Oihana Basabe-Burgos1, Jakub Zebialowicz1, Guido Stichtenoth2,3, Tore Curstedt3, Peter Bergman4, Jan Johansson1, Anna Rising1,5. 1. 1 Division for Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet , Huddinge, Sweden . 2. 2 Department of Pediatrics, University of Lübeck , Lübeck, Germany . 3. 3 Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital , Stockholm, Sweden . 4. 4 Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital , Stockholm, Sweden . 5. 5 Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences , Uppsala, Sweden .
Abstract
BACKGROUND: Pulmonary surfactant spreads rapidly over the airway epithelium, a property that could be harnessed to transport drugs into the lungs. For efficient drug delivery, an interaction between pulmonary surfactant and the drug to be administered is likely needed. On the other hand, the interaction should not compromise the activity of surfactant or the drug once delivered in vivo. The antibiotics gentamicin (an aminoglycoside) and polymyxin E represent drugs that could benefit from being delivered directly to the lung, thereby increasing local concentrations and reducing systemic side effects. Our aim was to study how the animal-derived surfactant poractant alfa (Curosurf®) affects the activities of polymyxin E and gentamicin against Pseudomonas aeruginosa. METHODS: In vitro antimicrobial assays and a neonatal near-term rabbit model were used to evaluate the combinations of antibiotics and surfactant against Pseudomonas aeruginosa. RESULTS: The bactericidal activity of polymyxin E, but not of gentamicin, against P. aeruginosa was partly reduced in vitro in the presence of poractant alfa. In contrast, in the rabbit model of P. aeruginosa pneumonia, polymyxin E administrated together with surfactant was superior in lowering the bacterial load in the lungs compared to polymyxin E alone, without affecting plethysmographically recorded lung compliance. CONCLUSIONS: The results suggest that polymyxin E interacts with poractant alfa, which reduces the antibacterial effect in vitro. However, when polymyxin E mixed with surfactant is used in the in vivo pneumonia model, increased bactericidal effect was observed. This may be due to a more efficient spreading mediated by interactions between polymyxin E and surfactant. These results warrant further studies of surfactant preparations for drug delivery against lung infections.
BACKGROUND: Pulmonary surfactant spreads rapidly over the airway epithelium, a property that could be harnessed to transport drugs into the lungs. For efficient drug delivery, an interaction between pulmonary surfactant and the drug to be administered is likely needed. On the other hand, the interaction should not compromise the activity of surfactant or the drug once delivered in vivo. The antibiotics gentamicin (an aminoglycoside) and polymyxin E represent drugs that could benefit from being delivered directly to the lung, thereby increasing local concentrations and reducing systemic side effects. Our aim was to study how the animal-derived surfactant poractant alfa (Curosurf®) affects the activities of polymyxin E and gentamicin against Pseudomonas aeruginosa. METHODS: In vitro antimicrobial assays and a neonatal near-term rabbit model were used to evaluate the combinations of antibiotics and surfactant against Pseudomonas aeruginosa. RESULTS: The bactericidal activity of polymyxin E, but not of gentamicin, against P. aeruginosa was partly reduced in vitro in the presence of poractant alfa. In contrast, in the rabbit model of P. aeruginosa pneumonia, polymyxin E administrated together with surfactant was superior in lowering the bacterial load in the lungs compared to polymyxin E alone, without affecting plethysmographically recorded lung compliance. CONCLUSIONS: The results suggest that polymyxin E interacts with poractant alfa, which reduces the antibacterial effect in vitro. However, when polymyxin E mixed with surfactant is used in the in vivo pneumonia model, increased bactericidal effect was observed. This may be due to a more efficient spreading mediated by interactions between polymyxin E and surfactant. These results warrant further studies of surfactant preparations for drug delivery against lung infections.
Entities:
Keywords:
bacterial infection; drug delivery; gentamicin; polymyxin E; pulmonary surfactant
Authors: Juan Manuel Coya; Víctor Fraile-Ágreda; Lidia de Tapia; Belén García-Fojeda; Alejandra Sáenz; José A Bengoechea; Nina Kronqvist; Jan Johansson; Cristina Casals Journal: Front Immunol Date: 2022-09-07 Impact factor: 8.786
Authors: Riccardo Zecchi; Pietro Franceschi; Laura Tigli; Barbara Pioselli; Valentina Mileo; Xabier Murgia; Fabrizio Salomone; Giuseppe Pieraccini; Haruo Usada; Augusto F Schmidt; Noah H Hillman; Matthew W Kemp; Alan H Jobe Journal: Pharmaceutics Date: 2021-06-12 Impact factor: 6.321
Authors: Maros Kolomaznik; Jana Kopincova; Zuzana Nova; Juliana Topercerova; Ivan Zila; Pavol Mikolka; Petra Kosutova; Katarina Matasova; Henrieta Skovierova; Marian Grendar; Daniela Mokra; Andrea Calkovska Journal: Molecules Date: 2020-09-23 Impact factor: 4.411