Efficacy of Nikkomycin Z in the Treatment of Murine Histoplasmosis

ABSTRACT Immune-competent ICR and BALB/c athymic (nude) mice were infected intravenously with Histoplasma capsulatum and treated with either fluconazole or nikkomycin Z or 5% dextrose (controls). In immune-competent ICR mice, fluconazole and nikkomycin Z both prolonged survival when given at 5 mg/kg of body weight twice daily. When administered in doses as low as 2.5 mg/kg twice daily, nikkomycin Z reduced fungal counts in both the spleen and liver. When both drugs were combined, there was no antagonism, and in combined therapy spleen and liver counts were reduced more than for either drug alone. However, nikkomycin Z had no effect on brain fungal burden. In nude mice fluconazole and nikkomycin Z had an additive effect in prolongation of survival and reduction of liver and spleen burden. Nikkomycin Z is well tolerated, is at least as effective as fluconazole, and may interact beneficially with fluconazole for treatment of murine histoplasmosis.

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Efficacy of nikkomycin Z against experimental pulmonary blastomycosis.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.41.9.2026 ◽

1997 ◽

Vol 41 (9) ◽

pp. 2026-2028 ◽

Cited By ~ 32

Author(s):

K V Clemons ◽

D A Stevens

Keyword(s):

Body Weight ◽

Amphotericin B ◽

Murine Model ◽

Prolonged Survival ◽

Blastomyces Dermatitidis ◽

Good Activity ◽

Synthetase Inhibitor ◽

Chitin Synthetase ◽

Nikkomycin Z

Nikkomycin Z is a chitin synthetase inhibitor. In vitro, nikkomycin Z had good activity against Blastomyces dermatitidis, with an MIC of 0.78 microg/ml and a minimal fungicidal concentration of 3.1 microg/ml. The efficacies of various treatment durations (3, 5, or 10 days) and doses (200, 400, or 1,000 mg/kg of body weight) of nikkomycin Z given twice daily were compared with those of itraconazole at 200 mg/kg given twice daily and amphotericin B at 6.25 mg/kg in a murine model of pulmonary blastomycosis. All treatments prolonged survival compared with untreated controls (P < 0.05 to 0.01); 100% survival was achieved with 5 or 10 days of any nikkomycin Z dose or with amphotericin B. Amphotericin B and nikkomycin Z, but not itraconazole, reduced infection compared with controls. Amphotericin B and the 10-day regimens of all nikkomycin Z doses were equivalent and superior to itraconazole or nikkomycin Z for < or = 5 days at any dose (P < 0.05 to 0.01). Increased duration and/or dosage improved the efficacy of nikkomycin Z, with 10 days of each dose curing 50 to 90% of the animals. Only a 1,000-mg/kg/day dose of nikkomycin Z was curative when treatment lasted less than 10 days. In contrast, itraconazole cured no mice, while amphotericin B cured all mice. Based on the total amount of drug given, amphotericin B was estimated to be 32 times as active as nikkomycin Z and nikkomycin Z was estimated to be 3 times as active as itraconazole. Overall, nikkomycin Z given orally was well tolerated, had good activity against blastomycosis, and could result in biological cure, thus producing results equivalent to those of parenteral amphotericin B.

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Comparison of Nikkomycin Z with Amphotericin B and Itraconazole for Treatment of Histoplasmosis in a Murine Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.44.6.1624-1629.2000 ◽

2000 ◽

Vol 44 (6) ◽

pp. 1624-1629 ◽

Cited By ~ 24

Author(s):

Janet Goldberg ◽

Patricia Connolly ◽

Carol Schnizlein-Bick ◽

Michelle Durkin ◽

Stephen Kohler ◽

...

