Comparative Pharmacodynamics of Amphotericin B Lipid Complex and Liposomal Amphotericin B in a Murine Model of Pulmonary Mucormycosis

Abstract

We compared the kinetics of amphotericin B (AMB) lung accumulation and fungal clearance by liposomal amphotericin B (L-AMB) and amphotericin B lipid complex (ABLC) in a neutropenic murine model of invasive pulmonary mucormycosis (IPM).Immunosuppressed BALB/c mice were inoculated with 1 ؋ 10 6 Rhizopus oryzae spores and administered L-AMB or ABLC at daily intravenous doses of 1, 5, or 10 mg/kg of body weight for 5 days starting 12 h after infection. At a dose of 10 mg/kg/day, both L-AMB and ABLC were effective at reducing the R. oryzae lung fungal burden and achieved lung tissue concentrations exceeding the isolate mean fungicidal concentration (MFC) of 8 g/ml by 72 h. When ABLC was dosed at 5 mg/kg/day, the ABLC-treated animals had significantly higher AMB lung concentrations than the L-AMB treated animals at 24 h (6.64 and 1.44 g/g, respectively; P ‫؍‬ 0.013) and 72 h (7.49 and 1.03 g/g, respectively; P ‫؍‬ 0.005), and these higher concentrations were associated with improved fungal clearance, as determined by quantitative real-time PCR (mean conidial equivalent of R. oryzae DNA per lung, 4.44 ؎ 0.44 and 6.57 ؎ 0.74 log 10 , respectively; P < 0.001). Analysis of the AMB tissue concentration-response relationships revealed that the suppression of R. oryzae growth in the lung required tissue concentrations that approached the MFC for the infecting isolate (50% effective concentration, 8.19 g/g [95% confidence interval, 2.81 to 18.1 g/g]). The rates of survival were similar in the animals treated with L-AMB and ABLC at 10 mg/kg/day. These data suggest that higher initial doses may be required during L-AMB treatment than during ABLC treatment of experimental IPM.Invasive pulmonary mucormycosis (IPM) is an uncommon but frequently fatal angioinvasive mold infection that has increased in incidence over the last decade, especially in patients with hematological malignancies and recipients of hematopoietic stem cell transplantation (HSCT) (23). In a recent multicenter, prospective observational study of invasive fungal infections in HSCT recipients, mucormycosis was the third most common invasive fungal infection (7.2%), behind invasive aspergillosis (59.2%) and invasive candidiasis (24.8%) (21). Data from the Centers for Disease Control and Prevention Transplant Associated Infection Surveillance Network (TRANSNET) reported that the incidence of mucormycosis in U.S. transplant centers increased nearly sixfold from 2001 to 2004, with Rhizopus being the most frequently isolated genus (22).Although new diagnostic and treatment options have improved the survival rates in patients with invasive pulmonary aspergillosis (IPA) over the last decade, the prognosis for patients with IPM remains poor, as only one-third of the patients survive beyond 12 weeks after the diagnosis (13, 21, 23). The outcome of IPM is heavily dependent on a timely diagnosis, as the initial clinical manifestations and radiographic appearance of IPM are often indistinguishable from those of IPA, and the first-line antifungals used to treat aspergillosis, ...

Mucormycosis Caused by Unusual Mucormycetes, Non-Rhizopus, -Mucor, and -Lichtheimia Species

“…Use of higher dosages of L-AmB (i.e., 10 mg/ kg/day) may achieve high concentrations of AmB in diseasetargeted organs, such as the lung, earlier in the course of treatment (317). In a murine model of pulmonary Rhizopus oryzae mucormycosis, some differences in the pharmacodynamics of L-Amb and AmB lipid complex were observed; however, the survival rates for the two treatments were similar (188). The role of posaconazole is still unclear, as its use has been reported in few reported cases of unusual Mucormycetes infection (Table 4), and the precise efficacy of this drug is not known (297,317).…”

Comparative Pharmacodynamics of Posaconazole in Neutropenic Murine Models of Invasive Pulmonary Aspergillosis and Mucormycosis

“…The mice were held in an upright position and allowed to inhale the inoculum until normal breathing resumed and the animal regained consciousness. The administered inoculum was previously found to produce progressively fatal invasive pulmonary aspergillosis or mucormycosis by 5 to 7 days without the administration of antifungal therapy (19,22).…”

“…Our laboratory has characterized the pharmacodynamics of echinocandins and lipid amphotericin B formulations in neutropenic murine infection models of aspergillosis and mucormycosis, using standardized immunosuppression strategies and a quantitative PCR (qPCR) as a dynamic and sensitive indicator of lung fungal burden and treatment response (19)(20)(21)(22). Therefore, we performed a parallel analysis of posaconazole pharmacodynamics in neutropenic murine models of pulmonary aspergillosis and mucormycosis to examine if higher posaconazole serum AUC/MIC thresholds are required to reduce lung fungal burden in pulmonary mucormycosis.…”

Diagnosis and treatment of mucormycosis in patients with hematological malignancies: guidelines from the 3rd European Conference on Infections in Leukemia (ECIL 3)

“…62 Different findings were reported in another study in which the pharmacodynamics of ABLC and L-AmB were compared in a murine model of pulmonary mucormycosis. 63 The two drugs demonstrated different kinetics, with ABLC achieving higher concentrations in the lung tissue when administered at a dose of 5 mg/kg, while when given at 10 mg/kg both drugs achieved similar concentrations.…”