Treatment of Blastomycosis

Blastomycosis, disease caused by the thermally dimorphic fungus Blastomyces dermatitidis, occurs predominantly in the Midwest, south central, and northeastern United States. Spores from the environment are inhaled into the lungs where they may cause subclinical infection, acute or chronic pneumonia, or disseminated disease. The Infectious Diseases Society of America has recently published updated guidelines on the management of blastomycosis. Antifungal therapies that have proven effective for blastomycosis include itraconazole and amphotericin B. The lipid formulations of amphotericin B are preferred owing to reduced nephrotoxicity, especially when prolonged intravenous therapy is necessary. The more recently approved triazole voriconazole may play a greater role in treating blastomycosis, especially central nervous system disease, as more clinical data become available.     

Fine-Needle Aspiration Diagnosis of Thyroid Blastomycosis

ObjectiveTo describe an elusive case of blastomycosis involving the thyroid gland, which was ultimately diagnosed by use of ultrasound-guided fine-needle aspiration (FNA).MethodsWe present a case report, including clinical features, results of laboratory studies, and radiographic, computed tomographic, and ultrasonographic findings. In addition, the treatment and the utility of FNA of the thyroid relative to the diagnosis of blastomycosis are discussed.ResultsAn 18-year-old woman with no significant past medical history and with a competent immune system presented initially to her family physician because of headaches, lymphadenopathy, blurry vision, and fatigue. Radiography of the chest showed findings considered consistent with pneumonia, for which amoxicillin was prescribed. Subsequently, an ophthalmologist diagnosed anterior uveitis and initiated topical corticosteroid therapy. Worsening symptoms prompted performance of computed tomography of the chest, which suggested thyroid involvement. Ultimately, FNA of a thyroid nodule led to the cytologic diagnosis of blastomycosis. The patient was treated successfully with amphotericin for blastomycosis of the eye, lung, and thyroid.ConclusionPhysicians should consider the potential presence of blastomycosis when a lung lesion does not improve with typical treatment interventions. Disseminated blastomycosis can be diagnosed with use of FNA of the thyroid. (Endocr Pract. 2008;14:224-228)     

Experimental canine histoplasmosis and blastomycosis

Normal adult beagle dogs were experimentally infected withHistoplasma capsulatum orBlastomyces dermatitidis. Clinical signs of histoplasmosis and blastomycosis were similar to those seen in natural infections in dogs, although diarrhea was not seen in dogs with experimental histoplasmosis. Significant radiographic changes were seen in the lungs of all dogs inoculated with one of the organisms but not in the control dogs.Amphotericin B treatment of the dogs infected with mycelia ofBlastomyces dermatitidis resulted in clinical improvement and prevented death, but did not cure all of the dogs. Four of five dogs randomly selected for placebo treatment died within 34 days of inoculation, whereas all five dogs in the amphotericin B treated group were alive 14 weeks after inoculation.Since no deaths occurred in dogs inoculated with the mycelia ofHistoplasma capsulatum, weight loss was used as a measure of the degree of illness. No difference could be demonstrated between weight losses of three dogs treated with amphotericin B and of three dogs treated with a placebo. Four other dogs inoculated withH. capsulatum did not have a 20% weight loss, a criterion for treatment. The 10 control dogs maintained their preinoculation weight.From the Ecological Investigations Program, Center for Disease Control, Health Services and Mental Health Administration, Public Health Service, United States Department of Health, Education, and Welfare, Kansas City, Kansas.     

Treatment of the Midwestern Endemic Mycoses,Blastomycosis and Histoplasmosis

Purpose of Review

The purpose of this review is to assess the recommended treatment regimens for the major endemic mycoses, histoplasmosis and blastomycosis, which occur in the Midwestern USA and to provide information about the use of newer antifungal agents for these diseases.

Recent Findings

The basic approach to treatment of histoplasmosis and blastomycosis outlined in the IDSA Guidelines is helpful in managing these diseases. However, changes since these guidelines were published provide safer and better tolerated treatment regimens. Prolonged treatment with amphotericin B is rarely required, and lipid formulations of this drug have largely replaced the amphotericin B deoxycholate formulation. Although no clinical trials have been performed and the data are anecdotal, voriconazole and posaconazole are increasingly used in patients who cannot tolerate itraconazole. Voriconazole is especially useful when central nervous system infection is present. Posaconazole tablets provide consistently appropriate serum levels and the drug is well tolerated.

