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PubMed2001

Pharmacokinetics of sequential intravenous and enteral fluconazole in critically ill surgical patients with invasive mycoses and compromised gastro-intestinal function.

OBJECTIVES: (1) To determine the pharmacokinetics of sequential intravenous and enteral fluconazole in the serum of surgical intensive care unit (ICU) patients with deep mycoses. (2) To determine the concentrations of fluconazole reached at the site of infection. (3) To determine if enteral administration of fluconazole, which has an important pharmaco-economic advantage, is justified in this specific patient group. DESIGN: Descriptive, sequential study as a part of a therapeutic drug monitoring programme. SETTING: Eighteen-bed surgical ICU in a referral centre. PATIENTS: Fourteen critically ill surgical patients with recent gastro-intestinal (GI) surgery and deep mycosis caused by a fluconazole-susceptible fungus and a calculated creatinine clearance of more than 40 ml/min. INTERVENTIONS: Fluconazole dosage regimen: 400 mg i. v. every 24 h with an extra dose of 400 mg i.v. after 12 h on day 1. If the clinical condition allowed enteral administration on day 4, the content of two capsules of 200 mg was given via the feeding tube with concomitant enteral feeds. MEASUREMENTS AND MAIN RESULTS: Serum, exudate from the site of infection and urine samples collected at assumed steady state ( after > or = 5 doses). Fluconazole concentrations were determined by high-performance liquid chromatography (HPLC). The mean area under the concentration curve (AUC0-24 h) in serum after enteral administration did not significantly differ from the AUC0-24 h during intravenous treatment. The elimination half-life was longer compared to healthy volunteers. The mean (95% CI) estimated bioavailability was 124 (90-158)%. The mean (95% CI) area under the concentration time curves (AUCs) achieved in the exudate from the site of infection were 67 (55-79)% of the AUCs reached in serum for both regimens. CONCLUSIONS: In critically ill patients with recent GI surgery and/or peritonitis the bioavailability of enteral fluconazole was adequate. The concentrations of fluconazole reached in exudate were lower than those in serum for both regimens, but adequate to treat most cases of deep mycoses in this specific patient group.

Antifungal Agents↗

PubMed1983

Laboratory and clinical assessment of ketoconazole in deep-seated mycoses.

Forty-eight cases of deep mycoses were studied and treated with ketoconazole, each with in vitro evaluation of the minimum inhibitory concentrations (MIC) of the causative fungi, in vivo pharmacokinetic, clinical, and mycologic evaluations, several months to two years after the treatment was stopped. Excellent results were obtained in six cases of chronic mucocutaneous candidiasis, with restoration of immunologic disturbances; 23 cases of systemic candidiasis, including new aspects of heroin addicts with cutaneous, ocular, or osteoarticular manifestations; eight cases of histoplasmosis, five due to Histoplasma capsulatum and three to Histoplasma duboisii, with cure in seven and remission in one; one case of African blastomycosis (Blastomyces dermatitidis); three cases of mycetoma, two due to Monosporium apiospermum, one due to a dematiacious fungus; three cases of entomophthoromycosis with cure; one case of fungal arthritis, due to new hyphomycete similar to M. apiospermum, pathogenic for laboratory animals; one case of Drechslera longirostrata causing vertebral arthritis, following a fungal endocarditis and cured by combination of ketoconazole with amphotericin B, each agent alone being ineffective; and other deep mycoses.

Adolescent↗

PubMed1992

Oral mycoses in HIV infection.

Oral mycoses in human immunodeficiency virus (HIV) infection are becoming increasingly common. Of these, oral candidiasis is by far the most prevalent; fewer than 10 cases of cryptococcosis, histoplasmosis, and geotrichosis have thus far been reported. Oral candidiasis is one of the earliest premonitory signs of HIV infection and may present as erythematous, pseudomembranous, hyperplastic, or papillary variants, or as angular cheilitis. Cumulative data from 23 surveys (incorporating 3387 adults) suggest that in general, oral candidiasis may develop in one third to half of HIV-seropositive persons. Almost equal numbers of cases manifest with either erythematous or pseudomembranous variants. These and related concepts pertaining to oral mycoses in HIV infection are reviewed.

Acquired Immunodeficiency Syndrome↗

PubMedDate not supplied

A clinical study of fluconazole for the treatment of deep mycoses.

