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PubMed2003

Current perspectives on ophthalmic mycoses.

Fungi may infect the cornea, orbit and other ocular structures. Species of Fusarium, Aspergillus, Candida, dematiaceous fungi, and Scedosporium predominate. Diagnosis is aided by recognition of typical clinical features and by direct microscopic detection of fungi in scrapes, biopsy specimens, and other samples. Culture confirms the diagnosis. Histopathological, immunohistochemical, or DNA-based tests may also be needed. Pathogenesis involves agent (invasiveness, toxigenicity) and host factors. Specific antifungal therapy is instituted as soon as the diagnosis is made. Amphotericin B by various routes is the mainstay of treatment for life-threatening and severe ophthalmic mycoses. Topical natamycin is usually the first choice for filamentous fungal keratitis, and topical amphotericin B is the first choice for yeast keratitis. Increasingly, the triazoles itraconazole and fluconazole are being evaluated as therapeutic options in ophthalmic mycoses. Medical therapy alone does not usually suffice for invasive fungal orbital infections, scleritis, and keratitis due to Fusarium spp., Lasiodiplodia theobromae, and Pythium insidiosum. Surgical debridement is essential in orbital infections, while various surgical procedures may be required for other infections not responding to medical therapy. Corticosteroids are contraindicated in most ophthalmic mycoses; therefore, other methods are being sought to control inflammatory tissue damage. Fungal infections following ophthalmic surgical procedures, in patients with AIDS, and due to use of various ocular biomaterials are unique subsets of ophthalmic mycoses. Future research needs to focus on the development of rapid, species-specific diagnostic aids, broad-spectrum fungicidal compounds that are active by various routes, and therapeutic modalities which curtail the harmful effects of fungus- and host tissue-derived factors.

Antifungal Agents↗
PubMed1990

New antifungal agents for the systemic mycoses.

The azoles are the prominent broad spectrum oral antifungal agents in use or under clinical investigation for the systemic mycoses. This class of antifungal agents is represented by the marketed drug ketoconazole (Nizoral) and the experimental triazoles furthest along in clinical trials in the United States, itraconazole and fluconazole. Ketoconazole use is limited by its side effect profile and activity spectrum. Itraconazole appears to be better tolerated and less toxic to liver function, does not cause adrenal suppression and is more active against Aspergillus and Sporothrix schenckii. Fluconazole appears to be a highly promising agent due its highly favorable pharmacokinetic profile; it is water soluble, is well tolerated, is not metabolized to inactive constituents, it has a long half-life and, unlike the other azoles, high cerebrospinal fluid levels are readily attained for consideration in meningeal mycoses. It remains to be determined what place these new triazoles have in managing immunosuppressed patients including those with acquired immune deficiency syndrome known as AIDS. Other experimental antifungal agents, including ambruticin, amphotericin B methyl ester and saramycetin are also described. Sales figures are presented of drugs marketed in the United States for the systemic mycoses and reflect the growing problem of fungal diseases in the population.

Antifungal Agents↗
PubMed1993

Diagnosis of invasive mycoses in severely immunosuppressed patients.

In compromised patients, invasive mycoses are being observed at an increasing frequency and with a broadening spectrum of causative fungi. The rapid and definitive diagnosis of such opportunistic mycoses requires the synoptical consideration of predisposing clinical conditions, of culture isolates, and of the results of nonculture techniques. At present, the latter comprise the monitoring of specific antibodies and of fungal antigens, and the microscopical examination of suspected biopsies. The validity of the individual techniques (e.g., the monitoring of antibodies or antigens) varies with individual mycoses. Alternative methods for monitoring fungal metabolites or nucleic acids are still in the developmental stage. Particularly the amplification of DNA by the polymerase chain reaction (PCR) has a high diagnostic potential. However, at present, it is uncertain whether PCR allows the necessary distinction between colonization and truly invasive infection, and whether PCR can be simplified sufficiently to allow the continuous surveillance of high-risk patients.

Humans↗
PubMed2004

Incidence of systemic mycoses in autopsy material.

