudi A

PROVIDER: S-EPMC9686516 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Pharmacokinetic Characteristics of Nebulized Colistimethate Sodium Using Two Different Types of Nebulizers in Critically Ill Patients with Ventilator-Associated Respiratory Infections.

Kyriakoudi Anna A Pontikis Konstantinos K Valsami Georgia G Avgeropoulou Stavrina S Neroutsos Efthymios E Christodoulou Eirini E Moraitou Eleni E Markantonis Sophia L SL Dokoumetzidis Aristides A Rello Jordi J Koutsoukou Antonia A

Antibiotics (Basel, Switzerland) 20221101 11

<i>Background:</i> Rising antimicrobial resistance has led to a revived interest in inhaled colistin treatment in the critically ill patient with ventilator-associated respiratory infection (VARI). Nebulization via vibrating mesh nebulizers (VMNs) is considered the current standard-of-care, yet the use of generic jet nebulizers (JNs) is more widespread. Few data exist on the intrapulmonary pharmacokinetics of colistin when administered through VMNs, while there is a complete paucity regarding th ...[more]

PMID: 36358184

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Project description:ImportanceAlthough most critically ill patients receive invasive mechanical ventilation (IMV), few studies have characterized how IMV is discontinued in practice.ObjectiveTo describe practice variation in IMV discontinuation internationally, associations between initial discontinuation events and outcomes, and factors associated with the use of select discontinuation strategies and failed initial spontaneous breathing trials (SBTs).Design, setting, and participantsProspective, multinational, observational study of critically ill adults who received IMV for at least 24 hours from 142 intensive care units (ICUs) in 19 countries within 6 regions (27 in Canada, 23 in India, 22 in the UK, 26 in Europe, 21 in Australia/New Zealand, and 23 in the US).ExposuresReceiving IMV.Main outcomes and measuresPrimary analyses characterized types of initial IMV discontinuation events (extubation, SBT, or tracheostomy) and associations with clinical outcomes (including duration of ventilation, ICU and hospital mortality, and ICU and hospital length of stay). Secondary analyses examined the associations between SBT outcome and SBT timing and clinical outcomes.ResultsAmong 1868 patients (median [interquartile range] age, 61.8 [48.9-73.1] years; 1173 [62.8%] men) 424 (22.7%) underwent direct extubation, 930 (49.8%) had an initial SBT (761 [81.8%] successful), 150 (8.0%) underwent direct tracheostomy, and 364 (19.5%) died before a weaning attempt. Across regions, there was variation in the use of written directives to guide care, daily screening, SBT techniques, ventilator modes, and the roles played by clinicians involved in weaning. Compared with initial direct extubation, patients who had an initial SBT had higher ICU mortality (20 [4.7%] vs 96 [10.3%]; absolute difference, 5.6% [95% CI, 2.6%-8.6%]), longer duration of ventilation (median of 2.9 vs 4.1 days; absolute difference, 1.2 days [95% CI, 0.7-1.6]), and longer ICU stay (median of 6.7 vs 8.1 days; absolute difference, 1.4 days [95% CI, 0.8-2.4]). Patients whose initial SBT failed (vs passed) had higher ICU mortality (29 [17.2%] vs 67 [8.8%]; absolute difference, 8.4% [95% CI, 2.0%-14.7%]), longer duration of ventilation (median of 6.1 vs 3.5 days; absolute difference, 2.6 days [95% CI, 1.6-3.6]), and longer ICU stay (median of 10.6 vs 7.7 days; absolute difference, 2.8 days [95% CI, 1.1-5.2]). Compared with patients who underwent early initial SBTs, patients who underwent late initial SBTs (>2.3 days after intubation) had longer duration of ventilation (median of 2.1 vs 6.1 days; absolute difference, 4.0 days [95% CI, 3.7-4.5]), longer ICU stay (median of 5.9 vs 10.8 days; absolute difference, 4.9 days [95% CI, 4.0-6.3]), and longer hospital stay (median of 14.3 vs 22.8 days; absolute difference, 8.5 days [95% CI, 6.0-11.0]).Conclusions and relevanceIn this observational study of invasive mechanical ventilation discontinuation in 142 ICUs in Canada, India, the UK, Europe, Australia/New Zealand, and the US from 2013 to 2016, weaning practices varied internationally.Trial registrationClinicalTrials.gov Identifier: NCT03955874.

