A comparison of the efficacy of itraconazole, amphotericin B and 5-fluorocytosine in the treatment of <i>Aspergillus fumigatus</i> endocarditis in the rabbit

The triazole Bay R 3783 was compared with fluconazole, itraconazole, ketoconazole, and amphotericin B in rodent models of superficial and systemic candidiasis, meningocerebral cryptococcosis, and pulmonary aspergillosis. Overall, Bay R 3783 was comparable or slightly superior to fluconazole and markedly superior to itraconazole and ketoconazole in both survival and short-term organ load experiments in models of candidiasis and cryptococcosis but was less effective than amphotericin B. Of the antifungal agents tested, only Bay R 3783 and itraconazole showed any efficacy in the model of pulmonary aspergillosis.With the increasing numbers of immunocompromised patients seen over the last decade, there has been a concomitant increase in the incidence of opportunistic fungal infections (9, 31, .37). Indeed, with the prediction of. nearly 400,000 cumulative cases of acquired immunodeficiency syndrome patients by 1992 in the United States (17), this single segment of the population has created a need for new antifungal modalities because of the high incidence of cryptococcosis, among other fungal diseases, seen. To meet this need, a number of new antifungal agents have been introduced in the past 5 years. The majority of these agents have been of the azole class, which has as its mechanism of action the inhibition of ergosterol biosynthesis in the fungal cell membrane (2, 21). In this paper, we present data from experiments with rodent models of candidiasis, cryptococcosis, and aspergillosis and compare the new triazole Bay R 3783 with ketoconazole, itraconazole, fluconazole, and amphotericin B.MATERIALS AND METHODS Drugs. Bay R 3783 was received as a powder from Bayer AG (Wuppertal, Federal Republic of Germany), fluconazole was received as a powder from Pfizer Inc. (Groton, Conn.), itraconazole was received as a powder from Janssen (Piscataway, N.J.), ketoconazole was purchased as Nizoral (200-mg tablets) from Janssen, and amphotericin B. was purchased as Fungizone from E. R. Squibb & Sons (Princeton, N.J.). For administration, Bay R 3783 was prepared as a suspension in 0.1% agar with 0.5% glucose or dissolved by heating at 60°C in PEG 200. Ketoconazole was suspended and fluconazole was dissolved in the agar described above. Itraconazole was also dissolved in PEG 200. The concentrations of azoles were adjusted for oral delivery in 0.1-mi volumes. Amphotericin B was diluted in 5% glucose and injected intraperitoneally in 0.1-ml volumes.Animals Fig. 1 and 2). For the Cryptococcus meningitis model, the inoculum was delivered intracranially by puncturing the cranium with a 27-gauge needle and delivering 0.03-ml portions of the fungal suspension as shallowly as possible. For the aspergillosis pulmonary model, mice were given a single injection of 5 mg of cortisone acetate 18 h prior to infection. On the day of infection, the mice were first anesthetized with intraperitoneal pentobarbital (50 mg/kg of body weight), and then 0.03 ml of the inoculum was placed on the nares for inhalation.

Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 90%

Evaluation of Bay R 3783 in rodent models of superficial and systemic candidiasis, meningeal cryptococcosis, and pulmonary aspergillosis

Hector

Yee

1990

“…The P-cyclodextrins are naturally occurring cyclic oligosaccharides of seven glucose units and are produced as a product of the enzymatic degradation of starch by Bacillus macerans (10 fiumigatus from a significant number of the rabbits. Itraconazole has been shown to effectively reduce or eliminate A. fumigatus in experimental infections (11,16,18,19). The results of this study show that reduction in the tissue burden of infection and eradication of the organism from tissues correlated directly with the levels achieved in serum from these immunosuppressed rabbits.…”

Section: Resultsmentioning

confidence: 56%

Efficacy of itraconazole solution in a rabbit model of invasive aspergillosis

Patterson

Fothergill

Rinaldi

1993

The efficacy of an itraconazole-cyclodextrin solution against Aspergil1us fumigatus was assessed in an immunosuppressed, temporarily leukopenic rabbit model of invasive aspergillosis and compared with that of amphotericin B. Oral itraconazole solution at dosages of 20 and 40 mg/kg/day improved survival as compared with that of controls. Itraconazole (40 mg/kg/day) not only improved survival and reduced antigen levels but also significantly eradicated A. fumigatus from tissues and was as effective as amphotericin B in these studies.