Summary

New azole agents provide alternative therapeutic options for histoplasmosis and blastomycosis.

     

Endophthalmitis by Aspergillus fumigatus after retina detachment

A fungal infection in the right eye after retina detachment on an immunocompetent patient is reported. After surgery, she developed an infection that was empirically treated with antibiotics and corticoids. Later the patient developed another retina and choroid detachment. The infection evolved to endophthalmitis and a sample was sent to the microbiology laboratory, where Aspergillus fumigatus was isolated. In spite of treatment with intravenous and intravitreous amphotericin B, the eye was eventually removed by enucleation.     

Blastomyces dermatitidis produces melanin in vitro and during infection

Melanin is made by several important pathogenic fungi and is implicated in the pathogenesis of a number of mycoses. This study investigates whether the thermally dimorphic fungal pathogen Blastomyces dermatitidis produces melanin. Using techniques developed to study melanization in other fungi, we demonstrate that B. dermatitidis conidia and yeast produce melanin in vitro and that yeast cells synthesize melanin or melanin-like pigment in vivo. Melanization reduced susceptibility to amphotericin B, but not to itraconazole or voriconazole. Since melanin is an important virulence factor in other pathogenic fungi, this pigment may affect the pathogenesis of blastomycosis.     

How I Treat Blastomycosis

Blastomyces dermatitidis, a dimorphic fungus endemic to the Midwestern, South Central and Northeastern United States, causes the disease blastomycosis. Aerosolized spores from the environment are inhaled into the lungs where primary infection may be asymptomatic or subclinical. Pneumonia, the most common presentation of symptomatic blastomycosis, can be acute, subacute or chronic. Cutaneous, osteoarticular, genitourinary or central nervous system involvement may result from extra-pulmonary dissemination. The Infectious Diseases Society of America has published treatment guidelines for blastomycosis Chapman (Clin Infect Dis 46:1801-1812, 2008). Oral itraconazole has been the mainstay of therapy for mild to moderate infection, while amphotericin B, or alternatively a lipid formulation, is reserved for more severe infection. Newer triazoles, such as voriconazole and posaconazole, have shown clinical potential and expand available treatment options.     

Self-administration of intravenous antibiotics: an efficient,cost-effective home care program.

The effects of a home care program with 102 courses (2336 patient-days) of intravenous antibiotic therapy were evaluated. Home care nurses changed the intravenous cannula site every 3 days. The initial hospital stay averaged 11.8 days and the duration of home therapy averaged 22.9 days. The diseases treated included osteomyelitis, septic arthritis, endocarditis, cystic fibrosis and pneumonia, staphylococcal bacteremia, blastomycosis, actinomycosis and other soft tissue infections. All classes of commonly used antibiotics, including penicillins, cephalosporins, aminoglycosides and amphotericin B, were administered, alone or in combination. There were no side effects that necessitated discontinuation of home treatment or readmission to hospital. The average cost per patient-day was $58, compared with an estimated $193 for in-hospital therapy; in addition, 2336 hospital bed-days were made available. Most patients were able to resume many or all of their daily activities while receiving intravenous antibiotic therapy.     

Problemas clínicos en micología médica: problema número 49

The case of a 59-year-old female born in Buenos Aires (Argentina) is presented. She had been diagnosed with HIV in 2007 and received highly active antiretroviral therapy until 2011; she also suffered from diabetes type 2. She had received empirical treatment (pyrimethamine-clindamycin) for cerebral toxoplasmosis. Fifteen days later she suffered a drug-induced skin disorder and was treated in the Dermatology Service of the Hospital Muñiz with corticosteroids. After five weeks she was readmitted to the Infectious Disease Unit due to asthenia, weight loss, left hip pain and weakness in all four limbs. Septic arthritis and aseptic hip necrosis were ruled out. Blood cultures were positive for Staphylococcus aureus and Escherichia coli. The patient received intravenous antibiotics, but before being discharged Acinetobacter baumannii was isolated from blood, catheter and urine cultures, and a new series of antibiotics were prescribed. On the 3rd day she presented encephalic facies, changes of behaviour and disorientation, without nuchal rigidity, Kernig and Brudzinski signs or focal signs. An X-ray computed tomography did not show parenchymal lesions. A yeast identified as Candida albicans was isolated in a cerebrospinal fluid culture. The same yeast was recovered in a new cerebrospinal fluid sample. The isolate was susceptible to amphotericin B and susceptible dose dependent to fluconazole. The patient was treated with amphotericin B (0.7 mg/kg plus 800 mg fluconazole daily). Three weeks later, new cerebrospinal fluid cultures were negative. Unfortunately, the patient died soon afterwards.     