A multicenter clinical study of fluconazole was conducted at 41 hospital sites in Japan. Fluconazole was administered orally or intravenously at daily doses of 50 to 400 mg to 199 patients with deep-seated mycoses. Clinical efficacy was evaluable in 125 of these patients. Most cases were complicated with serious underlying diseases such as cancer, leukemia, or AIDS. Clinical cures were achieved in 56 (87.5%) of 64 cases of candidiasis, in 11 (68.8%) of 16 cases of cryptococcosis, in 19 (44.2%) of 43 cases of aspergillosis, and in one case each (100%) of mucormycosis and fungemia due to an unspecified yeast. Eradication rates of causative fungi were 87.9% in Candida spp., 62.5% in Cryptococcus neoformans, and 52.2% in Aspergillus spp. Side effects were observed in 13 cases, with an incidence rate of 6.5%. In most cases fluconazole was well tolerated. Changes in laboratory test values due to the drug were reported in 35 patients with an incidence rate of 17.6%. The changes were minor and transient; primarily increases in liver enzyme. Fluconazole is a useful antifungal agent for the treatment of systemic deep-seated mycoses.

Adolescent↗

PubMedDate not supplied

Advances and challenges in management of invasive mycoses.

Invasive mycoses pose a major diagnostic and therapeutic challenge. Advances in antifungal agents and diagnostic methods offer the potential for improved outcomes in patients with these infections, which are often lethal. Many fungal pathogens occur almost exclusively in opportunistic settings--in the immunocompromised host--and these infections are the focus of this review. Several areas of ongoing challenge remain, including the emergence of resistant organisms and the absence of reliable markers for early identification of patients at risk of developing invasive fungal disease. This Seminar reviews the changing epidemiology of invasive mycoses, new diagnostic methods, and recent therapeutic options and current management strategies for these opportunistic pathogens.

Antifungal Agents↗

PubMed1994

Treatment of tropical mycoses.

Several subcutaneous and deep-seated mycoses are either observed more frequently in the tropical areas or are restricted to certain regions within the tropics. These mycoses include sporotichosis, chromoblastomycosis, entomophthoromycosis, eumycetoma, lobomycosis, and paracoccidioidomycosis. In sporotrichosis and paracoccidioidomycosis, therapy often results in either complete resolution or marked improvement. For decades sporotrichosis has been treated successfully with potassium iodide, but recently the triazole compounds, especially itraconazole, have proved effective and free of major side effects. The usual therapy for paracoccidioidomycosis is sulfonamides or amphotericin B; the former requires prolonged treatment, whereas the latter causes a significant degree of toxicity. Various azole derivatives (ketoconazole, fluconazole, saperconazole, and itraconazole) allow shorter treatment courses, can be given orally, and are more effective. Presently, itraconazole is the drug of choice. Chromoblastomycosis is a difficult condition to treat, especially if it is caused by Fonsecaea pedrosoi. Several therapeutic approaches have been used, including heat, surgery, cryotherapy, thiabendazole, amphotericin B combined with flucytosine, and azole derivatives, but their success has been modest. A 65% response rate has been obtained with itraconazole given for periods of 6 to 19 months; in limited trials, saperconazole appears to be more effective and requires shorter treatment courses. Only a few patients with eumycetoma respond to therapy; 70% of patients with Madurella mycetomatis respond to prolonged treatment with ketoconazole. Griseofulvin has been tried in nonresponders with partial success. Limited data in patients with Fusarium species eumycetoma indicate good responses to itraconazole. Eumycetoma caused by Pseudallescheria boydii or Acremonium species has been refractory to therapy. Therapy of entomophthoromycosis is also difficult because the diagnosis is usually established late and not all patients respond to therapy; this situation applies to infection caused by either Basidiobolus haptosporus or Conidiobolus coronatus. Although there is no consensus, African physicians prefer to use potassium iodide or trimethoprim-sulfamethoxazole. Isolated reports indicate that the azole derivatives, including the triazoles, may be effective. As for lobomycosis, all attempts at medical treatment have failed. Surgery is successful only when the lesion is small and can be fully resected; repeated cryotherapy appears to be more successful.

Antifungal Agents↗

PubMed2005

[Mycoses of the head and neck].

