Co-Delivery of Ciprofloxacin and Colistin in Liposomal Formulations with Enhanced In Vitro Antimicrobial Activities against Multidrug Resistant Pseudomonas aeruginosa
This study aims to develop liposomal formulations containing synergistic antibiotics of colistin and ciprofloxacin for the treatment of infections caused by multidrug-resistant Pseudomonas aeruginosa.
Colistin (Col) and ciprofloxacin (Cip) were co-encapsulated in anionic liposomes by ammonium sulfate gradient. Particle size, encapsulation efficiency, in vitro drug release and in vitro antibiotic activities were evaluated.
The optimized liposomal formulation has uniform sizes of approximately 100 nm, with encapsulation efficiency of 67.0% (for colistin) and 85.2% (for ciprofloxacin). Incorporation of anionic lipid (DMPG) markedly increased encapsulation efficiency of colistin (from 5.4 to 67.0%); however, the encapsulation efficiency of ciprofloxacin was independent of DMPG ratio. Incorporation of colistin significantly accelerated the release of ciprofloxacin from the DMPG anionic liposomes. In vitro release of ciprofloxacin and colistin in the bovine serum for 2 h were above 70 and 50%. The cytotoxicity study using A549 cells showed the liposomal formulation is as non-toxic as the drug solutions. Liposomal formulations of combinations had enhanced in vitro antimicrobial activities against multidrug resistant P. aeruginosa than the monotherapies.
Liposomal formulations of two synergistic antibiotics was promising against multidrug resistant P. aeruginosa infections.
KEY WORDSantimicrobial activities ciprofloxacin colistin cytotoxicity in vitro release liposome Pseudomonas aeruginosa
Blank anionic liposomes
Ciprofloxacin/Colistin anionic liposomes
Ciprofloxacin/Colistin neutral liposomes
Ciprofloxacin anionic liposomes
Ciprofloxacin hydrochloride monohydrate
Colistin anionic liposomes
Colistin-loaded unilamellar liposomes
Cryogenic transmission electron microscopy
Molecular weight cut off
- 5.Johansen HK, Moskowitz SM, Ciofu O, Pressler T, Hoiby N. Spread of colistin resistant non-mucoid Pseudomonas aeruginosa among chronically infected Danish cystic fibrosis patients. Journal of cystic fibrosis: official journal of the European cystic fibrosis. Society. 2008;7(5):391–7.Google Scholar
- 14.Lin L, Nonejuie P, Munguia J, Hollands A, Olson J, Dam Q, et al. Azithromycin synergizes with cationic antimicrobial peptides to exert bactericidal and therapeutic activity against highly multidrug-resistant gram-negative bacterial pathogens. EBioMedicine. 2015;2(7):690–8.CrossRefPubMedPubMedCentralGoogle Scholar
- 16.Ly NS, Bulitta JB, Rao GG, Landersdorfer CB, Holden PN, Forrest A, et al. Colistin and doripenem combinations against Pseudomonas aeruginosa: profiling the time course of synergistic killing and prevention of resistance. J Antimicrob Chemother. 2015;70(5):1434–42.CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Hoiby N, Frederiksen B, Pressler T. Eradication of early Pseudomonas aeruginosa infection. J Cyst Fibros. 2005;4 Suppl 2:49–54.Google Scholar
- 27.Bachar M, Mandelbaum A, Portnaya I, Perlstein H, Even-Chen S, Barenholz Y, et al. Development and characterization of a novel drug nanocarrier for oral delivery, based on self-assembled beta-casein micelles. J Control Release: Official Journal of the Controlled Release Society. 2012;160(2):164–71.CrossRefGoogle Scholar
- 41.Bergen PJ, Forrest A, Bulitta JB, et al. Clinically relevant plasma concentrations of colistin in combination with imipenem enhance pharmacodynamic activity against multidrug-resistant Pseudomonas aeruginosa at multiple inocula. Antimicrob Agents Chemother. 2011;55(11):5134–42.CrossRefPubMedPubMedCentralGoogle Scholar
- 43.Li J, Poudyal A, Yu H, et al. Targeting multidrug-resistantpseudomonas aeruginosa: pharmacodynamics of the combination of colistin and ciprofloxacin. Clinical Microbiology & Infection. 2010;16:S469.Google Scholar