Blastomycosis: Report of three cases from Alberta with a review of Canadian cases

Approximately 120 cases of blastomycosis have been reported from Canada to-date. The great majority of these occurred in the Eastern provinces. Since 1970, three cases of blastomycosis have been seen in Alberta. The first case, with meningeal and pulmonary involvements, was diagnosed at post-mortem. The second case was that of a 75-year-old male with a history of pancytopenia, aortic arteriosclerosis, exposure to mercury, and fever. KOH and periodic-acid schiff (PAS) stained smears of the lung tissue, received after autopsy, showed numerous budding yeast cells of Blastomyces dermatitidis along with some hyphal filaments. Similarly, budding cells of B. dermatitidis and hyphal segments were observed in large numbers in the PAS and Gomori's methenamine-silver (GMS) stained sections made from adrenals, lung, kidney, and spleen tissues. Attempts to culture the fungus on a variety of selective and non-selective media were unsuccessful, due to heavy bacterial contamination. The indirect fluoroscent antibody results were 2+ with the B. dermatitidis conjugate. The third case was that of a 31-year-old male, who was admitted to the hospital with the chief complaint of chest pain. Biopsy tissue sections, stained with the GMS procedure revealed a few foci with B. dermatitidis yeast cells. The immunodiffusion and complement fixation (CF) tests gave positive results against B. dermatitidis antigen (titre, 116). The CF titre declined following treatment with amphotericin B and the immunodiffusion test became negative after the institution of antifungal therapy. Except for the last patient, the other two patients had no history of travel in any known endemic areas. In addition to these cases, a survey of blastomycosis occurring in this country has been presented along with on the disease in dogs and a cat.     

Safe and successful endoarterial infusion of liposomal amphotericin B in treatment of mucormycosis

Mucormycosis is a rare invasive mycotic infection treated by antifungini or amphotericin B. We describe the case of a patient with septic fever and a necrotic lesion, with phlegmon of medial left thigh. Surgery was performed to drain the abscess content and to remove the necrotic tissue; mucormycosis was diagnosized by histological and culture tests and treated by intravenous amphotericin B. Since the lesion worsened, liposomal amphotericin B was directly infused into the left common iliac artery, with progressive improvement, and treatment was continued until complete recovery. Therefore, the endoarterial infusion of liposomal amphotericin B was a safe and successful treatment of advanced lesions of mucormycosis. In such lesions, intravenous general antibiotic administration probably is not sufficient to reach the whole infected area.     

Effect of amphotericin B on the energy metabolism of tissue forms of Candida albicans]

Dehydrogenase activity of the tissue form cells of C. albicans during the infection process in albino mice with and without amphotericin B treatment was studied. The strength of the metabolic reactions resulting in accumulation of ATP was evident from the activity of 4 main enzymes, i.e. succinate dehydrogenase, lactate dehydrogenase, alcohol dehydrogenase and glucose-6-phosphate dehydrogenase. The enzymatic activity was determined by the tetrasol method based on formation of diphormazan. Investigation of the fungal cells 10 minutes after the infection showed that preliminary intravenous or intraperitoneal administration of amphotericin B did not change the activity of the tissue forms. The cytochemical characteristics of the fungal cells remained the same as that in the untreated animals. Six hours after infection of the animals treated with amphotericin B administered intravenously the fungus vegetation decreased from 52 to 38 per cent, while in the animals treated with amphotericin B administered intraperitoneally it was suppressed completely. Simultaneously the energy metabolism was also suppressed, the activity of alcohol dehydrogenase being suppressed most significantly. The activity of this enzyme in the cells of C. albicans isolated from the animals treated with the antibiotic administered intraperitoneally was 14 times lower than that in the cells of the culture isolated from the control animals.     