In recent years, mycoses have emerged as important infections in clinical practice. This phenomenon is explained by the ever growing number of immunocompromised patients and the increasing number of people travelling in areas where fungal diseases are endemic. Head and neck infections are common in disseminated mycoses and may simulate carcinoma or cause upper airway obstruction. The most frequent causative yeasts or yeast-like organisms include Candida albicans, Cryptococcus neoformans, Histoplasma capsulatum var capsulatum, Blastomyces dermatitidis, Paracoccidioides brasiliensis and Coccidioides immitis. Other causative fungal pathogens include Aspergillus fumigatus and less frequently, Rhizopus oryzae and Rhinosporidium seeberi. Since in most cases their pathophysiology is similar, those microorganisms share a common clinical pathological presentation. Symptoms such as dysphonia or dysphagia associated with hyperplastic and ulcerative lesions on endoscopic examination should prompt biopsies. A purulent or granulomatous inflammatory tissue reaction with pseudoepitheliomatous hyperplasia warrants caution since it may lead to a mistaken diagnosis of carcinoma. The pathologist must look carefully for microorganisms with Grocott and PAS stains. The causative agent can be identified if the pathologist is aware of the risk. Positive culture is needed to institute adequate treatment.

Aspergillosis↗

PubMed2001

Overview of host defense mechanisms in systemic mycoses and the basis for immunotherapy.

Host defense against systemic mycoses is multifactoral, depending on innate, as well as acquired, mechanisms. Innate resistance mechanisms include intact physical barriers, host proteins, nonspecific inflammatory responses, hormonal status, sex, and genetic make-up. However, the importance of any 1 factor in resistance to systemic fungal infections can vary depending on the causative agent. Macrophages and neutrophils play a critical role in the stasis or killing of these organisms by using the production of oxygen radicals, cationic proteins, nitric oxide (NO), and peroxides or iron deprivation. Although these cells are often ineffective in killing the organisms innately, activation of macrophages and neutrophils during an acquired immune response by the proinflammatory cytokine interferon-gamma as well as colony-stimulating factors increases the capacity of these cells for killing. A strong Th1 response can provide protective immunity, whereas a Th2 response can result in increased disease severity. The importance of native antibodies in resistance to mycoses remains in question.

Animals↗

PubMed2006

Hospitalizations for endemic mycoses: a population-based national study.

We performed a retrospective cohort study, using the 2002 Nationwide Inpatient Sample, a national database of hospital inpatient stays, to describe the incidence and epidemiology of endemic mycoses requiring hospitalization. An estimated 332 pediatric and 6003 adult patients with endemic mycoses required hospitalization (4.6 and 28.7 cases per 1 million children and adults, respectively). Crude mortality rates were 5% and 7% among children and adults, respectively.

Adolescent↗

PubMed1997

Cross-reactivity in Histoplasma capsulatum variety capsulatum antigen assays of urine samples from patients with endemic mycoses.

We evaluated cross-reactivity in the antigen assay used for the diagnosis of histoplasmosis by testing urine samples from patients with disseminated fungal infections. The mycoses chosen for this study were selected on the basis of the observation that during clinical testing, cross-reactions may occur between Histoplasma capsulatum var. capsulatum, Paracoccidioides brasiliensis, Blastomyces dermatitidis, Coccidioides immitis, and Penicillium marneffei. We detected antigen in 12 of 19 patients with blastomycosis, 8 of 9 with paracoccidioidomycois, in 17 of 18 with P. marneffei infection, and in one with disseminated H. capsulatum var. duboisii infection. Cross-reactions were not observed in the assays for six patients with disseminated coccidioidomycosis. Cross-reactivity between the agents of other endemic mycoses should be considered in interpreting a positive H. capsulatum var. capsulatum antigen assay. Antigen detection may provide a rapid, provisional diagnosis for patients with serious infections caused by one of these organisms.

Antigens, Fungal↗

PubMed1992

A Pan-American 5-year study of fluconazole therapy for deep mycoses in the immunocompetent host. Pan-American Study Group.