The incidence of systemic mycoses was investigated in the autopsy material of the Institute of Pathology of the Humaine Hospital in Bad Saarow, Germany. This hospital provides qualified standard care in east Brandenburg with a wide spectrum of medical disciplines caring for patients with acute medical conditions as well as oncological cases (660 beds). Between 1973 and 2001, 47 systemic mycoses were diagnosed in 4813 autopsies of deceased adults, corresponding to 0.98%. During the period of investigation, both the care provided by the hospital and the organization of the health service changed. The autopsy frequency fell from about 80% (1973-1991) to about 28% (1992-2001). This is thus still far higher than the average of about 3% assumed for the Federal Republic of Germany. Although the incidence of systemic mycoses increased during the entire 29-year period of investigation, the number of cases in whom this was the immediate cause of death decreased. Whereas candidoses predominated from 1973 to 1991, a shift in favor of aspergilloses was noticed in the period from 1992 to 2001. Systemic mycosis was diagnosed intravitally in only three of 47 cases. The present study therefore underscores the significance of clinical autopsy as a diagnostic method and means of medical quality control.

Adult↗
PubMed1985

[Deep mycoses in leukemias and malignant lymphomas].

Of 590 autopsies during the period 1976 to 1983 in patients with leukaemia and malignant lymphomas there were 89 cases (15%) involving deep-seated mycoses. In the last three years the frequency of mycotic infections has risen considerably even though effective drugs are available today. The increase occurred particularly in acute leukaemias but was also found in chronic myelogenous leukaemias and in cases with high-malignancy non-Hodgkin lymphomas. An opportunistic fungal infection in Hodgkin's disease and in patients with plasmocytoma was rare. Candidosis and aspergillosis predominated histologically. About 70% of deep-seated mycoses were severe infections having a decisive influence on the course of the disease. On the basis of this retrospective analysis it can be concluded that the occurrence of mycoses is influenced, first and foremost, by 3 factors: 1. The antineoplastic therapy 2. The nature of the underlying disease 3. The intensity of the supportive measures.

Aspergillosis↗
PubMed1992

Opportunistic mycoses in the immunocompromised host: experience at a cancer center and review.

The field of opportunistic mycoses in the patient with cancer is rapidly changing. Not only are fungal infections increasing in frequency in this patient population, but these infections are occurring earlier during the course of cytotoxic chemotherapy, and newer fungi are increasingly recognized as potentially lethal pathogens. Candidiasis remains the most commonly encountered infection. The spectrum of disease includes candidemia and acute and chronic disseminated candidiasis. Pulmonary aspergillosis and disseminated aspergillosis are common and remain relatively resistant to therapy. Disseminated fusariosis and trichosporosis are almost always fatal in the setting of persistent profound neutropenia. Therapy for these mycoses relies on the use of amphotericin B and 5-fluorocytosine. Newer antifungal agents, such as fluconazole and itraconazole, appear to exhibit good activity against a variety of fungi. Newer approaches need to be tested for the treatment of the more-resistant mycoses and may include the use of maximally tolerated doses of antifungal agents, colony-stimulating factors, and combination therapy.

Humans↗
PubMedDate not supplied

Itraconazole in the treatment of human mycoses: review of three years of clinical experience.

During the first three years of clinical investigation of itraconazole, more than 1,000 patients with mycoses were treated with the drug. Almost 50% were women with vaginal candidosis; a dosage of 200 mg per day for three days appeared to be optimal for their treatment. Several treatment regimens were tested for pityriasis versicolor; the minimum total dose necessary for optimal results was 1 g. A randomized comparison of 50-mg and 100-mg daily doses for the treatment of skin mycoses indicated that the optimal dosage is 100 mg. The results of short courses of treatment for superficial dermatophytoses suggest that such regimens may be effective, and the results of an ongoing double-blind comparison of itraconazole and griseofulvin suggest that itraconazole is superior in these infections. The outcome of treatment of systemic mycoses with itraconazole, especially sporotrichosis, chromomycosis, and aspergillosis, indicates that itraconazole may be useful in therapy for life-threatening fungal infections when standard therapy has failed.

Antifungal Agents↗
PubMed2002

Recent trends in the epidemiology of invasive mycoses.

