Antimicrobial properties of liposomal polymyxin B

The pulmonary residence time of polymyxin B has been shown to be substantia lly increased when administered as a liposomal formulation. The use of this system to improve the treatment of cystic fibrosis lung infections require s that the antimicrobial activity of polymyxin B is unaffected by the encap sulation process. To verify that activity against the target organism, Pseu domonas aeruginosa, was retained, the bactericidal activity and MICs of bot h free and encapsulated polymyxin B were determined. The roles of liposomal surface characteristics in determining interactions with bacterial cell su rfaces were also investigated. Encapsulation of polymyxin B was reduced whe n the positively charged amphiphile, stearylamine (SA) was present, with en trapment efficiencies being lower than with neutral (egg phosphatidylcholin e, EPC) or negatively charged (egg phosphatidylcholine:dicetylphosphate, EP C:DCP) formulations (EPC, 45.41% +/- 0.51%; EPC:DCP 9:1, 50.81% +/- 0.79%; EPC:SA 9:1, 31.92% +/- 2.08%, n x 3). The bactericidal activities were comp ared, and it was found that polymyxin B retained antimicrobial activity aft er encapsulation. At a polymyxin B concentration of 0.3 mg/L, both positive ly and negatively charged liposomal polymyxin B formulations, and free drug , killed all cells after 1 h. In contrast, neutral liposome formulations di d not significantly decrease the surviving cell fraction. At 0.1 mg/L, fewe r cells were killed, and all liposomal formulations produced a reduction in cell numbers;, which was not significantly different from free drug. It wa s found that the MICs of liposomal formulations were attributable to the fr ee drug concentration achieved through release of entrapped polymyxin B. En hanced activity was seen only with positively charged EPC:SA liposomes and those containing distearoylphosphatidylcholine (DSPC) as the bulk phospholi pid. This is likely to be the result of favourable electrostatic interactio ns and increased liposome:cell ratios respectively. In summary, liposome en capsulation of polymyxin B was not detrimental to antimicrobial activity, a nd liposome surface properties and release characteristics were important i n determining interactions with bacterial cells.