Specific Immunodiffusion Test for Blastomycosis

A specific immunodiffusion test for blastomycosis has been developed. The test permitted the detection of approximately 80% of 113 proven cases of blastomycosis. Two diagnostically important precipitins designated A and B were frequently recognized in patients with blastomycosis. Routine use of reference sera containing the A and B precipitins in immunodiffusion tests would permit the specific diagnosis of blastomycosis without the need for parallel tests with coccidioidin and histoplasmin.     

Comparative efficacy of fluconazole and amphotericin B in the parenteral treatment of experimental paracoccidioidomycosis in the rat

Patients with severe and complicated paracoccidioidomycosis are treated with amphotericin B by the intravenous route. Fluconazole is active in vitro against Paracoccidioides brasiliensis and can also be administered intravenously, but few clinical or experimental data are available about its action against the infection caused by this fungus. In the present study, the efficacy of fluconazole andamphotericin B was assessed comparatively in rats inoculated parenterally with P. brasiliensis. The treatment was performed 3 times a week for 4 weeks starting one week after infection. Fluconazole administered intraperitoneally (14 mg/kg bodyweight/dose) was more effective (P > 0.001)than amphotericin B (2 mg/kg body weight/dose) in reducing the number of colony forming units in the lungs and spleen. When administered intravenously at the dose of 3 mg/kg body weight, fluconazole was as effective as amphotericin B (0.8 mg/kg body weight) in reducing the pulmonary fungal burden. Under these conditions, the rats treated with fluconazole had a smaller number of colony forming units than untreated animals (P > 0.001), but amphotericin B was more effective than fluconazole in reducing spleen infection (P > 0.005). Except for this result obtained with a low dose, fluconazole showed an antifungal action equal to or higher than that of amphotericin B. The activity of fluconazole at doses equivalent to those used for human treatment suggests that this antifungal agent may be an alternative to amphotericin B for the early intravenous treatment of patients with paracoccidioidomycosis. This revised version was published online in June 2006 with corrections to the Cover Date.     

Characteristics of a strain of C. albicans resistant to polyene antibiotics]

It was found that a resistant strain R2 of C. albicans obtained as a result of passages on media containing increasing concentrations of amphotericin B differed from the initial strain by its lower pathogenicity. Treatment of the infection caused by the resistant strain on modeling of candidiasis in mice was not successful. The decrease in the average life span of the mice infected with the resistant strain R2 and treated with amphotericin B was lower than that in the control animals and such indices of the disease as the levels of the kidney dissemination and the cell vegetation even increased under the effect of amphotericin B. The results of the study suggest that the resistant strain R2 of C. albicans depend on amphotericin B in the host. The data obtained emphasize the necessity of determinining the antibiotic sensitivity of C. albicans strains isolated from patients.     

THIS ARTICLE HAS BEEN RETRACTEDHamycin treatment of candidiasis in normal and diabetic rats

Hamycin, a heptaene antifungal antibiotic was compared with amphotericin B in the treatment of established systemic infection with Candida albicans in normal and diabetic rats. In normal rats, orally administered hamycin at 10 mg kg(-1) per day for 7 days reduced Candida colony counts in the kidneys and livers as well as amphotericin B did and was nearly as effective as amphotericin B in a 21-day treatment trial. There was no further reduction in Candida colony counts when normal rats were treated with hamycin at 25 mg kg(-1) twice a day for 7 days. In streptozotocin induced diabetic rats, hamycin at 20 mg kg(-1) per day for either 7 or 21 days compared favourably with amphotericin B in efficacy. Results of the present study suggest that oral hamycin may be useful in the treatment of established disseminated candidiasis in normal as well as diabetic hosts.     

Freedom of information legislation and medical records.

In a previously healthy 13-year-old girl with disseminated blastomycosis, immunodeficiency was considered because of lymphopenia and the slow response of her lung disease to therapy with amphotericin B. Cellular immunity was found to be profoundly impaired, with absent delayed cutaneous hypersensitivity to several common antigens, a decreased count of thymus-dependent lymphocytes in the peripheral blood and a greatly diminished in-vitro proliferative response of lymphocytes to phytohemagglutinin (PHA). Humoral immunity was intact. Two additional types of therapy were assessed: subcutaneous injection of transfer factor was associated with an unsustained increase in lymphocyte counts and a positive cutaneous response to PHA but no clinical change; parenteral alimentation to ensure an adequate energy intake was associated with rapid clinical improvement, the development of delayed hypersensitivity to four additional antigens, and the return of lymphocyte counts and proliferative response to normal. These findings suggest that increased energy intake rather than transfer factor therapy was responsible for the child''s recovery, and they emphasize the importance of adequate nutrition in the maintenance of intact cellular immunity.     

