Systemic air embolism in a fungal pneumonia patient with lung cavities formation and review of literature.

Systemic air embolism is a rare but potentially fatal complication related to many factors. The purpose of this article is to alert clinicians once patients occurs an abnormal neurological and cardiovascular status, following minor traumatic treatment, air embolism should be considered. A 20-year-old man who presented with fungal pneumonia with lung cavities formation was admitted to an intensive care unit (ICU) and received positive airway pressure ventilation. Four days later, the fungal pneumonia was improved, but the patient's blood pressure and arterial oxygen saturation deteriorated, so computed tomography (CT) scans were preformed to reevaluate him. The scans detected air embolism in the left atrium and ventricle, ascending aorta, aortic arch and its branches (right brachiocephalic, bilateral common carotid and right subclavian arteries), descending aorta and right coronary artery. A CT scan of the abdomen revealed air in the spleen, cauda pancreatic, superior mesenteric artery and right external iliac artery. The patient died two days later from multiple organ dysfunction. We suggest that vascular air embolism should be considered under mechanical ventilation when patients' neurologic and cardiovascular status deteriorates, and hyperbaric oxygen therapy should be conducted immediately.

Disseminated Hormographiella aspergillata infection with involvement of the lung, brain, and small intestine following allogeneic hematopoietic stem cell transplantation: case report and literature review.

Disseminated infection by Hormographiella aspergillata is extremely rare and small intestine involvement has not been reported previously. A 51-year-old man with myelodysplastic syndrome developed pneumonia after cord blood cell transplantation. Fungal growth from the biopsied lung was identified as H. aspergillata by morphology and the gene analysis. Although antifungal agents including voriconazole and liposomal amphotericin B were administered, he died of disseminated H. aspergillata infection. We review the literature and discuss the treatment and prognosis.

Proangiogenic growth factors potentiate in situ angiogenesis and enhance antifungal drug activity in murine invasive aspergillosis.

In invasive pulmonary aspergillosis, direct invasion and occlusion of pulmonary vasculature by Aspergillus hyphae causes tissue hypoxia, which is enhanced by secreted fungal metabolites that downregulate compensatory angiogenic signaling pathways. We assessed the effects of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) on survival rates, fungal burden, and in situ angiogenesis in a murine invasive pulmonary aspergillosis model. bFGF and VEGF monotherapy significantly increased survival rates and potentiated the activity of amphotericin B. bFGF-containing regimens were associated with reduced tissue fungal burdens. bFGF and VEGF reversed the antiangiogenic activity of Aspergillus fumigatus; however, VEGF induced the formation of immature neovessels, providing an explanation for its lesser efficacy. Treatment with bFGF plus amphotericin B was associated with neutrophil influx into Aspergillus-infected pulmonary tissue, suggesting that this combination limits fungal growth through neutrophil trafficking. Vasculogenic pathways are unexplored targets for the treatment of invasive pulmonary aspergillosis and may potentiate both innate immunity and antifungal drug activity against A. fumigatus.

Mucormicosis: Una micosis emergente / Mucormycosis: An emergent mycosis

El objetivo de este trabajo es presentar la incidencia, frecuencia, características clínicas y evolución de los pacientes con mucormicosis atendidos en el Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, entre los años 1982 y 2010. Durante ese período se diagnosticaron 10 casos de mucormicosis. Los tres primeros entre 1982 y 2004 y los últimos 7 entre 2005 y 2010. La incidencia y frecuencia de esta enfermedad, para el período 1980-2004 fue 0.13 pacientes/año y 0.1 casos/10 000 egresos (IC 95%: 0.00 a 0.3) respectivamente. En el período 2005-2010 la incidencia fue 0.86 pacientes/año y la frecuencia de 1.1 casos/10 000 egresos (IC 95%: 0.5 a 2.4). Hubo nueve casos de mucormicosis rinosinuso-orbitaria, siete en pacientes con diabetes mellitus, uno en una paciente con una hemopatía maligna y neutropenia, y el restante en un paciente con HIV/sida que además estaba neutropénico y con un síndrome hemofagocítico. En una paciente se realizó el diagnóstico post mortem de mucormicosis pulmonar. El diagnóstico se efectuó por la observación de filamentos cenocíticos en los diez casos. Hubo desarrollo de mucorales en los cultivos de 8/9 pacientes; cinco Rhizopus spp y tres Mucor spp. Todos los pacientes recibieron un tratamiento inicial con anfotericina B deoxicolato, que en tres de ellos fue continuado con anfotericina B liposomal, y cirugía. Tres enfermos recibieron además un tratamiento adyuvante con oxigeno hiperbárico. La mortalidad fue 30%.

