KY-62, a Polyene Analog of Amphotericin B, for Treatment of Murine Candidiasis

KY-62 is a water-soluble analog of amphotericin B. In vitro testing of five clinical isolates of Candida albicans showed KY-62 to have potency similar to that of amphotericin B. KY-62 was administered to mice infected intravenously with C. albicans. In vivo, KY-62 was effective in immunocompetent mice, with potency similar to that of amphotericin B. KY-62 was well tolerated up to 30 mg/kg of body weight per dose, an amount that would be lethal with amphotericin B. KY-62 was less effective in mice rendered neutropenic with 5-fluorouracil. The addition of flucytosine had little effect. KY-62 may have potential for clinical development.     

Control of a Candida glabrata prosthetic endovascular infection with posaconazole.

A 63-year-old man with a history of cirrhosis of the liver developed Candida glabrata fungemia after undergoing transjugular intrahepatic portosystemic shunt (TIPS) placement. Treatment with oral fluconazole was initially effective, but when the patient became neutropenic, subsequent blood cultures grew C. glabrata and a thrombus developed, which partially occluded the stent. Despite treatment with fluconazole, blood cultures remained positive for C. glabrata. Treatment with posaconazole resulted in clinical improvement and the patient had only intermittently positive fungal cultures for 6 weeks. A CT scan showed resolution of the inferior vena cava thrombus. Subsequently, the patient developed hepatocellular carcinoma and hepatic encephalopathy and became noncompliant with posaconazole. Blood cultures again became positive for C. glabrata. The patient died a few weeks after the diagnosis of hepatocellular carcinoma, but the cause of death was believed to be worsening liver dysfunction, not C. glabrata infection. Posaconazole had controlled the infection for about 3 months prior to his death. In conclusion, posaconazole may be a useful option in the management of prosthetic endovascular infections caused by C. glabrata.     

Comparative activities of Bay n7133, ICI 153,066, and ketoconazole in murine cryptococcosis

Two new antifungal triazoles, BAY n7133 and ICI 153,066, were compared with ketoconazole in treatment of mice challenged intraperitoneally with Cryptococcus neoformans. At high challenge doses, thymus-containing normal mice had prolonged survival after treatment with BAY n7133. Athymic mice, which have severely deficient cell-mediated immunity, were not protected. At low challenge doses, athymic mice also had prolonged survival. Although BAY n7133 was protective, it was less effective than either ketoconazole or ICI 153,066. BAY n7133 was also less effective in mice challenged intracerebrally than in those challenged intraperitoneally. Both ketoconazole and ICI 153,066 prolonged survival and lowered cryptococcal spleen counts to a greater extent than did BAY n7133.     

Oral fluconazole therapy for patients with acquired immunodeficiency syndrome and cryptococcosis: experience with 22 patients

PURPOSE: Cryptococcus neoformans causes infections in up to 10 percent of patients with the acquired immunodeficiency syndrome (AIDS). Nearly 50 percent of AIDS patients with previously treated cryptococcal meningitis will experience a relapse within six months. To reduce the likelihood of relapse, a maintenance regimen of amphotericin B is often administered weekly. However, the drug's intravenous route of administration and considerable toxicity have led to a search for alternative antifungal agents. In this report, we document our experience with fluconazole, a new oral triazole antifungal agent. PATIENTS AND METHODS: Twenty-two patients with AIDS and various forms of cryptococcosis were treated in an open-label study with 50 to 400 mg/day of fluconazole. The following laboratory studies were done on a monthly basis: complete blood cell count, liver function tests, serum creatinine level, serum cryptococcal antigen level, and serum fluconazole level. Lumbar puncture was performed in patients with meningitis every four to eight weeks to evaluate cerebrospinal fluid cryptococcal antigen, India ink preparation findings, fungal culture, fluconazole level, and protein, glucose, and cell count. RESULTS: Of seven patients with active culture-positive infections, four showed clinical and microbiologic responses (three of four with meningitis, one of three with extraneural cryptococcosis). Fifteen patients who had already undergone successful amphotericin B therapy for either meningitis (n = 14) or pneumonia (n = 1) received fluconazole as prophylaxis against relapse. Fourteen patients remained free of infection during 11 to 64 weeks of suppressive therapy; one patient with meningitis experienced relapse after 26 weeks of treatment. Reverse reactions were limited to increases in hepatic enzyme levels in four patients. CONCLUSION: These results appear sufficiently encouraging to warrant further trials of this oral agent in the suppression of chronic cryptococcosis and perhaps in the treatment of acute infection.     

