Amikacin liposomal 590mg nebuliser dispersion vials with device

Guideline-based combination therapy achieves sputum culture conversion rates in 23%-34% of patients with Mycobacterium abscessus-complex lung disease. Thus, new therapies are needed. We performed a systematic review to validate and benchmark the hollow fiber system model of M. abscessus lung disease for drug development. We performed a literature search to identify all published hollow fiber system pharmacokinetic-pharmacodynamic studies. Preferred Reporting Items for Systematic Reviews and Meta-Analyses was used for bias minimization. A total of 12 studies were identified. The average quality score was 13.7 out of 21. Eight were monotherapy (exposure-effect and dose-fractionation), one double β-lactam, and three guideline-based therapy studies. For omadacycline and imipenem, hollow fiber system data were accompanied by clinical real-world evidence confirmation. Microbial kill was always terminated by antimicrobial resistance. We used quantitative analyses to rank drugs' efficacy based on CFU/mL kill below day 0 bacterial burden normalized to multi-drug guideline-based therapy kill. The highest-ranked drugs were sulbactam-durlobactam-ceftriaxone (177-fold), epetraborole (15-fold), and omadacycline (7-fold) better than guideline-based therapy. We used the target exposures identified in the systematic analysis in Monte Carlo experiments to identify optimal doses for inhaled formulations. The optimal inhalational dose of imipenem was 250 mg/day, for tigecycline 4 mg/day, for cefoxitin 50 mg/day, and for amikacin liposome inhalation suspension 590 mg once weekly. The hollow fiber system model of M. abscessus lung disease is tractable for exposure-effect, dose-fractionation, and factorial design combination studies. It could also be used to rank drugs and inform on which drugs to test in novel combinations.IMPORTANCECurrent treatments for Mycobacterium abscessus lung disease fail in 70%-80% of patients and are toxic. The hollow fiber system has been used to study old and new potential treatments for this disease. We performed a systematic review of this methodology, for lessons learned. We found 12 studies, which were of adequate quality. Efficacy was always terminated by antimicrobial resistance. The top three drugs in terms of efficacy were sulbactam-durlobactam-ceftriaxone, epetraborole, and omadacycline, which were 7 to 177 times better than standard of care. These drugs could be combined into a new treatment regimen better than current treatments. We also calculated new doses for imipenem, tigecycline, cefoxitin, and amikacin when administered as inhalational therapy. The inhaled doses were multiple-fold lower than intravenous ones, which could be less toxic. The hollow fiber system model is an easily managed system from drug development and dose finding for M. abscessus lung disease.

Abstract licence: CC BY

Extracorporeal membrane oxygenation (ECMO) is increasingly used to support critically ill adults with severe cardiac or respiratory failure, but ECMO circuits and the physiological disturbances of critical illness significantly alter drug pharmacokinetics (PK) and pharmacodynamics (PD), complicating dosing and monitoring. This narrative review synthesizes current clinical evidence on ECMO-related PK/PD alterations and provides practical guidance for optimizing pharmacotherapy in adult intensive care. A structured literature search (January-May 2025) was conducted across PubMed/MEDLINE, EMBASE, Scopus, Cochrane Library, Sage Journals, ScienceDirect, Taylor & Francis Online, SpringerLink, and specialized databases, focusing on seven therapeutic classes commonly used in ECMO patients. Eligible studies included clinical trials, observational studies, systematic reviews, and practice guidelines in adults, while pediatric and preclinical data were excluded. Evidence quality varied substantially across drug classes. Hydrophilic, low-protein-bound agents such as β-lactams, aminoglycosides, fluconazole, and caspofungin generally showed minimal ECMO-specific PK alterations, with dose adjustment mainly driven by renal function. Conversely, lipophilic and highly protein-bound drugs including fentanyl, midazolam, propofol, voriconazole, and liposomal amphotericin B exhibited substantial circuit adsorption and variability, often requiring higher loading doses, prolonged infusions, and rigorous therapeutic drug monitoring. No ECMO-specific data were identified for certain neuromuscular blockers, antivirals, and electrolytes. Overall, individualized dosing guided by therapeutic drug monitoring (TDM), organ function, and validated PK principles remains essential to optimize therapy in this complex population.

Abstract licence: CC BY