Mucormycosis is an opportunistic infection caused by fungi of the order Mucorales. It is characterized by rapid progression and high morbidity and mortality in the absence of early diagnosis and prompt treatment. It was an infrequent disease, but in recent years, its incidence appears to have increased. The aim of this paper is to report the cases of mucormycosis diagnosed from 1982 to 2010 at the Hospital de Clinicas José de San Martín, University of Buenos Aires. We diagnosed 10 cases of mucormycosis; the first three between 1982 and 2004 and the last 7 between 2005 and 2010. The incidence from 1980 to 2004 was 0.13 patient-years and the frequency 0.1/10 000 discharges (95% CI 0.00- 0.3). In the period 2005 to 2010, the incidence was 0.86 patients per year with 1.1/10 000 discharges (95% CI 0.5-2.4). There was a pulmonary mucormycosis case (in a patient treated with corticosteroids) and nine rhinocerebral cases, two in neutropenic and seven in diabetic patients. The diagnosis was made by observation of cenocytic hyphae in 10/10 patients. Mucorales were recovered in 8/9 cultures (5 Rhizopus spp and 3 Mucor spp.). In one case diagnosis of pulmonary mucormycosis was made post-mortem. Nine patients were treated with amphotericin B deoxycholate (in 3 patients supplemented with liposomal amphotericin B) and surgery. Three patients underwent hyperbaric chamber. Seven patients had favorable outcome. In conclusion, mucormycosis is a rare disease, but its incidence has increased over the past five years. A good evolution of the patients is linked to early diagnosis and treatment.

Mucormicosis: Una micosis emergente / Mucormycosis: An emergent mycosis

El objetivo de este trabajo es presentar la incidencia, frecuencia, características clínicas y evolución de los pacientes con mucormicosis atendidos en el Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, entre los años 1982 y 2010. Durante ese período se diagnosticaron 10 casos de mucormicosis. Los tres primeros entre 1982 y 2004 y los últimos 7 entre 2005 y 2010. La incidencia y frecuencia de esta enfermedad, para el período 1980-2004 fue 0.13 pacientes/año y 0.1 casos/10 000 egresos (IC 95%: 0.00 a 0.3) respectivamente. En el período 2005-2010 la incidencia fue 0.86 pacientes/año y la frecuencia de 1.1 casos/10 000 egresos (IC 95%: 0.5 a 2.4). Hubo nueve casos de mucormicosis rinosinuso-orbitaria, siete en pacientes con diabetes mellitus, uno en una paciente con una hemopatía maligna y neutropenia, y el restante en un paciente con HIV/sida que además estaba neutropénico y con un síndrome hemofagocítico. En una paciente se realizó el diagnóstico post mortem de mucormicosis pulmonar. El diagnóstico se efectuó por la observación de filamentos cenocíticos en los diez casos. Hubo desarrollo de mucorales en los cultivos de 8/9 pacientes; cinco Rhizopus spp y tres Mucor spp. Todos los pacientes recibieron un tratamiento inicial con anfotericina B deoxicolato, que en tres de ellos fue continuado con anfotericina B liposomal, y cirugía. Tres enfermos recibieron además un tratamiento adyuvante con oxigeno hiperbárico. La mortalidad fue 30%.(AU)

