Liposomal Amphotericin B and Echinocandins as Monotherapy or Sequential or Concomitant Therapy in Murine Disseminated and Pulmonary Aspergillus fumigatus Infections

Abstract

Monotherapy and combination therapy were compared using optimal doses of liposomal amphotericin B, micafungin, or caspofungin in Aspergillus fumigatus pulmonary and disseminated infections. Mice were challenged intravenously (2.8 ؋ 10 4 to 5.7 ؋ 10 4 conidia) or intranasally (5.8 ؋ 10 7 conidia) with A. fumigatus. Drugs (5, 10, or 15 mg/kg of body weight) were given for 3 or 6 days as single, concomitant, or sequential therapy (i.e., days 1 to 3 and then days 4 to 6). Mice were monitored for survival, and tissues were assayed for fungal burden and drug concentrations. Treatments starting 24 h postchallenge significantly prolonged survival in disseminated aspergillosis (P < 0.002), but only liposomal amphotericin B treatments or treatments beginning with liposomal amphotericin B increased survival to 100% in the pulmonary aspergillosis model. Fungi in kidneys and spleens (disseminated) and lungs (pulmonary) were significantly decreased (P < 0.04) by liposomal amphotericin B, liposomal amphotericin B plus echinocandin, or liposomal amphotericin B prior to echinocandin. In the disseminated infection, liposomal amphotericin B and micafungin (10 or 15 mg/kg) had similar kidney drug levels, while in the spleen, 5 and 15 mg/kg liposomal amphotericin B gave higher drug levels than micafungin (P < 0.02). In the pulmonary infection, drug levels in lungs and spleen with 5-mg/kg dosing were significantly higher with liposomal amphotericin B than with caspofungin (P < 0.002). In summary, treatment of A. fumigatus infections with liposomal amphotericin B plus echinocandin or liposomal amphotericin B prior to echinocandin was as effective as liposomal amphotericin B alone, and a greater decrease in the fungal burden with liposomal amphotericin B supports using liposomal amphotericin B prior to echinocandin.

Pharmacodynamics and Dose-Response Relationships of Liposomal Amphotericin B against Different Azole-Resistant Aspergillus fumigatus Isolates in a Murine Model of Disseminated Aspergillosis

“…These results are similar to the present results, as the maximum effect (100% survival) was reached at a dose of 4 or 16 mg/kg for all isolates. Our observations are also in keeping with previously published experimental studies of aspergillosis (18,19,(36)(37)(38)(39)(40). Leenders et al reported that in a pulmonary aspergillosis infection in rats, L-AmB monotherapy at 5 and 10 mg/kg was effective in preventing dissemination from the lungs to the kidneys, liver, and spleen (36).…”

Combination Therapy of Murine Mucormycosis or Aspergillosis with Iron Chelation, Polyenes, and Echinocandins

“…Several animal studies demonstrated the benefit of using a dual combination of LAmB and echinocandins or LAmB and Def over monotherapy in treating IPA (9,17,24) or mucormycosis (8,10,22), while others showed an indifferent effect (23). We show in this study that triple combination therapy consistently enhanced survival and reduced the tissue fungal burden of mice infected with mucormycosis compared to placebo, monotherapy, or dual drug therapy.…”

Duality of liver and kidney lesions after systemic infection of immunosuppressed and immunocompetent mice withAspergillus fumigatus

“…13 Although intracerebral or intravenous infections are not assumed to play an important natural route for the acquisition of invasive aspergillosis, such infections are frequently used to test the efficiency of antifungal drugs and to study the dissemination and disease progression in brain and kidneys. [5][6][7]14 The ability to detect luminescence from all deep tissues including liver and kidneys is an essential prerequisite for a potential use of luminescence based systems for monitoring drug efficiency from in vivo conditions. Our previous studies using an intranasal infection model revealed a localization of fungi that was mainly restricted to the lung and, in some cases, the nasal sinus.…”