Caspofungin and liposomal amphotericin B therapy of experimental murine scedosporiosis

Immunosuppressed mice were infected intravenously with conidia of Scedosporium prolificans. Treatment was begun 1 day later with liposomal amphotericin B, caspofungin, or both drugs initiated concurrently. Amphotericin B and caspofungin were each effective, but combined therapy did not appear to offer advantages over liposomal amphotericin B alone.     

Treatment of murine cryptococcal meningitis with UR-9751 and UR-9746.

In these studies, we compare the efficacy of two new azole antifungals with fluconazole in a murine model of cryptococcal meningitis. Mice were infected intracranially. Beginning one day later, groups of 7-10 mice were treated through to day 10 orally with UR-9751 or UR-9746 at 0.1, 0.25, 0.5, 1 or 10 mg kg(-1) day(-1) or fluconazole at 10 mg kg(-1) day(-1). At 10 mg kg(-1) day(-1), all three drugs prolonged survival over controls, but at 1 mg kg(-1) day(-1) only UR-9746 prolonged survival. Tissue counts were more varied on mice sacrificed 8 days after infection. In general, both UR drugs were equal or more potent than fluconazole, and UR-9751 was more effective than UR-9746.     

EPIDEMIOLOGY OF BLACKHEAD IN TURKEYS UNDER APPROXIMATELY NATURAL CONDITIONS

The foregoing experiments in outdoor, unprotected enclosures demonstrates the difficulties surrounding the rearing of turkeys. These are discussed from another view-point and to avoid repetition only a few outlying facts should be considered here. The occasional presence of coccidia, the presence of Heterakis papillosa in the ceca, the occurrence of cases of aspergillosis and of chicken-pox in incubator-bred birds which did not come in contact with other domesticated birds, except in a few cases with incubator-bred chickens, show clearly that turkeys are picking up from the ground material deposited by other birds. The agent of blackhead must come from the same sources. The field experiments show a steadily increasing concentration of the infection from 1917 to 1919, even though the ground had been ploughed and seeded before use. As a result, the various groups of turkeys became infected to a greater degree. The growth in the intensity of the disease may be in part ascribed to an accumulation on the soil of infectious agents during any given season after they had been introduced, but it is hardly acceptable as an explanation from season to season, when the soul was either virgin, as regards poultry yards, or ploughed deep and seeded before use. A more rational hypothesis is the gradual attraction of birds in larger numbers and greater variety on account of the food supply in the turkey enclosures and the more intensive cultivation of the land surrounding the laboratory and animal buildings since the beginning of the experiments in 1917. The intensity of the outbreaks due to the confining of young turkeys with birds over a year old which had been infected during the preceding year, or on ground previously occupied by them, was in all instances much greater than in the spontaneous outbreaks. The cases amounted to nearly 100 per cent of the exposed. On the other hand, the number of cases in the control flocks varied and was very low in some groups. It could have been kept down if the sick birds had been promptly removed and not permitted to recover on the same ground. However, the object of the experiment was not to suppress the disease, but to see to what extent it would develop. It is self-evident that the results obtained apply strictly only to that part of the country where the experiments were made. We have at present no means of knowing whether the sources of infection would become more numerous and concentrated with a higher mean annual temperature, or the reverse. Only by using incubator turkeys exclusively for such tests and eliminating the older turkeys and domesticated birds as carriers, can the miscellaneous, at present not controllable sources of the agents of this disease in different localities and the chances of successful rearing be determined.     