Keyword(s):

Amphotericin B ◽

Clinical Isolate ◽

Murine Model ◽

Histoplasma Capsulatum ◽

Vehicle Control ◽

In Vitro Susceptibility ◽

Fungal Burden ◽

Nikkomycin Z

ABSTRACT Nikkomycin Z was tested both in vitro and in vivo for efficacy against Histoplasma capsulatum. Twenty clinical isolates were tested for susceptibility to nikkomycin Z in comparison to amphotericin B and itraconazole. The median MIC was 8 μg/ml with a range of 4 to 64 μg/ml for nikkomycin Z, 0.56 μg/ml with a range of 0.5 to 1.0 μg/ml for amphotericin B, and ≤0.019 μg/ml for itraconazole. Primary studies were carried out by using a clinical isolate of H. capsulatum for which the MIC of nikkomycin Z was greater than or equal to 64 μg/ml. In survival experiments, mice treated with amphotericin B at 2.0 mg/kg/dose every other day (QOD) itraconazole at 75 mg/kg/dose twice daily (BID), and nikkomycin Z at 100 mg/kg/dose BID survived to day 14, while 70% of mice receiving nikkomycin Z at 20 mg/kg/dose BID and none of the mice receiving nikkomycin Z at 5 mg/kg/dose BID survived to day 14. All vehicle control mice died by day 12. Fungal burden was assessed on survivors. Mice treated with nikkomycin Z at 20 and 100 mg/kg/dose BID had significantly higher CFUs per gram of organ weight in quantitative cultures and higher levels of Histoplasma antigen in lung and spleen homogenates than mice treated with amphotericin B at 2.0 mg/kg/dose QOD or itraconazole at 75 mg/kg/dose BID. Studies also were carried out with a clinical isolate for which the MIC of nikkomycin Z was 4 μg/ml. All mice treated with amphotericin B at 2.0 mg/kg/dose QOD; itraconazole at 75 mg/kg/dose BID; and nikkomycin Z at 100, 20, and 5 mg/kg/dose BID survived until the end of the study at day 17 postinfection, while 30% of the untreated vehicle control mice survived. Fungal burden assessed on survivors showed similar levels ofHistoplasma antigen in lung and spleen homogenates of mice treated with amphotericin B at 2.0 mg/kg/dose QOD; itraconazole at 75 mg/kg/dose BID; and nikkomycin Z at 100, 20, and 5 mg/kg/dose BID. The three surviving vehicle control mice had significantly higher antigen levels in lung and spleen than other groups (P < 0.05). The efficacy of nikkomycin Z at preventing mortality and reducing fungal burden correlates with in vitro susceptibility.

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Treatment of Histoplasmosis with MK-991 (L-743,872)

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.1.151 ◽

1998 ◽

Vol 42 (1) ◽

pp. 151-153 ◽

Cited By ~ 55

Author(s):

John R. Graybill ◽

Laura K. Najvar ◽

Eleanor M. Montalbo ◽

Francesco J. Barchiesi ◽

Michael F. Luther ◽

...

Keyword(s):

Body Weight ◽

Histoplasma Capsulatum ◽

Clinical Development ◽

Yeast Cells ◽

Prolonged Survival ◽

Athymic Mice ◽

Once Daily ◽

Immunocompetent Mice

ABSTRACT BALB/c nu/+ immunocompetent and athymic (nu/nu) mice were infected intravenously with yeast cells of Histoplasma capsulatum. Mice were either given water (controls) intraperitoneally (i.p.) or given MK-991 i.p. once daily or twice daily. Protection was measured as prolonged survival or reduction in tissue counts. MK-991 was protective in immunocompetent mice, prolonging survival and reducing counts in spleen and livers at a dose as low as 0.05 mg/kg of body weight/day. MK-991 was modestly effective in athymic mice at a higher dose, 5 mg/kg/day. These studies suggest that MK-991 may be appropriate for clinical development in histoplasmosis.

