RESUMO
Mucormycosis is a life-threatening respiratory fungal infection predominantly caused by Rhizopus species. Mucormycosis has incompletely understood pathogenesis, particularly how abnormalities in iron metabolism compromise immune responses. Here we show how, as opposed to other filamentous fungi, Rhizopus spp. establish intracellular persistence inside alveolar macrophages (AMs). Mechanistically, lack of intracellular swelling of Rhizopus conidia results in surface retention of melanin, which induces phagosome maturation arrest through inhibition of LC3-associated phagocytosis. Intracellular inhibition of Rhizopus is an important effector mechanism, as infection of immunocompetent mice with swollen conidia, which evade phagocytosis, results in acute lethality. Concordantly, AM depletion markedly increases susceptibility to mucormycosis. Host and pathogen transcriptomics, iron supplementation studies, and genetic manipulation of iron assimilation of fungal pathways demonstrate that iron restriction inside macrophages regulates immunity against Rhizopus. Our findings shed light on the pathogenetic mechanisms of mucormycosis and reveal the role of macrophage-mediated nutritional immunity against filamentous fungi.
Assuntos
Interações Hospedeiro-Patógeno , Ferro/metabolismo , Pulmão/microbiologia , Macrófagos Alveolares/metabolismo , Rhizopus/fisiologia , Animais , Parede Celular/metabolismo , Regulação da Expressão Gênica , Macrófagos Alveolares/ultraestrutura , Melaninas/metabolismo , Camundongos Endogâmicos C57BL , Viabilidade Microbiana , Modelos Biológicos , Mucormicose/genética , Mucormicose/microbiologia , Mucormicose/patologia , Fagossomos/metabolismo , Fagossomos/ultraestrutura , Rhizopus/crescimento & desenvolvimento , Esporos Fúngicos/fisiologiaRESUMO
We studied the efficacy of pentamidine (PNT) as prophylaxis or early treatment in acute pulmonary fusariosis in neutropenic mice. PNT-preexposed mice had significantly improved survival and reduced fungal burden compared to amphotericin B-preexposed and untreated mice. PNT-treated mice had increased survival but no difference in fungal burden versus untreated mice.
Assuntos
Antifúngicos/uso terapêutico , Fusarium/efeitos dos fármacos , Pneumopatias Fúngicas/tratamento farmacológico , Pentamidina/uso terapêutico , Animais , Antifúngicos/farmacocinética , Modelos Animais de Doenças , Fusarium/isolamento & purificação , Pneumopatias Fúngicas/patologia , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Neutropenia/complicações , Neutropenia/metabolismo , Infecções Oportunistas , Pentamidina/farmacologiaRESUMO
Paecilomyces variotii, an emerging hyalohyphomycetes, has been reported to be susceptible in vitro to voriconazole. We describe a case of disseminated P. variotii infection in a neutropenic child with relapsed leukaemia who was on voriconazole prophylaxis. The P. variotii isolate was resistant to voriconazole in vitro. The patient responded to liposomal amphotericin B.
Assuntos
Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Micoses/tratamento farmacológico , Paecilomyces/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Pirimidinas/uso terapêutico , Triazóis/uso terapêutico , Adolescente , Anfotericina B/farmacologia , Antifúngicos/farmacologia , Dermatomicoses/tratamento farmacológico , Dermatomicoses/microbiologia , Farmacorresistência Fúngica , Fungemia/tratamento farmacológico , Fungemia/microbiologia , Humanos , Pneumopatias Fúngicas/tratamento farmacológico , Pneumopatias Fúngicas/microbiologia , Masculino , Testes de Sensibilidade Microbiana , Micoses/diagnóstico por imagem , Micoses/prevenção & controle , Neutropenia/complicações , Neutropenia/tratamento farmacológico , Paecilomyces/isolamento & purificação , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Pirimidinas/farmacologia , Radiografia , Resultado do Tratamento , Triazóis/farmacologia , VoriconazolRESUMO
STUDY OBJECTIVES: As the failure of amphotericin B therapy in patients with invasive aspergillosis often exceeds 50%, we sought to determine the relationship between in vitro amphotericin B resistance and clinical failure of amphotericin B against invasive aspergillosis. DESIGN: Retrospective study. SETTING: University cancer center. PATIENTS: One hundred sixteen patients with cancer and invasive aspergillosis. MEASUREMENTS AND MAIN RESULTS: The correlation between in vitro amphotericin B susceptibility, defined by both the National Committee for Clinical Laboratory Standards and Etest methods, and other prognostic factors with failure of initial amphotericin B therapy was retrospectively evaluated. Data for correlation could be clearly assessed in only 18 (16%) of the 116 patients. Admission to the intensive care unit was the only prognostic factor associated with failure of initial amphotericin B treatment in these 18 patients (p = 0.01). CONCLUSIONS: Several important obstacles underlie the correlation of in vitro susceptibility testing with in vivo efficacy of individual antifungal agents in the treatment of invasive aspergillosis. Such correlations could be determined in only a small subset of patients.
Assuntos
Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Aspergilose/tratamento farmacológico , Aspergillus/efeitos dos fármacos , Neoplasias Hematológicas/complicações , Aspergilose/etiologia , Aspergillus/isolamento & purificação , Farmacorresistência Fúngica , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Oral-based antibiotic therapy is the standard of care in the management of cancer patients with low-risk neutropenic fever. Nevertheless, to the authors' knowledge, the best antibiotic regimen and the feasibility of ambulatory treatment have not been clearly defined. METHODS: The authors evaluated the efficacy and safety of moxifloxacin as outpatient treatment in cancer patients with febrile neutropenia who were selected according to the recently proposed Multinational Association for Supportive Care in Cancer (MASCC) risk assessment model. Moxifloxacin was given at a dose of 400 mg orally once daily. RESULTS: Fifty-four patients with solid and hematologic malignancies, the majority of whom (84%) had advanced disease, were included in the current study. The median neutrophil count at the time of study entry was 340/mm3 (range, 20-950/mm3) and the median duration of neutropenia was 4 days (range, 3-14 days). Of 55 neutropenic episodes, 50 (91%) had a successful outcome with a median time to defervescence of 2 days (range, 1-5 days). A multivariate analysis indicated that severe neutropenia (an absolute neutrophil count of < 100 mm3) was the only independent factor associated with treatment failure (P < 0.04). Moxifloxacin was found to be well tolerated and there were no infectious deaths reported. CONCLUSIONS: The results of the current study demonstrated that moxifloxacin was a highly effective and safe regimen in the outpatient treatment of cancer patients with febrile neutropenia.