Therapeutic efficacy of caspofungin alone and in combination with amphotericin B deoxycholate for coccidioidomycosis in a mouse model

OBJECTIVES: The therapeutic efficacy of caspofungin alone and in combination with amphotericin B deoxycholate was evaluated in treatment of murine coccidioidomycosis. METHODS: Survival and tissue burdens of the spleens and livers were used as antifungal response markers. In a monotherapy study, caspofungin was injected intraperitoneally at 0.1, 0.2, 0.5, 1 and 5 mg/kg per day on days 2 through 15. Amphotericin B deoxycholate was given at 0.1, 0.2 and 0.5 mg/kg intravenously and 1 and 5 mg/kg intraperitoneally three times per week for 2 weeks. In a combination therapy study, amphotericin B deoxycholate at 0.1 mg/kg was administered intravenously three times per week for 2 weeks, respectively, with and without caspofungin intraperitoneally given at 0.1, 0.5 and 5 mg/kg daily on days 2 through 15 post-infection. RESULTS: The study shows that caspofungin and amphotericin B deoxycholate at > or =0.5 and > or =0.1 mg/kg, respectively, were significant in both prolongation of survival and reduction of the tissue fungal burdens of mice compared with controls. No sterilization of either organ was observed with caspofungin doses. In combination therapy, any combination of caspofungin (0.1, 0.5 and 5 mg/kg) with amphotericin B deoxycholate (0.1 mg/kg) improved the period of survival and significantly reduced spleen and liver counts compared with controls. CONCLUSIONS: This study indicates that caspofungin has efficacy against systemic coccidioidomycosis in a murine model given in combination with amphotericin B deoxycholate.     

Activity of posaconazole in the treatment of central nervous system fungal infections

OBJECTIVES: A multinational, multicentre, open-label clinical trial was conducted to evaluate the safety and efficacy of posaconazole, an extended-spectrum triazole antifungal agent, in subjects with invasive fungal infections who had refractory disease or who were intolerant of standard antifungal therapy. In this subanalysis, we report on those subjects in this trial who had a fungal infection that involved the CNS. METHODS: Subjects received posaconazole oral suspension 800 mg/day in divided doses for up to 1 year; however, subjects could receive additional therapy as part of a treatment-use extension protocol. A blinded, third-party data review committee determined subject eligibility and outcome. RESULTS: Of the 330 subjects who enrolled in the study, 53 had infections of the CNS, of which 39 were considered evaluable for efficacy. Most had refractory disease (37 of 39) and underlying HIV infection (29 of 39). Twenty-nine subjects had cryptococcal infections, and 10 had infections caused by other fungal pathogens [Aspergillus spp. (four), Pseudallescheria boydii (two), Coccidioides immitis (one), Histoplasma capsulatum (one), Ramichloridium mackenziei (one), and Apophysomyces elegans plus a Basidiomycetes sp. (one)]. Successful outcomes were observed in 14 of 29 (48%) subjects with cryptococcal meningitis and five of 10 (50%) subjects with CNS infections due to other fungal pathogens. Posaconazole was well tolerated. CONCLUSIONS: These data suggest that posaconazole, as an oral medication, has clinical activity against fungal infections of the CNS and may provide a valuable alternative to parenteral therapy in patients failing existing antifungal agents.     

Effect of fluconazole on fungicidal activity of flucytosine in murine cryptococcal meningitis.

Both animal and in vitro studies have demonstrated that combinations of flucytosine with amphotericin B and with fluconazole have significantly improved activity against cryptococcal meningitis compared with the activity of each drug used alone. However, very few dose levels of these agents have been tested in combination. This study evaluated the efficacy of fluconazole plus flucytosine in a murine model of cryptococcal meningitis over a broad range of dose combinations (fluconazole, 0 to 40 micrograms/g of body weight per day; flucytosine, 0 to 200 micrograms/g/day). Both drugs were dissolved in drinking water, with treatment on days 2 to 11. In this highly reproducible model, fluconazole had a dramatic effect on the fungicidal activity of flucytosine. Flucytosine at dose levels of as much as 200 micrograms/g/day alone or in combination with low doses of fluconazole had minimal fungicidal activity, whereas in combination with fluconazole at 24 to 40 micrograms/g/day, flucytosine showed fungicidal activity in the range of 45 to 65% of the animals treated at doses of 40 to 100 micrograms/g/day. This striking effect of fluconazole is consistent with the results of both in vitro and clinical studies. In the clinic, the use of flucytosine is often limited by severe toxicity, while toxicity is rarely observed with fluconazole. These results suggest that when flucytosine is given with higher doses of fluconazole, the maximum therapeutic effect of the former in the clinic may be observed at dose levels that are far less than the doses commonly employed (150 micrograms/g daily).