Nebulized Colistin in Ventilator-Associated Pneumonia and Tracheobronchitis: Historical Background, Pharmacokinetics and Perspectives

Colistin; Phramacokinetic; Technique of nebulizationColistina; Farmacocinètica; Tècnica de nebulitzacióColistina; Farmacocinético; Técnica de nebulizaciónClinical evidence suggests that nebulized colistimethate sodium (CMS) has benefits for treating lower respiratory tract infections caused by multidrug-resistant Gram-negative bacteria (GNB). Colistin is positively charged, while CMS is negatively charged, and both have a high molecular mass and are hydrophilic. These physico-chemical characteristics impair crossing of the alveolo-capillary membrane but enable the disruption of the bacterial wall of GNB and the aggregation of the circulating lipopolysaccharide. Intravenous CMS is rapidly cleared by glomerular filtration and tubular excretion, and 20–25% is spontaneously hydrolyzed to colistin. Urine colistin is substantially reabsorbed by tubular cells and eliminated by biliary excretion. Colistin is a concentration-dependent antibiotic with post-antibiotic and inoculum effects. As CMS conversion to colistin is slower than its renal clearance, intravenous administration can lead to low plasma and lung colistin concentrations that risk treatment failure. Following nebulization of high doses, colistin (200,000 international units/24h) lung tissue concentrations are > five times minimum inhibitory concentration (MIC) of GNB in regions with multiple foci of bronchopneumonia and in the range of MIC breakpoints in regions with confluent pneumonia. Future research should include: (1) experimental studies using lung microdialysis to assess the PK/PD in the interstitial fluid of the lung following nebulization of high doses of colistin; (2) superiority multicenter randomized controlled trials comparing nebulized and intravenous CMS in patients with pandrug-resistant GNB ventilator-associated pneumonia and ventilator-associated tracheobronchitis; (3) non-inferiority multicenter randomized controlled trials comparing nebulized CMS to intravenous new cephalosporines/ß-lactamase inhibitors in patients with extensive drug-resistant GNB ventilator-associated pneumonia and ventilator-associated tracheobronchitis.This research received no external funding

e-Pilly TROP Maladies infectieuses tropicales

L’e-Pilly TROP est un ouvrage d’infectiologie tropicale destiné aux médecins et aux étudiants en médecine des pays francophones du Sud. La prise en compte des différents niveaux de la pyramide sanitaire dans ces pays le rend aussi accessible aux infirmiers des centres de santé communautaires urbains et des structures de santé intermédiaires des zones rurales. Par définition, les Pays En Développement accroissant progressivement leurs capacités de diagnostic biologique et de traitement, les outils de prise en charge correspondent aux moyens des niveaux périphériques comme à ceux des niveaux hospitaliers de référence

Understanding the nebulisation of antibiotics: The key role of lung microdialysis studies

BACKGROUND: Nebulisation of antibiotics is a promising treatment for ventilator-associated pneumonia (VAP) caused by multidrug-resistant organisms. Ensuring effective antibiotic concentrations at the site of infection in the interstitial space fluid is crucial for clinical outcomes. Current assessment methods, such as epithelial lining fluid and tissue homogenates, have limitations in providing longitudinal pharmacokinetic data. MAIN BODY: Lung microdialysis, an invasive research technique predominantly used in animals, involves inserting probes into lung parenchyma to measure antibiotic concentrations in interstitial space fluid. Lung microdialysis offers unique advantages, such as continuous sampling, regional assessment of antibiotic lung concentrations and avoidance of bronchial contamination. However, it also has inherent limitations including the cost of probes and assay development, the need for probe calibration and limited applicability to certain antibiotics. As a research tool in VAP, lung microdialysis necessitates specialist techniques and resource-intensive experimental designs involving large animals undergoing prolonged mechanical ventilation. However, its potential impact on advancing our understanding of nebulised antibiotics for VAP is substantial. The technique may enable the investigation of various factors influencing antibiotic lung pharmacokinetics, including drug types, delivery devices, ventilator settings, interfaces and disease conditions. Combining in vivo pharmacokinetics with in vitro pharmacodynamic simulations can become feasible, providing insights to inform nebulised antibiotic dose optimisation regimens. Specifically, it may aid in understanding and optimising the nebulisation of polymyxins, effective against multidrug-resistant Gram-negative bacteria. Furthermore, lung microdialysis holds promise in exploring novel nebulisation therapies, including repurposed antibiotic formulations, bacteriophages and immunomodulators. The technique\u27s potential to monitor dynamic biochemical changes in pneumonia, such as cytokines, metabolites and inflammation/infection markers, opens avenues for developing theranostic tools tailored to critically ill patients with VAP. CONCLUSION: In summary, lung microdialysis can be a potential transformative tool, offering real-time insights into nebulised antibiotic pharmacokinetics. Its potential to inform optimal dosing regimen development based on precise target site concentrations and contribute to development of theranostic tools positions it as key player in advancing treatment strategies for VAP caused by multidrug-resistant organisms. The establishment of international research networks, exemplified by LUMINA (lung microdialysis applied to nebulised antibiotics), signifies a proactive step towards addressing complexities and promoting multicentre experimental studies in the future

