Prognostic Association of Liposomal Amphotericin B Doses Above 5 mg/kg/d in Mucormycosis: A Nationwide Epidemiologic and Treatment Analysis in Japan

Abstract Background Mucormycosis is a potentially fatal fungal infection, and there is limited information on its precise epidemiology and treatment practices, including the optimal dosage of liposomal amphotericin B. Methods A retrospective, multicenter, nationwide analysis of 82 proven and probable cases of mucormycosis was performed. Cases between 2015 and 2022 were collected from 51 hospitals in Japan by hematologists and infectious disease specialists. The study included the epidemiology, treatment details, and association between the dose of liposomal amphotericin B and the outcome. Results The lungs were the most commonly involved organ (70.7% of cases), and 35.4% of patients had disseminated disease. Rhizopus spp., Cunninghamella spp., and Mucor spp. were the most common organisms. Mortality at 4 weeks was 41.5%. The survivors had a shorter duration of neutropenia (P = .006) and less persistent hyperglycemia (P = .023). The site of infection and species of Mucorales had no detectable effect on survival. Survival did not differ between patients receiving liposomal amphotericin B at 5 mg/kg/d relative to those receiving >5 mg/kg/d (P = .625). Using Cox proportional hazards models and adjusting for confounders, the hazard ratio for the influence of >5 mg/kg/d liposomal amphotericin B on 4-week survival was 0.86 (95% CI, 0.28–2.68; P = .796) compared with 5 mg/kg/d. Conclusions This study provides important insights into the precise epidemiology and treatment practices of mucormycosis. Treatment with liposomal amphotericin B at doses higher than 5 mg/kg/d did not improve outcomes relative to 5 mg/kg/d.

Other organs included the thyroid, bronchus, heart, pleura, spine, liver, pancreas, spleen, kidney, bladder, and retroperitoneum.b.Cases with confirmed infection of two or more organs were defined as disseminated.c.All patients with proven mucormycosis here meet one or more of the criteria for the rationale for proven.d.Histopathologic, cytopathologic, or direct microscopic examination of a specimen obtained by needle aspiration or biopsy in which hyphae are seen accompanied by evidence of associated tissue damage.e. Recovery of a mold by the culture of a specimen obtained by a sterile procedure from a normally sterile and clinically or radiologically abnormal site consistent with an infectious disease process, f.All patients with probable mucormycosis here are immunocompromised and meet the criteria of at least 1 host factor, a clinical feature, and mycologic evidence.g.The three elements used to determine probable were the definitions provided by the Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium in the 2020 publication.h.The test results for the difference in the distribution of Mucorale genera per infected organ were as follows: Pulmonary (p = 0.227), Sinus (p = 0.324), Skin (p = 0.983), Cerebral (p = 0.499), Blood (p < 0.001), Gastrointestinal (p = 0.978), and Disseminated (p = 0.737).The distribution of Mucorale genera showed a significant difference only in blood.i.If more than one identification method was used, each was counted.b.Cases with confirmed infection of two or more organs were defined as disseminated.c.There were no patients with inherited severe immunodeficiency or human immunodeficiency virus infection.d.Prolonged use of corticosteroids at a therapeutic dose of ≥0.3 mg/kg corticosteroids for ≥3 weeks in the past 60 days.e. T-cell immunosuppressants, such as calcineurin inhibitors, tumor necrosis factor-a blockers, lymphocyte-specific monoclonal antibodies, and immunosuppressive nucleoside analogs during the past 90 days.
f. B-cell immunosuppressants, such as Bruton's tyrosine kinase inhibitors, e.g., ibrutinib.g.Neutrophil status data were not available in 2 cases.(24.1%)Percentages were calculated based on the number of patients in each group.Cases for each organ include duplicates.No cases of orbital lesions were identified.The definition of "diagnosis" here refers to the date on which the specimen with Mucorales was collected.a.Other organs included the thyroid, bronchus, heart, pleura, spine, liver, pancreas, spleen, kidney, bladder, and retroperitoneum.b.Cases with confirmed infection of two or more organs were defined as disseminated.c.Isavuconazole was not approved in Japan at the time of data collection.d.One case of a combination of posaconazole and caspofungin was included.e.Other antifungals used in combination were fluconazole and itraconazole in 1 case each and voriconazole in 4 cases.f.Patients not receiving liposomal amphotericin B or posaconazole.Cases for each organ include duplicates.There were no cases of orbital lesions.Percentages were calculated based on the number of patients in each group.a.Other organs included the thyroid, bronchus, heart, pleura, spine, liver, pancreas, spleen, kidney, bladder, and retroperitoneum.b.Cases with confirmed infection of two or more organs were defined as disseminated.
c.In the "other organs" category, cases who were diagnosed at post-mortem examination (p = 0.006) and non-survivors within 12 weeks of diagnosis (p = 0.0409) were significantly more common.However, no significant differences were found in the other combinations.

Table S1 .
The number of responding institutions, mucormycosis cases, and distribution of Mucorales in each prefectural region of Japan.
a. Names of regions in Japan are arranged in order from north to south in this table.b.Population data are based on demographic information published by the Ministry of Internal Affairs and Communications of Japan.

Table S2 .
The number of patients per year by organ, the reasons for the diagnosis, the causative organisms, and the reasons for the identification of the causative organisms.Percentages were calculated based on the number of patients in each group.The number of infection sites and causative organisms includes duplicates.No cases of orbital lesions were identified.

Table S3 .
Comparison of characteristics of mucormycosis patients by organ.Percentages were calculated based on the number of patients in each group.Cases for each organ include duplicates.There were no cases of orbital lesions.The definition of 'time of diagnosis' here refers to the date on which the specimen with Mucorales was collected.a.Other organs included the thyroid, bronchus, heart, pleura, spine, liver, pancreas, spleen, kidney, bladder, and retroperitoneum.

Table S4 .
Comparison of mucormycosis treatment characteristics by organ.

Table S5 .
Prognosis of Mucormycosis Patients

Table S6 .
Cox regression analysis of factors associated with 4 weeks mortality in mucormycosis patients treated with liposomal amphotericin B Data apply to 49 patients who were subjects for analysis of the efficacy of liposomal amphotericin B treatment.a The reference category was set at patients treated with 5 mg/kg liposomal amphotericin B.