Eighty-eight immunocompetent patients with deep mycoses from eight countries were evaluated with the same protocol for efficacy of fluconazole monotherapy. Entry doses were raised from 100 to 400 mg as safety was shown in initial cohorts, and dosages up to 2,400 mg daily and durations up to 44 months were studied. Results were very similar in different countries. Twenty-seven of 28 evaluable patients with paracoccidioidomycosis, 13 of 19 with sporotrichosis, 14 of 16 with coccidioidomycosis, and eight of eight with histoplasmosis demonstrated objective responses to therapy, as did one patient each with zygomycosis and alternariosis. For these patients, relapses have been unusual thus far. In contrast, one patient with chromoblastomycosis responded but relapsed, and six did not respond; one patient with mycetoma responded but relapsed, and two did not respond. The drug was well tolerated by patients, including six who received intravenous therapy. In vitro susceptibility tests suggested that clinical response was correlated with susceptibility but that resistance did not preclude clinical response. Fluconazole therapy appears efficacious for several deep mycoses; dosages of greater than 200 mg daily may be needed for some diseases. The further evaluation of fluconazole for these entities is warranted.

Adolescent↗

PubMed1995

The safety and efficacy of amphotericin B colloidal dispersion in the treatment of invasive mycoses.

Amphotericin B colloidal dispersion (ABCD), a novel formulation of amphotericin B and cholesteryl sulfate in a 1:1 ratio, was developed to reduce the toxicity of amphotericin B yet retain its antifungal efficacy. In an open-label trial, ABCD at dosages as high as 6 mg/(kg.d) was administered to 168 patients with documented or presumed systemic mycoses. All patients had responded incompletely to at least 7 days' treatment with conventional amphotericin B (CAB), had experienced CAB-induced nephrotoxic effects, had preexisting renal impairment, or had experienced other CAB-related, treatment-limiting toxic effects. The clinical response to ABCD could be evaluated in 97 patients. Complete clinical response or improvement was noted in 48 (49%) of them after a mean treatment duration of 18.5 days. All 168 enrolled patients were evaluated with regard to safety of the treatment. Even at daily doses as high as 6 mg/kg, and mean and median cumulative doses of 4.0 g and 2.4 g, respectively, ABCD had little renal toxicity: the mean change in serum level of creatinine from baseline to final value was -0.02 mg/dL. Hypokalemia developed in eight patients (5%). This study provides preliminary evidence that ABCD is effective in treating invasive mycoses and lacks the dose-limiting nephrotoxicity of CAB.

Adult↗

PubMed1999

Endemic mycoses: a treatment update.

Endemic mycoses remain a major public health problem in several countries and they are becoming increasingly frequent with the spread of HIV infection. Amphotericin B remains the drug of choice during the acute stage of life-threatening endemic mycoses occurring in both immunocompetent and immunocompromised hosts. Ketoconazole is effective in non-AIDS patients with non-life-threatening histoplasmosis, blastomycosis, or paracoccidioidomycosis. Itraconazole is the treatment of choice for non-life-threatening Histoplasma capsulatum or Blastomyces dermatitidis infections occurring in immunocompetent individuals and is the most efficient secondary prophylaxis of histoplasmosis in AIDS patients. Itraconazole is also effective in lymphocutaneous and visceral sporotrichosis, in paracoccidioidomycosis, for Penicillum marneffei infection, and is an alternative to amphotericin B for Histoplasma duboisii infection. Coccidioidomycosis may be effectively treated with prolonged and sometimes life-long itraconazole or fluconazole therapy. Fluconazole has relatively poor efficacy against histoplasmosis, blastomycosis and sporotrichosis. New antifungal agents have been tested in vitro or in animal models and may soon be evaluated in clinical trials.

AIDS-Related Opportunistic Infections↗

PubMed2002

Prophylaxis of invasive mycoses in solid organ transplantation.

PURPOSE OF REVIEW: Solid organ transplantation is emerging as a life-saving procedure for increasing numbers of patients and invasive fungal infections are a significant cause of mortality and morbidity for patients undergoing these procedures. This paper will review the latest data pertinent to the development of effective regimens aimed at preventing invasive mycoses in the solid organ transplantation population. RECENT FINDINGS: Risks for developing invasive fungal infections are continuing to evolve, leading to shifts in the epidemiology of invasive mycoses occurring after transplantation. For instance, risks for the development of invasive candidiasis in the immediate postoperative period following orthotopic liver transplantation have decreased dramatically while the incidence of invasive aspergillosis appears to be on the rise. New agents have recently been approved for use in the United States and may have a role in prophylactic strategies aimed at preventing these fungal infections. SUMMARY: An understanding of these issues is crucial to the development of targeted prophylactic regimens for the successful prevention of invasive fungal infections in the solid organ transplant recipient.