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Efficacy of Micafungin Alone or in Combination against Systemic Murine Aspergillosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.47.4.1452-1455.2003 ◽

2003 ◽

Vol 47 (4) ◽

pp. 1452-1455 ◽

Cited By ~ 75

Author(s):

Javier Capilla Luque ◽

Karl V. Clemons ◽

David A. Stevens

Keyword(s):

Body Weight ◽

Combination Therapy ◽

Amphotericin B ◽

Prolonged Survival ◽

Nikkomycin Z ◽

The Brain ◽

Body Weight Dose

ABSTRACT We tested the efficacy of micafungin (FK) alone or in combination with other antifungals against systemic murine aspergillosis. FK alone at 10 mg/kg of body weight/dose prolonged survival (P = 0.01) and reduced CFU in the brain and kidney. Combination therapy that used suboptimal FK with amphotericin B or itraconazole prolonged survival. Although no survivors were free of infection, no antagonism was seen. Nikkomycin Z with FK showed significantly greater potency (P < 0.01) than either alone.

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Efficacy of Ravuconazole in Treatment of Systemic Murine Histoplasmosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.46.3.922-924.2002 ◽

2002 ◽

Vol 46 (3) ◽

pp. 922-924 ◽

Cited By ~ 20

Author(s):

K. V. Clemons ◽

M. Martinez ◽

L. Calderon ◽

D. A. Stevens

Keyword(s):

Body Weight ◽

Prolonged Survival ◽

Murine Models ◽

Fungal Burden ◽

Disseminated Histoplasmosis

ABSTRACT Ravuconazole (RCZ) was evaluated for efficacy in comparison to fluconazole (FCZ) and itraconazole (ITZ) in murine models of disseminated histoplasmosis. All regimens tested prolonged survival (P < 0.05 to 0.0001). At equivalent doses of 50 mg/kg of body weight, RCZ and ITZ were equally effective and RCZ was more effective than FCZ (P = 0.02). Clearance of fungal burden from the livers and spleens of mice showed RCZ and ITZ at doses of 50 mg/kg to be efficacious but not curative. These data indicate that RCZ should be studied further.

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Efficacy of Voriconazole in Treatment of Murine Pulmonary Blastomycosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.45.2.601-604.2001 ◽

2001 ◽

Vol 45 (2) ◽

pp. 601-604 ◽

Cited By ~ 54

Author(s):

Alan M. Sugar ◽

Xiu-Ping Liu

Keyword(s):

Body Weight ◽

Broad Spectrum ◽

Grapefruit Juice ◽

Prolonged Survival ◽

Antifungal Compound ◽

Fungal Burden ◽

Dose Dependent Fashion ◽

Dose Dependent

ABSTRACT We evaluated the efficacy of voriconazole, a new broad-spectrum triazole antifungal compound, in the treatment of murine pulmonary blastomycosis. Since mice metabolize voriconazole rapidly, we took advantage of our previous observation that administration of grapefruit juice to mice resulted in suitable serum voriconazole concentrations so that treatment studies with mice could be done (A. M. Sugar and X.-P. Liu, Med. Mycol. 38:209–121, 2000). Our results show that voriconazole prolonged survival in a dose-dependent fashion and that the fungal burden in the lungs was decreased by voriconazole administered at 40 mg/kg of body weight/day. Voriconazole should be studied in humans with blastomycosis.

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Ultrastructure of NPC/HK1 cells heterotransplanted in athymic nude mice

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010005384x ◽

1982 ◽

Vol 40 ◽

pp. 236-237

Author(s):

E.C. Chew ◽

C.L. Li ◽

D.P. Huang ◽

H.C. Ho ◽

L.S. Mak ◽

...

Keyword(s):

Cell Line ◽

Nude Mice ◽

Biopsy Specimen ◽

Epithelial Cell Line ◽

Present Communication ◽

Recurrent Tumour ◽

Athymic Nude Mice ◽

Cell Line Establishment ◽

Fine Structures ◽

Well Differentiated

An epithelial cell line, NPC/HK1, has recently been established from a biopsy specimen of a recurrent tumour of the nasopharynx which was histologically diagnosed as a moderately to well differentiated squamous cell carcinoma. A definite decrease in the amount of tonofilaments and desmosomes in the NPC/HK1 cells during the cell line establishment was observed. The present communication reports on the fine structures of the NPC/HK1 cells heterotraneplanted in athymic nude mice.

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