PURPOSE OF REVIEW: Invasive mycoses are emerging as an important public health problem. This development has occurred in large measure due to the increasing numbers of persons at risk. In addition, advances in therapeutic technologies and in particular the development of novel immunosuppressive therapies have prolonged the period of risk for many individuals. RECENT FINDINGS: Although rates of candida bloodstream infections have been increasing over the past several decades, recent evidence suggests this trend may be reversing. The emergence of non-albicans Candida species, and in particular C. glabrata, has been documented. Invasive aspergillosis and other mold infections have become a significant and increasing problem in hematopoietic stem cell transplant recipients and certain high-risk groups of solid organ transplant recipients. These infections are associated with high mortality rates. Despite marked reductions in the rates of AIDS-associated fungal infections in the USA and other developed countries, the burden of these mycoses in developing countries is large and increasing. SUMMARY: While gains have been made in the treatment and prevention of invasive mycoses, changes in the epidemiology of these infections and in healthcare practices have resulted in the emergence of new at-risk populations. A better understanding of specific risk factors will be needed if prevention strategies, such as chemoprophylaxis and environmental control measures, are to become more widely applicable and cost-effective.

Aspergillosis↗
PubMed1997

The deep mycoses in HIV infection.

The deep mycoses are uncommon infections, usually acquired from the inhalation or ingestion of fungal spores, sometimes from the soil in areas of endemicity, such as in the Americas and south-east Asia, or from decaying vegetable matter. They are also seen in immunocompromised persons and, increasingly, in HIV-infected persons. Respiratory involvement is frequent, with granuloma formation, and mucocutaneous involvement may be seen. Oral lesions of the deep mycoses are typically chronic but non-specific, though nodular or ulcerative appearances are common. Person-to-person transmission is rare. In HIV disease, the most common orofacial involvement of deep mycoses has been in histoplasmosis, cryptococcosis, aspergillosis and zygomycosis. Diagnosis is usually confirmed by lesional biopsy although culture may also be valuable. Treatment is with amphotericin or an azole.

AIDS-Related Opportunistic Infections↗
PubMed1988

Treatment of mycoses with itraconazole.

The efficacy of itraconazole, a new oral triazole, was evaluated at doses of 50-400 mg/day in 64 courses: 39 with coccidioidomycosis, and 25 with other mycoses. Among patients with coccidioidomycosis, 21 had pulmonary disease; 10, bone and joint; 8, lymphatic; 6, skin and soft tissue; 3, meningeal; and 1, urogenital. After a mean of 7.1 months of treatment, 17 of 27 evaluable courses (63%) have shown a full response; 8 (30%), a partial response; and 2 (7%), no response. Response to treatment was higher in patients with a shorter duration of illness and in patients with no previous treatment. After a mean of 12 months of treatment, two of five responders off therapy have relapsed. In patients with other mycoses, diagnoses include aspergillosis in six patients; histoplasmosis and tinea in three each; alternariosis, candidiasis, cryptococcosis, blastomycosis, and chromomycosis in two each; and pseudallescheriosis in one. After a mean of 9.4 months of treatment, 14 of 23 evaluable patients (61%) have shown a full response; 2 (8%), a partial response; and 7 (30%), no response. All patients with histoplasmosis and blastomycosis have responded to therapy. There are no relapses among five evaluable responders after a mean of 9.2 months off therapy. In 512 patient months of therapy, toxicity has been minimal. Mean serum levels in patients receiving 200 mg twice daily range from 3.9 to 5.9 micrograms/ml for 8 hr after dosing, with a peak at 7 hr and wide interpatient variability. Itraconazole is well tolerated and has continued to demonstrate efficacy in the treatment of a variety of systemic and superficial mycoses.

Adult↗
PubMed1991

[Clinical and pathological analysis of deep mycoses].