Mucormycosis is an opportunistic infection caused by fungi of the order Mucorales. It is characterized by rapid progression and high morbidity and mortality in the absence of early diagnosis and prompt treatment. It was an infrequent disease, but in recent years, its incidence appears to have increased. The aim of this paper is to report the cases of mucormycosis diagnosed from 1982 to 2010 at the Hospital de Clinicas José de San Martín, University of Buenos Aires. We diagnosed 10 cases of mucormycosis; the first three between 1982 and 2004 and the last 7 between 2005 and 2010. The incidence from 1980 to 2004 was 0.13 patient-years and the frequency 0.1/10 000 discharges (95% CI 0.00- 0.3). In the period 2005 to 2010, the incidence was 0.86 patients per year with 1.1/10 000 discharges (95% CI 0.5-2.4). There was a pulmonary mucormycosis case (in a patient treated with corticosteroids) and nine rhinocerebral cases, two in neutropenic and seven in diabetic patients. The diagnosis was made by observation of cenocytic hyphae in 10/10 patients. Mucorales were recovered in 8/9 cultures (5 Rhizopus spp and 3 Mucor spp.). In one case diagnosis of pulmonary mucormycosis was made post-mortem. Nine patients were treated with amphotericin B deoxycholate (in 3 patients supplemented with liposomal amphotericin B) and surgery. Three patients underwent hyperbaric chamber. Seven patients had favorable outcome. In conclusion, mucormycosis is a rare disease, but its incidence has increased over the past five years. A good evolution of the patients is linked to early diagnosis and treatment.(AU)

Mucormicosis: Una micosis emergente / Mucormycosis: An emergent mycosis

El objetivo de este trabajo es presentar la incidencia, frecuencia, características clínicas y evolución de los pacientes con mucormicosis atendidos en el Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, entre los años 1982 y 2010. Durante ese período se diagnosticaron 10 casos de mucormicosis. Los tres primeros entre 1982 y 2004 y los últimos 7 entre 2005 y 2010. La incidencia y frecuencia de esta enfermedad, para el período 1980-2004 fue 0.13 pacientes/año y 0.1 casos/10 000 egresos (IC 95%: 0.00 a 0.3) respectivamente. En el período 2005-2010 la incidencia fue 0.86 pacientes/año y la frecuencia de 1.1 casos/10 000 egresos (IC 95%: 0.5 a 2.4). Hubo nueve casos de mucormicosis rinosinuso-orbitaria, siete en pacientes con diabetes mellitus, uno en una paciente con una hemopatía maligna y neutropenia, y el restante en un paciente con HIV/sida que además estaba neutropénico y con un síndrome hemofagocítico. En una paciente se realizó el diagnóstico post mortem de mucormicosis pulmonar. El diagnóstico se efectuó por la observación de filamentos cenocíticos en los diez casos. Hubo desarrollo de mucorales en los cultivos de 8/9 pacientes; cinco Rhizopus spp y tres Mucor spp. Todos los pacientes recibieron un tratamiento inicial con anfotericina B deoxicolato, que en tres de ellos fue continuado con anfotericina B liposomal, y cirugía. Tres enfermos recibieron además un tratamiento adyuvante con oxigeno hiperbárico. La mortalidad fue 30%.(AU)

Mucormycosis is an opportunistic infection caused by fungi of the order Mucorales. It is characterized by rapid progression and high morbidity and mortality in the absence of early diagnosis and prompt treatment. It was an infrequent disease, but in recent years, its incidence appears to have increased. The aim of this paper is to report the cases of mucormycosis diagnosed from 1982 to 2010 at the Hospital de Clinicas José de San Martín, University of Buenos Aires. We diagnosed 10 cases of mucormycosis; the first three between 1982 and 2004 and the last 7 between 2005 and 2010. The incidence from 1980 to 2004 was 0.13 patient-years and the frequency 0.1/10 000 discharges (95% CI 0.00- 0.3). In the period 2005 to 2010, the incidence was 0.86 patients per year with 1.1/10 000 discharges (95% CI 0.5-2.4). There was a pulmonary mucormycosis case (in a patient treated with corticosteroids) and nine rhinocerebral cases, two in neutropenic and seven in diabetic patients. The diagnosis was made by observation of cenocytic hyphae in 10/10 patients. Mucorales were recovered in 8/9 cultures (5 Rhizopus spp and 3 Mucor spp.). In one case diagnosis of pulmonary mucormycosis was made post-mortem. Nine patients were treated with amphotericin B deoxycholate (in 3 patients supplemented with liposomal amphotericin B) and surgery. Three patients underwent hyperbaric chamber. Seven patients had favorable outcome. In conclusion, mucormycosis is a rare disease, but its incidence has increased over the past five years. A good evolution of the patients is linked to early diagnosis and treatment.(AU)

[Mucormycosis. An emergent mycosis]. / Mucormicosis. Una micosis emergente.