“…In Aspergillus endocarditis, treatment of infected rabbits with 5FC (25 or 50 mg/kg) significantly lowered the number of CFU per gram of vegetation (10). In another endocarditis model, 5FC (35 mg/kg) eradicated Aspergillus from the cardiac vegetation in 1 of the 10 rabbits tested, but it had no appreciable effect on mortality or survival time (14). In general, the activity of 5FC monotherapy against A. fumigatus in animal models has been marginal.…”

Section: Discussionmentioning

confidence: 95%

Efficacy and Pharmacodynamics of Flucytosine Monotherapy in a Nonneutropenic Murine Model of Invasive Aspergillosis

Dorsthorst

Verweij

Meis

et al. 2005

The therapeutic efficacy of flucytosine (5FC) monotherapy and the pharmacodynamic index predictive of efficacy were evaluated in a nonneutropenic mouse model of acute invasive aspergillosis. Mice were infected intravenously with an Aspergillus fumigatus isolate (the median MICs of 5FC were 128 g/ml under the standard condition, 0.5 g/ml at pH 6.0, and 0.031 g/ml at pH 5.0) 2 h prior to the start of therapy and were treated for 7 days with different 5FC dosing regimens. The total doses ranged from 50 to 800 mg/kg of body weight/day and were administered at 6-, 12-, and 24-h intervals. The efficacy was assessed by means of survival. The survival rates of the treatment groups ranged from 40 to 90%, while the survival rate of the control group was 20%. The efficacy found depended primarily on the total daily dose. However, the power of our sample size may have been too low to exclude an effect of dose fractionation. The pharmacodynamic index that most strongly correlated with the efficacy was the area under the serum concentration-time curve and MIC ratio (R 2 ‫؍‬ 0.86). We conclude that 5FC monotherapy is efficacious in a murine Aspergillus fumigatus infection model.Flucytosine (5FC) is the fluorinated analogue of cytosine which was first used for the treatment of human invasive mycoses in 1968 (21). The drug has a narrow spectrum of activity and is seldom used as monotherapy due to the emergence of resistance. 5FC monotherapy is presently used only for the treatment of some cases of chromoblastomycosis and uncomplicated lower urinary tract candidiasis and vaginal candidiasis. In all other cases, 5FC is used in combination with other agents, usually amphotericin B, for the treatment of systemic mycoses (24). Its use for the treatment of infections caused by filamentous fungi is controversial because there is currently insufficient scientific evidence for such an indication.Filamentous fungi are usually not susceptible to 5FC in vitro (16). However, in a recent study (22) we demonstrated that the in vitro activity of 5FC against Aspergillus fumigatus increased when the medium pH was lowered from 7.0, which is the pH recommended by the Clinical and Laboratory Standards Institute (formerly the National Committee for Clinical Laboratory Standards) (16), to 5.0. For most A. fumigatus isolates, high MICs at pH 7.0 (MIC range, 2 to Ͼ256 g/ml; median MIC, 16 g/ml) were converted to very low MICs at pH 5.0 (MIC range, 0.031 to 0.5 g/ml; median MIC, 0.125 g/ml). At pH 5.0 the MICs were below the concentrations achievable in vivo. Based on these findings, we speculated that 5FC monotherapy could be effective for the treatment of infections caused by filamentous fungi.We therefore investigated whether 5FC treatment prolonged survival in a nonneutropenic murine model of acute invasive aspergillosis. In this model, the duration of 5FC treatment was 7 days, and the therapeutic efficacy was assessed by survival rather than by CFU quantitation, because CFU counts do not accurately reflect the number of viable cells in infections ca...