Clinical and pathological analysis were performed on 127 cases of deep mycoses diagnosed by autopsy during the 24 years between 1964 and 1987 in Juntendo University Hospital. The following findings were obtained. 1) There has been a tendency for the number of mycoses to increase each year, especially notable for candidiasis and aspergillosis. 2) Underlying diseases were, in order of incidence, various hematologic diseases, solid tumors, inflammatory diseases and collagen diseases; the most common were various types of leukemia. 3) Candidiasis was often observed in patients with gastrointestinal tract cancers. Aspergillosis was often observed in patients with collagen diseases. 4) Regarding the visceral distribution of mycoses, aspergillosis was observed in the lung, candidiasis was observed in the lung, kidney and intestinal tract in decreasing order, and cryptococcosis was also observed in the lung and central nervous system. 5) There was a probability of fungal infections occurring in cases of lymphopenia. 6) A fever was present at the time of hospitalization in many cases of aspergillosis, and the presence of an indwelling catheter was a common feature in cases of candidiasis. 7) Fungemia was frequently observed in candidiasis, but very rarely in cases of aspergillosis. 8) The large amounts of corticosteroid hormones and blood transfusions were suspected as causative factors of fungal infections.

Adolescent↗
PubMed1992

Tropical mycoses.

The most common tropical subcutaneous and deep mycoses include chromomycosis, sporotrichosis and mycetoma. All are commonly found in Natal and in other subtropical countries. Although blastomycosis is endemic in North America, only 4 cases have been identified in Natal during the last 25 years, and all presented with atypical clinical features. African histoplasmosis, caused by Histoplasma capsulatum var. duboisii and limited mainly to central and western Africa, has been found in only 1 patient in Natal. Paracoccidioidomycosis, though the most common deep mycosis in Latin America, is limited to that area and there is no experience of this disease in South Africa. Over the past 8 years, itraconazole has been used in clinical trials for all 3 mycoses. The results in sporotrichosis, non-meningeal blastomycosis and paracoccidioidomycosis suggest that for these diseases itraconazole may be the drug of choice. The results in histoplasmosis are encouraging, as are the results in chromomycosis, particularly those cases associated with Cladosporium carrionii. Where Fonsecaea pedrosoi is the causal agent and in mycetomas, however, successful management still remains a therapeutic problem. Enhanced efficacy by combining flucytosine and itraconazole was seen in 3 patients. Even over prolonged periods, itraconazole has an impressive safety profile. In the present series of 41 patients, no side-effects were observed, no adverse reactions occurred, and serum chemistry values remained within normal limits. It appears, therefore, that itraconazole, though not the final answer to management of deep mycoses, is certainly a major improvement on previous drugs.

Adult↗
PubMedDate not supplied

Virulence factors in fungi of systemic mycoses.

Pathogenic fungi that cause systemic mycoses retain several factors which allow their growth in adverse conditions provided by the host, leading to the establishment of the parasitic relationship and contributing to disease development. These factors are known as virulence factors which favor the infection process and the pathogenesis of the mycoses. The present study evaluates the virulence factors of pathogenic fungi such as Blastomyces dermatitidis, Coccidioides immitis, Cryptococcus neoformans, Histoplasma capsulatum and Paracoccidioides brasiliensis in terms of thermotolerance, dimorphism, capsule or cell wall components as well as enzyme production. Virulence factors favor fungal adhesion, colonization, dissemination and the ability to survive in hostile environments and elude the immune response mechanisms of the host. Both the virulence factors presented by different fungi and the defense mechanisms provided by the host require action and interaction of complex processes whose knowledge allows a better understanding of the pathogenesis of systemic mycoses.

Cell Adhesion Molecules↗
PubMed1997

Clinical pharmacokinetics of fluconazole in superficial and systemic mycoses.