Comparative levels of amphotericin B in the skin and subcutaneous fatty tissue after cutaneous application of amphotericin ointment by phonophoresis and with preliminary treatment by dimethyl sulfoxide]

A comparative study of the amphotericin B contents in the skin and subcutaneous fatty tissue was performed on guinea pigs after local application of amphotericin ointment by phonophoresis and with preliminary treatment of the skin by dimethyl sulfoxide (DMSO). When the amphotericin ointment was used in combination with ultrasound the content of amphotericin B in the skin and subcutaneous fatty tissue 1, 3, 24, 48 and 72 hours after the application was much higher than that after the ointment local application without the ultrasonic treatment. When the amphotericin ointment was applied locally after the preliminary treatment with DMSO the maximum content of the antibiotic in the skin and subcutaneous fatty tissue was observed 3 hours after the application which was significantly higher than the content observed after the ointment application by phonophoresis and especially locally without the ultrasonic treatment. In 24, 48 and 72 hours the amphotericin B concentration in the skin and subcutaneous fatty tissue under any conditions lowered and in 24 hours had a tendency to level in the areas treated with ultrasound and DMSO. In 48 and 72 hours the highest concentrations of the antibiotic were in the skin and subcutaneous fatty tissue after the ointment application by phonophoresis.     

The use of amphotericin B to detect inhibitors of cellular cholesterol biosynthesis

Pores formed in the membranes of animal cells by complexes of sterols and the polyene antibiotic amphotericin B can efficiently kill the cells. Thus, in the absence of exogenous sources of cholesterol, inhibitors of enzymes in the cholesterol biosynthetic pathway render cells resistant to amphotericin B. Preincubation of Chinese hamster ovary cells with compactin or 25-hydroxycholesterol, inhibitors of the synthesis of the key intermediate mevalonate, protected cells from amphotericin B killing and this protection was reversed by the addition of exogenous mevalonate. The ability of compactin to confer amphotericin B resistance on normal cells was abolished when cells were provided exogenous cholesterol by the receptor-mediated endocytosis of low density lipoprotein. Low density lipoprotein receptor-defective Chinese hamster ovary cells were not subject to this low density lipoprotein-dependent amphotericin B killing. Exogenous mevalonate did not prevent 4,4,10 beta-trimethyl-trans-decal-3 beta-ol, an inhibitor of mevalonate conversion to sterols, from protecting cells from amphotericin B. A simple two-step protocol in which cells are preincubated (15-24 h) with potential inhibitors and then treated (3-6 h) with amphotericin B was devised to provide a sensitive method for detecting direct (e.g., competitive) and regulatory inhibitors of cholesterol biosynthesis. This protocol may prove useful in detecting potential antihypercholesterolemia drugs and is currently being used to isolate mutants in receptor-mediated endocytosis.     

Amphotericin B-induced changes in K+ content, viability, and ultrastructure of yeast-phase Histoplasma capsulatum.

Yeast-phase cells of Histoplasma capsulatum were challenged with amphotericin B, and membrane perturbation was monitored by K+ efflux. Suspensions of washed cells readily absorbed about 1.12 microgram of amphotericin B per mg (dry weight) and further nonspecific sites were also apparent. The dose-response curve for initial rate of K+ efflux was sigmoidal within the range 0.1 to 1.0 microgram of amphotericin B per ml. A fungistatic concentration of amphotericin B (0.3 microgram/ml) evoked an efflux of 85 to 90% K+ from the cells within 15 min, but cell viability decreased only 13% (yeast phase) or 33% (transformed to mycelial units). Ultrastructural changes in treated cells were detected within 5 min, and the hallmark was expansion of vacuoles during the 1-h monitoring period. In contradistinction to a previous report, the appearance of the protoplasmic membrane was not altered by fungistatic concentration. When treated cells were returned to a fresh growth medium, there was a pronounced lag (20 h). During this apparent recovery phase, the large vacuoles fragmented and returned to normal size. It is proposed that vacuoles of H. capsulatum act as a spatial buffer of considerable survival value to stressed cells.