Efficacy of voriconazole in treatment of murine pulmonary blastomycosis.

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.

Effectiveness of quinolone antibiotics in modulating the effects of antifungal drugs.

Quinolone antibacterial drugs inhibit DNA gyrase, a type 2 topoisomerase. Since topoisomerases are present in eukaryotic cells, it was of interest to evaluate the antifungal activities of two clinically available quinolones, ciprofloxacin and trovafloxacin, alone and in combination with amphotericin B or fluconazole, in vitro against Candida albicans and in a murine model of invasive candidiasis. The in vitro activity of trovafloxacin was also tested against other yeasts and molds. In vitro, trovafloxacin exhibited no antifungal activity against any of the fungi (MIC, >250 microg/ml). There was also no effect of the quinolone on the in vitro activity of either antifungal drug. Marked antifungal effects were seen, however, in the murine model of candidiasis. In all experiments, control mice infected intravenously with C. albicans were dead by day 24. While either quinolone had minimal effects on survival of mice when used alone in oral doses of up to 40 mg/kg twice daily, the combination of the quinolone with fluconazole (40 or 80 mg/kg given twice daily by oral gavage) was more effective in prolonging survival than was fluconazole alone. Colony counts of kidneys on days 12 and 30 showed similar reductions in C. albicans recovered from mice treated with fluconazole with or without trovafloxacin or amphotericin B with or without trovafloxacin. Survival of mice treated with a suboptimal dose of amphotericin B (0.2 mg/kg/day) was also improved when trovafloxacin (40 mg/kg) given twice daily was included (0 versus 27%, respectively; P < 0.05). While the mechanisms of action of the combination of trovafloxacin and amphotericin B or fluconazole are unclear, further work focused on fungal topoisomerase inhibition and the mechanism of the antifungal effect of quinolone antibacterial drugs is warranted.

In vitro and in vivo activities of SCH 56592 against Blastomyces dermatitidis.

The new triazole derivative SCH 56592 has been tested in a National Committee for Clinical Laboratory Standards-adapted in vitro susceptibility test, and its activity against 12 isolates of Blastomyces dermatitidis yeast-like forms has been compared with those of amphotericin B, itraconazole, and fluconazole. SCH 56592 was the most active of the four compounds, with an MIC at which 90% of the isolates are inhibited of 0.06 microgram/ml and a minimal fungicidal concentration at which 90% of the isolates are inhibited of 4 micrograms/ml. The results of the treatment of mice infected with B. dermatitidis with three different doses of SCH 56592 (25, 5, or 1 mg/kg of body weight), amphotericin B (1 mg/kg), or itraconazole (150 mg/kg) confirmed the potent activity of SCH 56592. Survival was prolonged at each dose of SCH 56592, and sterilization of the lungs occurred in the high-dose group but not in the groups treated with itraconazole or fluconazole. SCH 56592 is a promising new azole antifungal drug that should be studied in humans with blastomycosis.

Mucormycosis.

Mucormycosis refers to the disease caused by a growing number of members of the Mucorales. Typically an airborne infection, primary disease is initiated in the upper or lower airways and is associated with the clinical development of sinusitis, rhinocerebral mucormycosis, or pulmonary infection. Dissemination of infection to skin, brain, and other sites is less common, but direct extension of the infection to contiguous sites is common if patients do not receive aggressive surgical and medical therapy. Risk factors for the development of mucormycosis include diabetic ketoacidosis; neutropenia; protein-calorie malnutrition; and iron overload, with or without the concomitant use of deferoxamine. This last association has only recently been recognized and has emerged as a major life-threatening complication for patients who are undergoing hemodialysis. Intravenous drug abusers may inject spores of Mucorales with their drugs and may present with space-occupying lesions of the CNS. The underlying immunologic defects that are responsible for predisposing different populations of patients to the development of mucormycosis are not well understood, and there is no unifying theory to explain why most individuals have innate immunity to this group of fungi. Patients with mucormycosis who are managed aggressively (i.e., those who undergo surgical debridement and who receive therapy with iv amphotericin B) may have increased rates of survival. The role of new azole derivatives in the treatment of mucormycosis is unknown.

P&T Committee review of fluconazole: an effective alternative to antifungal therapy.

Fluconazole is a new antifungal agent available in both oral and parenteral formulations. According to the experts in this roundtable discussion, fluconazole represents a major clinical advance in the treatment of candidiasis and cryptococcosis in cancer patients, patients with AIDS, organ transplant recipients, and other patients at risk for opportunistic mycoses. The pharmacokinetic profile for fluconazole permits infrequent dosing and also makes it ideal for tissue site infections. Fluconazole's low toxicity gives it an advantage over currently available antifungal therapy and will permit prompt presumptive treatment of selected infections.

Gonococcal endocarditis in a patient with mitral valve prolapse: study of host immunology and organism characteristics.

The first case of gonococcal endocarditis on a prolapsing mitral valve is reported. The organism was found to be highly sensitive to penicillin G, Arg- Hyp- Ura-, and sensitive to the bactericidal action of normal serum. This combination of characteristics in a strain of Neisseria gonorrheae causing systemic disease is distinctly unusual. With high dose penicillin therapy the immunologic parameters returned to normal and the patient made an uneventful recovery. High levels of circulating immune complexes were detected in the patient's serum.