The bis triazole agent fluconazole is used widely in the treatment of superficial and deep mycoses. A single oral dose of fluconazole 150 mg gives a mean long term clinical cure rate of 84 +/- 5% and is considered a valuable alternative to other topical antifungal drugs for vaginal candidiasis. A clinical cure rate of 90.4% for oropharyngeal candidiasis was obtained with 100mg daily for a minimum of 14 days; however, as for the other azoles the rate of relapse was large (40%) in immunocompromised patients. A daily dose of 100mg for at last 3 weeks gave satisfying outcomes for oesophageal candidiasis. Most patients (71 to 86%) with signs and symptoms of urinary tract candidiasis show beneficial clinical results when given oral fluconazole 50mg for several weeks. Fluconazole 50 to 150 mg given for weeks or months results in over 90% clinical cure or improvement for cutaneous mycosis including tinea, pityriasis, cryptococcosis and candidiasis. Prolonged (6 to 12 months) fluconazole 150 mg once a week is needed to treat onychomycosis successfully. Higher oral doses (200 to 400 mg daily) for long periods are generally used to treat deep mycoses such as meningitis, ophthalmitis, pneumonia, hepatosplenic mycosis and endocarditis. Fluconazole is effective for treating the fungal peritonitis which can complicate continuous ambulatory peritoneal dialysis (CAPD). A regimen of 50 mg intraperitoneally or 100 mg orally was used in these patients with impaired renal function. The dosage schedules used to treat disseminated fungal infections due to systemic mycoses with different or multiple foci of infections vary widely, with doses of 50 to 400 mg given orally or intravenously for between 1 week and several months. The most recent clinical reports have investigated the use of prophylaxis with fluconazole 100 to 400 mg daily, in immunocompromised patients. Fluconazole is found in body fluids such as vaginal secretions, breast milk, saliva, sputum and cerebrospinal fluid at concentrations comparable with those determined in blood after single or multiple doses. There is an excellent linear plasma concentration-dose relationship, but the mycological and clinical responses do not appear to be well correlated with the dose. A total maximum daily dose of 1600 mg is recommended to avoid neurological toxicity. Data from pharmacokinetic studies conducted in patients, mainly those with AIDS, and using a 1-compartment model give very constant parameters similar to those obtained in healthy individuals. Bioavailability, measured in HIV-positive patients and those with AIDS, exceeded 93% for tablets, suspension and suppositories. The time to reach peak plasma concentrations (tmax) was 2.4 to 3.7 hours. The peak plasma drug concentration (Cmax) obtained after a 100 mg oral dose was 2 mg/L. Areas under the concentration-time curve (AUC) obtained in different studies all correlate well with the dose (r = 0.926). The AUC determined after 200 and 25 mg suppositories were similarly well correlated. Hypochlorhydria does not affect the absorption of fluconazole, neither does food intake, race (Japanese or Caucasian) or gastrointestinal resection. Binding to plasma protein is low (11.14%) and is increased to 23% in cancer patients. Fluconazole is rapidly distributed to the tissue, where it accumulates. Tissues fall into 1 of 4 groups of increasing drug concentration: blood, bone and brain have the lowest concentrations, and spleen has the highest. The volume of distribution (Vd) remains stable at 46.3 +/- 7.9L and is considered to be an 'invariant' parameter across species. Fluconazole is poorly metabolised and is mainly eliminated unchanged in the urine. The percentage of the dose recovered in the urine in 48 hours is close to 60%. Concentrations in the urine are high and the half-life (t1/2) is long (37.2 +/- 5.5h) in patients, mainly those with AIDS, which is not significantly different from the t1/2 (31.4 +/- 4.7 hours) in healthy individuals. (ABSTRACT TRUN

Age Factors↗
PubMed1990

Fluconazole. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in superficial and systemic mycoses.

