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.     

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.

     

Blastomycosis during pregnancy.

Disseminated blastomycosis with extensive involvement of the lungs, skin and bones was diagnosed in a 31-year-old woman who was 36 weeks pregnant. No antifungal treatment had been given while she was pregnant, and she gave birth shortly after admission to hospital. The child was healthy and uninfected, and there were no signs of inflammation or infection in the placenta. Post partum the mother was treated with 2 g of amphotericin B, with resolution of her symptoms. A literature review suggested that blastomycosis and other systemic fungal infections are more likely to occur during pregnancy because of immunosuppression and that disseminated blastomycosis in pregnant women should be treated with amphotericin B.     

Secondary Intracerebral Blastomycosis with Giant Yeast Forms

Secondary central nervous system (CNS) blastomycosis is an unusual manifestation of blastomycosis. We report a case of recurrent intracerebral blastomycosis that presented histopathologically with giant yeast-like cells and multinucleation that mimicked Coccidioides immitis. The yeast forms of Blastomyces dermatitidis usually range in size from 8 to 20 μm in diameter. Large or giant yeast forms (20–40 μm) are rare. The four cases previously reported in the literature involving giant yeast cell forms of B. dermatitidis are reviewed here. Intracerebral blastomycosis should be suspected in patients with signs and symptoms of CNS lesions and histories of primary blastomycosis, or treatment with corticosteroids, or comprised immune systems. The diagnosis should be confirmed by culture which presents typical biphasic microbiologic features.     

Blastomycosis in Africa

The known African cases of blastomycosis to 1987 are presented, including thirteen previously undescribed cases. This brings to 81 the total number of cases known to have occurred in Africa. The question of whether the disease in Africa is the same in all respects as that in North America is addressed; the age and sex distributions of patients are similar. Minor differences in the clinical features relate particularly to the type of skin lesion, the more frequent bone involvement and the less frequent central nervous system involvement in the African patient. Little is known about the epidemiology of blastomycosis in Africa; one noteworthy feature is the apparent absence of the disease in dogs. Isolates of Blastomyces dermatitidis from the two continents, although closely related, differ in some respects.     

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.     

Paracoccidioidomycosis

Paracoccidioidomycosis is the most frequent endemic mycosis in South America. The infection is more prevalent in rural workers, and recent epidemiologic data suggest that changes in agricultural practices (such as a decrease in coffee plantations and an increase in sugar cane plantations) may result in a reduction in the incidence of infection. After being inhaled, Paracoccidioides brasiliensis usually causes a benign and transient pulmonary infection that may progress to an acute form or, more frequently, reactivate later as a chronic disease. The diagnosis is usually made by direct examination and culture of clinical specimens; serologic tests may be of help, especially antigen detection. The drug of choice for the chronic form is oral itraconazole, whereas patients with more severe forms may be treated with intravenous amphotericin B or sulfamethoxazoletrimethoprim. The newer azole voriconazole is also effective, and it may be a good alternative because it can be given by oral or intravenous route.     

Overview: Cryptococcosis in the patient with AIDS

Cryptococcosis is currently the most common life threatening mycoses found in patients with the acquired immunodeficiency syndrome (AIDS). Extrapulmonary involvement is most frequently seen, especially in the central nervous system and skin. Clinical findings are non-specific, even in patients with meningitis. Threshold for diagnosis of this infection should be low, with serum cryptococcal antigens, blood, urine and sputum cultures for Cryptococcus neoformans performed in febrile AIDS patients. Lumbar puncture should also be performed if unexplained headaches are included in a patient's complaints. There is currently no consensus for the most appropriate treatment strategy and the role of oral azoles versus amphotericin B or amphotericin B with flucytosine remains a serious question in need of further controlled studies. Patients eligible for multicentered trials should be encouraged to participate. Therapy for others should be individualized. This review will address some of these issues.     