Antifungal Agents↗

PubMed1995

[Laboratory diagnostic peculiarities of mycoses in immunosuppressed patients].

Domestic invasive mycoses are typically present as secondary diseases in patients definitely immunocompromised. This truth should not obscure the fact that a transient overload of the immune system, e.g. in the polytrauma patients, may likewise favour the development of mycoses. The two groups of patients show a comparable course of infection and, to some extent, diagnostic signs: surveillance cultures and monitoring of antibodies are more helpful with trauma patients and less reliable in the typically immunocompromised patients. In the latter, however, antigen tests may yield more reliable results than in the trauma patients. The different functional capacities of the immune system in the two groups of patients may also affect the appearance of fungal elements, particularly of aspergilli, in secretions and biopsies.

Adult↗

PubMed2005

[Intra-abdominal mycoses].

The incidence of invasive mycoses in patients undergoing abdominal surgery amounts to approximately 8% and shows an upward trend in epidemiological studies. The lethality of these systemic mycoses, which are mostly based on Candida infections constitutes up to 60%. The development of a sytemic mycosis is marked by exogenic, endogenic and iatrogenic risk factors and typically displays tissue invasion after an initial fungal contamination or systemic dissemination via fungal sepsis. Fungal peritonitis is generally a monoinfection with Candida spp., where Candida albicans outweighs in 70% of cases. Aspergillus spp. are only detected abdominally in rare cases. The histological verification of a fungal invasion is regarded as proof of the existence of an invasive mycosis, but typical macroscopic findings with corresponding cultural findings can also confirm the diagnosis. Systemic mycosis requires an early initiation of a consistent antimycotic therapy as well as definitive surgical eradication of the focus in order to reduce high lethal rate. Resistances or incorrect dosages can be validated objectively by means of histological monitoring of the antimycotic therapy, thus affording early recognition of the need to change the substance class.

Antifungal Agents↗

PubMed1991

High-dose itraconazole in the treatment of severe mycoses.

Eight patients with systemic mycoses and with prior treatment failures were treated with itraconazole (600 mg/day) for a mean duration of 5.5 months. All six patients without AIDS experienced improvement or stabilization of their fungal infections while receiving high-dose itraconazole, although two patients later experienced treatment failures, one by relapse and one by progression, on lower doses. Treatment failures also occurred in the two patients with AIDS and cryptococcal meningitis. The failures were associated with low serum itraconazole concentrations (less than 2.5 micrograms/ml) in both patients. All other patients had mean trough levels in serum above 5 micrograms/ml. One patient who was improving on 600 mg/day developed a progressive infection after reduction of the dose to 400 mg/day. Side effects included reversible adrenal insufficiency in one patient; severe hypokalemia, mild diastolic hypertension, and rhabdomyolysis in one patient; mild hypokalemia and hypertension in four other patients; and breast tenderness in one patient. The mean decrease in serum potassium during treatment was statistically significant (P = 0.05). Selected patients with severe systemic mycoses may benefit from prolonged high-dose itraconazole treatment. However, 600 mg/day may be approaching the upper limits of acceptable dosing for long-term treatment.

Acquired Immunodeficiency Syndrome↗

PubMed1982

Epidemiology, pathology and clinical features of genital mycoses--1981 status.

The clinical picture of candidal vaginitis was described for the first time in 1792. The connection with yeasts was already discovered in the 19th century. Not until the last 35 years, however, have the epidemiologic aspects of genital mycoses and the diagnostic and therapeutic principles been systematically developed. The rise in the incidence of the disease is due to several factors: the administration of corticosteroids, cystostatic agents, and oral contraceptives as well as socioeconomic circumstances. Two serious complications of vaginal yeast infection in pregnant women should be noted: the amniotic infection syndrome and neonatal contamination at the time of delivery. Vulvovaginitis is one of the most common genital diseases in childhood and adolescence. Mycoses can be diagnosed in daily gynecological practice by simple, reliable methods, but only culture on prepared media or by incubation of standardized plates can be depended upon to establish or rule out a mycosis. Effective antimycotics with a broad spectrum of activity have been developed in the last 15 years. We have been primarily concerned with clotrimazole because of our own investigations and impartial comparisons with other fungicidal drugs. Studies of patient compliance have shown that the diseased women accept short-term therapy most readily. However, appropriate control examinations are needed to document the results of treatment.

Anti-Bacterial Agents↗