title: Differences in efficacy and cytokine profiles following echinocandin or liposomal amphotericin B monotherapy or combination therapy for murine pulmonary or systemic Aspergillus flavus infections.
abstract: Given the recent increase in aspergillosis caused by species other than Aspergillus fumigatus, micafungin, caspofungin, and liposomal amphotericin B (L-AmBi) were investigated as monotherapy or combination therapy for murine systemic or pulmonary Aspergillus flavus infection. Treatment for 3 or 6 days was begun at 24 h (intravenous [i.v.], 2.8 × 10(4) conidia) or 2 h (intranasal, 4.1 × 10(6) to 6.75 × 10(6) conidia) postchallenge as follows: 5 or 10 mg/kg L-AmBi, 10 mg/kg caspofungin, 15 mg/kg micafungin, L-AmBi plus echinocandin, L-AmBi on days 1 to 3 and echinocandin on days 4 to 6, or echinocandin on days 1 to 3 and L-AmBi on days 4 to 6. Mice were monitored for survival, fungal burden, serum or tissue cytokines, and lung histopathology. In the systemic infection, micafungin or caspofungin was more effective than L-AmBi in prolonging survival (P < 0.05), and L-AmBi was associated with significantly elevated serum levels of interleukin-6 (IL-6), macrophage inflammatory protein 1α (MIP-1α), and IL-12 (P < 0.05). In contrast, L-AmBi was significantly more effective than the echinocandins in reducing fungal growth in most tissues (P < 0.05). Concomitant therapies produced significantly enhanced survival, reduction in fungal burden, and low levels of proinflammatory cytokines, while antagonism was seen with some sequential regimens. In comparison, in the pulmonary infection, L-AmBi was significantly better (P < 0.05) than caspofungin or the combination of L-AmBi and caspofungin in prolonging survival and reducing lung fungal burden. Caspofungin stimulated high lung levels of IL-1α, tumor necrosis factor alpha (TNF-α), and IL-6, with extensive tissue damage. In summary, systemic A flavus infection was treated effectively with L-AmBi plus micafungin or caspofungin provided that the drugs were administered concomitantly and not sequentially, while pulmonary A. flavus infection responded well to L-AmBi but not to caspofungin.
authors.affiliation: Department of Biological Sciences, California State Polytechnic University, Pomona, California, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Olson
authors.forename: J
authors.initials: J
authors.lastname: Schwartz
authors.forename: D
authors.initials: D
authors.lastname: Hahka
authors.forename: A
authors.initials: A
authors.lastname: George
authors.forename: R T
authors.initials: RT
authors.lastname: Proffitt
authors.forename: J P
authors.initials: JP
authors.lastname: Adler-Moore
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage*; D000818:Animals; D000935:Antifungal Agents; D001228:Aspergillosis / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D001231:Aspergillus flavus / Q000187:drug effects* / Q000254:growth & development; D000077336:Caspofungin; D054405:Chemokine CCL3 / Q000096:biosynthesis; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D054714:Echinocandins / Q000008:administration & dosage*; D005260:Female; D018664:Interleukin-12 / Q000096:biosynthesis; D053582:Interleukin-1alpha / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D055666:Lipopeptides / Q000008:administration & dosage; D008168:Lung / Q000187:drug effects* / Q000382:microbiology; D000077551:Micafungin; D051379:Mice; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000935:Antifungal Agents; D054405:Chemokine CCL3; D054714:Echinocandins; D053582:Interleukin-1alpha; D015850:Interleukin-6; D055666:Lipopeptides; D014409:Tumor Necrosis Factor-alpha; C068538:liposomal amphotericin B; D018664:Interleukin-12; D000666:Amphotericin B; D000077336:Caspofungin; D000077551:Micafungin