Activities of poloxamer CRL-1072 against Myobacterium avium in macrophage culture and in mice

Earlier studies reported that certain large hydrophobic poloxamer surfactants were able to inhibit the growth of Mycobacterium avircm-M intracellulare complex (MAI) in broth and to produce synergistic enhancement of the activity of rifampin, CRL-1072 was synthesized to have an optimal structure for antimicrobic effects and greater purity. Its MIC for MAI in broth was greater than 100 mu g/ml. Surprisingly, its MIC for MAI growing in human U937 monocytoid cells was much lower, 5 mu g/ml. A still lower concentration, 0.1 mu g/ml, produced synergistic enhancement of the activities of clarithromycin, rifampin, amikacin, streptomycin, and clindamycin, but not isoniazid, against MAI infecting monocytoid cells. Mice tolerated injection of doses of CRL-1072 as high as 125 mg/kg of body weight. Pharmacokinetic analysis revealed that the copolymer had an elimination half-life of 60 h and suggested dosing regimens that might produce therapeutic concentrations in tissue, In a mouse model of acute MAI infection, CRL-1072 significantly enhanced the bactericidal activities of clarithromycin and rifampin when it was administered at 1.0 mg/kg intravenously (i,v,) three times per week CRL-1072 given i,v, or orally also enhanced the bactericidal activity of clindamycin against MAI.