Activity and interactions of liposomal antibiotics in presence of polyanions and sputum of patients with cystic fibrosis.
BACKGROUND
To compare the effectiveness of liposomal tobramycin or polymyxin B against Pseudomonas aeruginosa in the Cystic Fibrosis (CF) sputum and its inhibition by common polyanionic components such as DNA, F-actin, lipopolysaccharides (LPS), and lipoteichoic acid (LTA).


METHODS
Liposomal formulations were prepared from a mixture of 1,2-Dimyristoyl-sn-Glycero-3-Phosphocholine (DMPC) or 1,2-Dipalmitoyl-sn-Glycero-3-Phosphocholine (DPPC) and Cholesterol (Chol), respectively. Stability of the formulations in different biological milieus and antibacterial activities compared to conventional forms in the presence of the aforementioned inhibitory factors or CF sputum were evaluated.


RESULTS
The formulations were stable in all conditions tested with no significant differences compared to the controls. Inhibition of antibiotic formulations by DNA/F-actin and LPS/LTA was concentration dependent. DNA/F-actin (125 to 1000 mg/L) and LPS/LTA (1 to 1000 mg/L) inhibited conventional tobramycin bioactivity, whereas, liposome-entrapped tobramycin was inhibited at higher concentrations--DNA/F-actin (500 to 1000 mg/L) and LPS/LTA (100 to 1000 mg/L). Neither polymyxin B formulation was inactivated by DNA/F-actin, but LPS/LTA (1 to 1000 mg/L) inhibited the drug in conventional form completely and higher concentrations of the inhibitors (100 to 1000 mg/L) was required to inhibit the liposome-entrapped polymyxin B. Co-incubation with inhibitory factors (1000 mg/L) increased conventional (16-fold) and liposomal (4-fold) tobramycin minimum bactericidal concentrations (MBCs), while both polymyxin B formulations were inhibited 64-fold.


CONCLUSIONS
Liposome-entrapment reduced antibiotic inhibition up to 100-fold and the CFU of endogenous P. aeruginosa in sputum by 4-fold compared to the conventional antibiotic, suggesting their potential applications in CF lung infections.
Alipour
Misagh
M
The Novel Drug & Vaccine Delivery Systems Facility, Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Ontario, Canada.
Suntres
Zacharias E
ZE
Halwani
Majed
M
Azghani
Ali O
AO
Omri
Abdelwahab
A
D000199:Actins / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D003550:Cystic Fibrosis / Q000382:microbiology*; D004247:DNA / Q000494:pharmacology; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008081:Liposomes / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D000071228:Polyelectrolytes; D011108:Polymers / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D011817:Rabbits; D013183:Sputum / Q000187:drug effects* / Q000382:microbiology*; D013682:Teichoic Acids / Q000494:pharmacology; D014031:Tobramycin / Q000494:pharmacology
D000199:Actins; D000900:Anti-Bacterial Agents; D004247:DNA; D008070:Lipopolysaccharides; D008081:Liposomes; D000071228:Polyelectrolytes; D011108:Polymers; D013682:Teichoic Acids; D014031:Tobramycin; C009900:lipoteichoic acid