Epidemiology of 46 wisconsin cases of north american blastomycosis, 1960–1964

Summary In an attempt to find the source of infection 45 Wisconsin North American blastomycosis patients or their immediate relatives were interviewed and the records studied. B. dermatitidis was considered to have been proved to be endemic in Wisconsin, since infection took place in several parts of the state, and a large proportion of the patients were shown to have been infected while living in the state.A study of the yearly occurrence of cases of blastomycosis in Wisconsin, 1960–1964, revealed an unequal distribution. A noticeably small number of cases occurred in 1963. Since this was the driest year in Milwaukee and many other parts of the state in 30 years, further work on a possible relationship between the disease and annual precipitation was suggested.The seasonal distributions of both onset and diagnosis were found to differ significantly from an even distribution among the seasons. The distributions were found to be compatible with the hypothesis that infection took place toward the end of the growing season.Evidence was presented that the American Indian in Wisconsin may have a racial susceptibility or an environmental relationship favoring infection byB. dermatitidis.When compared with other published series of blastomycosis cases, an unusually large number of women patients was found resulting in a 3.5 : 1 male to female ratio.The study failed to show an occupational connection with the disease.This investigation was supported in part by Public Health Service Research Grant AI-02211 (03–07) from the National Institute of Allergy and Infectious Diseases.     

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.     

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.     

Is There Still a Place for Conventional Amphotericin B in the Treatment of Neonatal Fungal Infections?

Neonatal invasive fungal infections (IFIs) remain an increasing problem associated with high rates of morbidity and mortality, as well as late-onset neurodevelopmental implications. Invasive candidiasis remains the leading neonatal IFI. Candida albicans is the fungal species most often affecting this population, although a changing epidemiologic incidence to non-albicans Candida species is reported in some neonatal intensive care units. Many treatment recommendations are extrapolated from adult populations, emphasizing the need to establish the optimal antifungal agent, dosage, and duration of therapy in neonates. Historically, conventional amphotericin B has been considered an efficient and safe treatment approach for most neonatal IFIs. More recently, lipid formulations of amphotericin B have been studied, used alone or in combination with other antifungal agents such as azoles or echinocandins. The aim of this article is to review the published experience in the use of amphotericin B formulations to treat neonatal IFIs.     

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.     

How I Treat Histoplasmosis

Histoplasmosis is an endemic mycosis caused by the dimorphic fungus Histoplasma capsulatum. Some important manifestations of infection include acute or chronic pulmonary disease, histoplasmomas, progressive disseminated histoplasmosis, and central nervous system infection. Depending on the clinical presentation, site of infection and severity of disease, either amphotericin B preparations followed by itraconazole, or itraconazole alone have become the preferred treatments. Because prolonged therapy (6 weeks to 24 months) may be required, careful monitoring for nephrotoxicity in patients on amphotericin B preparations is necessary. In addition, in patients receiving itraconazole, vigilance for drug interactions and pharmacokinetic properties is warranted. Histoplasma antigen testing has improved rapidity of diagnosis and the ability of long-term monitoring for clinical response in patients with histoplasmosis.     

Detection of antibody responses and delayed dermal hypersensitivity with Blastomyces dermatitidis yeast and mycelial lysate antigens

Yeast cell lysate and mycelial lysate antigens prepared from one strain (T-58) of Blastomyces dermatitidis were evaluated with respect to the detection of antibodies and delayed dermal hypersensitivity. Comparable ELISA sensitivity values were evidenced with the two antigens when assayed against serum specimens from dogs with blastomycosis, sera from non-infected dogs residing in endemic and nonendemic areas for blastomycosis and sera from rabbits that were hyperimmunized with B. dermatitidis antigens. Specificity determinations with anti -Histoplasma capsulatum rabbit sera indicated that both reagents exhibited only minimal cross-reactivity; the mycelial antigen was slightly more specific than the yeast phase reagent. Similar sensitivity and specificity results were experienced when the two antigens were used to detect delayed dermal hypersensitivity in guinea pigs previously sensitized with B. dermatitidis or H. capsulatum.     

Synergistic effects of low doses of histatin 5 and its analogues on amphotericin B anti-mycotic activity

The increase in the use of antifungal agents for prophylaxis and therapy has led to the development of antifungal drug resistance. Drug combinations may prevent or delay resistance development. The aim of the present study was to investigate whether naturally and designed cationic antifungal peptides act synergistically with commonly used antimycotics. No enhanced activity was found upon addition of dhvar4, a designed analogue of the human salivary peptide histatin 5, or PGLa to fluconazole or 5–flucytosine, respectively. In contrast, strong synergism of amphotericin B with the peptides was found against several Aspergillus, Candida, and Cryptococcus strains, and against an amphotericin B-resistant C. albicans laboratory mutant in the standardised broth microdilution assays according to the NCCLS standard method M27–T. Amphotericin B showed synergism with dhvar5, another designed analogue of histatin 5, and with magainin 2 against all seven tested strains. Combinations of amphotericin B with histatin 5, dhvar4, and PGLa showed synergism against four of the seven strains. The growth inhibitory activity of amphotericin B was enhanced by sub-MIC concentrations of peptide, but its haemolytic activity remained unaffected, suggesting that its cytotoxicity to host cells was not increased and that peptides may be suitable candidates for combination therapy.     

