Antifungal activity of colistin against mucorales species in vitro and in a murine model of Rhizopus oryzae pulmonary infection.
In immunosuppressed hosts, mucormycosis is a life-threatening infection with few treatment options. We studied the activity of colistin (polymyxin E) against Mucorales species in vitro and in a murine model of pulmonary Rhizopus oryzae infection. Colistin exhibited fungicidal activity in vitro against Mucorales spores and mycelia. At the colistin MIC, initial R. oryzae hyphal damage was followed by rapid regrowth; however, regrowth was prevented by combining colistin with a subinhibitory concentration of amphotericin B. Using electron microscopy and FM4-64 staining, we demonstrated that colistin disrupts R. oryzae cytoplasmic and vacuolar membranes, resulting in the leakage of intracellular contents. The prophylactic intranasal treatment of immunosuppressed mice with colistimethate significantly reduced the mortality rate and pulmonary fungal burden resulting from inhalational challenge with R. oryzae spores, whereas intraperitoneal colistimethate treatment had no effect. We conclude that colistin has modest in vitro and in vivo fungicidal activity against Mucorales spp. Further studies are warranted to assess the use of this drug in the prevention and treatment of mucormycosis.
Department of Infectious Diseases, Infection Control and Employee Health, Unit 1460, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Ronen
R
Ben-Ami
Russell E
RE
Lewis
Jeffrey
J
Tarrand
Konstantinos
K
Leventakos
Dimitrios P
DP
Kontoyiannis
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D003091:Colistin / Q000494:pharmacology*; D003593:Cytoplasm / Q000187:drug effects / Q000648:ultrastructure; D005260:Female; D025301:Hyphae / Q000187:drug effects / Q000648:ultrastructure; D008168:Lung / Q000382:microbiology; D008172:Lung Diseases, Fungal / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D046529:Microscopy, Electron, Transmission; D009090:Mucorales / Q000187:drug effects* / Q000648:ultrastructure; D009091:Mucormycosis / Q000188:drug therapy* / Q000382:microbiology; D012233:Rhizopus / Q000187:drug effects* / Q000648:ultrastructure; D013172:Spores, Fungal / Q000187:drug effects; D013778:Tetrazolium Salts; D014617:Vacuoles / Q000187:drug effects / Q000648:ultrastructure
D000935:Antifungal Agents; D013778:Tetrazolium Salts; C059087:2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-((phenylamino)carbonyl)-2H-tetrazolium hydroxide; D000255:Adenosine Triphosphate; D003091:Colistin