JAC Advance Access originally published online on May 22, 2009
Journal of Antimicrobial Chemotherapy 2009 64(2):317-325; doi:10.1093/jac/dkp165
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Original research |
Importance of DNase and alginate lyase for enhancing free and liposome encapsulated aminoglycoside activity against Pseudomonas aeruginosa
1 The Novel Drug & Vaccine Delivery Systems Facility, Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Ontario, P3E 2C6, Canada 2 Medical Sciences Division, Northern Ontario School of Medicine, Lakehead University, 955 Oliver Road, Thunder Bay, Ontario, P7B 5E1, Canada
Received 4 March 2009; returned 6 April 2009; revised 7 April 2009; accepted 8 April 2009
* Corresponding author. Tel: +1-705-675-1151, ext. 2190; Fax: +1-705-675-4844; E-mail: aomri{at}laurentian.ca
Objectives: This study evaluated the potential of DNase, alginate lyase (AlgL) and N-acetylcysteine (NAC) in enhancing the in vitro bactericidal activity of conventional (free) and vesicle-entrapped (liposomal) gentamicin, amikacin and tobramycin.
Methods: The MICs and biofilm eradication for two clinical isolates of Pseudomonas aeruginosa (a mucoid strain and a non-mucoid strain) were determined in the presence and absence of AlgL. The co-activity of aminoglycosides with DNase and/or AlgL against endogenous P. aeruginosa in cystic fibrosis (CF) sputum was also measured. The inhibitory effects of mucin in the presence and absence of the mucolytic agent NAC on aminoglycosidic activity were also examined.
Results: The MIC values of the liposomal aminoglycosides were similar to or lower than those of free aminoglycosides. Biofilm formation increased the bactericidal concentrations of these drugs by 8- to 256-fold and treatment with AlgL improved killing of the mucoid strain. The activity of some aminoglycosides against the sputum was increased by the addition of DNase or AlgL (P < 0.05), and was increasingly evident with concurrent DNase and AlgL administration. Addition of mucin inhibited liposomal aminoglycosidic activity (up to 32-fold) evidently more than the free aminoglycosides (up to 8-fold). The addition of NAC did not improve activity significantly (P > 0.05). Tobramycin was the most effective aminoglycoside to reduce biofilms and sputum.
Conclusions: Liposomal aminoglycosides do not fare better than conventional forms. The co-administration of DNase and AlgL is essential for enhanced activity in reducing biofilm growth and sputum bacterial counts. While mucin retards bactericidal activity, NAC does not improve aminoglycosidic activity.
Keywords: antibiotics , cystic fibrosis , sputum , biofilm , mucin