FORMULATION AND EFFICACY OF LIPOSOME-ENCAPSULATED ANTIBIOTICS FOR THERAPY OF INTRACELLULAR MYCOBACTERIUM-AVIUM INFECTION

Mycobacterium avium is an intracellular pathogen that can invade and m ultiply within macrophages of the reticuloendothelial system. Current therapy is not highly effective. Particulate drug carriers that are ta rgeted to the reticuloendothelial system may provide a means to delive r antibiotics more efficiently to M. avium-infected cells, We investig ated the formulation of the antibiotics ciprofloxacin and azithromycin in liposomes and tested their antibacterial activities in vitro again st M. avium residing within J774, a murine macrophagelike cell line. A conventional passive-entrapment method yielded an encapsulation effic iency of 9% for ciprofloxacin and because of aggregation mediated by t he cationic drug was useful only with liposomes containing less than o r equal to 50 mol% negatively charged phospholipid. In contrast, cipro floxacin was encapsulated with >90% efficiency, regardless of the cont ent of negatively charged lipids, by a remote-loading technique that u tilized both pH and potential gradients to drive drug into preformed l iposomes. Both the cellular accumulation and the antimycobacterial act ivity of ciprofloxacin increased in proportion to the liposome negativ e charge; the maximal enhancement of potency was 43-fold in liposomes of distearoylphosphatidylglycerol-cholesterol (DSPG-Chol) (10:5), Azit hromycin liposomes were prepared as a freeze dried preparation to avoi d chemical instability during storage, and drug could be incorporated at 33 mol% (with respect to phospholipid). Azithromycin also showed en hanced antimycobacterial effect in liposomes, and the potency increase d in parallel to the moles percent of negatively charged lipids; azith romycin in DSPG-Chol (10:5) liposomes inhibited intracellular M. avium growth 41-fold more effectively than did free azithromycin, Thus, cip rofloxacin or azithromycin encapsulated in stable liposomes having sub stantial negative surface charge is superior to nonencapsulated drug i n inhibition of M. avium growth within cultured macrophages and may pr ovide more effective therapy of M. avium. infections.