Mucormycosis is an opportunistic infection caused by fungi of the order Mucorales. It is characterized by rapid progression and high morbidity and mortality in the absence of early diagnosis and prompt treatment. It was an infrequent disease, but in recent years, its incidence appears to have increased. The aim of this paper is to report the cases of mucormycosis diagnosed from 1982 to 2010 at the Hospital de Clinicas José de San Martín, University of Buenos Aires. We diagnosed 10 cases of mucormycosis; the first three between 1982 and 2004 and the last 7 between 2005 and 2010. The incidence from 1980 to 2004 was 0.13 patient-years and the frequency 0.1/10 000 discharges (95% CI 0.00- 0.3). In the period 2005 to 2010, the incidence was 0.86 patients per year with 1.1/10 000 discharges (95% CI 0.5-2.4). There was a pulmonary mucormycosis case (in a patient treated with corticosteroids) and nine rhinocerebral cases, two in neutropenic and seven in diabetic patients. The diagnosis was made by observation of cenocytic hyphae in 10/10 patients. Mucorales were recovered in 8/9 cultures (5 Rhizopus spp and 3 Mucor spp.). In one case diagnosis of pulmonary mucormycosis was made post-mortem. Nine patients were treated with amphotericin B deoxycholate (in 3 patients supplemented with liposomal amphotericin B) and surgery. Three patients underwent hyperbaric chamber. Seven patients had favorable outcome. In conclusion, mucormycosis is a rare disease, but its incidence has increased over the past five years. A good evolution of the patients is linked to early diagnosis and treatment.

EDTA as an adjunct antifungal agent for invasive pulmonary aspergillosis in a rodent model.

Rats immunosuppressed by the administration of cyclophosphamide and cortisone acetate and then infected with Aspergillus fumigatus were treated with an antifungal drug, EDTA, or a combination of one of the antifungal agents, amphotericin B lipid complex (ABLC; 5 mg/kg of body weight/day for 7 days), and EDTA (30 mg/kg/day for 7 days). The mortality rate was reduced, the duration of survival was increased, fewer A. fumigatus organisms were recovered from the lungs, and less-severe lung lesions were seen histopathologically in the rats receiving the combination treatment than in the rats receiving either an antifungal agent or EDTA alone. Further studies regarding the mechanisms of EDTA and its interactions with ABLC are warranted, and further studies are needed to more fully examine the safety, tolerance, and optimal dosing of EDTA in the treatment of this and other fungal infections.

Pentamidine is active in a neutropenic murine model of acute invasive pulmonary fusariosis.

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.

The Aspergillus fumigatus siderophore biosynthetic gene sidA, encoding L-ornithine N5-oxygenase, is required for virulence.

Aspergillus fumigatus is the leading cause of invasive mold infection and is a serious problem in immunocompromised populations worldwide. We have previously shown that survival of A. fumigatus in serum may be related to secretion of siderophores. In this study, we identified and characterized the sidA gene of A. fumigatus, which encodes l-ornithine N(5)-oxygenase, the first committed step in hydroxamate siderophore biosynthesis. A. fumigatus sidA codes for a protein of 501 amino acids with significant homology to other fungal l-ornithine N(5)-oxygenases. A stable DeltasidA strain was created by deletion of A. fumigatus sidA. This strain was unable to synthesize the siderophores N',N",N'''-triacetylfusarinine C (TAF) and ferricrocin. Growth of the DeltasidA strain was the same as that of the wild type in rich media; however, the DeltasidA strain was unable to grow in low-iron defined media or media containing 10% human serum unless supplemented with TAF or ferricrocin. No significant differences in ferric reduction activities were observed between the parental strain and the DeltasidA strain, indicating that blocking siderophore secretion did not result in upregulation of this pathway. Unlike the parental strain, the DeltasidA strain was unable to remove iron from human transferrin. A rescued strain (DeltasidA + sidA) was constructed; it produced siderophores and had the same growth as the wild type on iron-limited media. Unlike the wild-type and rescued strains, the DeltasidA strain was avirulent in a mouse model of invasive aspergillosis, indicating that sidA is necessary for A. fumigatus virulence.

Experimental pulmonary aspergillosis due to Aspergillus terreus: pathogenesis and treatment of an emerging fungal pathogen resistant to amphotericin B.

