A patient with azole-refractory thrush-esophagitis responded initially to caspofungin, but the treatment eventually failed. In a murine model, caspofungin was effective against two early isolates for which the MICs of caspofungin were low, but it was less effective against a late isolate for which the MIC of caspofungin was greater. We concluded that there is a correlation between in vivo failure and rising in vitro caspofungin MICs.

Posaconazole and/or amphotericin B was given to mice pretreated with a steroid and then infected by inhalation of Aspergillus flavus conidia. Two laboratories conducted studies using almost identical protocols to evaluate both survival and lung tissue burdens 8 days after infection. The results of the in vivo studies performed at both laboratories were consistent. We found that (i) up to 5 mg of amphotericin B per kg of body weight was poorly effective in treating invasive aspergillosis; (ii) posaconazole at 2 or 10 mg/kg/dose prolonged survival and reduced lung tissue CFU; and (iii) there was generally no antagonistic interaction of the drugs in combination, even when the experiments were designed to maximize the likelihood of antagonism. These studies do not confirm the antagonistic interaction of triazoles and polyenes reported by others.Acute invasive aspergillosis (AIA) is one of the most feared infections of immunosuppressed patients. Both corticosteroids and neutropenia predispose to this infection, which almost invariably occurs after inhalation of infectious conidia (1). The speed of dissemination or pulmonary spread of the infection, and ultimately survival, depend in large part on the nature and severity of the predisposing host immune defect(s). In patients with the most fulminating forms of AIA, it has been difficult to demonstrate efficacy of antifungal therapy (7, 11). To date, there have been three approaches in the management of aspergillosis. The first is reversal of the predisposing conditions if possible. The second is antifungal therapy, and the third is resection when possible (18). Animal studies have been increasingly used to help determine whether a particular antifungal drug is effective against invasive aspergillosis. Some advantages of animal studies include (i) information in ascertaining the relative efficacy and dose-dependent toxicity of antifungal agents; (ii) assessing the contributions of immune deficiency to the outcome of aspergillosis; (iii) evaluating combinations of antifungals; and (iv) controlling for a variety of conditions that are thought to contribute to human invasive aspergillosis and its outcome but that cannot be controlled in clinical studies.The experiment quoted most often, an experiment using amphotericin B and ketoconazole, was conducted by Schaffner and Frick (15) some years ago. When mice with AIA were treated with ketoconazole before amphotericin B, Schaffner and Frick noted a marked decrease in the efficacy of amphotericin B (15). They theorized that the azole blocked the synthesis of the ergosterol target necessary for the binding of amphotericin B. Polak et al. also found somewhat similar results (13,14). These studies led to the concern that azole antifungal agents would antagonize the effects of amphotericin B in humans and that therefore they should not be used in combination with amphotericin B clinically.In a large review of 595 cases of aspergillosis, Patterson et al. found that patients treated with amphotericin B and then with itraconazole fare...

Outbred ICR mice were rendered neutropenic, infected intravenously with Fusarium solani and treated orally with voriconazole. When given alone, voriconazole was not protective up to 40 mg/kg/day. When grapefruit juice was administered before infection, mice were protected by voriconazole. The mechanism may be inhibition of gut mucosal cytochrome enzymes that rapidly degrade voriconazole in the mouse. These murine studies support expansion of voriconazole therapy in other highly resistant systemic mycoses.

Aspergillus terreus is a species which is being seen increasingly frequently and which is highly resistant to amphotericin B in vitro and clinically. We evaluated amphotericin B, caspofungin, and posaconazole in a murine model of acute invasive aspergillosis. Caspofungin and posaconazole both appeared beneficial and may be reasonable treatment alternatives for infection with A. terreus

Fosfomycin, a nontoxic broad-spectrum antibiotic, different in structure from all previously described antibiotics, acts selectively by inhibiting cell wall formation. It was overlooked during many years of screening because of antagonism by culture medium ingredients and frequent occurrence of resistant mutants. It is effective in man because the neutralizing substances are not present and resistant mutants of most species are avirulent. Fosfomycin has favorable pharmacologic characteristics. It is not cross resistant, does not show antagonism, and has been used successfully in combinations. An insoluble calcium salt is used in oral formulation and a sodium salt for parenteral administration. Overall success rates of 86% were reported with 1,000 patients in Spain and 79% in Japan.