Fluconazole is a bis-triazole antifungal drug with novel pharmacokinetic properties (metabolic stability, relatively high water solubility) which contribute to its therapeutic activity. Clinical experience is limited to a relatively small number of mycoses and, as might be expected at this early stage of development, optimal dosage and duration of treatment for some serious mycoses is not yet established. Further study to evaluate higher dosages and to establish the efficacy of fluconazole relative to more established antifungal agents is required. In patients with oropharyngeal or oesophageal candidiasis, fluconazole produces rapid relief and eradicates the yeast in 50 to 90% of patients. Relapse of oral infection is common in chronically immunocompromised patients regardless of the antifungal used, and adequate primary therapy plus long term prophylaxis appears necessary in patients with AIDS. A single oral dose of fluconazole was comparable to standard topical azole therapy in women with acute vaginal candidiasis. Preliminary reports of success against deep-seated candidiasis are encouraging; moreover, experience in noncomparative clinical trials suggests that fluconazole 200 to 400mg once daily resolves infection in the majority of seriously ill patients. Clinical improvement has been reported in a few cases of pulmonary Aspergillus infection but the overall efficacy of conventional dosages of fluconazole in this mycosis has not been as impressive. Early experience in coccidioidosis, predominantly meningitis, suggests a beneficial clinical effect with oral fluconazole in this difficult to treat mycosis but relapse remains a problem. Fluconazole is a promising treatment of cryptococcal meningitis. The rate of clinical resolution and eradication of Cryptococcus neoformans from cerebrospinal fluid has been similar between fluconazole and amphotericin B treatment groups in comparative trials. Comparative trials of maintenance therapy indicate a similar low rate of relapse among patients given oral fluconazole once daily and intravenous amphotericin B once weekly. However, these results are preliminary and further study is required. Fluconazole has been well tolerated to date but wider clinical experience is needed, especially with regard to the rate occurrence of hepatotoxicity and exfoliative skin reactions. The promising clinical response of patients with various forms of candidiasis or cryptococcosis--together with convenient administration regimens--recommends fluconazole as a useful addition to currently available systemic antifungal therapies, in particular for the treatment of mycoses in patients with AIDS.

Animals↗
PubMed2003

[Cutaneous manifestations of systemic mycoses].

The systemic mycoses are increasing in importance as opportunistic infections. Cutaneous lesions resulting from systemic mycoses may first alert clinicians to the presence of a life-threatening disorder, or even the presence of an unsuspected immunodeficiency state. Skin involvement is generally uncommon in disseminated aspergillosis, zygomycosis but is more common in systemic candidiasis (candidemia) and cryptococcosis. The blanket terms, hyalohyphomycosis and phaeohyphomycosis, cover the infections caused by diverse fungal opportunists. A variety of manifestations of skin lesions of the systemic mycoses are reviewed. These specific and/or non-specific lesions require early recognition, diagnosis, and aggressive antifungal treatment.

Aspergillosis↗
PubMed2000

[Analysis of deep mycoses in autopsy cases].

The deep mycosis in compromised patients is increasing. We examined 40 cases (3%) of the deep mycoses out of 1170 autopsy cases experienced in Saint Luke's International Hospital from 1987 to 1996. The deep mycosis was highly associated with hematologic malignancies(23%) but not with solid tumors(2%). The common mycoses were aspergillosis and candidiasis, which were observed in 27(68%) and 14 (35%) cases, respectively. Most of the patients received broad-spectrum antibiotics, anticancer agents and corticosteroids, and showed granulocytopenia. The symptoms of deep mycoses were non-specific, for example, pyrexia and/or respiratory symptoms. The clinical diagnosis was established in 8 cases and the appropriate antifungal agents were used in 12 cases(30%). Thus, empiric amphotericin-B therapy should be started early in-patients with granulocytopenia, respiratory symptoms, and pyrexia.

Adolescent↗
PubMed2003

[Development of a PCR-based method for diagnostics of mycoses].

Since the express-diagnostics of mycoses in immune-deficit patients still remains an acute problem, we developed an effective test system (Kan-Am) to detect DNA Candida albicans, which is a leader in the list of causative agents of candidosis. A comparison study of three PCR-systems used to detect a broad spectrum of fungoid pathogens was carried out, and a universal system (FungAm), which ensures the detection of DNAs of above 78 strains of 25 types of pathogenic fungi, was selected. The results of clinical testing of the species-specific and universal PCR-systems are well confirmed by the culture method, and they are indicative of the efficacy of applying them for the diagnostics of mycoses in neonatology. The use of the mentioned systems is a promising factor for the express-diagnostics of mycoses in immunodeficiency patients. The high sensitivity of the method makes it possible to detect 10 to 100 cells of a causative agent in 100 mcl of the examined biological material, which is compatible with the culture method. A kit of dry reagents (IonoMix) designed for an accelerated sample preparation and isolation, from them, of DNAs on the basis of Chelex-100 and of proteinase K was worked out; the kit is portable and meant for a long-term storing.

Base Sequence↗