Aspergillus terreus is an uncommon but emerging fungal pathogen, which causes lethal infections that are often refractory to amphotericin B (AmB). In comparison to Aspergillus fumigatus, A. terreus was resistant to the in vitro fungicidal effects of safely achievable concentrations of AmB. These in vitro findings correlated directly with resistance of A. terreus to AmB in experimental invasive pulmonary aspergillosis. Residual fungal pulmonary burden and galactomannan antigenemia demonstrated persistent infection, despite therapy with deoxycholate AmB or liposomal AmB. By comparison, posaconazole and itraconazole resolved GM antigenemia, reduced residual fungal burden, and improved survival. There were no differences in phagocytic host response to A. terreus versus A. fumigatus; however, the rate of conidial germination of A. terreus was slower. The strain of A. terreus with the highest minimum inhibitory and minimum lethal concentration of AmB also had the lowest membrane ergosterol content. The hyphae of A. terreus in vivo displayed distinctive aleurioconidia, which may be a practical microscopic feature for rapid preliminary diagnosis.

Itraconazole preexposure attenuates the efficacy of subsequent amphotericin B therapy in a murine model of acute invasive pulmonary aspergillosis.

Antagonism has been described in vitro and in vivo for azole-polyene combinations against Aspergillus species. Using an established murine model of invasive pulmonary aspergillosis, we evaluated the efficacy of several amphotericin B (AMB) dosages given alone or following preexposure to itraconazole (ITC). Mice were immunosuppressed with cortisone acetate and cyclophosphamide. During immunosuppression, animals were administered either ITC solution (50 mg/kg of body weight) or saline by oral gavage twice daily for 3 days prior to infection. Infection was induced by intranasally inoculating mice with a standardized conidial suspension (1 x 10(8) CFU/ml) of Aspergillus fumigatus strain AF 293. AMB was then administered by daily intraperitoneal injections (0.25, 0.5, 1.0, and 3.0 mg/kg) starting 24 h after inoculation and continuing for a total of 72 h. Drug pharmacokinetics of AMB and ITC in plasma were determined by high-performance liquid chromatography. Four different endpoints were used to examine the efficacy of antifungal therapy: (i) viable counts from harvested lung tissue (in CFU per milliliter), (ii) the whole-lung chitin assay, (iii) mortality at 96 h, and (iv) histopathology of representative lung sections. At AMB doses of >0.5 mg/kg/day, fewer ITC-preexposed mice versus non-ITC-preexposed mice were alive at 96 h (0 to 20 versus 60%, respectively). At all time points, the fungal lung burden was consistently and significantly higher in animals preexposed to ITC, as measured by the CFU counts (P = 0.001) and the chitin assay (P = 0.03). Higher doses of AMB did not overcome this antagonism. ITC preexposure was associated with poorer mycological efficacy and survival in mice treated subsequently with AMB for invasive pulmonary aspergillosis.

Aerosol and parenteral pneumocandins are effective in a rat model of pulmonary aspergillosis.

The pneumocandins are semisynthetic analogs of echinocandin-like compounds that have shown efficacy in animal models of systemic candidiasis, disseminated aspergillosis, and pneumocystis pneumonia. However, the most common form of Aspergillus infection in susceptible patients is pulmonary aspergillosis, which was not directly tested in the mouse models used in the past. We have evaluated three pneumocandins, L-693,989, L-731,373, and L-733,560, in a rat model of pulmonary aspergillosis. Male Sprague-Dawley rats were treated for 2 weeks with cortisone and tetracycline and fed a low-protein diet before being inoculated via the trachea with 10(6) conidia of Aspergillus fumigatus H11-20. In the absence of drug treatment, the animals developed a progressive, rapidly fatal bronchopneumonia. All three pneumocandins at doses of 5 mg/kg (intraperitoneally [i.p.] every 12 h [q12h]) were effective in delaying mortality in this model. Survival at day 7 postinfection was 20% among controls (n = 10 for all groups), while it was 60, 80, and 90% in groups that were treated with L-693,989, L-731,373, and L-733,560, respectively. In another trial, survival at day 7 postinfection was 25% among controls (n = 8 for all groups); it was 87.5% in a group treated with amphotericin B (0.5 mg/kg i.p. q12h) and was 100% in a group treated with L-733,560 (0.625 mg/kg i.p. q12h). In a separate trial, aerosol L-693,989 administered 2 h before infection (5 mg/kg) delayed mortality. Eight of the 10 animals treated with aerosol L-693,989 survived for 7 days, whereas only 2 of 10 control animals survived. We conclude that the pneumocandins we tested were highly effective in an animal model of pulmonary aspergillosis.