Project description:The potential relationship among airway Candida spp. de-colonization, nebulized amphotericin B (NAB), and occurrence of ventilator-associated pneumonia (VAP) in patients who are critically ill has not been fully investigated, especially concerning effects on survival. In this observational, retrospective, cohort study in a 22-bed central intensive care unit, we included patients aged >18 years who required mechanical ventilation (MV) for >48 h, with at least two consecutive positive Candida spp. test results. Patients were categorized into NAB and no NAB (control) groups. Propensity matching at 1:1 was performed according to strict standards, and multiple Cox proportional hazard model and multivariate analyses were performed to evaluate the effects of NAB treatment. Throughout an 8-year study period, 526 patients had received MV and had positive respiratory tract Candida spp. cultures. Of these, we included 275 patients and excluded 251 patients. In total, we successfully matched 110 patients from the two groups (each group, n = 55; total population median age, 64 years; Acute Physiology and Chronic Health Evaluation II [APACHE II] score, 25.5; sequential organ failure assessment score, 9). The Candida spp. de-colonization rate was 69.1% in patients treated with NAB. VAP incidence did not differ significantly between the NAB (10.91%) and control (16.36%) groups (P = 0.405). Pseudomonas aeruginosa-related VAP rates differed significantly between the NAB (10.91%) and control (25.45%) groups (P = 0.048). Five (9.1%) patients in the NAB group died during hospitalization compared with 17 (30.9%) controls (P = 0.014). At 28 days, 9 (16.4%) and 16 (29.1%) deaths occurred in the NAB and control groups, respectively, (P = 0.088). The cumulative 90-day mortality rate differed significantly between the two groups (23.6 vs. 43.6%, P = 0.015). Multivariate logistic regression analyses indicated a decreased 90-day mortality in the NAB group (adjusted odds ratio 0.413; 95% confidence interval 0.210-0.812; P = 0.01). In subgroup analyses, the NAB-associated decreased risk of death at 90 days was consistent across subgroups of patients with a Candida score of 2, younger age (<64 years), a higher APACHE II score (≥25), fewer Candida sites (<2), or MV at admission. NAB treatment contributed to Candida spp. airway de-colonization, was associated with a reduced risk of P. aeruginosa-related VAP, and improved 90-day mortality in patients critically ill with Candida spp. tracheobronchial colonization who had received MV for >2 days. NAB may be an alternative treatment option for critically ill patients with VAP.

Project description:BackgroundAntimicrobial resistance (AMR) is rising at an alarming rate and complicating the management of infectious diseases including lower respiratory tract infections (LRTI). Metagenomic next-generation sequencing (mNGS) is a recently established method for culture-independent LRTI diagnosis, but its utility for predicting AMR has remained unclear. We aimed to assess the performance of mNGS for AMR prediction in bacterial LRTI and demonstrate proof of concept for epidemiological AMR surveillance and rapid AMR gene detection using Cas9 enrichment and nanopore sequencing.MethodsWe studied 88 patients with acute respiratory failure between 07/2013 and 9/2018, enrolled through a previous observational study of LRTI. Inclusion criteria were age ≥ 18, need for mechanical ventilation, and respiratory specimen collection within 72 h of intubation. Exclusion criteria were decline of study participation, unclear LRTI status, or no matched RNA and DNA mNGS data from a respiratory specimen. Patients with LRTI were identified by clinical adjudication. mNGS was performed on lower respiratory tract specimens. The primary outcome was mNGS performance for predicting phenotypic antimicrobial susceptibility and was assessed in patients with LRTI from culture-confirmed bacterial pathogens with clinical antimicrobial susceptibility testing (n = 27 patients, n = 32 pathogens). Secondary outcomes included the association between hospital exposure and AMR gene burden in the respiratory microbiome (n = 88 patients), and AMR gene detection using Cas9 targeted enrichment and nanopore sequencing (n = 10 patients).ResultsCompared to clinical antimicrobial susceptibility testing, the performance of respiratory mNGS for predicting AMR varied by pathogen, antimicrobial, and nucleic acid type sequenced. For gram-positive bacteria, a combination of RNA + DNA mNGS achieved a sensitivity of 70% (95% confidence interval (CI) 47-87%) and specificity of 95% (CI 85-99%). For gram-negative bacteria, sensitivity was 100% (CI 87-100%) and specificity 64% (CI 48-78%). Patients with hospital-onset LRTI had a greater AMR gene burden in their respiratory microbiome versus those with community-onset LRTI (p = 0.00030), or those without LRTI (p = 0.0024). We found that Cas9 targeted sequencing could enrich for low abundance AMR genes by > 2500-fold and enabled their rapid detection using a nanopore platform.ConclusionsmNGS has utility for the detection and surveillance of resistant bacterial LRTI pathogens.

Dataset Information

Pharmacokinetic Characteristics of Nebulized Colistimethate Sodium Using Two Different Types of Nebulizers in Critically Ill Patients with Ventilator-Associated Respiratory Infections.

Publications

Pharmacokinetic Characteristics of Nebulized Colistimethate Sodium Using Two Different Types of Nebulizers in Critically Ill Patients with Ventilator-Associated Respiratory Infections.

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