Stability of long-sustained oscillations induced by electron tunneling

Self-oscillations are the result of an efficient mechanism generating periodic motion from a constant power source. In quantum devices, these oscillations may arise due to the interaction between single electron dynamics and mechanical motion. Due to the complexity of this mechanism, these self-oscillations may irrupt, vanish, or exhibit a bistable behavior causing hysteresis cycles. We observe these hysteresis cycles and characterize the stability of different regimes in single and double quantum dot configurations. In particular cases, we find these oscillations stable for over 20 seconds, many orders of magnitude above electronic and mechanical characteristic timescales, revealing the robustness of the mechanism at play. The experimental results are reproduced by our theoretical model that provides a complete understanding of bistability in nanoelectromechanical devices.Comment: 11 pages, 10 figures, includes the complete paper and the Supplemental Materia

Trichophyton mentagrophytes genotype infections among men who have sex with men in France: An ongoing phenomenon

Background: Trichophyton mentagrophytes ITS genotype VII (TMVII) has recently been identified in France as the causative agent of dermatophyte infections transmitted during sexual activity among men who have sex with men (MSM). Objectives: Our objective was to provide new insights into the epidemiology, clinical presentation and treatment of TMVII infections based on cases diagnosed from October 2022 to September 2023 in three medical mycology laboratories in Paris. Additionally, we aimed to perform molecular characterization of TMVII strains collected in Paris, as well as in Switzerland. Methods: We identified all isolates from skin and hair belonging to the T. mentagrophytes complex by sequencing the ITS region. For isolates corresponding to TMVII, clinical data were retrieved from medical records. For all available TMVII strains that we isolated since January 2021, we sequenced tef1α and tubb and determined the MAT locus idiomorph. Results: We identified 32 cases of TMVII Infections. All cases occurred in men, 30 of whom reported having sex with men. Fifteen cases were sporadic cases including four among sex workers. The other 17 cases belonged to a single cluster involving a tantric masseur who infected 15 clients and his roommate. The median time from massage to lesion onset was 16 [2–52] days. Except for one patient, all other patients received systemic antifungal treatment with terbinafine. We observed five patients whose cultures remained positive even after 3–4 weeks of treatment and five patients experienced a relapse of the infection after discontinuing antifungal treatment. All French isolates exhibited identical tef1α and tubb sequences, as well as the same MAT idiomorph locus. They displayed variations in the tef1α sequence compared to isolates from Switzerland and the Czech Republic. Conclusions: We confirm the active circulation of TMVII among MSM in France, which is associated with challenges in diagnosis, treatment and prevention

Future Perspectives of Bone Tissue Engineering with Special Emphasis on Extracellular Vesicles

Peer reviewe

Neutrophil expression of glucocorticoid-induced leucine zipper (GILZ) anti-inflammatory protein is associated with acute respiratory distress syndrome severity

BACKGROUND: Glucocorticoid-induced leucine zipper (GILZ) is a potent anti-inflammatory protein involved in neutrophil apoptosis and the resolution of inflammation. Given the numerous pathophysiologic roles of neutrophils in the acute respiratory distress syndrome (ARDS), we postulated that neutrophil GILZ expression might be induced during ARDS, to modulate the inflammatory process and participate in lung repair. METHODS: This single-center, prospective, observational cohort study took place in the surgical intensive care unit of Bichat Hospital (Paris, France) and involved 17 ARDS patients meeting the Berlin criteria at inclusion, and 14 ventilated controls without ARDS. Serial blood samples were obtained every 2 days until extubation or death (from 1 to 9 samples per patient). GILZ protein and gene expression was quantified in blood neutrophils, along with markers of inflammation (CRP, extracellular DNA) or its resolution (Annexin A1). RESULTS: Neutrophil GILZ expression was detected at the transcriptional and/or translational level in 9/17 ARDS patients (in particular 7/10 severe ARDS) and in 2/14 ventilated controls. The highest mRNA levels were observed in the most severely ill patients (p < 0.028). GILZ was expressed in about ¾ of the corticosteroid-treated patients and its expression could also occur independently of corticosteroids, suggesting that inflammatory signals may also induce neutrophil GILZ expression in vivo. CONCLUSIONS: In this pilot study, we show for the first time that blood neutrophils from patients with ARDS can express GILZ, in keeping with an anti-inflammatory and regulatory endogenous role of GILZ in humans. Contrary to some markers of inflammation or its resolution, the levels of gilz gene expression were related to ARDS severity