Cloning and disruption of the gene encoding an extracellular metalloprotease of Aspergillus fumigatus.

Aspergillus fumigatus secretes a serine alkaline protease (ALP) and a metalloprotease (MEP) when the fungus is cultivated in the presence of collagen as sole nitrogen and carbon source. The gene encoding ALP was isolated and characterized previously. We report here the cloning and the sequencing of the gene encoding MEP. Genomic and cDNA clones were isolated from A. fumigatus libraries using synthetic oligonucleotides as probes. Stretches of the deduced amino acid sequence were found to be in agreement with the N-terminal amino acid sequence of MEP and with internal peptide sequences. The amino acid sequence of the enzyme contains a putative active-site sequence HEYTH homologous to the active site of other bacterial and eukaryotic zinc metalloproteases. Sequence analysis reveals that MEP has a pre-proregion consisting of 245 amino acid residues preceding the 388 amino acid residues of the mature region (molecular mass of 42 kDa). An alp mep mutant, deficient in proteolytic activity at neutral pH in vitro, was constructed and tested for pathogenicity in a murine model. No difference in pathogenicity was observed between the wild-type strain and the alp mep double mutant, suggesting that ALP and MEP are not essential for the invasion of the lung tissues by A. fumigatus.

La coccidioidomicosis en el I.N.E.R / The coccidiodomycosis in the INER

Estudio retrospectivo de 12 enfermos con coccidioidomicosis pulmonar atendidos en el INER de 1987 a 1991. Como elementos claves en el diagnóstico se refieren los factores de riesgo y la identificación del hongo, lo cual es posible en el examen directo de la expectoración en el 75 por ciento de os casos, cifra que se eleva al 91.6 por ciento cuando las secreciones se obtienen mediante broncoscopia. Es útil la biopsia del órgano enfermo. Se ofrece una clasificación clínica del padecimiento y la experiencia obtenida con la anfotericina B, el ketoconazol y el itraconazol

[Comparative study of the efficiency of itraconazole and ketoconazole in the treatment of experimental paracoccidioidomycosis]. / Estudio comparativo de la eficacia del itraconazol y el ketoconazol en el tratamiento de la paracoccidioidomicosis experimental.

A comparative study between ketoconazole and itraconazole in the prophylactic and curative treatment of experimental paracoccidioidomycosis in rats and guinea pigs was carried out. Ninety seven Wistar rats were inoculated intracardiacally with the yeast-phase of P. brasiliensis with the purpose of evaluating the prophylactic treatment. Eighty one guinea pigs were injected intratesticularly with the same microorganism with the aim of studying the healing treatment. Both drugs were administered by gavage once a day. The prophylactic treatment started 3 days before the challenger inoculation and the healing treatment begun 10 days after the challenger inoculation. The animals were divided in four groups: I), control animals to which only the solvents of both drugs were administered; II), those which received ketoconazole 40 mg/kg/day; III), those treated with the same drug 80 mg/kg/day, and IV), animals treated with itraconazole 8 mg/kg/day. Seven to 30 days after starting the healing and prophylactic treatments the results were evaluated. Itraconazole seems to be as effective as ketoconazole at 5 fold lower dosage.

Oral therapy for experimental coccidioidomycosis with R41 400 (ketoconazole), a new imidazole.

Oral treatment of mice with R41 400, ketoconazole, after intranasal challange with arthrospores of Coccidioides immitis prevented death at doses of 40 mg per kg of body weight per day. Doses of 160 mg per kg of body weight per day during 50 to 100 days eradicated the fungus from the lungs, liver, spleen and kidneys of approximately one half of the infected animals. Resistance to the drug was not induced during prolonged treatment. Hydropic changes in the liver occurred in animals receiving doses of 160 mg per kg of body weight per day by the fiftieth day of treatment, but did not occur at lower doses.