Isavuconazole Therapy Protects Immunosuppressed Mice from Mucormycosis

Abstract

We studied the in vitro and in vivo efficacies of the investigational drug isavuconazole against mucormycosis due to Rhizopus delemar. Isavuconazole was effective, with MIC and minimal fungicidal concentration (MFC) values ranging between 0.125 and 1.00 g/ml. A high dose of isavuconazole prolonged the survival time and lowered the tissue fungal burden of cyclophosphamide/cortisone acetate-treated mice infected with R. delemar and was as effective as a high-dose liposomal amphotericin B treatment. These results support the further development of this azole against mucormycosis. Mucormycoses are among the most common infections afflicting immunocompromised hosts and are occurring at an increasing frequency (1-3). The risk factors for mucormycosis include compromised immune status due to hematologic malignancies, neutropenia, steroid treatment, hyperglycemia, ketoacidosis and other forms of acidosis, deferoxamine therapy, and trauma (4-6). Despite disfiguring surgical debridement and adjunctive antifungal therapy, the overall mortality rate of mucormycosis remains approximately 50% and can approach 100% in hematogenously disseminated and central nervous system disease and in patients with prolonged neutropenia (2, 7-11). Clearly, new strategies for preventing and treating mucormycosis are urgently needed.The new investigational drug isavuconazole (BAL4815) (ISA) is the active compound of the water-soluble prodrug isavuconazonium sulfate (BAL8557). Following administration, the prodrug isavuconazonium sulfate is rapidly converted by esterases in plasma to isavuconazole (isavuconazole is the term used here to describe the medicinal product). ISA shows broad-spectrum activity against fungi and is currently in late-stage clinical development for invasive fungal diseases, including invasive mucormycosis and invasive aspergillosis. (19,20). Recent studies demonstrated promising in vitro activity of ISA against Mucorales (12, 21, 22) fungi that cause mucormycosis. Therefore, the activity of ISA was compared to that of liposomal amphotericin B (LAmB) in a murine model of mucormycosis. Since Rhizopus species are the most common Mucorales isolates obtained from patients with mucormycosis (8,23,24), these studies focused on Rhizopus delemar.The MIC 100 (defined as the lowest concentration that causes 100% growth inhibition relative to the drug-free growth control) values of ISA (Astellas Pharma Global Development, Inc., Northbrook, IL) were determined against four clinical isolates of R. delemar (fumaric-malic acid producers) or four clinical isolates of Rhizopus oryzae (lactic acid producers) (25) using the Clinical Laboratory and Standards Institute (CLSI) M38-A2 method (26). The minimal fungicidal concentrations (MFCs) were also determined by spotting samples from all of the 96-well plates on potato dextrose agar (PDA) plates supplemented with 0.1% Triton X-100 and incubating them at 37°C for 2 days. The MFC was defined as the lowest concentration of the drug at which the organism failed to grow on the PDA plate. Against ...

Prophylaxis with Isavuconazole or Posaconazole Protects Immunosuppressed Mice from Pulmonary Mucormycosis

“…An analytical method that uses ultraperformance liquid chromatography and single-quad mass spectrometry (UPLC/MS) for the determination of itraconazole and hydroxylitraconazole was adapted and validated for the measurement of ISA and POS (20,22), while high-performance liquid chromatography (HPLC) was used to measure VOR levels. All three drugs demonstrated serum drug levels in excess of MIC values (defined as the lowest drug concentration that causes 100% growth inhibition) against R. delemar 99-880 (MIC values of 0.5, 0.78, and 8.0 g/ml for ISA, POS, and VOR, respectively [17,23]) (Fig. 1A).…”

“…We have demonstrated the efficacy of ISA in treating mice infected with Rhizopus delemar (17). Hence, we wanted to assess the prophylactic activity of ISA compared to POS and VOR in protecting neutropenic mice from pulmonary mucormycosis.…”

Safety and Pharmacokinetics of Isavuconazole as Antifungal Prophylaxis in Acute Myeloid Leukemia Patients with Neutropenia: Results of a Phase 2, Dose Escalation Study

“…The results of in vitro and animal model studies have shown that isavuconazole is active against Candida spp. (both fluconazole-sensitive and fluconazole-resistant strains), Aspergillus spp., Cryptococcus spp., and other molds, including the Mucorales and Scedosporium species (21)(22)(23)(24)(25)(26)(27)(28).…”

Tratamiento exitoso de una mucormicosis rinocerebral persistente en un paciente pediátrico durante el debut de una leucemia aguda

“…Las equinocandinas no tienen actividad in vitro contra los mucorales; sin embargo, los estudios tradicionales de susceptibilidad podrían no reflejar la verdadera actividad de las equinocandinas contra los hongos filamentosos en general y contra los agentes productores de mucormicosis en particular. Existen reportes de que R. oryzae, el principal agente etiológico de mucormicosis, es capaz de expresar el blanco de acción de las equinocandinas; la 1,3 β-D glucano sintetasa; codificado por el gen FKS y que caspofungina inhibiría la actividad de la enzima in vitro y tendría actividad in vivo en modelos murinos diabéticos de mucormicosis diseminada 22,23 . Existen dos posibles mecanismos que explicarían por qué la adición de una equinocandina podría mejorar la eficacia del tratamiento con AmB en la mucormicosis: por disrupción de los enlaces β-glucano de la pared celular permitiendo una mayor llegada de AmB a la membrana celular, y por alteración de la virulencia del hongo retrasando la filamentación o alterando el contenido de la pared celular 22 .…”

“…Existen dos posibles mecanismos que explicarían por qué la adición de una equinocandina podría mejorar la eficacia del tratamiento con AmB en la mucormicosis: por disrupción de los enlaces β-glucano de la pared celular permitiendo una mayor llegada de AmB a la membrana celular, y por alteración de la virulencia del hongo retrasando la filamentación o alterando el contenido de la pared celular 22 . La asociación de caspofungina con AmB en complejo lipídico ha mostrado sinergia in vitro y eficacia en los mismos modelos murinos 22,23 . En adultos se ha podido comprobar que pacientes tratados con la combinación polieno-caspofungina tienen una mejor sobrevida a los 30 www.sochinf.cl días del alta y a largo plazo.…”