Effect of amphotericin B on the lipids of five different strains ofCryptococcus neoformans

Cells of five strains ofCryptococcus neoformans were obtained for partial analysis of lipid composition. Quantitative analysis of lipids and sterols were completed, as well as qualitative analysis of sterols by thin-layer chromatography and by the ultraviolet spectra. Such determinations were made on cells cultured in the absence and presence of amphotericin B at sub-MIC (minimal inhibitory concentration) levels. Marked alterations of the lipid and sterol contents were observed in the amphotericin B — treated cells. Moreover, ergosterol disappeared in these antibiotic-exposed cells. It is concluded that amphotericin B altered the lipid profiles, especially sterols ofC. neoformans.     

Sensitivity of scopulariopsis brevicaulis to some antimicrobial agents

Sensitivity tests were done against two isolates of Scopulariopsis brevicaulis, using amphotericin B in combination with chloramphenicol, Chloramphenicol alone, amphotericin B in combination with 5-fluorocytosine, and 5-fluorocytosine, myxin and clotrimazole alone. Results indicated that the effectiveness of amphotericin B was improved in the presence of chloramphenicol or 5-fluorocytosine. Growth inhibitory values recorded for chloramphenicol alone and combined with amphotericin B did not show much variation. Resistance of the fungus has been noticed to 5-fluorocytosine; but the organism's response was much better when tested against 5-fluorocytosine in the presence of amphotericin B. Both myxin and clotrimazole proved very effective and their ED50 was 50 and 2.5 ug/ml of the medium, respectively. Thus, clotrimazole may be the drug of choice in the cases of deep scopulariopsis.     

Blastomycosis in indoor cats: Suburban Chicago, Illinois, USA

Blastomyces dermatitidis, the etiologic agent of blastomycosis, a potentially life-threatening systemic mycosis of humans and animals, is acquired from a yet incompletely defined environmental niche. There is controversy regarding the potential for contact with the fungus in or near one’s home, particularly in urban areas. We investigated an outbreak of blastomycosis among five urban, indoor cats diagnosed at three veterinary clinics March 3–July 13, 2005, in suburban Chicago, Illinois, by owner interviews, site visits, environmental cultures for B. dermatitidis, GIS analysis, and analysis of local weather data. There were no environmental exposures common to the five cats that lived a median of 300 m from nearest body of water, in homes on a loam soil. Closest and farthest case home sites were 3.4 and 26.1 km, respectively. All cats were confined indoors except one cat that averaged 15 min/week in his backyard and was exposed to excavation. B. dermatitidis was not isolated from any of 60 environmental samples. The annualized incidence rate March through July 2005 among 6,761 cats in these practices was 178/100,000, compared to none in the previous 4 years, and 0.14/100,000 cat visits from a nationwide animal hospital registry. Precipitation January through June 2005 was 9.30 versus period mean of 14.05 ± 1.69 inches the previous 4 years (P = 0.01). Circumstantial evidence suggests acquisition of B. dermatitidis from the home site environment in five cats. Relative drought may have contributed to an apparent outbreak of blastomycosis in this urban locale.     

North American blastomycosis in Central Canada: A review of 36 cases

Experience with 36 cases of North American blastomycosis in Central Canada is reported. Symptoms referable to the respiratory tract predominated, but no uniform clinical pattern for the disease process was evident. Cutaneous and genitourinary tract involvement was present in only a small proportion of patients. The majority of the patients resided in rural areas or were associated with some form of outdoor occupation or activity. No characteristic radiologic appearance could be identified in this series. Amphotericin B administered intravenously is the treatment of choice for this condition. North American blastomycosis is more widespread on this continent than has been previously demonstrated.