Activities of poloxamer CRL-1072 against Mycobacterium avium in macrophage culture and in mice.
Earlier studies reported that certain large hydrophobic poloxamer surfactants were able to inhibit the growth of Mycobacterium avium-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 microg/ml. Surprisingly, its MIC for MAI growing in human U937 monocytoid cells was much lower, 5 microg/ml. A still lower concentration, 0.1 microg/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.
Jagannath
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C
Department of Pathology and Laboratory Medicine, University of Texas Health Sciences Center at Houston, Houston, Texas 77030, USA.
Emanuele
M R
MR
Hunter
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RL
D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D002478:Cells, Cultured; D002981:Clindamycin / Q000494:pharmacology; D015169:Colony Count, Microbial; D004357:Drug Synergism; D005079:Excipients; D006801:Humans; D008264:Macrophages / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015269:Mycobacterium avium Complex / Q000187:drug effects*; D015270:Mycobacterium avium-intracellulare Infection / Q000188:drug therapy* / Q000382:microbiology; D020442:Poloxamer / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D014018:Tissue Distribution
D000900:Anti-Bacterial Agents; D005079:Excipients; D020442:Poloxamer; D002981:Clindamycin