Itraconazole and fluconazole, two new triazoles, were examined for their antifungal activity in rabbits. Fluconazole easily crossed the blood-cerebrospinal fluid barrier, and active drug was eliminated in high concentrations in the urine. On the other hand, itraconazole did not cross the blood-cerebrospinal fluid barrier in measurable amounts, and urine concentrations were variable. Despite differences in pharmacokinetics at the site of infection, both agents were equally effective ill treating cryptococcal meningitis and candida pyelonephritis in animals. By using a ketoconazole-resistant strain of Candida albicans, we showed that there was cross-resistance in vivo between these two new triazole compounds.For over 25 years, amphotericin B has provided the standard treatment for most systemic mycotic infections (13,14). However, this drug is less than ideal in many respects, especially with regard to toxicity. In the search for alternative therapies, the azole compounds represent an important development. Imidazoles, such as clotrimazole and miconazole, have proven very effective for treating superficial dermatophyte and yeast infections. An intravenous preparation of miconazole had some success against disseminated mycoses (4, 11), but lack of clinical experience has limited its use for systemic disease. Ketoconazole is the most recently licensed addition to the meager stockpile of systemic antifungal drugs. It has proven to be effective against both superficial dermatophyte and yeast infections (9, 10), and some disseminated mycoses such as paracoccidioidomycosis, blastomycosis, histoplasmosis, and coccidioidomycosis (5,19,21).In the quest for new antifungal agents with lower toxicity, broader spectrum, and better pharmacokinetic profiles, the progressive development of azole compounds has produced the triazoles. These include itraconazole and fluconazole.In this study, we compared the pharmacokinetics, in vitro activity, and in vivo efficacy of these two agents in two animal model infections: cryptococcal meningitis in cortisone-treated rabbits and candida pyelonephritis in rabbits. In the first model, we evaluated the effect of these agents on a central nervous system infection in a compromised host. In the second model, we examined the treatment of the most common pathogenic yeast in the urinary tract (6).

We studied the penetration of three azole compounds, ketoconazole, itraconazole, and fluconazole, into the ocular tissues and fluids of rabbits in the presence and absence of ocular inflammation. Drug concentrations were compared with those found in serum and cerebrospinal fluid. The rank order of penetration into eye tissue was fluconazole > ketoconazole > itraconazole. Fluconazole penetrated freely into both inflamed and uninflamed eyes. The presence of inflammation improved penetration of all three compounds into ocular fluids and tissues. Penetration of these azoles into the anterior chamber of uninflamed eyes and into the cerebrospinal fluid was similar. All three azole compounds reduced the number of yeasts found in the eye in hematogenous Candida albicans endophthalmitis in rabbits when therapy was initiated within 24 h of inoculation. However, only ketoconazole significantly reduced yeast counts in the eye when therapy was postponed for 7 days.The incidence of ocular fungal infections has increased (10, 11, 26) due to a number of factors: increased prevalence of immunosuppression associated with organ transplantation and malignancies; prolonged recovery from complex surgical procedures; and increasing use of antibiotics, immunosuppressive agents, intravenous catheters, and hyperalimentation fluids. Endogenous Candida endophthalmitis (ECE) also occurs in heroin addicts

Itraconazole is a broad-spectrum potent triazole antifungal agent. Its efficacy in treatment cannot always be explained by body fluid drug levels. In this study, itraconazole was shown to accumulate into host cells. Its intracellular accumulation in cells is greater than that of the antibacterial agent clindamycin, which is known for intracellular localization, and the uptake process does not appear to be active. This ability to reach high concentrations intracellularly may be an important property for the in vivo efficacy of itraconazole.Itraconazole is a promising new triazole antifungal agent which has been used successfully to treat a variety of deep-seated mycoses in animals and humans. In animal models, it has been as effective as fluconazole for treatment of cryptococcal meningitis despite undetectable drug levels in the cerebrospinal fluid (6); this finding contrasts with the high penetration of fluconazole into the subarachnoid space. These experiments showing success of itraconazole in treatment of central nervous system infections in animals (2, 6) were confirmed in human cases of cryptococcal meningitis (1,7,8). Possible explanations for the efficacy of itraconazole in the central nervous system include an effect of itraconazole on host cells by immune stimulation or intracellular accumulation of drug which is not detected by drug assays of biological fluids. We believe that part of the explanation resides in the latter hypothesis. Previously, we have shown that host cells can accumulate a large amount of itraconazole (5). The present study measured the uptake of itraconazole by alveolar macrophages and the factors which influence this interaction. Itraconazole was also compared with clindamycin, an antimicrobial agent known to accumulate inside macrophages. Alveolar macrophages were obtained by lung lavage from 2-to 3-kg New Zealand White rabbits which had received 108 to 109 CFU of Mycobactenum bovis BCG intravenously 3 to 4 weeks before. In each assay, 107 cells per ml were used; each variable was tested in triplicate, and a mean value was recorded. A velocity gradient centrifugation assay was used to test for the partition of drug (4). Macrophages in Hanks' balanced salt solution containing tritium-labelled itraconazole supplied by Janssen Pharmaceutica, Beerse, Belgium, or tritium-labelled clindamycin supplied by Upjohn Co., Kalamazoo, Mich., were layered over a phthalate bed in microcentrifuge tubes. Cells and labelled drug were incubated in 5% CO2 at 37°C for 10 min except as stated otherwise below. The cells were pelleted through phthalate at 15,000 x g. The supernatants and cell pellets were cut off at the bottom of the tube and placed in a 0.5% deoxycholate solution to lyse the cells. The supernatants and lysed cells were added to scintillation fluid for counting of disintegrations per minute. The compounds examined were f3H]itraconazole (1 ,ug/ml), [3H]clindamycin (10 ,ug/rml), [ H] Figure 1 shows the kinetics of intracellular uptake of itraconazole by alveolar macrophages. The uptake is ...

Ciprofloxacin appears to be a safe and effective option for treating renal cyst infections. Further controlled studies evaluating its clinical efficacy are warranted.